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    Clinical Trial Results:
    A multi-center, randomized, double-blind, placebo controlled, parallel group study to compare cessation versus continuation of long-term mepolizumab treatment in patients with severe eosinophilic asthma (201810)

    Summary
    EudraCT number
    		 2015-002361-32
    Trial protocol
    		 DE   NL   RO   FR   PL   Outside EU/EEA  
    Global end of trial date
    24 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Feb 2020
    First version publication date
    08 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    201810
    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 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate whether patients with severe eosinophilic asthma who have received long term treatment with mepolizumab (at least 3 years) need to maintain treatment with mepolizumab to continue to receive benefit.
    Protection of trial subjects
    Numbing cream or spray was permitted at the site of injection and rescue medications (salbutamol/albuterol) are available to the participant throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jan 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Ethical reason
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 11
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 28
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Romania: 20
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Ukraine: 41
    Country: Number of subjects enrolled
    United States: 46
    Worldwide total number of subjects
    306
    EEA total number of subjects
    116
    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)
    1
    Adults (18-64 years)
    234
    From 65 to 84 years
    71
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A multi-center, randomized, double-blind, placebo controlled, parallel group study to compare cessation versus continuation of long-term mepolizumab treatment. Participants (par.) who completed the Follow Up/Exit Visit or Early Withdrawal Visit from study MEA115666 (NCT01691859) or 201312 (NCT02135692) were eligible to participate in this study.

    Pre-assignment
    Screening details
    		 This is a 3 period study including variable open-label (OL) run-in, double-blind (DB) treatment period and open-label treatment switch period. The study was conducted in 75 centers across 14 countries from 07-Jan-2016 to 24-Jul-2019.

    Period 1
    Period 1 title
    PartA(Upto 132W)+PartB(Upto 8W)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part A/B: Mepolizumab 100mg SC
    Arm description
    		 Participants with less than 3 years of mepolizumab treatment entered variable open-label run-in period-Part A in order to reach 3 years of exposure and received 100 mg of mepolizumab injected subcutaneously (SC) once every 4 weeks (W) up to 132 weeks. Upon achieving 3 years exposure, participants entered Part B. Participants with at least 3 years of mepolizumab treatment directly entered fixed open-label run-in period-Part B and received 100 mg of mepolizumab injected SC once every 4 weeks up to 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mepolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Mepolizumab was available as lyophilized cake in sterile vial which was reconstituted using sterile water for injection and was administered 100 mg SC into the upper arm or thigh approximately every 4 weeks

    Number of subjects in period 1
    		Part A/B: Mepolizumab 100mg SC
    Started
    306
    Completed
    295
    Not completed
    11
         Consent withdrawn by subject
    5
         Physician decision
    1
         Adverse event, non-fatal
    1
         Failure to meet continuation criteria
    2
         Lack of efficacy
    2
    Period 2
    Period 2 title
    Part C (Up to 52W)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part C: Placebo
    Arm description
    		 Upon completion of the fixed run-in period, participants entered a double-blind study treatment and received placebo SC every 4 weeks up to 52 weeks. Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Sterile normal saline was administered as Placebo

    Arm title
    		 Part C: Mepolizumab 100mg SC
    Arm description
    		 Upon completion of the fixed run-in period, participants entered a double-blind study treatment and received continued mepolizumab 100 mg SC every 4 weeks up to 52 weeks. Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mepolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Mepolizumab was available as lyophilized cake in sterile vial which was reconstituted using sterile water for injection and was administered 100 mg SC into the upper arm or thigh approximately every 4 weeks

    Number of subjects in period 2
    		Part C: Placebo Part C: Mepolizumab 100mg SC
    Started
    151
    144
    Completed
    62
    96
    Not completed
    89
    48
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    2
    2
         Adverse event, non-fatal
    1
    1
         Switched to Part D treatment
    84
    45
         Lack of efficacy
    1
    -
    Period 3
    Period 3 title
    PartD (OL mepolizumab Period:Up to 52 W)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part D: Mepolizumab 100mg SC (Previous Placebo)
    Arm description
    		 Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mepolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Mepolizumab was available as lyophilized cake in sterile vial which was reconstituted using sterile water for injection and was administered 100 mg SC into the upper arm or thigh approximately every 4 weeks

    Arm title
    		 Part D: Mepolizumab 100mg SC (Previous Mepolizumab)
    Arm description
    		 Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mepolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Mepolizumab was available as lyophilized cake in sterile vial which was reconstituted using sterile water for injection and was administered 100 mg SC into the upper arm or thigh approximately every 4 weeks

    Number of subjects in period 3 [1]
    		Part D: Mepolizumab 100mg SC (Previous Placebo) Part D: Mepolizumab 100mg SC (Previous Mepolizumab)
    Started
    84
    45
    Completed
    80
    42
    Not completed
    4
    3
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    1
    -
         Physician decision
    2
    -
         Lost to follow-up
    -
    2
         Lack of efficacy
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A/B: Mepolizumab 100mg SC
    Reporting group description
    		 Participants with less than 3 years of mepolizumab treatment entered variable open-label run-in period-Part A in order to reach 3 years of exposure and received 100 mg of mepolizumab injected subcutaneously (SC) once every 4 weeks (W) up to 132 weeks. Upon achieving 3 years exposure, participants entered Part B. Participants with at least 3 years of mepolizumab treatment directly entered fixed open-label run-in period-Part B and received 100 mg of mepolizumab injected SC once every 4 weeks up to 8 weeks.

    Reporting group values
    		 Part A/B: Mepolizumab 100mg SC Total
    Number of subjects
    		 306 306
    Age categorical
    Units: Subjects
        Overall Participants
    		 306 306
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 55.6 ± 11.74 -
    Sex: Female, Male
    Units: Participants
        Female
    		 180 180
        Male
    		 126 126
    Race/Ethnicity, Customized
    Units: Subjects
        ASIAN - CENTRAL/SOUTH ASIAN HERITAGE
    		 1 1
        ASIAN - EAST ASIAN HERITAGE
    		 28 28
        ASIAN - JAPANESE HERITAGE
    		 21 21
        BLACK OR AFRICAN AMERICAN
    		 8 8
        WHITE - ARABIC/NORTH AFRICAN HERITAGE
    		 3 3
        WHITE - WHITE/CAUCASIAN/EUROPEAN HERITAGE
    		 245 245
    Subject analysis sets

    Subject analysis set title
    Parts A/B: Mepolizumab 100mg SC
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with less than 3 years of mepolizumab treatment entered variable open-label run-in period-Part A in order to reach 3 years of exposure and received 100 mg of mepolizumab injected subcutaneously (SC) once every 4 weeks up to 132 weeks. Upon achieving 3 years exposure, participants entered Part B. Participants with at least 3 years of mepolizumab treatment directly entered fixed open-label run-in period-Part B and received 100 mg of mepolizumab injected SC once every 4 weeks up to 8 weeks.

    Subject analysis set title
    Part C: Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Upon completion of the fixed run-in period, participants entered a double-blind study treatment and received placebo SC every 4 weeks up to 52 weeks. Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).

    Subject analysis set title
    Part C: Mepolizumab 100mg SC
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Upon completion of the fixed run-in period, participants entered a double-blind study treatment and received continued mepolizumab 100 mg SC every 4 weeks up to 52 weeks. Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).

    Subject analysis sets values
    		 Parts A/B: Mepolizumab 100mg SC Part C: Placebo Part C: Mepolizumab 100mg SC
    Number of subjects
    306
    151
    144
    Age categorical
    Units: Subjects
        Overall Participants
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    55.6 ± 11.74
    ±
    ±
    Sex: Female, Male
    Units: Participants
        Female
    180
        Male
    126
    Race/Ethnicity, Customized
    Units: Subjects
        ASIAN - CENTRAL/SOUTH ASIAN HERITAGE
    1
    0
    0
        ASIAN - EAST ASIAN HERITAGE
    28
    0
    0
        ASIAN - JAPANESE HERITAGE
    21
    0
    0
        BLACK OR AFRICAN AMERICAN
    8
    0
    0
        WHITE - ARABIC/NORTH AFRICAN HERITAGE
    3
    0
    0
        WHITE - WHITE/CAUCASIAN/EUROPEAN HERITAGE
    245
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Part A/B: Mepolizumab 100mg SC
    Reporting group description
    		 Participants with less than 3 years of mepolizumab treatment entered variable open-label run-in period-Part A in order to reach 3 years of exposure and received 100 mg of mepolizumab injected subcutaneously (SC) once every 4 weeks (W) up to 132 weeks. Upon achieving 3 years exposure, participants entered Part B. Participants with at least 3 years of mepolizumab treatment directly entered fixed open-label run-in period-Part B and received 100 mg of mepolizumab injected SC once every 4 weeks up to 8 weeks.
    Reporting group title
    Part C: Placebo
    Reporting group description
    		 Upon completion of the fixed run-in period, participants entered a double-blind study treatment and received placebo SC every 4 weeks up to 52 weeks. Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).

    Reporting group title
    Part C: Mepolizumab 100mg SC
    Reporting group description
    		 Upon completion of the fixed run-in period, participants entered a double-blind study treatment and received continued mepolizumab 100 mg SC every 4 weeks up to 52 weeks. Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).
    Reporting group title
    Part D: Mepolizumab 100mg SC (Previous Placebo)
    Reporting group description
    		 Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).

    Reporting group title
    Part D: Mepolizumab 100mg SC (Previous Mepolizumab)
    Reporting group description
    		 Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).

    Subject analysis set title
    Parts A/B: Mepolizumab 100mg SC
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants with less than 3 years of mepolizumab treatment entered variable open-label run-in period-Part A in order to reach 3 years of exposure and received 100 mg of mepolizumab injected subcutaneously (SC) once every 4 weeks up to 132 weeks. Upon achieving 3 years exposure, participants entered Part B. Participants with at least 3 years of mepolizumab treatment directly entered fixed open-label run-in period-Part B and received 100 mg of mepolizumab injected SC once every 4 weeks up to 8 weeks.

    Subject analysis set title
    Part C: Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Upon completion of the fixed run-in period, participants entered a double-blind study treatment and received placebo SC every 4 weeks up to 52 weeks. Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).

    Subject analysis set title
    Part C: Mepolizumab 100mg SC
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Upon completion of the fixed run-in period, participants entered a double-blind study treatment and received continued mepolizumab 100 mg SC every 4 weeks up to 52 weeks. Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).

    Primary: Percentage of participants with first clinically significant exacerbation in Part C

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    End point title
    		 Percentage of participants with first clinically significant exacerbation in Part C
    End point description
    Clinically significant exacerbation was defined as worsening of asthma which requires use of systemic corticosteroids (e.g., prednisone) for at least 3 days or a single intramuscular (IM) corticosteroid dose and/or hospitalization and/or emergency department (ED) visits. For participants on maintenance systemic corticosteroids, at least double the existing maintenance dose for at least 3 days is required. Percentage of participants with clinically significant exacerbation over time during the on-treatment period of Part C and 95% confidence interval were estimated using Kaplan-Meier estimates. Intent-to-Treat Population includes all randomized participants who received at least one dose of double-blind study medication within Part C.
    End point type
    Primary
    End point timeframe
    Weeks 12, 24, 36 and 52
    End point values
    		 Part C: Placebo Part C: Mepolizumab 100mg SC
    Number of subjects analysed
    151 [1]
    144 [2]
    Units: Percentage of participants
    number (confidence interval 95%)
        Week 12
    31.8 (25.0 to 39.9)
    20.2 (14.5 to 27.7)
        Week 24
    49.3 (41.5 to 57.6)
    32.3 (25.3 to 40.7)
        Week 36
    56.0 (48.1 to 64.2)
    40.3 (32.8 to 48.9)
        Weeks 52
    60.7 (52.7 to 68.8)
    47.1 (39.2 to 55.7)
    Notes
    [1] - Intent-to-Treat Population.
    [2] - Intent-to-Treat Population.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Treatment comparison between mepolizumab 100 mg SC and placebo using hazards ratio and 95% confidence interval has been presented.
    Comparison groups
    Part C: Placebo v Part C: Mepolizumab 100mg SC
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.86

    Secondary: Ratio to Baseline in blood eosinophil count in Part C

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    End point title
    		 Ratio to Baseline in blood eosinophil count in Part C
    End point description
    Blood samples were collected at specific time points to measure blood eosinophils level. Baseline was defined as the latest available assessment prior to first dose of double-blind treatment within Part C. Ratio to Baseline is defined as visit value divided by Baseline value and was analyzed using Mixed Model Repeated Measures with covariates of Baseline, region, exacerbations in the year prior to randomization (as an ordinal variable), Baseline maintenance oral corticosteroids (OCS) therapy (OCS vs. no OCS), treatment and visit, plus interaction terms for visit by Baseline and visit by treatment group. The log transformation was applied to blood eosinophil counts prior to analysis. If a blood eosinophil count of zero was reported, a small value was added prior to log transforming the data. The dispersion measure used was log standard error.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 12, 24, 36 and 52
    End point values
    		 Part C: Placebo Part C: Mepolizumab 100mg SC
    Number of subjects analysed
    121 [3]
    120 [4]
    Units: Ratio
    least squares mean (standard error)
        Week 12, n=121, 120
    6.03 ± 0.077
    1.16 ± 0.078
        Week 24, n= 79, 106
    6.58 ± 0.095
    1.03 ± 0.084
        Week 36, n= 65, 99
    6.48 ± 0.093
    1.20 ± 0.079
        Week 52, n=60, 92
    6.17 ± 0.091
    1.00 ± 0.077
    Notes
    [3] - Intent-to-Treat Population.
    [4] - Intent-to-Treat Population.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Treatment comparison between mepolizumab 100 mg SC and placebo using ratio of mepolizumab to placebo and its 95% confidence interval at Week 12 has been presented.
    Comparison groups
    Part C: Placebo v Part C: Mepolizumab 100mg SC
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Ratio
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.24
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Treatment comparison between mepolizumab 100 mg SC and placebo using ratio of mepolizumab to placebo and its 95% confidence interval at Week 24 has been presented.
    Comparison groups
    Part C: Placebo v Part C: Mepolizumab 100mg SC
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Ratio
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 0.2
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Treatment comparison between mepolizumab 100 mg SC and placebo using ratio of mepolizumab to placebo and its 95% confidence interval at Week 36 has been presented.
    Comparison groups
    Part C: Placebo v Part C: Mepolizumab 100mg SC
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Ratio
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.24
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Treatment comparison between mepolizumab 100 mg SC and placebo using ratio of mepolizumab to placebo and its 95% confidence interval at Week 52 has been presented.
    Comparison groups
    Part C: Placebo v Part C: Mepolizumab 100mg SC
    Number of subjects included in analysis
    241
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Ratio
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.2

    Secondary: Percentage of participants with 0.5 Point or More Increase in Asthma Control Questionnaire (ACQ)-5 Score from Baseline in Part C

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    End point title
    		 Percentage of participants with 0.5 Point or More Increase in Asthma Control Questionnaire (ACQ)-5 Score from Baseline in Part C
    End point description
    The ACQ-5 is a five-item, self-completed questionnaire. Five questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) enquire about the frequency and/or severity of symptoms over the previous week. The response ranges from zero (no impairment/limitation) to six (total impairment/ limitation) scale. Increase in score of >= 0.5 units from Baseline indicates decrease in asthma control. Baseline is the latest available assessment prior to first dose of double-blind treatment within Part C. Percentage of participants with a 0.5 point or more increase in ACQ-5 score from Baseline over time during the on-treatment period of Part C and its 95% confidence interval were estimated using Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 12, 24, 36 and 52
    End point values
    		 Part C: Placebo Part C: Mepolizumab 100mg SC
    Number of subjects analysed
    151 [5]
    144 [6]
    Units: Percentage of participants
    number (confidence interval 95%)
        Week 12
    44.5 (36.9 to 52.8)
    39.3 (31.8 to 47.8)
        Week 24
    69.5 (61.6 to 77.1)
    49.3 (41.3 to 57.9)
        Week 36
    74.9 (67.1 to 82.1)
    56.0 (47.8 to 64.6)
        Weeks 52
    79.0 (71.3 to 85.7)
    63.1 (54.8 to 71.5)
    Notes
    [5] - Intent-to-Treat Population
    [6] - Intent-to-Treat Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Treatment comparison between mepolizumab 100 mg SC and placebo using hazards ratio and 95% confidence interval has been presented.
    Comparison groups
    Part C: Placebo v Part C: Mepolizumab 100mg SC
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.88

    Secondary: Percentage of participants with time to first exacerbation requiring hospitalization or ED visit in Part C

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    End point title
    		 Percentage of participants with time to first exacerbation requiring hospitalization or ED visit in Part C
    End point description
    Exacerbations of asthma requiring hospitalization or ED visit were assessed. The analysis was performed from Cox Proportional Hazards Model with covariates of treatment group, region, exacerbations in the year prior to randomization (as an ordinal variable) and Baseline maintenance OCS therapy (OCS vs. no OCS). Kaplan-Meier estimates of the probability of an exacerbation and its 95% confidence interval was expressed as percentage of participants with an exacerbation over time.
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24, 36 and 52
    End point values
    		 Part C: Placebo Part C: Mepolizumab 100mg SC
    Number of subjects analysed
    151 [7]
    144 [8]
    Units: Percentage of participants
    number (confidence interval 95%)
        Week 12
    2.9 (1.1 to 7.5)
    2.8 (1.1 to 7.2)
        Week 24
    5.7 (2.7 to 11.8)
    5.1 (2.4 to 10.3)
        Week 36
    5.7 (2.7 to 11.8)
    5.9 (3.0 to 11.6)
        Weeks 52
    5.7 (2.7 to 11.8)
    7.9 (4.3 to 14.3)
    Notes
    [7] - Intent-to-Treat Population
    [8] - Intent-to-Treat Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Treatment comparison between mepolizumab 100 mg SC and placebo using hazards ratio and 95% confidence interval has been presented.
    Comparison groups
    Part C: Placebo v Part C: Mepolizumab 100mg SC
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.57
    Method
    		 Cox Proportional Hazards Model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 3.51

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For Part A/B: from first dose of open-label mepolizumab up to 132 weeks, for Part C: from start of double blind treatment up to 52 weeks, and for Part D: from start of first dose of open-label treatment in Part D upto 52 weeks post-randomization in Part C
    Adverse event reporting additional description
    AEs and SAEs were collected for As Treated Population which comprised of all participants who received at least one dose of open label mepolizumab for Parts A/B and Part D. Intent-to-Treat (ITT) Population was used for Part C which comprised of all randomized participants who received at least one dose of double-blind study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Part A/B: Mepolizumab 100mg SC
    Reporting group description
    		 Participants with less than 3 years of mepolizumab treatment entered variable open-label run-in period-Part A in order to reach 3 years of exposure and received 100 mg of mepolizumab injected subcutaneously (SC) once every 4 weeks (W) up to 132 weeks. Upon achieving 3 years exposure, participants entered Part B. Participants with at least 3 years of mepolizumab treatment directly entered fixed open-label run-in period-Part B and received 100 mg of mepolizumab injected SC once every 4 weeks up to 8 weeks.

    Reporting group title
    Part C: Placebo
    Reporting group description
    		 Upon completion of the fixed run-in period, participants entered a double-blind study treatment and received placebo SC every 4 weeks up to 52 weeks. Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).

    Reporting group title
    Part C: Mepolizumab 100mg
    Reporting group description
    		 Upon completion of the fixed run-in period, participants entered a double-blind study treatment and received continued mepolizumab 100 mg SC every 4 weeks up to 52 weeks. Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).

    Reporting group title
    Part D: Mepolizumab 100mg SC (Previous Placebo)
    Reporting group description
    		 Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).

    Reporting group title
    Part D: Mepolizumab 100mg SC (Previous Mepolizumab)
    Reporting group description
    		 Participants who experienced a clinically significant asthma exacerbation were assessed by the investigator to determine if they could continue double-blind treatment or should instead enter OL mepolizumab 100 mg SC every 4 weeks for the remainder of the treatment period (up to 52 weeks after randomization).

    Serious adverse events
    		 Part A/B: Mepolizumab 100mg SC Part C: Placebo Part C: Mepolizumab 100mg Part D: Mepolizumab 100mg SC (Previous Placebo) Part D: Mepolizumab 100mg SC (Previous Mepolizumab)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 306 (2.29%)
    10 / 151 (6.62%)
    9 / 144 (6.25%)
    10 / 84 (11.90%)
    4 / 45 (8.89%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant polyp
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign ovarian tumour
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 151 (0.66%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer stage 0
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    1 / 144 (0.69%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal papillary mucinous neoplasm
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    1 / 144 (0.69%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    1 / 144 (0.69%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 151 (0.66%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 151 (0.66%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    1 / 144 (0.69%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Myasthenia gravis
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    1 / 144 (0.69%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device related thrombosis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 151 (0.66%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    1 / 144 (0.69%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    1 / 144 (0.69%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary gland calculus
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    3 / 306 (0.98%)
    6 / 151 (3.97%)
    2 / 144 (1.39%)
    4 / 84 (4.76%)
    4 / 45 (8.89%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 2
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paranasal cyst
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 151 (0.66%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    1 / 144 (0.69%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 151 (0.66%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    1 / 144 (0.69%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia pyelonephritis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 151 (0.66%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis fungal
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Part A/B: Mepolizumab 100mg SC Part C: Placebo Part C: Mepolizumab 100mg Part D: Mepolizumab 100mg SC (Previous Placebo) Part D: Mepolizumab 100mg SC (Previous Mepolizumab)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 306 (4.58%)
    69 / 151 (45.70%)
    82 / 144 (56.94%)
    44 / 84 (52.38%)
    32 / 45 (71.11%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 151 (0.66%)
    5 / 144 (3.47%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    1
    6
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 306 (0.00%)
    9 / 151 (5.96%)
    9 / 144 (6.25%)
    6 / 84 (7.14%)
    4 / 45 (8.89%)
         occurrences all number
    0
    11
    12
    7
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    0
    1
    2
    Diarrhoea
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    3 / 84 (3.57%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Large intestine polyp
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 306 (0.00%)
    14 / 151 (9.27%)
    10 / 144 (6.94%)
    7 / 84 (8.33%)
    4 / 45 (8.89%)
         occurrences all number
    0
    16
    14
    7
    12
    Cough
         subjects affected / exposed
    0 / 306 (0.00%)
    6 / 151 (3.97%)
    1 / 144 (0.69%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    7
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    3 / 84 (3.57%)
    1 / 45 (2.22%)
         occurrences all number
    0
    0
    0
    3
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 306 (0.00%)
    6 / 151 (3.97%)
    6 / 144 (4.17%)
    3 / 84 (3.57%)
    2 / 45 (4.44%)
         occurrences all number
    0
    12
    8
    4
    2
    Arthralgia
         subjects affected / exposed
    0 / 306 (0.00%)
    3 / 151 (1.99%)
    6 / 144 (4.17%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    3
    6
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    2 / 84 (2.38%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    0
    2
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 306 (4.58%)
    26 / 151 (17.22%)
    27 / 144 (18.75%)
    16 / 84 (19.05%)
    9 / 45 (20.00%)
         occurrences all number
    23
    44
    36
    22
    12
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 306 (0.00%)
    14 / 151 (9.27%)
    12 / 144 (8.33%)
    5 / 84 (5.95%)
    3 / 45 (6.67%)
         occurrences all number
    0
    18
    14
    5
    3
    Sinusitis
         subjects affected / exposed
    0 / 306 (0.00%)
    9 / 151 (5.96%)
    13 / 144 (9.03%)
    7 / 84 (8.33%)
    5 / 45 (11.11%)
         occurrences all number
    0
    10
    14
    11
    8
    Bronchitis
         subjects affected / exposed
    0 / 306 (0.00%)
    5 / 151 (3.31%)
    14 / 144 (9.72%)
    7 / 84 (8.33%)
    8 / 45 (17.78%)
         occurrences all number
    0
    5
    14
    8
    13
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 306 (0.00%)
    2 / 151 (1.32%)
    6 / 144 (4.17%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    2
    11
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 306 (0.00%)
    5 / 151 (3.31%)
    3 / 144 (2.08%)
    0 / 84 (0.00%)
    0 / 45 (0.00%)
         occurrences all number
    0
    7
    3
    0
    0
    Influenza
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 151 (0.66%)
    5 / 144 (3.47%)
    1 / 84 (1.19%)
    2 / 45 (4.44%)
         occurrences all number
    0
    1
    5
    1
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    4 / 84 (4.76%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    6
    0
    Chronic sinusitis
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    0
    1
    4
    Pneumonia
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    3 / 84 (3.57%)
    0 / 45 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    0
    0
    2
    Tooth infection
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    0 / 84 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    0
    0
    2
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 306 (0.00%)
    0 / 151 (0.00%)
    0 / 144 (0.00%)
    1 / 84 (1.19%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    0
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Nov 2015
    Amendment 1: Clarified when a participant switches from Part C to Part D; Removed the process of withdrawing a participant due to unblinding; Several minor changes to the Time and Events Table and corresponding text within the protocol to ensure participants entering from MEA115666 and 201312 were consistently and correctly monitored; Removed urinalysis testing; Updated contraception requirements.
    07 Jul 2016
    Amendment 2: Amended Section 5.6.1 Risk Assessment; Amended exclusion criterion No. 7-Other Monoclonal Antibodies in Section 6.2: Exclusion Criteria to also include Xolair; Amended Randomization Exclusion criterion No. 7-Current Asthma Exacerbation in Section 6.3.2: Randomization Exclusion Criteria to also include asthma worsening; Added text to Section 7.1 Investigational Product and Other Study Treatment providing details for general safety monitoring and in cases of acute severe reaction; Removed Xolair from Section 7.9.1 Permitted Medications and Non-Drug Therapies; Multiple changes to Section 7.9.2 Prohibited Medications and Non-Drug Therapies; Removed interactive response technology requirements from certain visits of the Time and Events Tables; Added Physical Examination at Visit C1 in Time and Events Table; Updated Participant/Clinician Rating of Global Impression of Disease Severity and Response to Therapy; Clarified unblinding risk when performing local laboratory testing.

    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.
    Numbing cream or spray was permitted at the site of injection and rescue medications (salbutamol/albuterol) are available to the participant throughout the study.
    For support, Contact us.
    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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