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    Clinical Trial Results:
    Study 117113: Mepolizumab vs. Placebo as add-on treatment for frequently exacerbating COPD patients characterized by eosinophil level

    Summary
    EudraCT number
    2013-004297-98
    Trial protocol
    NL   SK   DE   GB   DK   RO  
    Global end of trial date
    16 Jan 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    25 Mar 2018
    First version publication date
    28 Jan 2018
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    117113
    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
    24 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 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 milligrams (mg) and 300 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
    24 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
    Denmark: 23
    Country: Number of subjects enrolled
    Germany: 93
    Country: Number of subjects enrolled
    Netherlands: 52
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    Romania: 76
    Country: Number of subjects enrolled
    Slovakia: 30
    Country: Number of subjects enrolled
    Ukraine: 32
    Country: Number of subjects enrolled
    Japan: 40
    Country: Number of subjects enrolled
    Korea, Republic of: 70
    Country: Number of subjects enrolled
    Taiwan: 12
    Country: Number of subjects enrolled
    United States: 79
    Country: Number of subjects enrolled
    Argentina: 84
    Country: Number of subjects enrolled
    Chile: 34
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Canada: 17
    Worldwide total number of subjects
    675
    EEA total number of subjects
    296
    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)
    316
    From 65 to 84 years
    356
    85 years and over
    3

    Subject disposition

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    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 study. Participants were randomized to receive mepolizumab (100 or 300 milligrams [mg]) or placebo by subcutaneous (SC) injection every 4 weeks for 52 week

    Pre-assignment
    Screening details
    A total of 674 participants were randomized and received at least one dose of study treatment and were included in the modified intent to treat (mITT) population. One participant randomized to the mepolizumab 300 mg 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
    Arm description
    Eligible participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks in addition to 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 as three SC injections every 4 weeks up to 52 weeks along with standard of care therapy.

    Arm title
    Mepolizumab 100 mg SC
    Arm description
    Eligible 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.
    Arm type
    Experimental

    Investigational medicinal product name
    Mepolizumab 100 mg
    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 mg was administered as three SC injections given every 4 weeks for up to 52 weeks along with standard of care therapy.

    Arm title
    Mepolizumab 300 mg SC
    Arm description
    Eligible participants were randomized to and received mepolizumab 300 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.
    Arm type
    Experimental

    Investigational medicinal product name
    Mepolizumab 300 mg
    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 300 mg was administered as three SC injections given every 4 weeks for up to 52 weeks along with standard of care therapy.

    Number of subjects in period 1 [1]
    Placebo Mepolizumab 100 mg SC Mepolizumab 300 mg SC
    Started
    226
    223
    225
    Completed Investigational Product (IP)
    170 [2]
    196 [3]
    183 [4]
    Not completed IP
    56 [5]
    27 [6]
    42 [7]
    Withdrew IP due to: Adverse event
    27 [8]
    9 [9]
    25 [10]
    Withdrew IP due to: stopping criteria
    1 [11]
    1 [12]
    0 [13]
    Withdrew IP due to: Lack of efficacy
    6 [14]
    2 [15]
    2 [16]
    Withdrew IP due to: Protocol deviation
    2 [17]
    0 [18]
    1 [19]
    Withdrew IP due to: Lost to Follow-up
    1 [20]
    1 [21]
    1 [22]
    Withdrew IP due to: Physician decision
    2 [23]
    3 [24]
    1 [25]
    Withdrew IP due to: Withdrawal by subj.
    16 [26]
    11 [27]
    11 [28]
    Withdrew IP due to: site closed
    1 [29]
    0 [30]
    1 [31]
    Completed
    185
    206
    195
    Not completed
    41
    17
    30
         Physician decision
    3
    3
    2
         Lack of efficacy
    3
    -
    3
         Adverse event, serious fatal
    7
    4
    8
         Adverse event, non-fatal
    11
    3
    5
         Consent withdrawn by subject
    15
    7
    11
         Lost to follow-up
    2
    -
    1
    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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.
    [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: This number indicates the number of participants with withdrawal from investigational product only.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Eligible participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks in addition to 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 SC
    Reporting group description
    Eligible 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.

    Reporting group title
    Mepolizumab 300 mg SC
    Reporting group description
    Eligible participants were randomized to and received mepolizumab 300 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.

    Reporting group values
    Placebo Mepolizumab 100 mg SC Mepolizumab 300 mg SC Total
    Number of subjects
    226 223 225
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.8 ± 8.64 64.8 ± 9.06 64.8 ± 8.96 -
    Gender categorical
    Units: Subjects
        Female
    70 91 67 228
        Male
    156 132 158 446
    Race/Ethnicity, Customized
    Units: Subjects
        Asian-Central/South Asian Heritage
    0 0 1 1
        Asian-East Asian Heritage
    25 26 26 77
        Asian-Japanese Heritage
    14 13 13 40
        Asian-South East Asian Heritage
    3 2 1 6
        Black or African American
    2 4 2 8
        White-White/Caucasian/European Heritage
    182 178 182 542

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Eligible participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks in addition to 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 SC
    Reporting group description
    Eligible 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.

    Reporting group title
    Mepolizumab 300 mg SC
    Reporting group description
    Eligible participants were randomized to and received mepolizumab 300 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

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    End point title
    Rate of moderate or severe exacerbations
    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 IP by participants who remained in the study, were included in the analysis. The analysis was performed on the modified intent-to-treat (mITT) Population (all randomized participants who received at least one dose of study treatment).
    End point type
    Primary
    End point timeframe
    From randomization to Week 52
    End point values
    Placebo Mepolizumab 100 mg SC Mepolizumab 300 mg SC
    Number of subjects analysed
    226 [1]
    223 [2]
    225 [3]
    Units: Moderate/severe exacerbations per year
    least squares mean (confidence interval 95%)
        Moderate/severe exacerbations per year
    1.49 (1.29 to 1.72)
    1.19 (1.02 to 1.38)
    1.27 (1.09 to 1.48)
    Notes
    [1] - mITT Population
    [2] - mITT Population
    [3] - 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 SC v Placebo
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.068 [4]
    Method
    Negative binomial model
    Parameter type
    Rate ratio (Mepolizumab 100/Placebo)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    0.98
    Notes
    [4] - Adjusted p-value; Family wise type I error controlled within each endpoint using a Hochberg testing procedure
    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 SC v Placebo
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.034 [5]
    Method
    Negative binomial model
    Parameter type
    Rate ratio (Mepolizumab 100/Placebo)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    0.98
    Notes
    [5] - Unadjusted p-value
    Statistical analysis title
    Statistical analysis 3
    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 300 mg SC v Placebo
    Number of subjects included in analysis
    451
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14 [6]
    Method
    Negative binomial model
    Parameter type
    Rate ratio (Mepolizumab 300/Placebo)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.05
    Notes
    [6] - Adjusted p-value; Family wise type I error controlled within each endpoint using a Hochberg testing procedure
    Statistical analysis title
    Statistical analysis 4
    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 300 mg SC v Placebo
    Number of subjects included in analysis
    451
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14 [7]
    Method
    Negative binomial model
    Parameter type
    Rate ratio (Mepolizumab 300/Placebo)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.05
    Notes
    [7] - Unadjusted p-value

    Secondary: Time to first moderate/severe exacerbation

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    End point title
    Time to first moderate/severe exacerbation
    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 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 SC Mepolizumab 300 mg SC
    Number of subjects analysed
    226 [8]
    223 [9]
    225 [10]
    Units: Percentage of participants
    number (confidence interval 95%)
        Week 8
    22.6 (17.7 to 28.6)
    22.9 (17.9 to 29.0)
    18.3 (13.8 to 24.0)
        Week 16
    40.7 (34.6 to 47.5)
    36.0 (30.0 to 42.6)
    29.0 (23.5 to 35.4)
        Week 24
    51.1 (44.6 to 57.8)
    42.4 (36.2 to 49.2)
    36.7 (30.8 to 43.4)
        Week 32
    58.3 (51.8 to 64.9)
    46.1 (39.8 to 52.9)
    44.9 (38.7 to 51.7)
        Week 40
    62.3 (55.8 to 68.7)
    50.8 (44.4 to 57.6)
    51.8 (45.4 to 58.6)
        Week 48
    64.2 (57.8 to 70.6)
    55.5 (49.1 to 62.2)
    58.3 (51.9 to 64.9)
        Week 52
    66.7 (60.2 to 73.1)
    57.9 (51.5 to 64.5)
    58.8 (52.4 to 65.3)
    Notes
    [8] - mITT Population
    [9] - mITT Population
    [10] - 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, number of moderate/severe exacerbations in previous year, Baseline percent predicted FEV1 and smoking status
    Comparison groups
    Mepolizumab 100 mg SC v Placebo
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14 [11]
    Method
    Cox Proportional Hazards Model
    Parameter type
    Hazard Ratio (Mepolizumab 100/Placebo)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    1.04
    Notes
    [11] - Adjusted p-value; Family wise type I error controlled within each endpoint using a Hochberg testing procedure
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Analysis performed using a Cox Proportional Hazards Model with covariates of treatment, geographic region, number of moderate/severe exacerbations in previous year, Baseline percent predicted FEV1 and smoking status
    Comparison groups
    Mepolizumab 100 mg SC v Placebo
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.103 [12]
    Method
    Cox Proportional Hazards Model
    Parameter type
    Hazard Ratio (Mepolizumab 100/Placebo)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    1.04
    Notes
    [12] - Unadjusted p-value
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    Analysis performed using a Cox Proportional Hazards Model with covariates of treatment, geographic region, number of moderate/severe exacerbations in previous year, Baseline percent predicted FEV1 and smoking status
    Comparison groups
    Mepolizumab 300 mg SC v Placebo
    Number of subjects included in analysis
    451
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14 [13]
    Method
    Cox Proportional Hazards Model
    Parameter type
    Hazard Ratio (Mepolizumab 300/Placebo)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    0.97
    Notes
    [13] - Adjusted p-value; Family wise type I error controlled within each endpoint using a Hochberg testing procedure
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    Analysis performed using a Cox Proportional Hazards Model with covariates of treatment, geographic region, number of moderate/severe exacerbations in previous year, Baseline percent predicted FEV1 and smoking status
    Comparison groups
    Mepolizumab 300 mg SC v Placebo
    Number of subjects included in analysis
    451
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.03 [14]
    Method
    Cox Proportional Hazards Model
    Parameter type
    Hazard Ratio (Mepolizumab 300/Placebo)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    0.97
    Notes
    [14] - Unadjusted p-value

    Secondary: Rate of COPD exacerbations requiring emergency department (ED) visits and/or hospitalizations (hosp)

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    End point title
    Rate of COPD exacerbations requiring emergency department (ED) visits and/or hospitalizations (hosp)
    End point description
    COPD exacerbations requiring an ED visit and/or hosp 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. This analysis was performed on the mITT population.
    End point type
    Secondary
    End point timeframe
    From randomization to Week 52
    End point values
    Placebo Mepolizumab 100 mg SC Mepolizumab 300 mg SC
    Number of subjects analysed
    226 [15]
    223 [16]
    225 [17]
    Units: Exacerbations requiring ED/hosp per year
    least squares mean (confidence interval 95%)
        Exacerbations requiring ED/hosp per year
    0.28 (0.20 to 0.40)
    0.17 (0.11 to 0.25)
    0.23 (0.16 to 0.33)
    Notes
    [15] - mITT Population
    [16] - mITT Population
    [17] - 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
    Placebo v Mepolizumab 100 mg SC
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14 [18]
    Method
    Negative binomial model
    Parameter type
    Rate ratio (Mepolizumab 100/Placebo)
    Point estimate
    0.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.35
         upper limit
    0.98
    Notes
    [18] - Adjusted p-value; Family wise type I error controlled within each endpoint using a Hochberg testing procedure
    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
    Placebo v Mepolizumab 100 mg SC
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.042 [19]
    Method
    Negative binomial model
    Parameter type
    Rate ratio (Mepolizumab 100/Placebo)
    Point estimate
    0.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.35
         upper limit
    0.98
    Notes
    [19] - Unadjusted p-value
    Statistical analysis title
    Statistical analysis 3
    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
    Placebo v Mepolizumab 300 mg SC
    Number of subjects included in analysis
    451
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.447 [20]
    Method
    Negative binomial model
    Parameter type
    Rate ratio (Mepolizumab 300/Placebo)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.34
    Notes
    [20] - Adjusted p-value; Family wise type I error controlled within each endpoint using a Hochberg testing procedure
    Statistical analysis title
    Statistical analysis 4
    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
    Placebo v Mepolizumab 300 mg SC
    Number of subjects included in analysis
    451
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.447 [21]
    Method
    Negative binomial model
    Parameter type
    Rate ratio (Mepolizumab 300/Placebo)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.34
    Notes
    [21] - Unadjusted p-value

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

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    End point title
    Change from Baseline in mean total St. George’s Respiratory Questionnaire (SGRQ) score
    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 range 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. Participants analyzed represents those with a Baseline and at least one post-Baseline assessment, and with no missing covariates.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo Mepolizumab 100 mg SC Mepolizumab 300 mg SC
    Number of subjects analysed
    218 [22]
    218 [23]
    219 [24]
    Units: Score on SGRQ scale
    least squares mean (standard error)
        Score on SGRQ scale
    -3.1 ± 0.98
    -5.0 ± 0.95
    -3.3 ± 0.96
    Notes
    [22] - mITT Population
    [23] - mITT Population
    [24] - 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
    Placebo v Mepolizumab 100 mg SC
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.447 [25]
    Method
    Mixed Model Repeated Measures Analysis
    Parameter type
    Mean difference(Mepolizumab 100-Placebo)
    Point estimate
    -1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.5
         upper limit
    0.8
    Notes
    [25] - Adjusted p-value; Family wise type I error controlled within each endpoint using a Hochberg testing procedure
    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
    Placebo v Mepolizumab 100 mg SC
    Number of subjects included in analysis
    436
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.18 [26]
    Method
    Mixed Model Repeated Measures Analysis
    Parameter type
    Mean difference(Mepolizumab 100-Placebo)
    Point estimate
    -1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.5
         upper limit
    0.8
    Notes
    [26] - Unadjusted p-value
    Statistical analysis title
    Statistical analysis 3
    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
    Placebo v Mepolizumab 300 mg SC
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.926 [27]
    Method
    Mixed Model Repeated Measures Analysis
    Parameter type
    Mean difference(Mepolizumab 300-Placebo)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.8
         upper limit
    2.6
    Notes
    [27] - Adjusted p-value; Family wise type I error controlled within each endpoint using a Hochberg testing procedure
    Statistical analysis title
    Statistical analysis 4
    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
    Placebo v Mepolizumab 300 mg SC
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.926 [28]
    Method
    Mixed Model Repeated Measures Analysis
    Parameter type
    Mean difference(Mepolizumab 300-Placebo)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.8
         upper limit
    2.6
    Notes
    [28] - Unadjusted p-value

    Secondary: Change from Baseline in Mean COPD assessment test (CAT) score

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    End point title
    Change from Baseline in Mean COPD assessment test (CAT) score
    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. Mean change from Baseline in CAT score at Week 52 has been presented. Participants analyzed represents those with a Baseline and at least one post-Baseline assessment, and with no missing covariates.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Placebo Mepolizumab 100 mg SC Mepolizumab 300 mg SC
    Number of subjects analysed
    222 [29]
    216 [30]
    219 [31]
    Units: Score on CAT scale
    least squares mean (standard error)
        Score on CAT scale
    -0.4 ± 0.42
    -1.6 ± 0.42
    -0.8 ± 0.42
    Notes
    [29] - mITT Population
    [30] - mITT Population
    [31] - 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
    Mepolizumab 100 mg SC v Placebo
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.926 [32]
    Method
    Mixed Model Repeated Measures Analysis
    Parameter type
    Mean difference(Mepolizumab 100-Placebo)
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    0
    Notes
    [32] - Adjusted p-value; Family wise type I error controlled within each endpoint using a Hochberg testing procedure
    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 SC v Placebo
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.055 [33]
    Method
    Mixed Model Repeated Measures Analysis
    Parameter type
    Mean difference(Mepolizumab 100-Placebo)
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    0
    Notes
    [33] - Unadjusted p-value
    Statistical analysis title
    Statistical analysis 3
    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 300 mg SC v Placebo
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.926 [34]
    Method
    Mixed Model Repeated Measures Analysis
    Parameter type
    Mean difference(Mepolizumab 300-Placebo)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    0.8
    Notes
    [34] - Adjusted p-value; Family wise type I error controlled within each endpoint using a Hochberg testing procedure
    Statistical analysis title
    Statistical analysis 4
    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 300 mg SC v Placebo
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.547 [35]
    Method
    Mixed Model Repeated Measures Analysis
    Parameter type
    Mean difference(Mepolizumab 300-Placebo)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    0.8
    Notes
    [35] - 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
    Reporting group description
    Eligible 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.

    Reporting group title
    Mepolizumab 100 mg SC
    Reporting group description
    Eligible 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.

    Reporting group title
    Mepolizumab 300 mg SC
    Reporting group description
    Eligible participants were randomized to and received mepolizumab 300 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.

    Serious adverse events
    Placebo Mepolizumab 100 mg SC Mepolizumab 300 mg SC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 226 (30.09%)
    57 / 223 (25.56%)
    60 / 225 (26.67%)
         number of deaths (all causes)
    9
    4
    8
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Essential hypertension
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign lung neoplasm
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal cancer
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular stent thrombosis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatic obstruction
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injection related reaction
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Haematocrit increased
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    3 / 226 (1.33%)
    1 / 223 (0.45%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    3 / 226 (1.33%)
    3 / 223 (1.35%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    37 / 226 (16.37%)
    25 / 223 (11.21%)
    32 / 225 (14.22%)
         occurrences causally related to treatment / all
    0 / 52
    0 / 34
    0 / 54
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    Acute respiratory failure
         subjects affected / exposed
    2 / 226 (0.88%)
    3 / 223 (1.35%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Pulmonary embolism
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Macular fibrosis
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 226 (0.00%)
    3 / 223 (1.35%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spondyloarthropathy
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    18 / 226 (7.96%)
    16 / 223 (7.17%)
    15 / 225 (6.67%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 21
    0 / 16
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    5 / 226 (2.21%)
    1 / 223 (0.45%)
    3 / 225 (1.33%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 226 (0.44%)
    3 / 223 (1.35%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 226 (0.00%)
    3 / 223 (1.35%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 226 (0.44%)
    1 / 223 (0.45%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    2 / 225 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical mycobacterial infection
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia necrotising
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 223 (0.00%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 226 (0.00%)
    0 / 223 (0.00%)
    1 / 225 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 223 (0.45%)
    0 / 225 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Placebo Mepolizumab 100 mg SC Mepolizumab 300 mg SC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    137 / 226 (60.62%)
    147 / 223 (65.92%)
    137 / 225 (60.89%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 226 (0.88%)
    7 / 223 (3.14%)
    3 / 225 (1.33%)
         occurrences all number
    2
    7
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 226 (1.33%)
    8 / 223 (3.59%)
    7 / 225 (3.11%)
         occurrences all number
    3
    9
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 226 (5.31%)
    14 / 223 (6.28%)
    16 / 225 (7.11%)
         occurrences all number
    16
    14
    22
    Dyspnoea
         subjects affected / exposed
    18 / 226 (7.96%)
    12 / 223 (5.38%)
    10 / 225 (4.44%)
         occurrences all number
    19
    14
    17
    Oropharyngeal pain
         subjects affected / exposed
    4 / 226 (1.77%)
    15 / 223 (6.73%)
    11 / 225 (4.89%)
         occurrences all number
    4
    15
    13
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    5 / 226 (2.21%)
    8 / 223 (3.59%)
    10 / 225 (4.44%)
         occurrences all number
    9
    12
    24
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 226 (8.85%)
    34 / 223 (15.25%)
    22 / 225 (9.78%)
         occurrences all number
    29
    62
    39
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    10 / 226 (4.42%)
    6 / 223 (2.69%)
    11 / 225 (4.89%)
         occurrences all number
    17
    6
    27
    Pyrexia
         subjects affected / exposed
    9 / 226 (3.98%)
    6 / 223 (2.69%)
    12 / 225 (5.33%)
         occurrences all number
    9
    7
    17
    Non-cardiac chest pain
         subjects affected / exposed
    7 / 226 (3.10%)
    5 / 223 (2.24%)
    7 / 225 (3.11%)
         occurrences all number
    7
    8
    8
    Fatigue
         subjects affected / exposed
    4 / 226 (1.77%)
    6 / 223 (2.69%)
    8 / 225 (3.56%)
         occurrences all number
    4
    6
    8
    Oedema peripheral
         subjects affected / exposed
    3 / 226 (1.33%)
    7 / 223 (3.14%)
    4 / 225 (1.78%)
         occurrences all number
    3
    7
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    14 / 226 (6.19%)
    13 / 223 (5.83%)
    8 / 225 (3.56%)
         occurrences all number
    14
    16
    12
    Constipation
         subjects affected / exposed
    10 / 226 (4.42%)
    7 / 223 (3.14%)
    5 / 225 (2.22%)
         occurrences all number
    10
    8
    6
    Nausea
         subjects affected / exposed
    3 / 226 (1.33%)
    9 / 223 (4.04%)
    9 / 225 (4.00%)
         occurrences all number
    3
    10
    13
    Abdominal pain upper
         subjects affected / exposed
    1 / 226 (0.44%)
    9 / 223 (4.04%)
    5 / 225 (2.22%)
         occurrences all number
    1
    9
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    11 / 226 (4.87%)
    15 / 223 (6.73%)
    17 / 225 (7.56%)
         occurrences all number
    11
    18
    21
    Pain in extremity
         subjects affected / exposed
    5 / 226 (2.21%)
    7 / 223 (3.14%)
    6 / 225 (2.67%)
         occurrences all number
    6
    7
    10
    Arthralgia
         subjects affected / exposed
    6 / 226 (2.65%)
    10 / 223 (4.48%)
    6 / 225 (2.67%)
         occurrences all number
    7
    10
    6
    Musculoskeletal pain
         subjects affected / exposed
    2 / 226 (0.88%)
    4 / 223 (1.79%)
    7 / 225 (3.11%)
         occurrences all number
    2
    4
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    48 / 226 (21.24%)
    39 / 223 (17.49%)
    40 / 225 (17.78%)
         occurrences all number
    65
    57
    52
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 226 (8.85%)
    16 / 223 (7.17%)
    12 / 225 (5.33%)
         occurrences all number
    27
    19
    15
    Pneumonia
         subjects affected / exposed
    8 / 226 (3.54%)
    10 / 223 (4.48%)
    10 / 225 (4.44%)
         occurrences all number
    9
    13
    11
    Bronchitis
         subjects affected / exposed
    8 / 226 (3.54%)
    8 / 223 (3.59%)
    11 / 225 (4.89%)
         occurrences all number
    8
    12
    15
    Sinusitis
         subjects affected / exposed
    7 / 226 (3.10%)
    8 / 223 (3.59%)
    7 / 225 (3.11%)
         occurrences all number
    11
    11
    9
    Oral candidiasis
         subjects affected / exposed
    5 / 226 (2.21%)
    3 / 223 (1.35%)
    8 / 225 (3.56%)
         occurrences all number
    7
    3
    9
    Influenza
         subjects affected / exposed
    11 / 226 (4.87%)
    6 / 223 (2.69%)
    3 / 225 (1.33%)
         occurrences all number
    11
    7
    3
    Rhinitis
         subjects affected / exposed
    5 / 226 (2.21%)
    7 / 223 (3.14%)
    4 / 225 (1.78%)
         occurrences all number
    6
    9
    4
    Urinary tract infection
         subjects affected / exposed
    7 / 226 (3.10%)
    7 / 223 (3.14%)
    1 / 225 (0.44%)
         occurrences all number
    8
    8
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2014
    Amendment No. 1 - Removal of 36-Item Short Form Survey (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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