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    Clinical Trial Results:
    Study MEA117106: Mepolizumab vs. Placebo as add-on treatment for frequently exacerbating COPD patients

    Summary
    EudraCT number
    		 2013-004298-28
    Trial protocol
    		 SE   CZ   PL   IT   BE   ES   EE   GR  
    Global end of trial date
    17 Jan 2017

    Results information
    Results version number
    		 v1
    This version publication date
    31 Jan 2018
    First version publication date
    31 Jan 2018
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    117106
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    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
    31 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of mepolizumab 100 mg subcutaneous (SC) given every 4 weeks compared to placebo on the frequency of moderate and severe exacerbations in chronic obstructive pulmonary disease (COPD) participants at high risk of exacerbations despite the use of optimized standard of care background therapy.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Apr 2014
    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
    Belgium: 40
    Country: Number of subjects enrolled
    France: 37
    Country: Number of subjects enrolled
    Greece: 61
    Country: Number of subjects enrolled
    Italy: 53
    Country: Number of subjects enrolled
    Norway: 12
    Country: Number of subjects enrolled
    Spain: 58
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    Czech Republic: 22
    Country: Number of subjects enrolled
    Estonia: 21
    Country: Number of subjects enrolled
    Poland: 79
    Country: Number of subjects enrolled
    United States: 89
    Country: Number of subjects enrolled
    Australia: 46
    Country: Number of subjects enrolled
    Canada: 106
    Country: Number of subjects enrolled
    Mexico: 88
    Country: Number of subjects enrolled
    Peru: 75
    Country: Number of subjects enrolled
    Russian Federation: 40
    Worldwide total number of subjects
    837
    EEA total number of subjects
    393
    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)
    375
    From 65 to 84 years
    460
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants with chronic obstructive pulmonary disease (COPD) with frequent exacerbations and on high dose inhaled corticosteroid (ICS)-based triple inhaled maintenance therapy were included in this study. Participants were randomized to receive mepolizumab 100 milligrams (mg) or placebo by subcutaneous (SC) injection every 4 weeks for 52 weeks.

    Pre-assignment
    Screening details
    		 A total of 1161 participants were enrolled of which 79 were pre-screen failures; 245 were screen failures. 836 participants were randomized and received at least one dose of study treatment and included in the modified intent to treat (mITT) population. One participant randomized to the placebo group was withdrawn without receiving study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo - High stratum
    Arm description
    		 Participants with blood eosinophil counts >=150 cells per microliter (cells/µL) at Screening or >=300 cells/µL in the 12 months prior were assigned to the high stratum group. These participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks along with their standard of care (SoC) therapy. Salbutamol metered dose inhaler (MDI) was issued for use as rescue medication throughout the study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo was 0.9 percent sodium chloride solution which was administered via SC route every 4 weeks for up to 52 weeks in addition to SoC therapy.

    Arm title
    		 Mepolizumab 100 mg - High stratum
    Arm description
    		 Participants with blood eosinophil counts >=150 cells/µL at Screening or >=300 cells/ µL in the 12 months prior were assigned to the high stratum group. These participants were randomized to and received mepolizumab 100 mg by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mepolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Mepolizumab was available as lyophilized cake which was reconstituted with Sterile water for injection prior to use. Mepolizumab 100 milligrams (mg) injection was administered via SC route every 4 weeks up to 52 weeks in addition to SoC therapy.

    Arm title
    		 Placebo - Low stratum
    Arm description
    		 Participants with blood eosinophil counts <150 cells/µL at Screening and no evidence of blood eosinophil counts >=300 cells/µL in the 12 months prior were assigned to the low stratum group. These participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo was 0.9 percent sodium chloride solution which was administered via SC route every 4 weeks for up to 52 weeks in addition to SoC therapy.

    Arm title
    		 Mepolizumab 100 mg - Low stratum
    Arm description
    		 Participants with blood eosinophil counts <150 cells/µL at Screening and no evidence of blood eosinophil counts >=300 cells/µL in the 12 months prior were assigned to the low stratum group. These participants were randomized to and received mepolizumab 100 mg by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mepolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Mepolizumab was available as lyophilized cake which was reconstituted with Sterile water for injection prior to use. Mepolizumab 100 milligrams (mg) injection was administered via SC route every 4 weeks up to 52 weeks in addition to SoC therapy.

    Number of subjects in period 1 [1]
    		Placebo - High stratum Mepolizumab 100 mg - High stratum Placebo - Low stratum Mepolizumab 100 mg - Low stratum
    Started
    229
    233
    190
    184
    Completed Investigational Product (IP)
    185 [2]
    203 [3]
    148 [4]
    149 [5]
    Not completed IP
    44 [6]
    30 [7]
    42 [8]
    35 [9]
    Withdrew IP due to: Adverse event
    20 [10]
    16 [11]
    15 [12]
    13 [13]
    Withdrew IP Due to: Lack of efficacy
    5 [14]
    2 [15]
    8 [16]
    2 [17]
    Withdrew IP Due to: Protocol deviation
    1 [18]
    3 [19]
    3 [20]
    0 [21]
    Withdrew IP Due to: Lost to Follow-up
    0 [22]
    0 [23]
    1 [24]
    2 [25]
    Withdrew IP Due to: Withdrawal by subj.
    16 [26]
    8 [27]
    11 [28]
    15 [29]
    Withdrew IP Due to: Physician decision
    2 [30]
    1 [31]
    4 [32]
    2 [33]
    Withdrew IP due to: Stopping criteria
    0 [34]
    0 [35]
    0 [36]
    1 [37]
    Completed
    202
    213
    162
    157
    Not completed
    27
    20
    28
    27
         Adverse event, serious fatal
    6
    6
    7
    9
         Physician decision
    2
    2
    2
    2
         Consent withdrawn by subject
    15
    10
    10
    11
         Adverse event, non-fatal
    4
    1
    4
    2
         Lost to follow-up
    -
    -
    2
    1
         Lack of efficacy
    -
    1
    3
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [10] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [11] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [12] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [13] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [14] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [15] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [16] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [17] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [18] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [19] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [20] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [21] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [22] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [23] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [24] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [25] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [26] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [27] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [28] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [29] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [30] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [31] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [32] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [33] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [34] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [35] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [36] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.
    [37] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The other milestones presented represent the number of participants that completed investigational product and those not completed investigational product and the reasons why participants did not complete investigational product.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo - High stratum
    Reporting group description
    		 Participants with blood eosinophil counts >=150 cells per microliter (cells/µL) at Screening or >=300 cells/µL in the 12 months prior were assigned to the high stratum group. These participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks along with their standard of care (SoC) therapy. Salbutamol metered dose inhaler (MDI) was issued for use as rescue medication throughout the study.

    Reporting group title
    Mepolizumab 100 mg - High stratum
    Reporting group description
    		 Participants with blood eosinophil counts >=150 cells/µL at Screening or >=300 cells/ µL in the 12 months prior were assigned to the high stratum group. These participants were randomized to and received mepolizumab 100 mg by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Reporting group title
    Placebo - Low stratum
    Reporting group description
    		 Participants with blood eosinophil counts <150 cells/µL at Screening and no evidence of blood eosinophil counts >=300 cells/µL in the 12 months prior were assigned to the low stratum group. These participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Reporting group title
    Mepolizumab 100 mg - Low stratum
    Reporting group description
    		 Participants with blood eosinophil counts <150 cells/µL at Screening and no evidence of blood eosinophil counts >=300 cells/µL in the 12 months prior were assigned to the low stratum group. These participants were randomized to and received mepolizumab 100 mg by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Reporting group values
    		 Placebo - High stratum Mepolizumab 100 mg - High stratum Placebo - Low stratum Mepolizumab 100 mg - Low stratum Total
    Number of subjects
    		 229 233 190 184
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.3 ( 8.53 ) 65.2 ( 8.36 ) 65.2 ( 8.62 ) 66.1 ( 9.14 ) -
    Gender categorical
    Units: Subjects
        Female
    		 79 84 77 76 316
        Male
    		 150 149 113 108 520
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian/ Alaska native Heritage
    		 14 19 22 14 69
        Asian- East Asian Heritage
    		 0 2 0 0 2
        Asian- Japanese Heritage
    		 3 0 1 1 5
        Black/ African American Heritage
    		 4 2 3 2 11
        White- Arabic/ North African Heritage
    		 2 1 0 1 4
        White- White/ Caucasian/ European Heritage
    		 190 198 145 143 676
        Multiple - American Indian/Alaska native and White
    		 16 11 19 23 69
    Subject analysis sets

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks in addition to their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Subject analysis set title
    Mepolizumab 100 mg
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants were randomized to and received mepolizumab 100 mg by SC injection every 4 weeks for up to 52 weeks in addition to their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Subject analysis sets values
    		 Placebo Mepolizumab 100 mg
    Number of subjects
    419
    417
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    0 ( 0 )
    0 ( 0 )
    Gender categorical
    Units: Subjects
        Female
    0
    0
        Male
    0
    0
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian/ Alaska native Heritage
    0
    0
        Asian- East Asian Heritage
    0
    0
        Asian- Japanese Heritage
    0
    0
        Black/ African American Heritage
    0
    0
        White- Arabic/ North African Heritage
    0
    0
        White- White/ Caucasian/ European Heritage
    0
    0
        Multiple - American Indian/Alaska native and White
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Placebo - High stratum
    Reporting group description
    		 Participants with blood eosinophil counts >=150 cells per microliter (cells/µL) at Screening or >=300 cells/µL in the 12 months prior were assigned to the high stratum group. These participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks along with their standard of care (SoC) therapy. Salbutamol metered dose inhaler (MDI) was issued for use as rescue medication throughout the study.

    Reporting group title
    Mepolizumab 100 mg - High stratum
    Reporting group description
    		 Participants with blood eosinophil counts >=150 cells/µL at Screening or >=300 cells/ µL in the 12 months prior were assigned to the high stratum group. These participants were randomized to and received mepolizumab 100 mg by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Reporting group title
    Placebo - Low stratum
    Reporting group description
    		 Participants with blood eosinophil counts <150 cells/µL at Screening and no evidence of blood eosinophil counts >=300 cells/µL in the 12 months prior were assigned to the low stratum group. These participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Reporting group title
    Mepolizumab 100 mg - Low stratum
    Reporting group description
    		 Participants with blood eosinophil counts <150 cells/µL at Screening and no evidence of blood eosinophil counts >=300 cells/µL in the 12 months prior were assigned to the low stratum group. These participants were randomized to and received mepolizumab 100 mg by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks in addition to their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Subject analysis set title
    Mepolizumab 100 mg
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Participants were randomized to and received mepolizumab 100 mg by SC injection every 4 weeks for up to 52 weeks in addition to their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Primary: Rate of moderate or severe exacerbations in participants in the high stratum

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    End point title
    		 Rate of moderate or severe exacerbations in participants in the high stratum [1]
    End point description
    Moderate exacerbations are defined as clinically significant exacerbations that require treatment with oral/systemic corticosteroids and/or antibiotics. Severe exacerbations are defined as clinically significant exacerbations that require in-patient hospitalization ( >= 24 hours) or result in death. Moderate and severe exacerbations occurring from the start of investigational product (IP) up to the Week 52 visit, including exacerbations reported after early discontinuation from investigational product by subjects who remained in the study, were included in the analysis. The analysis was performed on the mITT high stratum (mITT-H) Population which comprised of participants in the mITT Population (all randomized participants who received at least one dose of study treatment) with blood eosinophil counts >=150 cells/µL at Screening or >=300 cells/ µL in the 12 months prior.
    End point type
    Primary
    End point timeframe
    From randomization to Week 52
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 Placebo - High stratum Mepolizumab 100 mg - High stratum
    Number of subjects analysed
    229 [2]
    233 [3]
    Units: Rate per year
    number (not applicable)
        Rate per year
    1.71
    1.40
    Notes
    [2] - mITT-H Population
    [3] - mITT-H Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis using a negative binomial model with covariates of treatment, geographic region, no.of moderate/severe exacerbations in previous year, Baseline percent predicted FEV1, smoking status and offset of log (time in on- and off-treatment period).
    Comparison groups
    Mepolizumab 100 mg - High stratum v Placebo - High stratum
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.036 [4]
    Method
    		 Negative binomial model
    Parameter type
    		 Rate ratio (mepolizumab/placebo)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.98
    Notes
    [4] - Adjusted p-value to account for two treatment comparisons
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Analysis using a negative binomial model with covariates of treatment, geographic region, no.of moderate/severe exacerbations in previous year, Baseline percent predicted FEV1, smoking status and offset of log (time in on- and off-treatment period).
    Comparison groups
    Mepolizumab 100 mg - High stratum v Placebo - High stratum
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.029 [5]
    Method
    		 Negative binomial mode
    Parameter type
    		 Rate ratio (mepolizumab/placebo)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 0.98
    Notes
    [5] - Unadjusted p-value.

    Primary: Rate of moderate or severe exacerbations in the mITT Population

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    End point title
    		 Rate of moderate or severe exacerbations in the mITT Population
    End point description
    Moderate and severe exacerbations occurring from the start of IP up to the Week 52 visit, including exacerbations reported after early discontinuation from IP by participants who remained in the study, were included in the analysis. The analysis was performed on mITT Population which comprised of all randomized participants who received at least one dose of trial medication.
    End point type
    Primary
    End point timeframe
    From randomization to Week 52
    End point values
    		 Placebo Mepolizumab 100 mg
    Number of subjects analysed
    419 [6]
    417 [7]
    Units: Rate per year
    number (not applicable)
        Rate per year
    1.52
    1.49
    Notes
    [6] - mITT Population
    [7] - mITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis using a negative binomial model with covariates of treatment, geographic region, no.of moderate/severe exacerbations in previous year, Baseline percent predicted FEV1, smoking status and offset of log (time in on- and off-treatment period).
    Comparison groups
    Mepolizumab 100 mg v Placebo
    Number of subjects included in analysis
    836
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999 [8]
    Method
    		 Negative Binomial Model
    Parameter type
    		 Rate ratio (mepolizumab/placebo)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.12
    Notes
    [8] - Adjusted p-value to account for two treatment comparisons
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Analysis using a negative binomial model with covariates of treatment, geographic region, no.of moderate/severe exacerbations in previous year, Baseline percent predicted FEV1, smoking status and offset of log (time in on and off-treatment period).
    Comparison groups
    Mepolizumab 100 mg v Placebo
    Number of subjects included in analysis
    836
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.731 [9]
    Method
    		 Negative binomial mode
    Parameter type
    		 Rate ratio (mepolizumab/placebo)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.12
    Notes
    [9] - Unadjusted p-value.

    Secondary: Time to first moderate/severe exacerbation in participants in the high stratum

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    End point title
    		 Time to first moderate/severe exacerbation in participants in the high stratum [10]
    End point description
    Kaplan Meier estimates of the probability of a moderate or severe exacerbation are expressed as the percentage of participants with an exacerbation over time (by Week 8, 16, 24, 32, 40, 48, 52). Analysis of time to first moderate/severe exacerbation was performed on the mITT-H Population and included exacerbations reported on-treatment and those reported after early discontinuation from IP by participants who remained in the study.
    End point type
    Secondary
    End point timeframe
    From randomization to Week 52
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 Placebo - High stratum Mepolizumab 100 mg - High stratum
    Number of subjects analysed
    229 [11]
    233 [12]
    Units: Percentage of participants
    number (confidence interval 95%)
        Week 8
    28.1 (22.7 to 34.4)
    20.2 (15.6 to 26.0)
        Week 16
    45.5 (39.3 to 52.3)
    34.9 (29.2 to 41.5)
        Week 24
    53.4 (47.0 to 60.1)
    45.8 (39.6 to 52.4)
        Week 32
    60.9 (54.5 to 67.4)
    55.3 (49.0 to 61.8)
        Week 40
    68.5 (62.2 to 74.5)
    59.3 (53.0 to 65.7)
        Week 48
    71.8 (65.7 to 77.6)
    62.0 (55.8 to 68.3)
        Week 52
    75.2 (69.3 to 80.8)
    64.6 (58.3 to 70.8)
    Notes
    [11] - mITT-H Population
    [12] - mITT-H Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis performed using a Cox Proportional Hazards Model with covariates of treatment, geographic region, no. moderate/severe exacerbations in previous year, Baseline percent predicted FEV1 and smoking status
    Comparison groups
    Placebo - High stratum v Mepolizumab 100 mg - High stratum
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.036 [13]
    Method
    		 Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (Mepolizumab/placebo)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.94
    Notes
    [13] - Adjusted p-value
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Analysis performed using a Cox Proportional Hazards Model with covariates of treatment, geographic region, no. moderate/severe exacerbations in previous year, Baseline percent predicted FEV1 and smoking status
    Comparison groups
    Placebo - High stratum v Mepolizumab 100 mg - High stratum
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012 [14]
    Method
    		 Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (Mepolizumab/placebo)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.94
    Notes
    [14] - Unadjusted p-value

    Secondary: Rate of COPD exacerbations requiring an emergency department (ED) visit and/or hospitalization in participants in the high stratum

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    End point title
    		 Rate of COPD exacerbations requiring an emergency department (ED) visit and/or hospitalization in participants in the high stratum [15]
    End point description
    COPD exacerbations requiring an ED visit and/or hospitalization occurring from the start of IP up to the Week 52 visit, including exacerbations reported after early discontinuation from IP by participants who remained in the study, were included in the analysis. The analysis was performed on mITT-H Population.
    End point type
    Secondary
    End point timeframe
    From randomization to Week 52
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 Placebo - High stratum Mepolizumab 100 mg - High stratum
    Number of subjects analysed
    229 [16]
    233 [17]
    Units: Rate per year
    number (not applicable)
        Rate per year
    0.26
    0.30
    Notes
    [16] - mITT-H Population
    [17] - mITT-H Population
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Analysis using a negative binomial model with covariates of treatment, geographic region, no. moderate/severe exacerbations in previous year, Baseline percent predicted FEV1, smoking status and offset of log (time in on- and off-treatment period).
    Comparison groups
    Mepolizumab 100 mg - High stratum v Placebo - High stratum
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.479 [18]
    Method
    		 Negative binomial model
    Parameter type
    		 Rate ratio (mepolizumab/placebo)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.75
    Notes
    [18] - Unadjusted p-value
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis using a negative binomial model with covariates of treatment, geographic region, no. moderate/severe exacerbations in previous year, Baseline percent predicted FEV1, smoking status and offset of log (time in on- and off-treatment period).
    Comparison groups
    Mepolizumab 100 mg - High stratum v Placebo - High stratum
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.598 [19]
    Method
    		 Negative binomial model
    Parameter type
    		 Rate ratio (mepolizumab/placebo)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.75
    Notes
    [19] - Adjusted p-value

    Secondary: Change from Baseline in mean total St. George’s Respiratory Questionnaire (SGRQ) score in participants in the high stratum

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    End point title
    		 Change from Baseline in mean total St. George’s Respiratory Questionnaire (SGRQ) score in participants in the high stratum [20]
    End point description
    The SGRQ for COPD is a 40-item questionnaire derived from the original SGRQ, designed to measure health impairment by addressing the frequency of respiratory symptoms and current state of the participant. SGRQ Total Scores ranges from 0 to 100 with higher scores indicating worse health-related quality of life and reductions indicating improvement. The Baseline value will be the last measurement collected prior to the first dose of investigational product. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Participants with a Baseline and at least one post-Baseline assessment were included in the analysis. Mean change from Baseline in SGRQ score at Week 52 has been presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 Placebo - High stratum Mepolizumab 100 mg - High stratum
    Number of subjects analysed
    214 [21]
    226 [22]
    Units: Score on SGRQ scale
    least squares mean (standard error)
        Score on SGRQ scale
    -3.0 ( 1.11 )
    -2.8 ( 1.06 )
    Notes
    [21] - mITT-H Population
    [22] - mITT-H Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis performed using mixed model repeated measures with covariates of Baseline SGRQ Total Score, geographic region, smoking status, treatment and visit, plus interaction terms for visit by Baseline and visit by treatment group.
    Comparison groups
    Mepolizumab 100 mg - High stratum v Placebo - High stratum
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999 [23]
    Method
    		 Mixed Model Repeated Measure Analysis
    Parameter type
    		 Mean Difference (Mepolizumab - Placebo)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 3.2
    Notes
    [23] - Adjusted p-value
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Analysis performed using mixed model repeated measures with covariates of Baseline SGRQ Total Score, geographic region, smoking status, treatment and visit, plus interaction terms for visit by Baseline and visit by treatment group.
    Comparison groups
    Mepolizumab 100 mg - High stratum v Placebo - High stratum
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.901 [24]
    Method
    		 Mixed Model Repeated Measure Analysis
    Parameter type
    		 Mean Difference (Mepolizumab - Placebo)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 3.2
    Notes
    [24] - Unadjusted p-value

    Secondary: Change from Baseline in Mean COPD assessment test (CAT) score in participants in the high stratum

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    End point title
    		 Change from Baseline in Mean COPD assessment test (CAT) score in participants in the high stratum [25]
    End point description
    The CAT is an 8-item questionnaire developed for use in routine clinical practice to measure the health status of participants with COPD. Each question is assessed on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment) with the CAT score ranging from 0-40. Higher scores indicate greater disease impact with reductions indicating improvement. The Baseline value will be the last measurement collected prior to the first dose of investigational product. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Participants with a Baseline and at least one post-Baseline assessment were included in the analysis. Mean change from Baseline in CAT score at Week 52 has been presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 Placebo - High stratum Mepolizumab 100 mg - High stratum
    Number of subjects analysed
    212 [26]
    224 [27]
    Units: Score on CAT scale
    least squares mean (standard error)
        Score on CAT scale
    0.0 ( 0.47 )
    -0.8 ( 0.45 )
    Notes
    [26] - mITT-H Population
    [27] - mITT-H Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis performed using mixed model repeated measures with covariates of Baseline CAT score, geographic region, smoking status, treatment and visit, plus interaction terms for visit by Baseline and visit by treatment group.
    Comparison groups
    Mepolizumab 100 mg - High stratum v Placebo - High stratum
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999 [28]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Mean Difference (Mepolizumab - Placebo)
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 0.5
    Notes
    [28] - Adjusted p-value
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Analysis performed using mixed model repeated measures with covariates of Baseline CAT score, geographic region, smoking status, treatment and visit, plus interaction terms for visit by Baseline and visit by treatment group.
    Comparison groups
    Mepolizumab 100 mg - High stratum v Placebo - High stratum
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.244 [29]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Mean Difference (Mepolizumab - Placebo)
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 0.5
    Notes
    [29] - Unadjusted p-value

    Secondary: Time to first moderate/severe exacerbation in the mITT Population

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    End point title
    		 Time to first moderate/severe exacerbation in the mITT Population
    End point description
    Kaplan Meier estimates of the probability of a moderate/severe exacerbation are expressed as the percentage of participants with an exacerbation over time (by Week 8, 16, 24, 32, 40, 48, 52). The analysis of time to first moderate/severe exacerbation was performed on the mITT population and included exacerbations reported on-treatment and those reported after early discontinuation from IP by participants who remained in the study.
    End point type
    Secondary
    End point timeframe
    From randomization to Week 52
    End point values
    		 Placebo Mepolizumab 100 mg
    Number of subjects analysed
    419 [30]
    417 [31]
    Units: Percentage of participants
    number (confidence interval 95%)
        Week 8
    25.1 (21.3 to 29.6)
    23.6 (19.8 to 28.0)
        Week 16
    39.8 (35.2 to 44.6)
    37.4 (32.9 to 42.3)
        Week 24
    49.2 (44.5 to 54.1)
    46.3 (41.6 to 51.3)
        Week 32
    57.3 (52.6 to 62.2)
    54.1 (49.3 to 59.0)
        Week 40
    63.8 (59.1 to 68.5)
    59.7 (54.9 to 64.5)
        Week 48
    67.3 (62.7 to 71.9)
    62.5 (57.8 to 67.2)
        Week 52
    71.2 (66.6 to 75.6)
    65.5 (60.7 to 70.1)
    Notes
    [30] - mITT Population
    [31] - mITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis performed using a Cox Proportional Hazards Model with covariates of treatment, geographic region, no. moderate/severe exacerbations in previous year, Baseline percent predicted FEV1 and smoking status
    Comparison groups
    Mepolizumab 100 mg v Placebo
    Number of subjects included in analysis
    836
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999 [32]
    Method
    		 Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (Mepolizumab/Placebo)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.05
    Notes
    [32] - Adjusted p-value
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Analysis performed using a Cox Proportional Hazards Model with covariates of treatment, geographic region, no. moderate/severe exacerbations in previous year, Baseline percent predicted FEV1 and smoking status
    Comparison groups
    Mepolizumab 100 mg v Placebo
    Number of subjects included in analysis
    836
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16 [33]
    Method
    		 Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (Mepolizumab/Placebo)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.05
    Notes
    [33] - Unadjusted p-value

    Secondary: Rate of COPD exacerbations requiring ED visit and/or hospitalization in the mITT Population

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    End point title
    		 Rate of COPD exacerbations requiring ED visit and/or hospitalization in the mITT Population
    End point description
    COPD exacerbations requiring ED visit and/or hospitalization occurring from the start of IP up to the Week 52 visit, including exacerbations reported after early discontinuation from IP by participants who remained in the study, were included in the analysis. The analysis was performed on mITT Population.
    End point type
    Secondary
    End point timeframe
    From randomization to Week 52
    End point values
    		 Placebo Mepolizumab 100 mg
    Number of subjects analysed
    419 [34]
    417 [35]
    Units: Rate per year
    number (not applicable)
        Rate per year
    0.26
    0.29
    Notes
    [34] - mITT Population
    [35] - mITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis using a negative binomial model with covariates of treatment, geographic region, no. moderate/severe exacerbations in previous year, Baseline percent predicted FEV1, smoking status and offset of log (time in on- and off-treatment period).
    Comparison groups
    Placebo v Mepolizumab 100 mg
    Number of subjects included in analysis
    836
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999 [36]
    Method
    		 Negative binomial model
    Parameter type
    		 Rate ratio (mepolizumab/placebo)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.49
    Notes
    [36] - Adjusted p-value
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Analysis using a negative binomial model with covariates of treatment, geographic region, no. moderate/severe exacerbations in previous year, Baseline percent predicted FEV1, smoking status and offset of log (time in on- and off-treatment period).
    Comparison groups
    Placebo v Mepolizumab 100 mg
    Number of subjects included in analysis
    836
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.556 [37]
    Method
    		 Negative binomial model
    Parameter type
    		 Rate ratio (mepolizumab/placebo)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.49
    Notes
    [37] - Unadjusted p-value

    Secondary: Change from Baseline in mean total SGRQ score in the mITT Population

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    End point title
    		 Change from Baseline in mean total SGRQ score in the mITT Population
    End point description
    The SGRQ for COPD is a 40-item questionnaire derived from the original SGRQ, designed to measure health impairment by addressing the frequency of respiratory symptoms and current state of the participant. SGRQ Total Scores ranges from 0 to 100 with higher scores indicating worse health-related quality of life and reductions indicating improvement. The Baseline value will be the last measurement collected prior to the first dose of investigational product. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Mean change from Baseline in SGRQ score at Week 52 has been presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Mepolizumab 100 mg
    Number of subjects analysed
    396 [38]
    397 [39]
    Units: Score on SGRQ scale
    least squares mean (standard error)
        Score on SGRQ scale
    -4.0 ( 0.81 )
    -3.2 ( 0.80 )
    Notes
    [38] - mITT Population
    [39] - mITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis performed using mixed model repeated measures with covariates of Baseline SGRQ Total Score, geographic region, smoking status, treatment and visit, plus interaction terms for visit by Baseline and visit by treatment group.
    Comparison groups
    Mepolizumab 100 mg v Placebo
    Number of subjects included in analysis
    793
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999 [40]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Mean difference (Mepolizumab - Placebo)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 2.9
    Notes
    [40] - Adjusted p-value
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Analysis performed using mixed model repeated measures with covariates of Baseline SGRQ Total Score, geographic region, smoking status, treatment and visit, plus interaction terms for visit by Baseline and visit by treatment group.
    Comparison groups
    Mepolizumab 100 mg v Placebo
    Number of subjects included in analysis
    793
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.532 [41]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Mean difference (Mepolizumab - Placebo)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 2.9
    Notes
    [41] - Unadjusted p-value

    Secondary: Change from Baseline in Mean CAT score in the mITT Population

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    End point title
    		 Change from Baseline in Mean CAT score in the mITT Population
    End point description
    The CAT is an 8-item questionnaire developed for use in routine clinical practice to measure the health status of participants with COPD. Each question is assessed on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment) with the CAT score ranging from 0-40. Higher scores indicate greater disease impact with reductions indicating improvement. The Baseline value will be the last measurement collected prior to the first dose of investigational product. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Participants with a Baseline and at least one post-Baseline assessment were included in the analysis. Mean change from Baseline in CAT score at Week 52 has been presented.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Mepolizumab 100 mg
    Number of subjects analysed
    392 [42]
    401 [43]
    Units: Score on CAT scale
    least squares mean (standard error)
        Score on CAT scale
    -0.4 ( 0.35 )
    -1.0 ( 0.34 )
    Notes
    [42] - mITT Population
    [43] - mITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis performed using mixed model repeated measures with covariates of Baseline CAT score, geographic region, smoking status, treatment and visit, plus interaction terms for visit by Baseline and visit by treatment group.
    Comparison groups
    Placebo v Mepolizumab 100 mg
    Number of subjects included in analysis
    793
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999 [44]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Mean difference (Mepolizumab - Placebo)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 0.4
    Notes
    [44] - Adjusted p-value
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Analysis performed using mixed model repeated measures with covariates of Baseline CAT score, geographic region, smoking status, treatment and visit, plus interaction terms for visit by Baseline and visit by treatment group.
    Comparison groups
    Placebo v Mepolizumab 100 mg
    Number of subjects included in analysis
    793
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.252 [45]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Mean difference (Mepolizumab - Placebo)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 0.4
    Notes
    [45] - Unadjusted p-value

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) collected from the start of study participation until the end of follow up (up to Week 60). On-treatment non-serious adverse events (AEs) reported from start of study treatment until 4 weeks after last dose.
    Adverse event reporting additional description
    AEs and SAEs were collected in Safety Population which comprised of all randomized participants who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo - High stratum
    Reporting group description
    		 Participants with blood eosinophil counts >=150 cells/µL at Screening or >=300 cells/µL in the 12 months prior were assigned to the high stratum group. These participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Reporting group title
    Placebo - Low stratum
    Reporting group description
    		 Participants with blood eosinophil counts <150 cells/µL at Screening and no evidence of blood eosinophil counts >=300 cells/µL in the 12 months prior were assigned to the low stratum group. These participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Reporting group title
    Mepolizumab 100 mg - Low stratum
    Reporting group description
    		 Participants with blood eosinophil counts <150 cells/µL at Screening and no evidence of blood eosinophil counts >=300 cells/µL in the 12 months prior were assigned to the low stratum group. These participants were randomized to and received mepolizumab 100 mg by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Reporting group title
    Mepolizumab 100 mg - High stratum
    Reporting group description
    		 Participants with blood eosinophil counts >=150 cells/µL at Screening or >=300 cells/ µL in the 12 months prior were assigned to the high stratum group. These participants were randomized to and received mepolizumab 100 mg by SC injection every 4 weeks for up to 52 weeks along with their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study.

    Serious adverse events
    		 Placebo - High stratum Placebo - Low stratum Mepolizumab 100 mg - Low stratum Mepolizumab 100 mg - High stratum
    Total subjects affected by serious adverse events
         subjects affected / exposed
    80 / 229 (34.93%)
    51 / 190 (26.84%)
    50 / 184 (27.17%)
    65 / 233 (27.90%)
         number of deaths (all causes)
    8
    9
    10
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Laryngeal cancer recurrent
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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 / 1
    0 / 0
    Lung adenocarcinoma stage IV
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Renal neoplasm
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Retinal melanoma
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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 / 1
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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 of skin
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    T-cell lymphoma
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Deep vein thrombosis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Haematoma
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Hypertension
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Hypotension
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Orthostatic hypotension
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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 ischaemia
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    43 / 229 (18.78%)
    31 / 190 (16.32%)
    31 / 184 (16.85%)
    33 / 233 (14.16%)
         occurrences causally related to treatment / all
    0 / 61
    1 / 44
    0 / 42
    1 / 59
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
    0 / 3
    Respiratory failure
         subjects affected / exposed
    5 / 229 (2.18%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    5 / 233 (2.15%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    3 / 229 (1.31%)
    3 / 190 (1.58%)
    0 / 184 (0.00%)
    2 / 233 (0.86%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    2 / 233 (0.86%)
         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
    Alveolitis allergic
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Bronchopneumopathy
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Bronchospasm
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Cough
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Interstitial lung disease
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Organising pneumonia
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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 arrest
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Alcohol abuse
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Confusional state
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Personality change due to a general medical condition
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Influenza B virus test positive
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Transaminases increased
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Contusion
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Facial bones fracture
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Fibula fracture
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Head injury
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Hip fracture
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Injection related reaction
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Jaw fracture
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Laceration
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Meniscus injury
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Periorbital haematoma
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Procedural haemorrhage
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Respiratory fume inhalation disorder
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Spinal fracture
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Thermal burn
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Tibia fracture
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Wound haemorrhage
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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 disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 229 (0.87%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    4 / 233 (1.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 229 (1.31%)
    0 / 190 (0.00%)
    3 / 184 (1.63%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 229 (0.44%)
    2 / 190 (1.05%)
    1 / 184 (0.54%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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 / 1
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    1 / 184 (0.54%)
    0 / 233 (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
    Acute coronary syndrome
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Angina pectoris
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Atrial flutter
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Bundle branch block left
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Cardiac failure acute
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Cardiomyopathy
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Cor pulmonale
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Pericarditis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Sinus tachycardia
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 190 (0.53%)
    1 / 184 (0.54%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    1 / 233 (0.43%)
         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
    Brain injury
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Cerebral haematoma
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Cerebral infarction
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Dizziness
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Sensory loss
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Anaemia
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Abdominal pain
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Colitis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Constipation
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Diverticulum
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Haemorrhoids
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Intestinal fistula
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Intestinal obstruction
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Pancreatitis
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Pancreatitis acute
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Pneumoperitoneum
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Rectal polyp
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Small intestinal obstruction
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    2 / 233 (0.86%)
         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
    Renal colic
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Urinary retention
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Acute prerenal failure
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Anuria
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Bladder dilatation
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Calculus urinary
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Nephrolithiasis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Renal failure
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Arthritis
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Osteonecrosis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    16 / 229 (6.99%)
    13 / 190 (6.84%)
    11 / 184 (5.98%)
    12 / 233 (5.15%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 15
    0 / 13
    1 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    2 / 233 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    1 / 184 (0.54%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 229 (0.87%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    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 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    1 / 233 (0.43%)
         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
    Gastroenteritis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Abscess limb
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Appendicitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Bronchiolitis
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Clostridium difficile infection
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Cystitis
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Influenza
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Klebsiella infection
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Lung infection
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Peritonitis
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Pneumococcal infection
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Pyelonephritis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Respiratory tract infection
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Rhinovirus infection
         subjects affected / exposed
    0 / 229 (0.00%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Salmonellosis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Dehydration
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 229 (0.00%)
    2 / 190 (1.05%)
    0 / 184 (0.00%)
    0 / 233 (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
    Hyponatraemia
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    1 / 184 (0.54%)
    0 / 233 (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
    Hypercalcaemia
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Hypoglycaemia
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 190 (0.00%)
    0 / 184 (0.00%)
    0 / 233 (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 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    2 / 233 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    1 / 233 (0.43%)
         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
    Acute hepatic failure
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    0 / 184 (0.00%)
    0 / 233 (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
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Placebo - High stratum Placebo - Low stratum Mepolizumab 100 mg - Low stratum Mepolizumab 100 mg - High stratum
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    146 / 229 (63.76%)
    116 / 190 (61.05%)
    108 / 184 (58.70%)
    136 / 233 (58.37%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 229 (1.31%)
    5 / 190 (2.63%)
    5 / 184 (2.72%)
    7 / 233 (3.00%)
         occurrences all number
    6
    6
    5
    7
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 229 (2.18%)
    3 / 190 (1.58%)
    4 / 184 (2.17%)
    8 / 233 (3.43%)
         occurrences all number
    5
    3
    4
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    31 / 229 (13.54%)
    25 / 190 (13.16%)
    18 / 184 (9.78%)
    24 / 233 (10.30%)
         occurrences all number
    71
    47
    36
    36
    Dizziness
         subjects affected / exposed
    6 / 229 (2.62%)
    11 / 190 (5.79%)
    7 / 184 (3.80%)
    3 / 233 (1.29%)
         occurrences all number
    6
    12
    9
    4
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    7 / 229 (3.06%)
    5 / 190 (2.63%)
    5 / 184 (2.72%)
    7 / 233 (3.00%)
         occurrences all number
    12
    6
    13
    9
    Oedema peripheral
         subjects affected / exposed
    5 / 229 (2.18%)
    8 / 190 (4.21%)
    1 / 184 (0.54%)
    8 / 233 (3.43%)
         occurrences all number
    5
    8
    1
    9
    Pyrexia
         subjects affected / exposed
    9 / 229 (3.93%)
    4 / 190 (2.11%)
    1 / 184 (0.54%)
    7 / 233 (3.00%)
         occurrences all number
    12
    6
    2
    9
    Asthenia
         subjects affected / exposed
    8 / 229 (3.49%)
    0 / 190 (0.00%)
    3 / 184 (1.63%)
    4 / 233 (1.72%)
         occurrences all number
    8
    0
    3
    4
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 229 (0.87%)
    6 / 190 (3.16%)
    2 / 184 (1.09%)
    5 / 233 (2.15%)
         occurrences all number
    2
    6
    2
    6
    Influenza like illness
         subjects affected / exposed
    7 / 229 (3.06%)
    2 / 190 (1.05%)
    0 / 184 (0.00%)
    2 / 233 (0.86%)
         occurrences all number
    8
    3
    0
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 229 (2.62%)
    9 / 190 (4.74%)
    8 / 184 (4.35%)
    10 / 233 (4.29%)
         occurrences all number
    8
    17
    11
    11
    Nausea
         subjects affected / exposed
    8 / 229 (3.49%)
    4 / 190 (2.11%)
    4 / 184 (2.17%)
    6 / 233 (2.58%)
         occurrences all number
    18
    6
    5
    7
    Abdominal pain
         subjects affected / exposed
    3 / 229 (1.31%)
    9 / 190 (4.74%)
    4 / 184 (2.17%)
    4 / 233 (1.72%)
         occurrences all number
    4
    9
    4
    4
    Constipation
         subjects affected / exposed
    5 / 229 (2.18%)
    1 / 190 (0.53%)
    6 / 184 (3.26%)
    5 / 233 (2.15%)
         occurrences all number
    6
    1
    7
    6
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    6 / 229 (2.62%)
    12 / 190 (6.32%)
    9 / 184 (4.89%)
    15 / 233 (6.44%)
         occurrences all number
    7
    13
    12
    15
    Cough
         subjects affected / exposed
    9 / 229 (3.93%)
    6 / 190 (3.16%)
    9 / 184 (4.89%)
    12 / 233 (5.15%)
         occurrences all number
    10
    7
    11
    17
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    7 / 229 (3.06%)
    8 / 190 (4.21%)
    10 / 184 (5.43%)
    10 / 233 (4.29%)
         occurrences all number
    13
    13
    22
    15
    Dyspnoea
         subjects affected / exposed
    8 / 229 (3.49%)
    4 / 190 (2.11%)
    6 / 184 (3.26%)
    11 / 233 (4.72%)
         occurrences all number
    10
    4
    9
    15
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 229 (1.31%)
    1 / 190 (0.53%)
    2 / 184 (1.09%)
    7 / 233 (3.00%)
         occurrences all number
    3
    1
    2
    7
    Pruritus
         subjects affected / exposed
    1 / 229 (0.44%)
    7 / 190 (3.68%)
    0 / 184 (0.00%)
    3 / 233 (1.29%)
         occurrences all number
    1
    7
    0
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    16 / 229 (6.99%)
    15 / 190 (7.89%)
    16 / 184 (8.70%)
    17 / 233 (7.30%)
         occurrences all number
    17
    17
    19
    20
    Pain in extremity
         subjects affected / exposed
    6 / 229 (2.62%)
    10 / 190 (5.26%)
    12 / 184 (6.52%)
    7 / 233 (3.00%)
         occurrences all number
    15
    12
    12
    7
    Arthralgia
         subjects affected / exposed
    8 / 229 (3.49%)
    11 / 190 (5.79%)
    4 / 184 (2.17%)
    9 / 233 (3.86%)
         occurrences all number
    16
    11
    5
    11
    Myalgia
         subjects affected / exposed
    4 / 229 (1.75%)
    7 / 190 (3.68%)
    4 / 184 (2.17%)
    4 / 233 (1.72%)
         occurrences all number
    8
    8
    5
    4
    Musculoskeletal pain
         subjects affected / exposed
    9 / 229 (3.93%)
    3 / 190 (1.58%)
    2 / 184 (1.09%)
    3 / 233 (1.29%)
         occurrences all number
    10
    4
    2
    5
    Muscle spasms
         subjects affected / exposed
    3 / 229 (1.31%)
    7 / 190 (3.68%)
    1 / 184 (0.54%)
    4 / 233 (1.72%)
         occurrences all number
    3
    7
    1
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    32 / 229 (13.97%)
    31 / 190 (16.32%)
    26 / 184 (14.13%)
    38 / 233 (16.31%)
         occurrences all number
    49
    39
    34
    50
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 229 (4.37%)
    11 / 190 (5.79%)
    11 / 184 (5.98%)
    10 / 233 (4.29%)
         occurrences all number
    10
    16
    13
    12
    Influenza
         subjects affected / exposed
    10 / 229 (4.37%)
    13 / 190 (6.84%)
    8 / 184 (4.35%)
    8 / 233 (3.43%)
         occurrences all number
    13
    16
    12
    9
    Sinusitis
         subjects affected / exposed
    7 / 229 (3.06%)
    6 / 190 (3.16%)
    5 / 184 (2.72%)
    14 / 233 (6.01%)
         occurrences all number
    8
    6
    5
    16
    Pharyngitis
         subjects affected / exposed
    12 / 229 (5.24%)
    6 / 190 (3.16%)
    5 / 184 (2.72%)
    7 / 233 (3.00%)
         occurrences all number
    13
    6
    5
    9
    Urinary tract infection
         subjects affected / exposed
    9 / 229 (3.93%)
    4 / 190 (2.11%)
    7 / 184 (3.80%)
    8 / 233 (3.43%)
         occurrences all number
    12
    4
    8
    9
    Oral candidiasis
         subjects affected / exposed
    7 / 229 (3.06%)
    5 / 190 (2.63%)
    6 / 184 (3.26%)
    8 / 233 (3.43%)
         occurrences all number
    9
    6
    8
    8
    Pneumonia
         subjects affected / exposed
    10 / 229 (4.37%)
    2 / 190 (1.05%)
    5 / 184 (2.72%)
    4 / 233 (1.72%)
         occurrences all number
    11
    2
    5
    4
    Bronchitis
         subjects affected / exposed
    7 / 229 (3.06%)
    3 / 190 (1.58%)
    4 / 184 (2.17%)
    5 / 233 (2.15%)
         occurrences all number
    10
    6
    4
    6
    Gastroenteritis
         subjects affected / exposed
    1 / 229 (0.44%)
    5 / 190 (2.63%)
    7 / 184 (3.80%)
    4 / 233 (1.72%)
         occurrences all number
    1
    5
    7
    4
    Conjunctivitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 190 (0.53%)
    6 / 184 (3.26%)
    3 / 233 (1.29%)
         occurrences all number
    0
    1
    6
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2013
    Amendment 1: To reflect that Investigational Product will be administered by a single SC injection.
    05 Mar 2014
    Amendment 2: Removal of short form (SF)-36 health outcomes endpoint; Removal of electrocardiogram (ECG) at Visit 2; Update of ECG exclusion and discontinuation criteria; Addition of adverse event causality assessment guidance language; Update of chest x-ray randomization criterion for Germany; Wording edited for consistency and clarification of statements in multiple sections.

    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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