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    Clinical Trial Results:
    MEA115666: A multi-centre, open-label, long term safety study of mepolizumab in asthmatic subjects who participated in the MEA112997 trial.

    Summary
    EudraCT number
    		 2012-001643-51
    Trial protocol
    		 GB   DE  
    Global end of trial date
    31 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 May 2018
    First version publication date
    05 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    115666
    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
    25 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to describe the long-term safety profile of mepolizumab.
    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
    28 Sep 2012
    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?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 30
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Germany: 56
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Romania: 28
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    Russian Federation: 47
    Country: Number of subjects enrolled
    Ukraine: 45
    Country: Number of subjects enrolled
    Argentina: 9
    Country: Number of subjects enrolled
    Chile: 27
    Country: Number of subjects enrolled
    Australia: 25
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 14
    Worldwide total number of subjects
    347
    EEA total number of subjects
    138
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    301
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multi-center, open-label, long term safety study of mepolizumab in 347 asthmatic participants who participated in the MEA112997 trial and were found eligible for this study after screening and run in phase. The study was conducted at 65 centers in 13 countries from 28 Sep 2012 to 31 May 2017.

    Pre-assignment
    Screening details
    		 A total of 362 participants were screened; 4 participants were screen failures (did not meet the inclusion/exclusion criteria); 11 participants were withdrawn during the run-in period (4 did not meet the continuation criteria, 4 withdrawal by participant and 3 following physician decision).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Mepolizumab 100 mg
    Arm description
    		 Participants received 100 milligram (mg) of mepolizumab injected subcutaneously (SC) once every 4 weeks until participant withdrawal or mepolizumab becomes commercially available in the relevant participating country. Participants remained on standard of care asthma therapy, which was adjusted during the study, at the discretion of their physician.
    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
    Participants received 100 mg of mepolizumab injected SC once every 4 weeks.

    Number of subjects in period 1
    		Mepolizumab 100 mg
    Started
    347
    Completed
    0
    Not completed
    347
         Study closed/terminated
    50
         Adverse event, serious fatal
    6
         Physician decision
    6
         Consent withdrawn by subject
    31
         Adverse event, non-fatal
    13
         Product commercially available
    221
         Lost to follow-up
    5
         Lack of efficacy
    11
         Protocol deviation
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Mepolizumab 100 mg
    Reporting group description
    		 Participants received 100 milligram (mg) of mepolizumab injected subcutaneously (SC) once every 4 weeks until participant withdrawal or mepolizumab becomes commercially available in the relevant participating country. Participants remained on standard of care asthma therapy, which was adjusted during the study, at the discretion of their physician.

    Reporting group values
    		 Mepolizumab 100 mg Total
    Number of subjects
    		 347
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.2 ( 10.73 ) -
    Gender categorical
    Units: Subjects
        Female
    		 224 224
        Male
    		 123 123
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    		 8 8
        American Indian or Alaskan Native
    		 2 2
        Asian - Central/South Asian Heritage
    		 4 4
        Asian - East Asian Heritage
    		 14 14
        White - Arabic/North African Heritage
    		 7 7
        White - White/Caucasian/European Heritage
    		 311 311
        Asian & Native Hawaiian or Other Pacific Islander
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Mepolizumab 100 mg
    Reporting group description
    		 Participants received 100 milligram (mg) of mepolizumab injected subcutaneously (SC) once every 4 weeks until participant withdrawal or mepolizumab becomes commercially available in the relevant participating country. Participants remained on standard of care asthma therapy, which was adjusted during the study, at the discretion of their physician.

    Primary: Number of participants who experienced on-treatment adverse events (AE) and on-treatment serious adverse events (SAE)

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    End point title
    		 Number of participants who experienced on-treatment adverse events (AE) and on-treatment serious adverse events (SAE) [1]
    End point description
    AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with use of a medicinal product (MP), whether or not considered related to MP. AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with use of MP. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or all events of possible drug induced liver injury with hyperbilirubinemia. As Treated (AT) Population consisted of participants who received at least one dose of open label mepolizumab. On-treatment AEs and on-treatment SAEs are the events occurring on/after the first dose of open-label mepolizumab date and before/on last dose of mepolizumab + 28 days.
    End point type
    Primary
    End point timeframe
    Baseline (Week 0) to Week 240
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There is no statistical data to report.
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [2]
    Units: Participants
        AE
    326
        SAE
    79
    Notes
    [2] - AT Population.
    No statistical analyses for this end point

    Secondary: Number of participants who experienced on-treatment systemic (i.e., allergic/Immunoglobulin E [IgE]-mediated and non-allergic) and on-treatment local site reactions

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    End point title
    		 Number of participants who experienced on-treatment systemic (i.e., allergic/Immunoglobulin E [IgE]-mediated and non-allergic) and on-treatment local site reactions
    End point description
    Systemic and local site reactions following mepolizumab dosing as identified by the investigator and the number of participants who experienced systemic and/or local site reactions are presented. On-treatment AEs and on-treatment SAEs are the events occurring on/after the first dose of open-label mepolizumab date and before/on last dose of mepolizumab + 28 days.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [3]
    Units: Participants
        Systemic reactions
    9
        Local site reactions
    42
    Notes
    [3] - AT Population.
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in QT interval corrected by Bazett's method (QTc[B])

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    End point title
    		 Mean change from Baseline in QT interval corrected by Bazett's method (QTc[B])
    End point description
    Twelve-lead ECGs were performed at Screening and every 24 weeks during the treatment period. ECG measurements were made after the participant had rested in the supine position for 5 minutes. Collection shortly after a meal or during sleep was avoided as QT prolongation can occur at these times. Baseline was the last available ECG prior to mepolizumab dosing. Change from Baseline was post-Baseline values minus Baseline values. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [4]
    Units: Milliseconds
    arithmetic mean (standard deviation)
        Week 24, n=330
    4.2 ( 18.57 )
        Week 48, n=319
    3.2 ( 17.19 )
        Week 72, n=307
    -0.5 ( 16.76 )
        Week 96, n=293
    1.3 ( 17.92 )
        Week 124, n=292
    1.5 ( 19.69 )
        Week 148, n=275
    1.6 ( 17.84 )
        Week 176, n=201
    0.6 ( 18.02 )
        Week 200, n=149
    3.3 ( 17.02 )
        Week 228, n=32
    1.5 ( 20.95 )
        Follow up, n=270
    2.5 ( 18.71 )
    Notes
    [4] - AT Population.
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in QT interval corrected by Fridericia's method (QTc[F])

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    End point title
    		 Mean change from Baseline in QT interval corrected by Fridericia's method (QTc[F])
    End point description
    Twelve-lead ECGs were performed at Screening and every 24 weeks during the treatment period. ECG measurements were made after the participant had rested in the supine position for 5 minutes. Collection shortly after a meal or during sleep was avoided as QT prolongation can occur at these times. Baseline was the last available ECG prior to mepolizumab dosing. Change from Baseline was post-Baseline values minus Baseline values. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [5]
    Units: Milliseconds
    arithmetic mean (standard deviation)
        Week 24, n=330
    5.1 ( 17.00 )
        Week 48, n=319
    4.1 ( 15.72 )
        Week 72, n=307
    0.2 ( 15.11 )
        Week 96, n=293
    2.2 ( 15.37 )
        Week 124, n=292
    3.2 ( 16.77 )
        Week 148, n=275
    2.9 ( 15.49 )
        Week 176, n=201
    2.0 ( 15.97 )
        Week 200, n=149
    4.3 ( 14.52 )
        Week 228, n=32
    0.4 ( 15.81 )
        Follow up, n=270
    3.9 ( 16.39 )
    Notes
    [5] - AT Population.
    No statistical analyses for this end point

    Secondary: Number of participants with a maximum change from Baseline for QTc(F) and QTc(B)

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    End point title
    		 Number of participants with a maximum change from Baseline for QTc(F) and QTc(B)
    End point description
    Twelve-lead ECGs were performed at Screening and every 24 weeks during the treatment period. ECG measurements were made after the participant had rested in the supine position for 5 minutes. Collection shortly after a meal or during sleep was avoided as QT prolongation can occur at these times. Baseline was the last available ECG prior to mepolizumab dosing. Change from Baseline was post-Baseline values minus Baseline values. Number of participants with a maximum change from Baseline for QTc(F) and QTc(B) at any time post Baseline are presented. Only those participants who provided ECG data at baseline and post-baseline were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    342 [6]
    Units: Participants
        QTc(F): < -60
    0
        QTc(F): >= -60 - < -30
    1
        QTc(F): >= -30 - < 0
    31
        QTc(F): >= 0 - < 30
    252
        QTc(F): >= 30 - < 60
    55
        QTc(F): >= 60
    3
        QTc(B): < -60
    0
        QTc(B): >= -60 - < -30
    1
        QTc(B): >= -30 - < 0
    36
        QTc(B): >= 0 - < 30
    228
        QTc(B): >= 30 - < 60
    69
        QTc(B): >= 60
    8
    Notes
    [6] - AT Population.
    No statistical analyses for this end point

    Secondary: Number of participants with clinical chemistry data of potential clinical concern

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    End point title
    		 Number of participants with clinical chemistry data of potential clinical concern
    End point description
    Clinical chemistry analytes with laboratory ranges defining values of potential clinical concern included sodium, potassium, calcium, phosphate, serum glucose and alanine aminotransferase. Number of participants with clinical chemistry abnormalities of potential clinical concern anytime post baseline are presented. Only those participants who provided lab data post-baseline were analyzed represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [7]
    Units: Participants
        Potassium high, n=346
    1
        Serum glucose high, n=346
    1
        Serum glucose low, n=346
    7
    Notes
    [7] - AT Population.
    No statistical analyses for this end point

    Secondary: Number of participants with hematology data of potential clinical concern

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    End point title
    		 Number of participants with hematology data of potential clinical concern
    End point description
    Hematology parameters with laboratory ranges defining values of potential clinical concern included hemoglobin, hematocrit, platelet count, white blood cell count. Number of participants with clinical hematology abnormalities of potential clinical concern anytime post baseline are presented, which only included participants with low hemoglobin values. Only those participants who provided lab data post-baseline were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    346 [8]
    Units: Participants
        Participants
    1
    Notes
    [8] - AT Population.
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in vital signs-Sitting diastolic blood pressure and sitting systolic blood pressure

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    End point title
    		 Mean change from Baseline in vital signs-Sitting diastolic blood pressure and sitting systolic blood pressure
    End point description
    Vital signs included sitting pulse rate and sitting blood pressure (diastolic and systolic). Measurements were done pre injection with the participant sitting, having rested in this position for at least 5 minutes before each reading. Baseline was Week 0. Change from Baseline was post-Baseline values minus Baseline values. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [9]
    Units: Millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Sitting Diastolic Blood Pressure: Week 4, n=346
    -1.0 ( 8.71 )
        Sitting Diastolic Blood Pressure: Week 8, n=345
    -1.5 ( 8.85 )
        Sitting Diastolic Blood Pressure: Week 12, n=342
    -0.7 ( 9.67 )
        Sitting Diastolic Blood Pressure: Week 16, n=341
    -1.6 ( 9.27 )
        Sitting Diastolic Blood Pressure: Week 20, n=338
    -1.6 ( 9.17 )
        Sitting Diastolic Blood Pressure: Week 24, n=336
    -0.7 ( 9.27 )
        Sitting Diastolic Blood Pressure: Week 28, n=332
    -1.3 ( 8.90 )
        Sitting Diastolic Blood Pressure: Week 32, n=333
    -1.0 ( 9.62 )
        Sitting Diastolic Blood Pressure: Week 36, n=329
    -1.8 ( 8.95 )
        Sitting Diastolic Blood Pressure: Week 40, n=329
    -1.2 ( 9.33 )
        Sitting Diastolic Blood Pressure: Week 44, n=326
    -1.1 ( 10.00 )
        Sitting Diastolic Blood Pressure: Week 48, n=325
    -0.7 ( 9.67 )
        Sitting Diastolic Blood Pressure: Week 52, n=322
    -1.1 ( 9.85 )
        Sitting Diastolic Blood Pressure: Week 56, n=320
    -1.3 ( 9.67 )
        Sitting Diastolic Blood Pressure: Week 60, n=318
    -0.9 ( 9.56 )
        Sitting Diastolic Blood Pressure: Week 64, n=318
    -1.0 ( 9.29 )
        Sitting Diastolic Blood Pressure: Week 68, n=317
    -1.1 ( 9.94 )
        Sitting Diastolic Blood Pressure: Week 72, n=312
    -1.5 ( 9.67 )
        Sitting Diastolic Blood Pressure: Week 76, n=313
    -1.1 ( 10.06 )
        Sitting Diastolic Blood Pressure: Week 80, n=311
    -1.6 ( 10.23 )
        Sitting Diastolic Blood Pressure: Week 84, n=310
    -1.7 ( 10.51 )
        Sitting Diastolic Blood Pressure: Week 88, n=310
    -1.4 ( 10.45 )
        Sitting Diastolic Blood Pressure: Week 92, n=311
    -1.0 ( 9.89 )
        Sitting Diastolic Blood Pressure: Week 96, n=303
    -1.2 ( 9.81 )
        Sitting Diastolic Blood Pressure: Week 100, n=300
    -0.3 ( 9.40 )
        Sitting Diastolic Blood Pressure: Week 104, n=301
    -1.0 ( 9.69 )
        Sitting Diastolic Blood Pressure: Week 108, n=300
    -0.9 ( 10.28 )
        Sitting Diastolic Blood Pressure: Week 112, n=299
    -0.9 ( 9.78 )
        Sitting Diastolic Blood Pressure: Week 116, n=297
    -0.7 ( 9.56 )
        Sitting Diastolic Blood Pressure: Week 120, n=295
    -0.8 ( 9.41 )
        Sitting Diastolic Blood Pressure: Week 124, n=294
    -1.3 ( 10.52 )
        Sitting Diastolic Blood Pressure: Week 128, n=293
    -1.2 ( 10.08 )
        Sitting Diastolic Blood Pressure: Week 132, n=289
    -1.0 ( 10.48 )
        Sitting Diastolic Blood Pressure: Week 136, n=288
    -0.7 ( 10.42 )
        Sitting Diastolic Blood Pressure: Week 140, n=287
    -0.6 ( 9.90 )
        Sitting Diastolic Blood Pressure: Week 144, n=290
    -0.9 ( 9.83 )
        Sitting Diastolic Blood Pressure: Week 148, n=287
    0.1 ( 10.22 )
        Sitting Diastolic Blood Pressure: Week 152, n=284
    -0.9 ( 10.17 )
        Sitting Diastolic Blood Pressure: Week 156, n=275
    -0.4 ( 10.44 )
        Sitting Diastolic Blood Pressure: Week 160, n=265
    -0.6 ( 9.93 )
        Sitting Diastolic Blood Pressure: Week 164, n=242
    -1.7 ( 10.83 )
        Sitting Diastolic Blood Pressure: Week 168, n=232
    -1.3 ( 10.46 )
        Sitting Diastolic Blood Pressure: Week 172, n=226
    -1.2 ( 10.18 )
        Sitting Diastolic Blood Pressure: Week 176, n=212
    -1.6 ( 9.84 )
        Sitting Diastolic Blood Pressure: Week 180, n=200
    -1.6 ( 10.42 )
        Sitting Diastolic Blood Pressure: Week 184, n=184
    -1.3 ( 9.94 )
        Sitting Diastolic Blood Pressure: Week 188, n=180
    -1.4 ( 9.81 )
        Sitting Diastolic Blood Pressure: Week 192, n=176
    -1.1 ( 10.25 )
        Sitting Diastolic Blood Pressure: Week 196, n=175
    -1.5 ( 10.18 )
        Sitting Diastolic Blood Pressure: Week 200, n=172
    -0.4 ( 10.07 )
        Sitting Diastolic Blood Pressure: Week 204, n=169
    -1.1 ( 10.25 )
        Sitting Diastolic Blood Pressure: Week 208, n=157
    -1.8 ( 9.48 )
        Sitting Diastolic Blood Pressure: Week 212, n=146
    -1.3 ( 9.53 )
        Sitting Diastolic Blood Pressure: Week 216, n=130
    -0.2 ( 9.55 )
        Sitting Diastolic Blood Pressure: Week 220, n=67
    -1.6 ( 10.85 )
        Sitting Diastolic Blood Pressure: Week 224, n=54
    -1.9 ( 11.97 )
        Sitting Diastolic Blood Pressure: Week 228, n=37
    -0.2 ( 9.60 )
        Sitting Diastolic Blood Pressure: Week 232, n=5
    4.6 ( 5.86 )
        Sitting Diastolic Blood Pressure: Follow-up, n=306
    -0.7 ( 10.03 )
        Sitting Systolic Blood Pressure: Week 4, n=346
    0.2 ( 10.79 )
        Sitting Systolic Blood Pressure: Week 8, n=345
    -0.7 ( 12.57 )
        Sitting Systolic Blood Pressure: Week 12, n=342
    -0.3 ( 12.59 )
        Sitting Systolic Blood Pressure: Week 16, n=341
    -0.5 ( 13.60 )
        Sitting Systolic Blood Pressure: Week 20, n=338
    -1.8 ( 13.31 )
        Sitting Systolic Blood Pressure: Week 24, n=336
    -0.8 ( 13.93 )
        Sitting Systolic Blood Pressure: Week 28, n=332
    -0.6 ( 13.61 )
        Sitting Systolic Blood Pressure: Week 32, n=333
    -1.0 ( 14.24 )
        Sitting Systolic Blood Pressure: Week 36, n=329
    -0.7 ( 14.19 )
        Sitting Systolic Blood Pressure: Week 40, n=329
    -0.6 ( 14.11 )
        Sitting Systolic Blood Pressure: Week 44, n=326
    -0.9 ( 14.87 )
        Sitting Systolic Blood Pressure: Week 48, n=325
    -0.1 ( 13.59 )
        Sitting Systolic Blood Pressure: Week 52, n=322
    -0.3 ( 13.63 )
        Sitting Systolic Blood Pressure: Week 56, n=320
    -0.3 ( 14.33 )
        Sitting Systolic Blood Pressure: Week 60, n=318
    0.0 ( 14.21 )
        Sitting Systolic Blood Pressure: Week 64, n=318
    -0.2 ( 13.99 )
        Sitting Systolic Blood Pressure: Week 68, n=317
    -1.1 ( 14.83 )
        Sitting Systolic Blood Pressure: Week 72, n=312
    -1.8 ( 13.16 )
        Sitting Systolic Blood Pressure: Week 76, n=313
    -0.8 ( 14.44 )
        Sitting Systolic Blood Pressure: Week 80, n=311
    -1.1 ( 14.49 )
        Sitting Systolic Blood Pressure: Week 84, n=310
    -1.9 ( 14.47 )
        Sitting Systolic Blood Pressure: Week 88, n=310
    -1.7 ( 14.94 )
        Sitting Systolic Blood Pressure: Week 92, n=311
    -0.3 ( 15.16 )
        Sitting Systolic Blood Pressure: Week 96, n=303
    0.1 ( 14.32 )
        Sitting Systolic Blood Pressure: Week 100, n=300
    0.7 ( 14.71 )
        Sitting Systolic Blood Pressure: Week 104, n=301
    0.3 ( 14.81 )
        Sitting Systolic Blood Pressure: Week 108, n=300
    0.5 ( 15.15 )
        Sitting Systolic Blood Pressure: Week 112, n=299
    -0.4 ( 14.83 )
        Sitting Systolic Blood Pressure: Week 116, n=297
    0.4 ( 14.31 )
        Sitting Systolic Blood Pressure: Week 120, n=295
    0.5 ( 14.37 )
        Sitting Systolic Blood Pressure: Week 124, n=294
    0.7 ( 14.80 )
        Sitting Systolic Blood Pressure: Week 128, n=293
    0.7 ( 14.68 )
        Sitting Systolic Blood Pressure: Week 132, n=289
    0.7 ( 14.51 )
        Sitting Systolic Blood Pressure: Week 136, n=288
    0.9 ( 16.81 )
        Sitting Systolic Blood Pressure: Week 140, n=287
    0.3 ( 15.48 )
        Sitting Systolic Blood Pressure: Week 144, n=290
    1.1 ( 15.79 )
        Sitting Systolic Blood Pressure: Week 148, n=287
    1.8 ( 13.59 )
        Sitting Systolic Blood Pressure: Week 152, n=284
    0.2 ( 15.53 )
        Sitting Systolic Blood Pressure: Week 156, n=275
    0.8 ( 14.56 )
        Sitting Systolic Blood Pressure: Week 160, n=265
    1.1 ( 15.34 )
        Sitting Systolic Blood Pressure: Week 164, n=242
    0.6 ( 15.51 )
        Sitting Systolic Blood Pressure: Week 168, n=232
    0.1 ( 14.87 )
        Sitting Systolic Blood Pressure: Week 172, n=226
    -0.8 ( 15.67 )
        Sitting Systolic Blood Pressure: Week 176, n=212
    0.4 ( 13.78 )
        Sitting Systolic Blood Pressure: Week 180, n=200
    0.6 ( 15.32 )
        Sitting Systolic Blood Pressure: Week 184, n=184
    -0.5 ( 16.36 )
        Sitting Systolic Blood Pressure: Week 188, n=180
    -1.0 ( 15.54 )
        Sitting Systolic Blood Pressure: Week 192, n=176
    -1.2 ( 16.60 )
        Sitting Systolic Blood Pressure: Week 196, n=175
    -0.8 ( 14.76 )
        Sitting Systolic Blood Pressure: Week 200, n=172
    -0.1 ( 15.28 )
        Sitting Systolic Blood Pressure: Week 204, n=169
    -0.4 ( 15.64 )
        Sitting Systolic Blood Pressure: Week 208, n=157
    -1.0 ( 16.92 )
        Sitting Systolic Blood Pressure: Week 212, n=146
    0.5 ( 14.98 )
        Sitting Systolic Blood Pressure: Week 216, n=130
    0.4 ( 15.52 )
        Sitting Systolic Blood Pressure: Week 220, n=67
    -4.2 ( 20.86 )
        Sitting Systolic Blood Pressure: Week 224, n=54
    -3.8 ( 17.87 )
        Sitting Systolic Blood Pressure: Week 228, n=37
    -3.6 ( 15.15 )
        Sitting Systolic Blood Pressure: Week 232, n=5
    -0.8 ( 6.30 )
        Sitting Systolic Blood Pressure: Follow-up, n=306
    0.0 ( 14.92 )
    Notes
    [9] - AT Population.
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Vital signs-Sitting pulse rate

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    End point title
    		 Mean change from Baseline in Vital signs-Sitting pulse rate
    End point description
    Vital signs included sitting pulse rate and blood pressure (diastolic and systolic). Measurements were done pre injection with the participant sitting, having rested in this position for at least 5 minutes before each reading. Baseline was Week 0. Change from Baseline was post-Baseline values minus Baseline values. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [10]
    Units: Beats per minute
    arithmetic mean (standard deviation)
        Sitting Pulse Rate: Week 4, n=346
    -0.3 ( 8.94 )
        Sitting Pulse Rate: Week 8, n=345
    1.0 ( 9.98 )
        Sitting Pulse Rate: Week 12, n=342
    0.0 ( 9.52 )
        Sitting Pulse Rate: Week 16, n=341
    -0.1 ( 10.08 )
        Sitting Pulse Rate: Week 20, n=338
    -0.3 ( 9.44 )
        Sitting Pulse Rate: Week 24, n=337
    -1.6 ( 9.83 )
        Sitting Pulse Rate: Week 28, n=332
    -0.2 ( 9.58 )
        Sitting Pulse Rate: Week 32, n=333
    -0.2 ( 9.74 )
        Sitting Pulse Rate: Week 36, n=329
    -0.6 ( 9.60 )
        Sitting Pulse Rate: Week 40, n=329
    -0.2 ( 9.56 )
        Sitting Pulse Rate: Week 44, n=327
    -0.4 ( 9.80 )
        Sitting Pulse Rate: Week 48, n=325
    -1.6 ( 9.65 )
        Sitting Pulse Rate: Week 52, n=322
    0.1 ( 9.56 )
        Sitting Pulse Rate: Week 56, n=320
    -0.3 ( 9.79 )
        Sitting Pulse Rate: Week 60, n=318
    -0.8 ( 9.54 )
        Sitting Pulse Rate: Week 64, n=318
    -0.9 ( 9.63 )
        Sitting Pulse Rate: Week 68, n=317
    -1.2 ( 9.51 )
        Sitting Pulse Rate: Week 72, n=312
    -1.8 ( 10.07 )
        Sitting Pulse Rate: Week 76, n=313
    -1.2 ( 9.65 )
        Sitting Pulse Rate: Week 80, n=311
    -0.5 ( 10.08 )
        Sitting Pulse Rate: Week 84, n=310
    -1.2 ( 9.80 )
        Sitting Pulse Rate: Week 88, n=310
    -0.6 ( 10.12 )
        Sitting Pulse Rate: Week 92, n=311
    -0.6 ( 9.36 )
        Sitting Pulse Rate: Week 96, n=303
    -1.7 ( 10.61 )
        Sitting Pulse Rate: Week 100, n=300
    -0.5 ( 9.81 )
        Sitting Pulse Rate: Week 104, n=301
    -0.9 ( 10.45 )
        Sitting Pulse Rate: Week 108, n=300
    -0.8 ( 10.04 )
        Sitting Pulse Rate: Week 112, n=299
    -0.5 ( 9.60 )
        Sitting Pulse Rate: Week 116, n=297
    -1.5 ( 9.33 )
        Sitting Pulse Rate: Week 120, n=294
    -1.2 ( 10.27 )
        Sitting Pulse Rate: Week 124, n=294
    -2.5 ( 10.27 )
        Sitting Pulse Rate: Week 128, n=293
    -1.2 ( 10.00 )
        Sitting Pulse Rate: Week 132, n=289
    -0.7 ( 9.20 )
        Sitting Pulse Rate: Week 136, n=288
    -0.6 ( 10.55 )
        Sitting Pulse Rate: Week 140, n=287
    -0.6 ( 9.71 )
        Sitting Pulse Rate: Week 144, n=290
    -0.7 ( 9.72 )
        Sitting Pulse Rate: Week 148, n=287
    -1.8 ( 9.82 )
        Sitting Pulse Rate: Week 152, n=284
    -0.9 ( 10.45 )
        Sitting Pulse Rate: Week 156, n=275
    -0.8 ( 9.83 )
        Sitting Pulse Rate: Week 160, n=265
    -0.5 ( 10.42 )
        Sitting Pulse Rate: Week 164, n=242
    -1.1 ( 11.07 )
        Sitting Pulse Rate: Week 168, n=232
    -0.5 ( 11.25 )
        Sitting Pulse Rate: Week 172, n=226
    -1.0 ( 9.80 )
        Sitting Pulse Rate: Week 176, n=212
    -2.9 ( 9.57 )
        Sitting Pulse Rate: Week 180, n=200
    -0.5 ( 10.01 )
        Sitting Pulse Rate: Week 184, n=184
    -1.3 ( 9.89 )
        Sitting Pulse Rate: Week 188, n=180
    -1.3 ( 10.38 )
        Sitting Pulse Rate: Week 192, n=176
    -1.6 ( 10.37 )
        Sitting Pulse Rate: Week 196, n=175
    -1.2 ( 9.79 )
        Sitting Pulse Rate: Week 200, n=172
    -2.3 ( 11.03 )
        Sitting Pulse Rate: Week 204, n=169
    -1.9 ( 10.67 )
        Sitting Pulse Rate: Week 208, n=157
    -0.6 ( 10.64 )
        Sitting Pulse Rate: Week 212, n=146
    -0.4 ( 10.09 )
        Sitting Pulse Rate: Week 216, n=130
    -1.4 ( 10.49 )
        Sitting Pulse Rate: Week 220, n=67
    0.0 ( 11.13 )
        Sitting Pulse Rate: Week 224, n=54
    -1.4 ( 13.19 )
        Sitting Pulse Rate: Week 228, n=37
    -2.4 ( 10.57 )
        Sitting Pulse Rate: Week 232, n=5
    -2.0 ( 16.63 )
        Sitting Pulse Rate: Follow-up, n=306
    -1.5 ( 10.72 )
    Notes
    [10] - AT Population.
    No statistical analyses for this end point

    Secondary: Annualized rate of on-treatment exacerbations

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    End point title
    		 Annualized rate of on-treatment exacerbations
    End point description
    Exacerbations were defined as worsening of asthma which required use of systemic corticosteroids and/or hospitalization and/or Emergency Department visits. Data is presented as mean which is exacerbation rate/year. Exacerbation data are performed using a negative binomial model with covariates of region, annualized rate of exacerbations in the interval between MEA112997 and MEA115666 (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [11]
    Units: Exacerbations per year
    arithmetic mean (confidence interval 95%)
        Exacerbations per year
    0.68 (0.60 to 0.78)
    Notes
    [11] - AT Population.
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Asthma Control Questionnaire (ACQ) score

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    End point title
    		 Mean change from Baseline in Asthma Control Questionnaire (ACQ) score
    End point description
    The ACQ-5 is a five-item questionnaire, which was developed as a measure of participant’ asthma control that was completed by the participant. The five questions enquire about the frequency and/or severity of symptoms (nocturnal awakening on waking in the morning, activity limitation, and shortness of breath, wheeze). The ACQ consists of 5 questions that are scored on a 7 point scale from 0 (totally controlled) to 6 (severely uncontrolled). The ACQ score was derived as mean of five questions: ACQ score = Question 1 (Q1)+Q2+Q3+Q4+Q5 divided by 5 where Q1, Q2,... Q5 are the scores of Q1, Q2, ..., Q5, respectively. The total score ranged from zero (no impairment/limitation) which indicated best condition to six (total impairment/ limitation) which indicated worst asthma. Baseline was Week 0. Change from Baseline was post-Baseline values minus Baseline values. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [12]
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Week 12, n=341
    -0.47 ( 0.991 )
        Week 24, n=335
    -0.55 ( 1.037 )
        Week 36, n=327
    -0.56 ( 1.088 )
        Week 48, n=324
    -0.55 ( 1.098 )
        Week 60, n=317
    -0.58 ( 1.126 )
        Week 72, n=311
    -0.51 ( 1.054 )
        Week 84, n=308
    -0.54 ( 1.090 )
        Week 96, n=301
    -0.44 ( 1.171 )
        Week 112, n=297
    -0.51 ( 1.228 )
        Week 124, n=293
    -0.66 ( 1.216 )
        Week 136, n=287
    -0.58 ( 1.215 )
        Week 148, n=286
    -0.54 ( 1.070 )
        Week 164, n=240
    -0.59 ( 1.221 )
        Week 176, n=211
    -0.49 ( 1.179 )
        Week 188, n=178
    -0.40 ( 1.310 )
        Week 200, n=171
    -0.45 ( 1.119 )
        Week 216, n=130
    -0.42 ( 1.161 )
        Week 228, n=37
    -0.47 ( 1.502 )
        Follow-up, n=301
    -0.53 ( 1.193 )
    Notes
    [12] - AT Population.
    No statistical analyses for this end point

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

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    End point title
    		 Mean change from Baseline in clinic pre-bronchodilator forced expiratory volume in 1 second (FEV1)
    End point description
    FEV1 is forced expiratory volume in the first second. The volume of air that can be forced out in one second after taking a deep breath, an important measure of pulmonary function. Forced expiratory volume (FEV) measures how much air a person can exhale during a forced breath. FEV1 was measured by clinic spirometry. Baseline was Week 0. Change from Baseline was post-Baseline values minus Baseline values. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [13]
    Units: Milliliters (mL)
    arithmetic mean (standard deviation)
        Week 12, n=340
    124 ( 346.9 )
        Week 24, n=334
    144 ( 335.0 )
        Week 48, n=325
    98 ( 395.2 )
        Week 72, n=312
    91 ( 405.5 )
        Week 96, n=301
    51 ( 385.8 )
        Week 124, n=292
    85 ( 395.5 )
        Week 148, n=281
    17 ( 370.2 )
        Week 176, n=210
    45 ( 352.2 )
        Week 200, n=171
    8 ( 375.7 )
        Week 228, n=37
    -23 ( 331.9 )
    Notes
    [13] - AT Population.
    No statistical analyses for this end point

    Secondary: Number of participants with positive anti-mepolizumab binding antibodies (ADA) and neutralizing antibodies (NAb)

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    End point title
    		 Number of participants with positive anti-mepolizumab binding antibodies (ADA) and neutralizing antibodies (NAb)
    End point description
    Immunogenicity testing included two types of assays: a binding antibody assay (anti-drug antibody; ADA) and a neutralizing antibody (NAb) assay for participants who were tested positive in the ADA assay. Blood samples were collected for the determination of anti-mepolizumab antibodies, just prior to administration of mepolizumab. Samples that test positive for anti-mepolizumab antibodies were further tested for the presence of neutralizing antibody. Number of participants with positive highest value post-Baseline have been presented. Only those participants available at the specified time points were analyzed represented by n=X in the category titles.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [14]
    Units: Participants
        Positive ADA result, n=346
    27
        Positive NAb result, n=27
    0
    Notes
    [14] - AT Population.
    No statistical analyses for this end point

    Secondary: Number of participants who withdrew due to lack of efficacy

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    End point title
    		 Number of participants who withdrew due to lack of efficacy
    End point description
    Lack of efficacy referred to failure of expected pharmacological action of Mepolizumab. Number of participants who withdrew due to lack of efficacy are presented.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [15]
    Units: Participants
        Participants
    11
    Notes
    [15] - AT Population.
    No statistical analyses for this end point

    Secondary: Number of participants requiring hospitalizations due to adverse events including asthma exacerbations

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    End point title
    		 Number of participants requiring hospitalizations due to adverse events including asthma exacerbations
    End point description
    AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or all events of possible drug induced liver injury with hyperbilirubinemia. Number of participants requiring hospitalization due to an on-treatment serious adverse event including asthma exacerbations are presented. On-treatment SAEs are the events occurring on/after the first dose of open-label mepolizumab date and before/on last dose of mepolizumab + 28 days.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [16]
    Units: Participants
        Participants
    71
    Notes
    [16] - AT Population.
    No statistical analyses for this end point

    Secondary: Number of participants who withdrew due to AE

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    End point title
    		 Number of participants who withdrew due to AE
    End point description
    AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or all events of possible drug induced liver injury with hyperbilirubinemia. Number of participants who withdrew due to AE are presented.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 240
    End point values
    		 Mepolizumab 100 mg
    Number of subjects analysed
    347 [17]
    Units: Participants
        Participants
    19
    Notes
    [17] - AT Population.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The on-treatment AEs and on-treatment SAEs are the events which happened on/after the first dose of open label mepolizumab date and before/on last dose of mepolizumab date + 28 days (up to 240 weeks)
    Adverse event reporting additional description
    AE and SAE were collected for all participants within the As Treated Population which comprised of all participants who received at least one dose of open label mepolizumab.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Mepolizumab
    Reporting group description
    		 Subjects will receive 100 mg of mepolizumab (in 1 ml polypropylene syringe) injected subcutaneously (SC) approximately every 4 weeks.

    Serious adverse events
    		 Mepolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    79 / 347 (22.77%)
         number of deaths (all causes)
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    2 / 347 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder papilloma
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Cervical polyp
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectocele
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    33 / 347 (9.51%)
         occurrences causally related to treatment / all
    0 / 47
         deaths causally related to treatment / all
    0 / 2
    Pneumonia aspiration
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Status asthmaticus
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Comminuted fracture
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    2 / 347 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sciatica
         subjects affected / exposed
    2 / 347 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal claudication
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Lymphocytosis
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric polyps
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 347 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder prolapse
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Basedow's disease
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thyroid mass
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    2 / 347 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 347 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuropathic arthropathy
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 347 (1.73%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 347 (0.58%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 347 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myelitis
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    1 / 347 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Mepolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    314 / 347 (90.49%)
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    15 / 347 (4.32%)
         occurrences all number
    24
    Contusion
         subjects affected / exposed
    13 / 347 (3.75%)
         occurrences all number
    15
    Ligament sprain
         subjects affected / exposed
    11 / 347 (3.17%)
         occurrences all number
    11
    Vascular disorders
    Hypertension
         subjects affected / exposed
    32 / 347 (9.22%)
         occurrences all number
    43
    Nervous system disorders
    Headache
         subjects affected / exposed
    99 / 347 (28.53%)
         occurrences all number
    386
    Sciatica
         subjects affected / exposed
    16 / 347 (4.61%)
         occurrences all number
    21
    Dizziness
         subjects affected / exposed
    23 / 347 (6.63%)
         occurrences all number
    31
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    42 / 347 (12.10%)
         occurrences all number
    129
    Fatigue
         subjects affected / exposed
    12 / 347 (3.46%)
         occurrences all number
    16
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    13 / 347 (3.75%)
         occurrences all number
    15
    Eye disorders
    Cataract
         subjects affected / exposed
    14 / 347 (4.03%)
         occurrences all number
    17
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    22 / 347 (6.34%)
         occurrences all number
    26
    Diarrhoea
         subjects affected / exposed
    26 / 347 (7.49%)
         occurrences all number
    38
    Abdominal pain
         subjects affected / exposed
    17 / 347 (4.90%)
         occurrences all number
    18
    Abdominal pain upper
         subjects affected / exposed
    15 / 347 (4.32%)
         occurrences all number
    21
    Nausea
         subjects affected / exposed
    17 / 347 (4.90%)
         occurrences all number
    25
    Gastrooesophageal reflux disease
         subjects affected / exposed
    14 / 347 (4.03%)
         occurrences all number
    14
    Vomiting
         subjects affected / exposed
    11 / 347 (3.17%)
         occurrences all number
    13
    Dyspepsia
         subjects affected / exposed
    12 / 347 (3.46%)
         occurrences all number
    15
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    69 / 347 (19.88%)
         occurrences all number
    116
    Rhinitis allergic
         subjects affected / exposed
    36 / 347 (10.37%)
         occurrences all number
    55
    Oropharyngeal pain
         subjects affected / exposed
    27 / 347 (7.78%)
         occurrences all number
    37
    Cough
         subjects affected / exposed
    22 / 347 (6.34%)
         occurrences all number
    32
    Productive cough
         subjects affected / exposed
    12 / 347 (3.46%)
         occurrences all number
    15
    Rhinorrhoea
         subjects affected / exposed
    12 / 347 (3.46%)
         occurrences all number
    17
    Dysphonia
         subjects affected / exposed
    11 / 347 (3.17%)
         occurrences all number
    11
    Dyspnoea
         subjects affected / exposed
    11 / 347 (3.17%)
         occurrences all number
    16
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    12 / 347 (3.46%)
         occurrences all number
    16
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    63 / 347 (18.16%)
         occurrences all number
    135
    Arthralgia
         subjects affected / exposed
    58 / 347 (16.71%)
         occurrences all number
    85
    Osteoarthritis
         subjects affected / exposed
    20 / 347 (5.76%)
         occurrences all number
    22
    Pain in extremity
         subjects affected / exposed
    40 / 347 (11.53%)
         occurrences all number
    52
    Myalgia
         subjects affected / exposed
    18 / 347 (5.19%)
         occurrences all number
    28
    Musculoskeletal pain
         subjects affected / exposed
    14 / 347 (4.03%)
         occurrences all number
    15
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    169 / 347 (48.70%)
         occurrences all number
    371
    Upper respiratory tract infection
         subjects affected / exposed
    81 / 347 (23.34%)
         occurrences all number
    195
    Bronchitis
         subjects affected / exposed
    73 / 347 (21.04%)
         occurrences all number
    165
    Sinusitis
         subjects affected / exposed
    57 / 347 (16.43%)
         occurrences all number
    111
    Influenza
         subjects affected / exposed
    43 / 347 (12.39%)
         occurrences all number
    53
    Respiratory tract infection
         subjects affected / exposed
    38 / 347 (10.95%)
         occurrences all number
    66
    Lower respiratory tract infection
         subjects affected / exposed
    31 / 347 (8.93%)
         occurrences all number
    64
    Gastroenteritis
         subjects affected / exposed
    27 / 347 (7.78%)
         occurrences all number
    32
    Pharyngitis
         subjects affected / exposed
    24 / 347 (6.92%)
         occurrences all number
    32
    Urinary tract infection
         subjects affected / exposed
    24 / 347 (6.92%)
         occurrences all number
    35
    Rhinitis
         subjects affected / exposed
    23 / 347 (6.63%)
         occurrences all number
    29
    Respiratory tract infection viral
         subjects affected / exposed
    20 / 347 (5.76%)
         occurrences all number
    27
    Viral infection
         subjects affected / exposed
    18 / 347 (5.19%)
         occurrences all number
    30
    Ear infection
         subjects affected / exposed
    15 / 347 (4.32%)
         occurrences all number
    21
    Acute sinusitis
         subjects affected / exposed
    14 / 347 (4.03%)
         occurrences all number
    21
    Cystitis
         subjects affected / exposed
    13 / 347 (3.75%)
         occurrences all number
    25
    Nasopharyngitis
         subjects affected / exposed
    13 / 347 (3.75%)
         occurrences all number
    29
    Oral candidiasis
         subjects affected / exposed
    13 / 347 (3.75%)
         occurrences all number
    17
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    11 / 347 (3.17%)
         occurrences all number
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2012
    Amendment 1: To clarify that the rationale and objective of the study includes long-term provision of mepolizumab therapy to participants who have severe asthma and participated in MEA112997 To clarify that only monoclonal antibodies are excluded, rather than all biologics To clarify reason for more frequent safety monitoring at the start of the study To correct Inclusion criterion 5 from Randomization Visit to Visit 2 To add exclusion criterion for significant cardiovascular disease To correct inconsistencies between protocol text and the Time and Events Table To correct bilirubin exclusion criterion at visit 2 To expand on requirements for designating a participant as lost to follow-up To add visit window for the follow-up visit To move Baseline spirometry from the screen visit to the Baseline visit To clarify that all participants will have an immunogenicity test 12 weeks after last dose To correct Section 8.3.5.2 wording “Efficacy” to “Safety” To add reference to support Appendix 6 and remove 3 references which are not cited in the protocol. To add Appendix 5 and Appendix 6 and amended Section 6.1 and Section 6.3.9. to support the determination of exclusion criteria 4.
    06 Mar 2013
    Amendment 2: To add two additional immunogenicity sample assessment time points when the 100 mg vial is introduced. To allow other syringe sizes for study drug administration To allow for study drug administration in the upper thigh or the arm To add the prohibited non-drug therapies to Section 5.7.2 To list Adverse Events and Serious Adverse Events on the same line in Table 3 To correct a formatting error for Section 4.6 To remove specific test name for confirming Hepatitis C positive sample To delete redundant text in Section 6.3.3.1 To remove from Section 6.3.7 the requirement to report outcome of pregnancy in female partners of male participants To include analyses of immunogenicity data in Section 8.3 and to clarify when interim analyses will be performed.
    19 Jun 2015
    Amendment 3: To reduce the Follow-up visit period from 12 weeks to 4 weeks post last dose of investigational product To update the time limit from reconstitution to administration of investigational product.

    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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