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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, parallel-group, multi-center 24-week study to evaluate the efficacy and safety of mepolizumab adjunctive therapy in subjects with severe eosinophilic asthma on markers of asthma control.

    Summary
    EudraCT number
    		 2014-002513-27
    Trial protocol
    		 IT   SK   BE   DE   CZ   GR   EE   ES   NL  
    Global end of trial date
    10 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2016
    First version publication date
    21 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    200862
    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
    17 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of mepolizumab 100 mg subcutaneous (SC) every 4 weeks versus placebo on health-related quality of life (HR-QoL) in adult and adolescent participants with severe eosinophilic asthma.
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 67
    Country: Number of subjects enrolled
    Belgium: 46
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Czech Republic: 17
    Country: Number of subjects enrolled
    Estonia: 15
    Country: Number of subjects enrolled
    France: 53
    Country: Number of subjects enrolled
    Germany: 56
    Country: Number of subjects enrolled
    Greece: 40
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Netherlands: 41
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Peru: 20
    Country: Number of subjects enrolled
    Russian Federation: 40
    Country: Number of subjects enrolled
    Slovakia: 9
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    Ukraine: 79
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    United States: 66
    Worldwide total number of subjects
    641
    EEA total number of subjects
    352
    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)
    10
    Adults (18-64 years)
    531
    From 65 to 84 years
    100
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 830 participants were screened (Visit 1) and entered into the run-in period, of which 556 participants were randomized and 551 participants received either mepolizumab 100 milligrams (mg) or placebo in addition to standard of care asthma 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
    		 Participants received placebo subcutaneously in upper arm or thigh following randomization at Visit 2 (Week 0) and every 4 weeks thereafter (last dose at Week 20) along with their standard of care asthma treatment up to 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received 0.9% Sodium Chloride subcutaneously into the upper arm or thigh

    Arm title
    		 Mepolizumab 100 mg
    Arm description
    		 Participants received mepolizumab 100 mg subcutaneously in upper arm or thigh following randomization at Visit 2 (Week 0) and every 4 weeks thereafter (last dose at Week 20) along with their standard of care asthma treatment up to 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mepolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received Mepolizumab 100 mg subcutaneously into the upper arm or thigh

    Number of subjects in period 1 [1]
    		Placebo Mepolizumab 100 mg
    Started
    277
    274
    Completed
    263
    269
    Not completed
    14
    5
         Physician decision
    2
    -
         Consent withdrawn by subject
    6
    2
         Adverse event, non-fatal
    2
    2
         Lost to follow-up
    2
    1
         Lack of efficacy
    2
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 830 participants were screened (Visit 1) and entered into the run-in period, of which 556 participants were randomized and 551 participants received either mepolizumab 100 milligrams (mg) or placebo in addition to standard of care asthma treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneously in upper arm or thigh following randomization at Visit 2 (Week 0) and every 4 weeks thereafter (last dose at Week 20) along with their standard of care asthma treatment up to 24 weeks.

    Reporting group title
    Mepolizumab 100 mg
    Reporting group description
    		 Participants received mepolizumab 100 mg subcutaneously in upper arm or thigh following randomization at Visit 2 (Week 0) and every 4 weeks thereafter (last dose at Week 20) along with their standard of care asthma treatment up to 24 weeks.

    Reporting group values
    		 Placebo Mepolizumab 100 mg Total
    Number of subjects
    		 277 274
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    		 52.1 ( 12.94 ) 49.8 ( 14.01 ) -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    		 176 149 325
        Male
    		 101 125 226
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 10 9 19
        Asian-Central/South Asian Heritage
    		 0 1 1
        Asian-East Asian Heritage
    		 0 2 2
        Asian-South East Asian Heritage
    		 0 1 1
        Black or African American
    		 7 8 15
        Native Hawaiian or Other Pacific Islander
    		 1 1 2
        White-Arabic/North African Heritage
    		 8 1 9
        White-White/Caucasian/European Heritage
    		 251 251 502

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneously in upper arm or thigh following randomization at Visit 2 (Week 0) and every 4 weeks thereafter (last dose at Week 20) along with their standard of care asthma treatment up to 24 weeks.

    Reporting group title
    Mepolizumab 100 mg
    Reporting group description
    		 Participants received mepolizumab 100 mg subcutaneously in upper arm or thigh following randomization at Visit 2 (Week 0) and every 4 weeks thereafter (last dose at Week 20) along with their standard of care asthma treatment up to 24 weeks.

    Primary: Mean change from Baseline in St. George’s Respiratory Questionnaire (SGRQ) score at Week 24

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    End point title
    		 Mean change from Baseline in St. George’s Respiratory Questionnaire (SGRQ) score at Week 24
    End point description
    SGRQ is an instrument, comprised of 50 questions (scored from 0-100) designed to measure Quality of Life in participants (par.) with diseases of airway obstruction, measuring symptoms, impact, and activity. The questions were designed to be self-completed by the par. with a recall over the past 4 weeks. The change from Baseline (BL) in SGRQ was calculated as value at Week 24 minus the value at BL for each par. and was analyzed using mixed model repeated measures allowing for covariates of BL value, region, BL maintenance oral corticosteroid (OCS) therapy, exacerbations in the year prior to the study (as an ordinal variable), BL % predicted FEV1 and visit, plus interaction terms for visit by BL and visit by treatment group. The Modified Intent-to-Treat (mITT) Population consisted of all randomized par. who received at least one dose of trial medication. Those with a missing BL covariate value or with no observed change from BL at any time point were excluded from the analysis model.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Mepolizumab 100 mg
    Number of subjects analysed
    260 [1]
    265 [2]
    Units: Scores on a scale
        least squares mean (standard error)
    -7.9 ( 1.01 )
    -15.6 ( 1 )
    Notes
    [1] - mITT Population.
    [2] - mITT Population.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Mepolizumab 100 mg v Placebo
    Number of subjects included in analysis
    525
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.5
         upper limit
    		 -4.9

    Secondary: Mean change from Baseline in clinic pre-bronchodilator Forced Expiratory Volume in one second (FEV1) at Week 24

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    End point title
    		 Mean change from Baseline in clinic pre-bronchodilator Forced Expiratory Volume in one second (FEV1) at Week 24
    End point description
    FEV1 is the volume of air that can be forced out in one second after taking a deep breath. The change from Baseline in pre-bronchodilator FEV1 was calculated as the value at Week 24 minus the value at Baseline for each subject and was analyzed using a mixed model repeated measures adjusting for Baseline absolute pre-bronchodilator FEV1, region, Baseline maintenance OCS therapy, exacerbations in the year prior to the study and visit, plus interaction terms for visit by Baseline and visit by treatment group. Participants with a missing Baseline covariate value or with no observed change from Baseline at any time point were excluded from the analysis model.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Mepolizumab 100 mg
    Number of subjects analysed
    259 [3]
    264 [4]
    Units: Milliliters (mL)
        least squares mean (standard error)
    56 ( 26.2 )
    176 ( 26.1 )
    Notes
    [3] - mITT Population.
    [4] - mITT Population.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Mepolizumab 100 mg v Placebo
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    120
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 47
         upper limit
    		 192

    Secondary: Percentage of participants achieving a 4 point or greater reduction from Baseline in SGRQ score at Week 24

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    End point title
    		 Percentage of participants achieving a 4 point or greater reduction from Baseline in SGRQ score at Week 24
    End point description
    The percentage of participants achieving a 4 point or greater reduction from Baseline in SGRQ at Week 24 was compared between treatment groups using a logistic regression model with covariates of Baseline value, region, Baseline maintenance OCS therapy, exacerbations in the year prior to the study (as an ordinal variable) and Baseline % predicted FEV1. Participants with a missing Baseline covariate value were excluded from the analysis model.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Placebo Mepolizumab 100 mg
    Number of subjects analysed
    275 [5]
    273 [6]
    Units: Percentage of participants
    55
    73
    Notes
    [5] - mITT Population.
    [6] - mITT Population.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Mepolizumab 100 mg v Placebo
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.55
         upper limit
    		 3.22

    Secondary: Mean change from Baseline in Asthma Control Questionnaire (ACQ-5) score at Week 24

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    End point title
    		 Mean change from Baseline in Asthma Control Questionnaire (ACQ-5) score at Week 24
    End point description
    The ACQ-5 is a five-item questionnaire, designed to be self-completed by the participants. The five questions inquired about the frequency and/or severity of symptoms over the previous week. The response options for all these questions consisted of a zero (no impairment/limitation) to six (total impairment/limitation) scale. The mean change from Baseline was calculated as the value at Week 24 minus the Baseline value for each participant and analyzed using a mixed model repeated measures allowing for covariates of Baseline value, region, Baseline maintenance OCS therapy, exacerbations in the year prior to the study (as an ordinal variable), Baseline % predicted FEV1 and visit, plus interaction terms for visit by Baseline and visit by treatment group. Participants with a missing Baseline covariate value or with no observed change from Baseline at any time point were excluded from the analysis model.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo Mepolizumab 100 mg
    Number of subjects analysed
    261 [7]
    266 [8]
    Units: Scores on a scale
        least squares mean (standard error)
    -0.4 ( 0.064 )
    -0.8 ( 0.064 )
    Notes
    [7] - mITT Population.
    [8] - mITT Population.
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Mepolizumab 100 mg v Placebo
    Number of subjects included in analysis
    527
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed model repeated measures analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 -0.22

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All serious adverse events (SAEs) and on-treatment non-serious adverse events (AEs) were collected from the start of investigational product and until 28 days after the IP stop date (on-treatment) and to the end of the study for SAEs (Week 24).
    Adverse event reporting additional description
    The Safety Population consisted of all randomized participants who received at least one dose of trial medication. Subjects were analysed according to treatment actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Mepolizumab 100 mg SC
    Reporting group description
    		 Participants received mepolizumab 100 mg subcutaneously in upper arm or thigh following randomization at Visit 2 (Week 0) and every 4 weeks thereafter (last dose at Week 20) along with their standard of care asthma treatment up to 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo subcutaneously in upper arm or thigh following randomization at Visit 2 (Week 0) and every 4 weeks thereafter (last dose at Week 20) along with their standard of care asthma treatment up to 24 weeks.

    Serious adverse events
    		 Mepolizumab 100 mg SC Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 273 (5.49%)
    23 / 278 (8.27%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic granulomatous angiitis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    3 / 273 (1.10%)
    9 / 278 (3.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural complication
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 278 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial ischemia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Hiatus hernia
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis atopic
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urethral stenosis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatic disorder
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemophilus infection
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localized infection
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteremia
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Mepolizumab 100 mg SC Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    124 / 273 (45.42%)
    140 / 278 (50.36%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    45 / 273 (16.48%)
    59 / 278 (21.22%)
         occurrences all number
    105
    123
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 273 (2.56%)
    11 / 278 (3.96%)
         occurrences all number
    9
    15
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    10 / 273 (3.66%)
    7 / 278 (2.52%)
         occurrences all number
    11
    8
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    4 / 273 (1.47%)
    14 / 278 (5.04%)
         occurrences all number
    5
    15
    Oropharyngeal pain
         subjects affected / exposed
    11 / 273 (4.03%)
    8 / 278 (2.88%)
         occurrences all number
    13
    9
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    13 / 273 (4.76%)
    18 / 278 (6.47%)
         occurrences all number
    17
    19
    Arthralgia
         subjects affected / exposed
    9 / 273 (3.30%)
    18 / 278 (6.47%)
         occurrences all number
    10
    21
    Muscle spasms
         subjects affected / exposed
    3 / 273 (1.10%)
    10 / 278 (3.60%)
         occurrences all number
    3
    12
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    31 / 273 (11.36%)
    46 / 278 (16.55%)
         occurrences all number
    41
    54
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 273 (6.23%)
    14 / 278 (5.04%)
         occurrences all number
    17
    16
    Sinusitis
         subjects affected / exposed
    11 / 273 (4.03%)
    12 / 278 (4.32%)
         occurrences all number
    12
    15
    Bronchitis
         subjects affected / exposed
    6 / 273 (2.20%)
    11 / 278 (3.96%)
         occurrences all number
    6
    14
    Rhinitis
         subjects affected / exposed
    10 / 273 (3.66%)
    7 / 278 (2.52%)
         occurrences all number
    12
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2014
    Amendment No. 1 • Text added to Section 7.2.2.1.4 Asthma Symptom Utility Index (ASUI) and Section 7.2.2.1.5 Sino-nasal Outcomes Test-22 (SNOT-22) to indicate that these questionnaires should only be administered to participants for whom an appropriate translation is available. • Time and Events Table (Table 7) updated
    17 Mar 2015
    Amendment No. 2 • The study acronym (MUSCA) has been included in the title. • The contact details of the Secondary Medical Monitor/SAE Contact have been updated to reflect a change in study personnel. • Details added on the Pre-Screening Visit, including the information to be captured in the eCRF for pre-screening failures. Several sections of the protocol have been amended accordingly. • As a result of now being able to test for immunogenicity after only 4 weeks postlast-dose, the overall safety profile of mepolizumab and pragmatic considerations to reduce participant burden and enable greater flexibility in their asthma management, the post-last-dose follow-up period has been reduced from 12 weeks to 4 weeks; therefore, Visit 9 has been removed from the study design. Several sections of the protocol have been amended accordingly. • The referenced mepolizumab Investigator’s Brochure (CM2003/00010/08) and associated supplement (2014N200212_00) have been replaced by a new version of the Investigator’s Brochure (CM2003/00010/09) throughout the protocol. • An endpoint related to the SNOT-22 questionnaire has been included in Table 1. • In Section 6.9.1, information has been added regarding the asthma exacerbation medication to be captured in the eCRF in the 12 months prior to Visit 1. • The Time and Events Schedule (Table 7) has been updated. • In Section 7.2.2.1.2, the areas covered by the 5 questions asked in the Asthma Control Questionnaire have been clarified. • In Section 7.2.2.4, the need to use eDiary data to verify the occurrence of a clinically significant asthma exacerbation has been removed. • In Section 7.3.5, it has been clarified that only a single twelve-lead ECG is needed at each time-point specified in the Time and Events Schedule (Table 7) unless a prolonged QT interval is observed in which case 2 further ECGs need to be collected (as defined in Section 5.5.4.). • Typographical errors have been corrected throughout the document.

    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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