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    Clinical Trial Results:
    MEA115588 A randomised, double-blind, double-dummy, placebo-controlled, parallel-group, multi-centre study of the efficacy and safety of mepolizumab adjunctive therapy in subjects with severe uncontrolled refractory asthma

    Summary
    EudraCT number
    		 2012-001251-40
    Trial protocol
    		 BE   GB   DE   ES   IT   Outside EU/EEA  
    Global end of trial date
    18 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    04 Jun 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MEA115588
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000069-PIP02-10
    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
    10 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of mepolizumab 75 mg intravenous (i.v.) or 100 mg subcutaneous (SC) every 4 weeks versus placebo on the frequency of clinically significant exacerbations in adult and adolescent subjects with severe, uncontrolled, refractory asthma
    Protection of trial subjects
    Numbing cream or spray was permitted at the site of injection and rescue medications (salbuterol/albuterol) are available to the participant throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Oct 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Belgium: 22
    Country: Number of subjects enrolled
    France: 72
    Country: Number of subjects enrolled
    Germany: 78
    Country: Number of subjects enrolled
    Italy: 58
    Country: Number of subjects enrolled
    Canada: 35
    Country: Number of subjects enrolled
    United States: 68
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Argentina: 43
    Country: Number of subjects enrolled
    Japan: 50
    Country: Number of subjects enrolled
    Korea, Republic of: 45
    Country: Number of subjects enrolled
    Ukraine: 18
    Country: Number of subjects enrolled
    Chile: 23
    Worldwide total number of subjects
    580
    EEA total number of subjects
    273
    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)
    25
    Adults (18-64 years)
    474
    From 65 to 84 years
    81
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Par. who met the eligibility criteria at screening, entered the Run-in period for a minimum of 1 week and a maximum of 6 weeks. Par. who received all 8 doses and met the eligibility criteria were offered the opportunity to participate in an open label extension (OLE) study. Par. not entering the OLE study completed the Follow-up Visit.

    Pre-assignment
    Screening details
    		 A total of 802 participants (par.) were enrolled; 82 were Screen failures; 140 were Run-in failures; 580 were randomized, of which 576 received at least 1 dose of study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo intravenously (IV) plus placebo subcutaneously (SC) every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (Normal Saline)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    IV and SC q4weeks

    Arm title
    		 Mepolizumab 75 mg IV
    Arm description
    		 Participants received mepolizumab 75 milligrams (mg) IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mepolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    75mg IV q4weeks x 8doses plus NS SC

    Arm title
    		 Mepolizumab 100 mg SC
    Arm description
    		 Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mepolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100mg SC q4 weeks x 8 doses plus NS IV

    Number of subjects in period 1 [1]
    		Placebo Mepolizumab 75 mg IV Mepolizumab 100 mg SC
    Started
    191
    191
    194
    Completed
    179
    175
    185
    Not completed
    12
    16
    9
         Adverse event, serious fatal
    1
    -
    -
         Physician decision
    2
    1
    -
         Consent withdrawn by subject
    5
    9
    4
         Adverse event, non-fatal
    3
    -
    1
         Lost to follow-up
    -
    2
    2
         Lack of efficacy
    1
    1
    2
         Protocol deviation
    -
    3
    -
    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: 580 participants were randomized, of which 576 received at least 1 dose of study drug. The baseline period represents the participants that received at least 1 dose of study drug.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo intravenously (IV) plus placebo subcutaneously (SC) every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.

    Reporting group title
    Mepolizumab 75 mg IV
    Reporting group description
    		 Participants received mepolizumab 75 milligrams (mg) IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.

    Reporting group title
    Mepolizumab 100 mg SC
    Reporting group description
    		 Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.

    Reporting group values
    		 Placebo Mepolizumab 75 mg IV Mepolizumab 100 mg SC Total
    Number of subjects
    		 191 191 194 576
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.2 ( 14.26 ) 50 ( 14.03 ) 51.2 ( 14.55 ) -
    Gender categorical
    Units: Subjects
        Female
    		 107 106 116 329
        Male
    		 84 85 78 247
    Race
    Units: Subjects
        African American/African Heritage
    		 3 6 7 16
        American Indian or Alaskan Native
    		 0 0 1 1
        Asian - Central/South Asian Heritage
    		 1 1 0 2
        Asian - East Asian Heritage
    		 15 15 15 45
        Asian - Japanese Heritage
    		 18 17 17 52
        Asian - South East Asian Heritage
    		 4 0 2 6
        White - Arabic/North African Heritage
    		 4 3 4 11
        White - White/Caucasian/European Heritage
    		 144 148 148 440
        Mixed Race
    		 2 1 0 3

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo intravenously (IV) plus placebo subcutaneously (SC) every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.

    Reporting group title
    Mepolizumab 75 mg IV
    Reporting group description
    		 Participants received mepolizumab 75 milligrams (mg) IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.

    Reporting group title
    Mepolizumab 100 mg SC
    Reporting group description
    		 Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.

    Primary: Number of clinically significant exacerbations of asthma per year

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    End point title
    		 Number of clinically significant exacerbations of asthma per year
    End point description
    Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization and/or emergency department (ED) visits. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.
    End point type
    Primary
    End point timeframe
    From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose
    End point values
    		 Placebo Mepolizumab 75 mg IV Mepolizumab 100 mg SC
    Number of subjects analysed
    191 [1]
    191 [2]
    194 [3]
    Units: Number of exacerbations per year
        number (not applicable)
    1.74
    0.93
    0.83
    Notes
    [1] - Modified ITT Population: all participants who were randomized and who received >1 dose of treatment.
    [2] - Modified ITT Population: all participants who were randomized and who received >1 dose of treatment.
    [3] - Modified ITT Population: all participants who were randomized and who received >1 dose of treatment.
    Statistical analysis title
    		 Analysis 1
    Comparison groups
    Placebo v Mepolizumab 75 mg IV
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.001 [5]
    Method
    		 Negative binomial model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.72
    Notes
    [4] - Number of exacerbations per year in the mepolizumab 75mg IV arm divided by the number of exacerbations per year in the placebo arm.
    [5] - Hochberg procedure with a gamma parameter of 1 used for multiplicity adjustment.
    Statistical analysis title
    		 Analysis 2
    Comparison groups
    Placebo v Mepolizumab 100 mg SC
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001 [7]
    Method
    		 Negative binomial model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 0.64
    Notes
    [6] - Number of exacerbations per year in the mepolizumab 100 mg SC arm divided by the number of exacerbations per year in the placebo arm.
    [7] - Hochberg procedure with a gamma parameter of 1 used for multiplicity adjustment.

    Secondary: Number of clinically significant exacerbations requiring hospitalization (including intubation and admittance to an intensive care unit [ICU]) or ED visits per year

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    End point title
    		 Number of clinically significant exacerbations requiring hospitalization (including intubation and admittance to an intensive care unit [ICU]) or ED visits per year
    End point description
    Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization and/or emergency department (ED) visits. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.
    End point type
    Secondary
    End point timeframe
    From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose
    End point values
    		 Placebo Mepolizumab 75 mg IV Mepolizumab 100 mg SC
    Number of subjects analysed
    191 [8]
    191 [9]
    194 [10]
    Units: Number of exacerbations per year
        number (not applicable)
    0.2
    0.14
    0.08
    Notes
    [8] - ITT Population
    [9] - ITT Population
    [10] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of clinically significant exacerbations requiring hospitalization (including intubation and admittance to an ICU) per year

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    End point title
    		 Number of clinically significant exacerbations requiring hospitalization (including intubation and admittance to an ICU) per year
    End point description
    Clinically significant exacerbations of asthma is defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.
    End point type
    Secondary
    End point timeframe
    From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose
    End point values
    		 Placebo Mepolizumab 75 mg IV Mepolizumab 100 mg SC
    Number of subjects analysed
    191 [11]
    191 [12]
    194 [13]
    Units: Number of exacerbations per year
        number (not applicable)
    0.1
    0.06
    0.03
    Notes
    [11] - ITT Population
    [12] - ITT Population
    [13] - ITT Population
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in clinic pre-bronchodilator forced expiratory volume in 1 second (FEV1) at Week 32

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    End point title
    		 Mean change from Baseline in clinic pre-bronchodilator forced expiratory volume in 1 second (FEV1) at Week 32
    End point description
    FEV1 is defined as the volume of air expelled from the lungs in 1 second. Pre-bronchodilator FEV1 measurements were taken by spirometry. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and the baseline value. Analysis performed using mixed model repeated measures with covariates of baseline, region, baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), treatment and visit, plus interaction terms for visit by baseline and visit by treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32
    End point values
    		 Placebo Mepolizumab 75 mg IV Mepolizumab 100 mg SC
    Number of subjects analysed
    189 [14]
    188 [15]
    192 [16]
    Units: Milliliters (mL)
        least squares mean (standard error)
    86 ( 31.4 )
    186 ( 31.5 )
    183 ( 31.1 )
    Notes
    [14] - ITT Population
    [15] - ITT Population
    [16] - ITT Population
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in the St. George’s Respiratory Questionnaire total score at Week 32

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    End point title
    		 Mean change from Baseline in the St. George’s Respiratory Questionnaire total score at Week 32
    End point description
    The St. George’s Respiratory Questionnaire is an established instrument, comprising 50 questions, evaluating symptoms, activity, and impacts; to measure Quality of Life in participants with diseases of airway obstruction and to elicit the participant's opinion of his/her health. The lowest possible value is zero and the highest possible value is 100. The higher values correspond to greater impairment in quality of life. The questionnaire was administered at Baseline (Visit 2) and at the Exit Visit (approximately 4 weeks after the last dose of study treatment). The change from baseline is defined as the difference between the value of the endpoint at the time point of interest and the baseline value. Analysis performed using analysis of covariance with covariates of baseline, region, baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), baseline % predicted FEV1, and treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32
    End point values
    		 Placebo Mepolizumab 75 mg IV Mepolizumab 100 mg SC
    Number of subjects analysed
    177 [17]
    174 [18]
    184 [19]
    Units: Scores on a scale
        least squares mean (standard error)
    -9 ( 1.16 )
    -15.4 ( 1.16 )
    -16 ( 1.13 )
    Notes
    [17] - ITT Population. Only participants with a Baseline and Week 32 assessment were included.
    [18] - ITT Population. Only participants with a Baseline and Week 32 assessment were included.
    [19] - ITT Population. Only participants with a Baseline and Week 32 assessment were included.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment serious adverse events (SAEs) and non-serious AEs were defined as events occurring from the first dose of investigational product until 28 days after the last dose of investigational product.
    Adverse event reporting additional description
    Serious adverse events (SAEs) and Non-serious AEs were collected in members of Intent-to-Treat (ITT) Population, comprised of all participants who were randomized and who received at least one dose of study medication. The number of occurrences for non-serious AEs was not collected; therefore, 0 has been entered.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.

    Reporting group title
    Mepolizumab 75 mg IV
    Reporting group description
    		 Participants received mepolizumab 75 mg IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.

    Reporting group title
    Mepolizumab 100 mg SC
    Reporting group description
    		 Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.

    Serious adverse events
    		 Placebo Mepolizumab 75 mg IV Mepolizumab 100 mg SC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 191 (14.14%)
    14 / 191 (7.33%)
    16 / 194 (8.25%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    14 / 191 (7.33%)
    9 / 191 (4.71%)
    5 / 194 (2.58%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 10
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Contusion
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Fractured coccyx
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 191 (0.52%)
    0 / 194 (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
    Heat stroke
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Inflammation of wound
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 191 (0.52%)
    0 / 194 (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
    Road traffic accident
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Tendon rupture
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 191 (0.52%)
    0 / 194 (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
    Congenital, familial and genetic disorders
    Intracranial lipoma
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Atrial flutter
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Sciatica
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 191 (0.52%)
    0 / 194 (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 disorders
    Gastrointestinal motility disorder
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 191 (0.52%)
    0 / 194 (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
    Large intestine perforation
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Hepatobiliary disorders
    Gallbladder disorder
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 191 (0.52%)
    0 / 194 (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
    Dyshidrotic eczema
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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 urethral
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Nephrogenic diabetes insipidus
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 191 (1.05%)
    0 / 191 (0.00%)
    0 / 194 (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
    Herpes zoster
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    2 / 194 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Croup infectious
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Urosepsis
         subjects affected / exposed
    0 / 191 (0.00%)
    0 / 191 (0.00%)
    1 / 194 (0.52%)
         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 upper respiratory tract infection
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 191 (0.52%)
    0 / 194 (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
    Vulval abscess
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 191 (0.00%)
    0 / 194 (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
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Placebo Mepolizumab 75 mg IV Mepolizumab 100 mg SC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    139 / 191 (72.77%)
    141 / 191 (73.82%)
    131 / 194 (67.53%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 191 (2.09%)
    6 / 191 (3.14%)
    3 / 194 (1.55%)
         occurrences all number
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    33 / 191 (17.28%)
    46 / 191 (24.08%)
    39 / 194 (20.10%)
         occurrences all number
    0
    0
    0
    Dizziness
         subjects affected / exposed
    8 / 191 (4.19%)
    4 / 191 (2.09%)
    6 / 194 (3.09%)
         occurrences all number
    0
    0
    0
    Migraine
         subjects affected / exposed
    6 / 191 (3.14%)
    1 / 191 (0.52%)
    5 / 194 (2.58%)
         occurrences all number
    0
    0
    0
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    6 / 191 (3.14%)
    5 / 191 (2.62%)
    17 / 194 (8.76%)
         occurrences all number
    0
    0
    0
    Fatigue
         subjects affected / exposed
    9 / 191 (4.71%)
    8 / 191 (4.19%)
    5 / 194 (2.58%)
         occurrences all number
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    3 / 191 (1.57%)
    6 / 191 (3.14%)
    2 / 194 (1.03%)
         occurrences all number
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 191 (5.76%)
    4 / 191 (2.09%)
    5 / 194 (2.58%)
         occurrences all number
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    4 / 191 (2.09%)
    7 / 191 (3.66%)
    7 / 194 (3.61%)
         occurrences all number
    0
    0
    0
    Nausea
         subjects affected / exposed
    8 / 191 (4.19%)
    4 / 191 (2.09%)
    5 / 194 (2.58%)
         occurrences all number
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 191 (1.57%)
    2 / 191 (1.05%)
    7 / 194 (3.61%)
         occurrences all number
    0
    0
    0
    Toothache
         subjects affected / exposed
    3 / 191 (1.57%)
    0 / 191 (0.00%)
    6 / 194 (3.09%)
         occurrences all number
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    16 / 191 (8.38%)
    11 / 191 (5.76%)
    9 / 194 (4.64%)
         occurrences all number
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    15 / 191 (7.85%)
    12 / 191 (6.28%)
    7 / 194 (3.61%)
         occurrences all number
    0
    0
    0
    Cough
         subjects affected / exposed
    9 / 191 (4.71%)
    8 / 191 (4.19%)
    5 / 194 (2.58%)
         occurrences all number
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 191 (0.52%)
    5 / 191 (2.62%)
    7 / 194 (3.61%)
         occurrences all number
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    4 / 191 (2.09%)
    6 / 191 (3.14%)
    2 / 194 (1.03%)
         occurrences all number
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    2 / 191 (1.05%)
    2 / 191 (1.05%)
    9 / 194 (4.64%)
         occurrences all number
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    7 / 191 (3.66%)
    11 / 191 (5.76%)
    14 / 194 (7.22%)
         occurrences all number
    0
    0
    0
    Arthralgia
         subjects affected / exposed
    9 / 191 (4.71%)
    10 / 191 (5.24%)
    11 / 194 (5.67%)
         occurrences all number
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    10 / 191 (5.24%)
    3 / 191 (1.57%)
    8 / 194 (4.12%)
         occurrences all number
    0
    0
    0
    Myalgia
         subjects affected / exposed
    6 / 191 (3.14%)
    3 / 191 (1.57%)
    3 / 194 (1.55%)
         occurrences all number
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    46 / 191 (24.08%)
    45 / 191 (23.56%)
    33 / 194 (17.01%)
         occurrences all number
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    27 / 191 (14.14%)
    22 / 191 (11.52%)
    24 / 194 (12.37%)
         occurrences all number
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    18 / 191 (9.42%)
    11 / 191 (5.76%)
    18 / 194 (9.28%)
         occurrences all number
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    16 / 191 (8.38%)
    14 / 191 (7.33%)
    9 / 194 (4.64%)
         occurrences all number
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    6 / 191 (3.14%)
    10 / 191 (5.24%)
    5 / 194 (2.58%)
         occurrences all number
    0
    0
    0
    Influenza
         subjects affected / exposed
    6 / 191 (3.14%)
    10 / 191 (5.24%)
    3 / 194 (1.55%)
         occurrences all number
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 191 (1.05%)
    5 / 191 (2.62%)
    8 / 194 (4.12%)
         occurrences all number
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    3 / 191 (1.57%)
    5 / 191 (2.62%)
    6 / 194 (3.09%)
         occurrences all number
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    4 / 191 (2.09%)
    7 / 191 (3.66%)
    1 / 194 (0.52%)
         occurrences all number
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2012
    Clarified 2 exclusion criteria

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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