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    Clinical Trial Results:
    An open label, randomised, three arm, single dose, multicentre, parallel group study in healthy subjects to compare the pharmacokinetics of subcutaneous mepolizumab when delivered as a liquid drug product in a safety syringe or an auto injector with a reconstituted lyophilised drug product from a vial

    Summary
    EudraCT number
    		 2016-002405-19
    Trial protocol
    		 DE   GB  
    Global end of trial date
    11 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Aug 2018
    First version publication date
    02 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    204958
    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
    29 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the pharmacokinetics of subcutaneous mepolizumab following a single dose of the liquid drug product in safety syringe with the lyophilized drug product. To compare the pharmacokinetics of subcutaneous mepolizumab following a single dose of the liquid drug product in autoinjector with the lyophilized drug product.
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 136
    Country: Number of subjects enrolled
    United Kingdom: 45
    Country: Number of subjects enrolled
    United States: 63
    Worldwide total number of subjects
    244
    EEA total number of subjects
    181
    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)
    209
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a randomized, multi-center, open-label, parallel-group, single-dose study in healthy participants. The participants were administered one of 3 different mepolizumab treatments (a liquid drug product in a safety syringe; a liquid drug product in an autoinjector; a reconstituted lyophilized drug product from a vial).

    Pre-assignment
    Screening details
    		 A total of 246 participants were randomized and 244 participants received study treatment. Two participants were randomized in error.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lyophilized vial
    Arm description
    		 Participants were administered 100 milligram per milliliter (mg/mL) subcutaneous (SC) dose of mepolizumab as lyophilized powder reconstituted with sterile water for injection from vial. Participants were administered a single SC dose in upper arm, abdomen or thigh.
    Arm type
    		 Active comparator

    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 were administered 100 milligram per milliliter (mg/mL) subcutaneous (SC) dose of mepolizumab as lyophilized powder reconstituted with sterile water for injection from vial. Participants were administered SC dose in upper arm, abdomen or thigh.

    Arm title
    		 Liquid autoinjector
    Arm description
    		 Participants were administered 100 mg/mL SC dose of mepolizumab liquid formulation via disposable pre-filled autoinjector. Participants were administered a single SC dose in upper arm, abdomen or thigh.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mepolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants were administered 100 mg/mL SC dose of mepolizumab liquid formulation via disposable pre-filled autoinjector. Participants were administered SC dose in upper arm, abdomen or thigh.

    Arm title
    		 Liquid safety syringe
    Arm description
    		 Participants were administered 100 mg/mL SC dose of mepolizumab liquid formulation via disposable pre-filled safety syringe. Participants were administered a single SC dose in upper arm, abdomen or thigh.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mepolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants were administered 100 mg/mL SC dose of mepolizumab liquid formulation via disposable pre-filled safety syringe. Participants were administered SC dose in upper arm, abdomen or thigh.

    Number of subjects in period 1
    		Lyophilized vial Liquid autoinjector Liquid safety syringe
    Started
    85
    79
    80
    Completed
    84
    79
    80
    Not completed
    1
    0
    0
         Consent withdrawn by subject
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lyophilized vial
    Reporting group description
    		 Participants were administered 100 milligram per milliliter (mg/mL) subcutaneous (SC) dose of mepolizumab as lyophilized powder reconstituted with sterile water for injection from vial. Participants were administered a single SC dose in upper arm, abdomen or thigh.

    Reporting group title
    Liquid autoinjector
    Reporting group description
    		 Participants were administered 100 mg/mL SC dose of mepolizumab liquid formulation via disposable pre-filled autoinjector. Participants were administered a single SC dose in upper arm, abdomen or thigh.

    Reporting group title
    Liquid safety syringe
    Reporting group description
    		 Participants were administered 100 mg/mL SC dose of mepolizumab liquid formulation via disposable pre-filled safety syringe. Participants were administered a single SC dose in upper arm, abdomen or thigh.

    Reporting group values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe Total
    Number of subjects
    		 85 79 80
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.1 ± 15.06 46.5 ± 15.00 47.5 ± 14.94 -
    Gender categorical
    Units: Subjects
        Female
    		 40 36 38 114
        Male
    		 45 43 42 130
    Race/Ethnicity, Customized
    Units: Subjects
        Black or African American
    		 18 15 18 51
        American Indian or Alaska native
    		 1 0 0 1
        Central/South Asian heritage
    		 1 0 0 1
        East Asian heritage
    		 0 1 0 1
        Native Hawaiian or other pacific islander
    		 0 1 0 1
        Arabic/ North African heritage
    		 0 0 1 1
        White/Caucasian/European heritage
    		 64 61 61 186
        Asian and White
    		 0 1 0 1
        Black or African American and White
    		 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Lyophilized vial
    Reporting group description
    		 Participants were administered 100 milligram per milliliter (mg/mL) subcutaneous (SC) dose of mepolizumab as lyophilized powder reconstituted with sterile water for injection from vial. Participants were administered a single SC dose in upper arm, abdomen or thigh.

    Reporting group title
    Liquid autoinjector
    Reporting group description
    		 Participants were administered 100 mg/mL SC dose of mepolizumab liquid formulation via disposable pre-filled autoinjector. Participants were administered a single SC dose in upper arm, abdomen or thigh.

    Reporting group title
    Liquid safety syringe
    Reporting group description
    		 Participants were administered 100 mg/mL SC dose of mepolizumab liquid formulation via disposable pre-filled safety syringe. Participants were administered a single SC dose in upper arm, abdomen or thigh.

    Primary: Maximum observed plasma concentration (Cmax) of mepolizumab

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    End point title
    		 Maximum observed plasma concentration (Cmax) of mepolizumab
    End point description
    Blood samples were collected at indicated time points. Cmax following a single dose administration of liquid mepolizumab using a safety syringe and an autoinjector were compared with reconstituted lyophilized drug product from the vial. Pharmacokinetic (PK) Population comprised of all participants receiving study drug for whom a pharmacokinetic sample was obtained and analyzed.
    End point type
    Primary
    End point timeframe
    Day 1 (pre-dose, 2 hours, and 8 hours post-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 22, 29, 43, 57 and 85 post-dose
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    85 [1]
    79 [2]
    80 [3]
    Units: micrograms per milliliter (µg/mL)
    geometric mean (geometric coefficient of variation)
        micrograms per milliliter (µg/mL)
    11.57 ± 27.43
    11.98 ± 24.96
    12.07 ± 27.29
    Notes
    [1] - PK Population
    [2] - PK Population
    [3] - PK Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Liquid autoinjector v Lyophilized vial
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    Method
    Parameter type
    		 Ratio
    Point estimate
    1.04
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.11
    Notes
    [4] - Interpretation of the comparability of the autoinjector and safety syringe with the reconstituted lyophilized drug product was guided by a two-sided 90% confidence interval (CI) for the ratio of the geometric mean of test treatment to reference treatment in the range (0.80, 1.25) for Cmax.
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Liquid safety syringe v Lyophilized vial
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    Method
    Parameter type
    		 Ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.12
    Notes
    [5] - Interpretation of the comparability of the autoinjector and safety syringe with the reconstituted lyophilized drug product was guided by a two-sided 90% CI for the ratio of the geometric mean of test treatment to reference treatment in the range (0.80, 1.25) for Cmax.

    Primary: Area under the plasma concentration time curve (AUC) from time zero to the time of last quantifiable concentration (AUC[0-t]), AUC from time zero extrapolated to infinite time (AUC[0-inf]) of mepolizumab

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    End point title
    		 Area under the plasma concentration time curve (AUC) from time zero to the time of last quantifiable concentration (AUC[0-t]), AUC from time zero extrapolated to infinite time (AUC[0-inf]) of mepolizumab
    End point description
    Blood samples were collected at indicated time points. AUC(0-t) and AUC(0-inf) following a single dose administration of liquid mepolizumab using a safety syringe and an autoinjector were compared with lyophilized drug product. Fixed effects analysis of covariance model was used for analysis. Only those participants with data available at the specified data points were analyzed (represented by n=X in category titles).
    End point type
    Primary
    End point timeframe
    Day 1 (pre-dose, 2 hours, and 8 hours post-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 22, 29, 43, 57 and 85 post-dose
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    85 [6]
    79 [7]
    80 [8]
    Units: Days*µg/mL
    geometric mean (geometric coefficient of variation)
        AUC(0-t), n=85, 79, 80
    403.84 ± 25.84
    434.49 ± 22.62
    415.15 ± 27.25
        AUC(0-inf), n=84, 79, 80
    450.83 ± 25.65
    478.06 ± 24.76
    454.11 ± 28.88
    Notes
    [6] - PK Population
    [7] - PK Population
    [8] - PK Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Lyophilized vial v Liquid autoinjector
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [9]
    Method
    Parameter type
    		 Ratio
    Point estimate
    1.08
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 1.15
    Notes
    [9] - Interpretation of the comparability of the autoinjector and safety syringe with the reconstituted lyophilized drug product was guided by a two-sided 90% CI for the ratio of the geometric mean of test treatment to reference treatment in the range (0.80, 1.25) for AUC (0-t)
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Liquid safety syringe v Lyophilized vial
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [10]
    Method
    Parameter type
    		 Ratio
    Point estimate
    1.04
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.12
    Notes
    [10] - Interpretation of the comparability of the autoinjector and safety syringe with the reconstituted lyophilized drug product was guided by a two-sided 90% CI for the ratio of the geometric mean of test treatment to reference treatment in the range (0.80, 1.25) for AUC (0-t).
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Lyophilized vial v Liquid autoinjector
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [11]
    Method
    Parameter type
    		 Ratio
    Point estimate
    1.07
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.13
    Notes
    [11] - Interpretation of the comparability of the autoinjector and safety syringe with the reconstituted lyophilized drug product was guided by a two-sided 90% CI for the ratio of the geometric mean of test treatment to reference treatment in the range (0.80, 1.25) for AUC (0-inf).
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Liquid safety syringe v Lyophilized vial
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [12]
    Method
    Parameter type
    		 Ratio
    Point estimate
    1.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.09
    Notes
    [12] - Interpretation of the comparability of the autoinjector and safety syringe with the reconstituted lyophilized drug product was guided by a two-sided 90% CI for the ratio of the geometric mean of test treatment to reference treatment in the range (0.80, 1.25) for AUC (0-inf).

    Secondary: Time to Cmax (tmax) and last time point where the concentration is above the limit of quantification (tlast) of mepolizumab

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    End point title
    		 Time to Cmax (tmax) and last time point where the concentration is above the limit of quantification (tlast) of mepolizumab
    End point description
    Blood samples were collected at indicated time points. Tmax and tlast following a single dose administration of liquid mepolizumab using a safety syringe and an autoinjector were compared with lyophilized drug product.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose, 2 hours, and 8 hours post-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 22, 29, 43, 57 and 85 post-dose
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    85 [13]
    79 [14]
    80 [15]
    Units: Days
    median (full range (min-max))
        tmax
    7.04 (0.9 to 14.1)
    7.05 (2.9 to 21.0)
    7.06 (1.9 to 14.0)
        tlast
    83.97 (14.0 to 87.0)
    83.98 (81.1 to 87.1)
    83.99 (55.9 to 87.9)
    Notes
    [13] - PK Population
    [14] - PK Population
    [15] - PK Population
    No statistical analyses for this end point

    Secondary: Apparent clearance (CL/F) of mepolizumab

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    End point title
    		 Apparent clearance (CL/F) of mepolizumab
    End point description
    Blood samples were collected at indicated time points . CL/F following a single dose administration of liquid mepolizumab using a safety syringe and an autoinjector were compared with lyophilized drug product. Only those participants with data available were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose, 2 hours, and 8 hours post-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 22, 29, 43, 57 and 85 post-dose
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    84 [16]
    79 [17]
    80 [18]
    Units: Liters per hour (L/h)
    geometric mean (geometric coefficient of variation)
        Liters per hour (L/h)
    0.009242 ± 27.91
    0.008716 ± 28.74
    0.009175 ± 39.30
    Notes
    [16] - PK Population
    [17] - PK Population
    [18] - PK Population
    No statistical analyses for this end point

    Secondary: Apparent volume of distribution (Vd/F) of mepolizumab

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    End point title
    		 Apparent volume of distribution (Vd/F) of mepolizumab
    End point description
    Blood samples were collected at indicated time points. Vd/F following a single dose administration of liquid mepolizumab using a safety syringe and an autoinjector were compared with lyophilized drug product. Only those participants with data available were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose, 2 hours, and 8 hours post-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 22, 29, 43, 57 and 85 post-dose
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    84 [19]
    79 [20]
    80 [21]
    Units: Liters (L)
    geometric mean (geometric coefficient of variation)
        Liters (L)
    7.02 ± 22.49
    6.74 ± 26.34
    6.94 ± 31.84
    Notes
    [19] - PK Population
    [20] - PK Population
    [21] - PK Population
    No statistical analyses for this end point

    Secondary: Terminal phase elimination rate constant (lambda z) of mepolizumab

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    End point title
    		 Terminal phase elimination rate constant (lambda z) of mepolizumab
    End point description
    Blood samples were collected at indicated time points. Lambda z following a single dose administration of liquid mepolizumab using a safety syringe and an autoinjector were compared with lyophilized drug product. Only those participants with data available were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose, 2 hours, and 8 hours post-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 22, 29, 43, 57 and 85 post-dose
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    84 [22]
    79 [23]
    80 [24]
    Units: Per hours
    geometric mean (geometric coefficient of variation)
        Per hours
    0.0013157 ± 21.51
    0.0012930 ± 26.20
    0.0013228 ± 26.71
    Notes
    [22] - PK Population
    [23] - PK Population
    [24] - PK Population
    No statistical analyses for this end point

    Secondary: Terminal phase half-life (t½) of mepolizumab

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    End point title
    		 Terminal phase half-life (t½) of mepolizumab
    End point description
    Blood samples were collected at indicated time points for calculating t½. t½ following a single dose administration of liquid mepolizumab using a safety syringe and an autoinjector were compared with lyophilized drug product. Only those participants with data available were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose, 2 hours, and 8 hours post-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 22, 29, 43, 57 and 85 post-dose
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    84 [25]
    79 [26]
    80 [27]
    Units: Days
    geometric mean (geometric coefficient of variation)
        Days
    21.95 ± 18.66
    22.34 ± 21.38
    21.83 ± 21.62
    Notes
    [25] - PK Population
    [26] - PK Population
    [27] - PK Population
    No statistical analyses for this end point

    Secondary: Percentage of AUC(0-inf) obtained by extrapolation (% AUCex) of mepolizumab

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    End point title
    		 Percentage of AUC(0-inf) obtained by extrapolation (% AUCex) of mepolizumab
    End point description
    Blood samples were collected at indicated time points. Percentage AUCex following a single dose administration of liquid mepolizumab using a safety syringe and an autoinjector were compared with lyophilized drug product. Only those participants with data available were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose, 2 hours, and 8 hours post-dose), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 22, 29, 43, 57 and 85 post-dose
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    84 [28]
    79 [29]
    80 [30]
    Units: Percentage
    geometric mean (geometric coefficient of variation)
        Percentage
    7.67 ± 42.06
    7.64 ± 47.30
    7.20 ± 48.24
    Notes
    [28] - PK Population
    [29] - PK Population
    [30] - PK Population
    No statistical analyses for this end point

    Secondary: Number of participants with on-treatment non-serious adverse events (AEs) and serious AEs (SAEs)

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    End point title
    		 Number of participants with on-treatment non-serious adverse events (AEs) and serious AEs (SAEs)
    End point description
    An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or events associated with liver injury and impaired liver function were categorized as SAE. All Treated Subjects (Safety) comprised of all participants who received mepolizumab. Participants with non-serious AEs (3 percentage threshold) and SAEs has been reported.
    End point type
    Secondary
    End point timeframe
    Up to 28 days post-dose
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    85 [31]
    79 [32]
    80 [33]
    Units: Participants
        Non-serious AEs
    11
    13
    14
        SAEs
    0
    0
    0
    Notes
    [31] - All Treated Subjects (Safety) Population
    [32] - All Treated Subjects (Safety) Population
    [33] - All Treated Subjects (Safety) Population
    No statistical analyses for this end point

    Secondary: Number of participants with on-treatment systemic reactions and injection site reactions

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    End point title
    		 Number of participants with on-treatment systemic reactions and injection site reactions
    End point description
    Adverse events of special interest like local injection site reactions and systemic reactions like allergic Type I hypersensitivity were reported along with AEs and SAEs. Participants with local injection site reaction and Allergic Type I hypersensitivity systemic reactions are reported here.
    End point type
    Secondary
    End point timeframe
    Up to 28 days post-dose
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    85 [34]
    79 [35]
    80 [36]
    Units: Participants
        Systemic reactions
    0
    0
    0
        Injection site reactions
    1
    1
    2
    Notes
    [34] - All Treated Subjects (Safety) Population
    [35] - All Treated Subjects (Safety) Population
    [36] - All Treated Subjects (Safety) Population
    No statistical analyses for this end point

    Secondary: Number of participants with hematology parameters shifts from Baseline relative to normal range

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    End point title
    		 Number of participants with hematology parameters shifts from Baseline relative to normal range
    End point description
    Hematology parameters included assessment of platelet count, erythrocytes, leukocytes, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), neutrophils, lymphocytes, monocytes, eosinophils, basophils, hemoglobin and hematocrit. Participants were counted in the worst case category that their value changes to Low, Normal or High. Participants whose value category was unchanged or whose value became normal, were recorded in the "To Normal or No Change" category. The worst case post-Baseline values has been reported. For basophils the “to low” category is not applicable (99999) as the lower limit of normal is zero for this parameter.
    End point type
    Secondary
    End point timeframe
    Up to Day 85
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    85 [37]
    79 [38]
    80 [39]
    Units: Participants
        Basophils, To low
    99999
    99999
    99999
        Basophils, To normal or no change
    85
    79
    80
        Basophils, To high
    0
    0
    0
        Eosinophils, To low
    58
    46
    55
        Eosinophils, To normal or no change
    27
    33
    24
        Eosinophils, To high
    0
    0
    1
        Hematocrit, To low
    8
    6
    4
        Hematocrit, To normal or no change
    76
    72
    75
        Hematocrit, To high
    1
    1
    1
        Hemoglobin, To low
    12
    8
    13
        Hemoglobin, To normal or no change
    73
    70
    67
        Hemoglobin, To high
    0
    1
    0
        Lymphocytes, To low
    2
    0
    1
        Lymphocytes, To normal or no change
    83
    79
    79
        Lymphocytes, To high
    0
    0
    0
        MCH, To low
    0
    5
    2
        MCH, To normal or no change
    84
    74
    78
        MCH, To high
    1
    0
    0
        MCV, To low
    1
    0
    1
        MCV, To normal or no change
    83
    79
    79
        MCV, To high
    1
    0
    0
        Monocytes, To low
    11
    8
    12
        Monocytes, To normal or no change
    74
    71
    68
        Monocytes, To high
    0
    0
    0
        Neutrophils, To low
    7
    11
    9
        Neutrophils, To normal or no change
    77
    68
    71
        Neutrophils, To high
    1
    0
    0
        Platelets, To low
    0
    0
    1
        Platelets, To normal or no change
    85
    78
    79
        Platelets, To high
    0
    1
    0
        Erythrocytes, To low
    4
    0
    3
        Erythrocytes, To normal or no change
    81
    78
    77
        Erythrocytes, To high
    0
    1
    0
        Leukocytes, To low
    11
    9
    8
        Leukocytes, To normal or no change
    73
    70
    72
        Leukocytes, To high
    1
    0
    0
    Notes
    [37] - All Treated Subjects (Safety) Population
    [38] - All Treated Subjects (Safety) Population
    [39] - All Treated Subjects (Safety) Population
    No statistical analyses for this end point

    Secondary: Number of participants with clinical chemistry parameters shifts from Baseline relative to normal range

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    End point title
    		 Number of participants with clinical chemistry parameters shifts from Baseline relative to normal range
    End point description
    Blood samples were collected to evaluate clinical chemistry parameters, which included assessment of creatinine, creatine kinase, glucose, protein, potassium, urea, sodium, calcium, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), direct bilirubin (D.bili) and bilirubin, and albumin. Participants were counted in the worst case category that their value changes to Low, Normal or High. Participants whose value category was unchanged or whose value became normal, were recorded in the "To Normal or No Change" category. The worst case post-Baseline values has been reported. Only those participants with data available at the specified data points were analyzed. For the category “to low ” 99999 indicates data was not available as the lower limit of normal is zero for this parameter.
    End point type
    Secondary
    End point timeframe
    Up to Day 85
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    84 [40]
    79 [41]
    80 [42]
    Units: Participants
        Glucose, To low
    1
    0
    0
        Glucose, To normal or no change
    83
    79
    80
        Glucose, To high
    0
    0
    0
        Albumin, To low
    0
    0
    0
        Albumin, To normal or no change
    83
    79
    80
        Albumin, To high
    1
    0
    0
        ALP, To low
    0
    0
    0
        ALP, To normal or no change
    84
    79
    80
        ALP, To high
    0
    0
    0
        ALT, To low
    99999
    99999
    99999
        ALT, To normal or no change
    84
    78
    80
        ALT, To high
    0
    1
    0
        AST, To low
    99999
    99999
    99999
        AST, To normal or no change
    84
    78
    80
        AST, To high
    0
    1
    0
        D.bilirubin, To low
    99999
    99999
    99999
        D.bilirubin, To normal or no change
    83
    79
    80
        D.bilirubin, To high
    1
    0
    0
        Bilirubin, To low
    99999
    99999
    99999
        Bilirubin, To normal or no change
    82
    79
    78
        Bilirubin, To high
    2
    0
    2
        Calcium, To low
    0
    0
    0
        Calcium, To normal or no change
    83
    79
    79
        Calcium, To high
    1
    0
    1
        Creatine kinase, To low
    99999
    99999
    99999
        Creatine kinase,To normal or no change
    76
    68
    70
        Creatine kinase, To high
    8
    11
    10
        Creatinine, To low
    4
    4
    1
        Creatinine, To normal or no change
    79
    75
    79
        Creatinine, To high
    1
    0
    0
        Potassium, To low
    0
    0
    0
        Potassium, To normal or no change
    84
    79
    80
        Potassium, To high
    0
    0
    0
        Protein, To low
    1
    1
    0
        Protein, To normal or no change
    83
    78
    80
        Protein, To high
    0
    0
    0
        Sodium, To low
    1
    0
    0
        Sodium, To normal or no change
    83
    79
    80
        Sodium, To high
    0
    0
    0
        Urea, To low
    1
    2
    1
        Urea, To normal or no change
    83
    75
    79
        Urea, To high
    0
    2
    0
    Notes
    [40] - All Treated Subjects (Safety) Population
    [41] - All Treated Subjects (Safety) Population
    [42] - All Treated Subjects (Safety) Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in Diastolic blood pressure (DBP) and systolic blood pressure (SBP)

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    End point title
    		 Change from Baseline in Diastolic blood pressure (DBP) and systolic blood pressure (SBP)
    End point description
    SBP and DBP were measured in supine position after 5 minutes rest. Baseline values for each assessment was the latest available assessment prior to receiving the single dose of mepolizumab. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Day 85
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    85 [43]
    79 [44]
    80 [45]
    Units: Millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        DBP, Day 2, n=85, 79, 80
    1.9 ± 7.36
    3.1 ± 6.90
    3.0 ± 6.47
        DBP, Day 3, n=85, 79, 79
    0.2 ± 7.06
    1.7 ± 6.60
    0.8 ± 7.90
        DBP, Day 4, n=85, 78, 80
    0.7 ± 6.44
    1.6 ± 7.55
    0.8 ± 6.33
        DBP, Day 5, n=85, 79, 80
    1.2 ± 7.04
    2.4 ± 7.48
    1.8 ± 6.40
        DBP, Day 6, n=85, 78, 80
    0.8 ± 6.80
    0.9 ± 7.11
    0.2 ± 7.96
        DBP, Day 7, n=85, 78, 80
    0.4 ± 7.44
    0.3 ± 6.70
    1.2 ± 7.50
        DBP, Day 43, n=84, 79, 80
    0.9 ± 8.04
    2.2 ± 6.70
    1.3 ± 7.22
        DBP, Follow up, n=84, 79, 80
    3.3 ± 8.26
    3.5 ± 6.69
    2.3 ± 6.70
        SBP, Day 2, n=85, 79, 80
    3.1 ± 10.61
    2.0 ± 11.15
    3.5 ± 11.25
        SBP, Day 3, n=85, 79, 79
    2.4 ± 10.45
    0.7 ± 10.28
    1.3 ± 11.12
        SBP, Day 4, n=85, 78, 80
    1.7 ± 9.51
    1.7 ± 9.95
    0.7 ± 10.07
        SBP, Day 5, n=85, 79, 80
    2.1 ± 11.03
    2.5 ± 10.39
    1.3 ± 9.67
        SBP, Day 6, n=85, 78, 80
    1.1 ± 9.38
    -0.6 ± 9.72
    -0.2 ± 10.81
        SBP, Day 7, n=85, 78, 80
    1.1 ± 10.95
    0.1 ± 10.37
    1.4 ± 11.30
        SBP, Day 43, n=84, 79, 80
    2.5 ± 11.21
    2.2 ± 10.70
    0.3 ± 11.93
        SBP, Follow up, n=84, 79, 80
    5.7 ± 10.21
    3.8 ± 11.93
    2.9 ± 11.67
    Notes
    [43] - All Treated Subjects (Safety) Population
    [44] - All Treated Subjects (Safety) Population
    [45] - All Treated Subjects (Safety) Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in pulse rate

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    End point title
    		 Change from Baseline in pulse rate
    End point description
    Pulse rate was measured in supine position after 5 minutes rest. Baseline values for each assessment was the latest available assessment prior to receiving the single dose of mepolizumab. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Day 85
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    85 [46]
    79 [47]
    80 [48]
    Units: Beats per minute
    arithmetic mean (standard deviation)
        Day 2, n=85, 79, 80
    5.3 ± 9.19
    5.6 ± 7.03
    6.1 ± 9.78
        Day 3, n= 85, 79, 79
    4.5 ± 8.01
    5.0 ± 8.85
    5.0 ± 9.37
        Day 4, n= 85, 78, 80
    3.7 ± 8.57
    3.9 ± 7.93
    3.2 ± 8.06
        Day 5, n= 85, 79, 80
    1.0 ± 9.02
    1.0 ± 7.58
    1.0 ± 8.73
        Day 6, n= 85, 78, 80
    2.4 ± 8.81
    3.4 ± 8.46
    4.3 ± 9.53
        Day 7, n= 85, 78, 80
    3.6 ± 9.05
    2.5 ± 8.15
    3.6 ± 10.33
        Day 43, n= 84, 79, 80
    3.6 ± 10.29
    3.7 ± 7.83
    3.7 ± 10.77
        Follow up, n= 84, 79, 80
    0.8 ± 10.56
    1.0 ± 8.47
    0.8 ± 8.91
    Notes
    [46] - All Treated Subjects (Safety) Population
    [47] - All Treated Subjects (Safety) Population
    [48] - All Treated Subjects (Safety) Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in temperature

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    End point title
    		 Change from Baseline in temperature
    End point description
    Temperature was measured in supine position after 5 minutes rest. Baseline values for each assessment was the latest available assessment prior to receiving the single dose of mepolizumab. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Day 85
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    85 [49]
    79 [50]
    80 [51]
    Units: degree Celsius
    arithmetic mean (standard deviation)
        Day 2, n=85, 79, 80
    0.08 ± 0.362
    0.08 ± 0.389
    0.01 ± 0.273
        Day 3, n=85, 79, 79
    0.09 ± 0.392
    0.07 ± 0.310
    -0.02 ± 0.272
        Day 4, n=85, 78, 80
    0.04 ± 0.289
    0.05 ± 0.329
    -0.01 ± 0.293
        Day 5, n=85, 79, 80
    -0.02 ± 0.264
    -0.02 ± 0.335
    -0.04 ± 0.317
        Day 6, n= 85, 78, 80
    0.01 ± 0.347
    0.05 ± 0.350
    0.00 ± 0.332
        Day 7, n= 85, 78, 80
    0.02 ± 0.281
    0.10 ± 0.348
    0.07 ± 0.280
        Day 43, n= 84, 79, 80
    0.04 ± 0.300
    0.06 ± 0.340
    -0.01 ± 0.293
        Follow up, n= 84, 79, 80
    0.02 ± 0.296
    0.02 ± 0.364
    0.02 ± 0.280
    Notes
    [49] - All Treated Subjects (Safety) Population
    [50] - All Treated Subjects (Safety) Population
    [51] - All Treated Subjects (Safety) Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in respiratory rate

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    End point title
    		 Change from Baseline in respiratory rate
    End point description
    Respiratory rate was measured in supine position after 5 minutes rest. Baseline values for each assessment was the latest available assessment prior to receiving the single dose of mepolizumab. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and up to Day 85
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    85 [52]
    79 [53]
    80 [54]
    Units: breaths per minute
    arithmetic mean (standard deviation)
        Day 2, n= 85, 79, 80
    0.0 ± 1.90
    0.3 ± 2.30
    0.5 ± 2.15
        Day 3, n= 85, 79, 79
    -0.2 ± 2.44
    0.3 ± 2.60
    0.1 ± 2.36
        Day 4, n= 85, 78, 80
    -0.5 ± 2.09
    0.4 ± 2.35
    0.1 ± 2.10
        Day 5, n= 85, 79, 80
    -0.2 ± 2.16
    0.0 ± 2.80
    0.2 ± 2.42
        Day 6, n= 85, 78, 80
    -0.1 ± 2.03
    0.2 ± 2.20
    0.5 ± 2.45
        Day 7, n= 85, 78, 80
    -0.2 ± 2.02
    0.1 ± 2.23
    0.2 ± 2.06
        Day 43, n= 84, 79, 80
    0.3 ± 2.03
    0.4 ± 2.14
    0.3 ± 2.07
        Follow up, n= 84, 79, 80
    -0.1 ± 2.17
    0.6 ± 2.11
    0.5 ± 2.07
    Notes
    [52] - All Treated Subjects (Safety) Population
    [53] - All Treated Subjects (Safety) Population
    [54] - All Treated Subjects (Safety) Population
    No statistical analyses for this end point

    Secondary: Number of participants with change from Baseline in electrocardiogram (ECG) findings

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    End point title
    		 Number of participants with change from Baseline in electrocardiogram (ECG) findings
    End point description
    Single measurements of 12-lead ECGs were obtained after 5 minutes of rest in a supine position for the participant. ECG was performed on Day 1 and Day 85 using an automated ECG machine. Baseline values for each assessment was the latest available assessment prior to receiving the single dose of mepolizumab. Change from Baseline was defined as difference between the post-Baseline visit value and the Baseline value. Participants with abnormal ECG findings that are clinically not significant and clinically significant data has been presented here. The data of worst case post-Baseline is presented here. Only those participants available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 85
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    84 [55]
    79 [56]
    80 [57]
    Units: Participants
        Abnormal not clinically significant
    15
    16
    19
        Abnormal clinically significant
    1
    0
    1
    Notes
    [55] - All Treated Subjects (Safety) Population
    [56] - All Treated Subjects (Safety) Population
    [57] - All Treated Subjects (Safety) Population
    No statistical analyses for this end point

    Secondary: Number of participants with positive anti-mepolizumab binding antibodies

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    End point title
    		 Number of participants with positive anti-mepolizumab binding antibodies
    End point description
    Blood samples were collected for the determination of anti-mepolizumab antibodies. A binding anti-drug antibody (ADA) assay was performed. There were three tiered analysis: screening, confirmation and titration. The results of binding ADA were categorized as negative, transient positive (defined as a single confirmatory positive immunogenic response that does not occur at the final study assessment) or persistent positive (defined as a confirmatory positive immunogenic response for at least 2 consecutive assessments excluding the Screening visit, or a single result at the final study assessment). A participant was considered positive if they had at least one positive post-Baseline ADA result. Number of participants with positive anti-mepolizumab antibodies at any time post-Baseline are presented here. Only those participants available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Day 85
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    84 [58]
    79 [59]
    80 [60]
    Units: Participants
        Transient positive
    1
    1
    0
        Persistent positive
    2
    4
    3
    Notes
    [58] - All Treated Subjects (Safety) Population
    [59] - All Treated Subjects (Safety) Population
    [60] - All Treated Subjects (Safety) Population
    No statistical analyses for this end point

    Secondary: Number of participants with positive neutralizing antibodies

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    End point title
    		 Number of participants with positive neutralizing antibodies
    End point description
    Blood samples were collected for the determination of positive neutralizing antibodies. A neutralizing antibody assay was performed. Neutralizing antibody test was only carried out for participants who have had a positive confirmatory binding antibody test result at visit. A participant was considered positive if they had at least one positive post-Baseline neutralizing antibody result. Number of participants with positive neutralizing antibodies at any time post-Baseline are presented here. Only those participants available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Day 85
    End point values
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Number of subjects analysed
    3 [61]
    5 [62]
    3 [63]
    Units: Participants
        Participants
    0
    0
    0
    Notes
    [61] - All Treated Subjects (Safety) Population
    [62] - All Treated Subjects (Safety) Population
    [63] - All Treated Subjects (Safety) Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study treatment and up to 28 days post-dose.
    Adverse event reporting additional description
    All Treated Subjects (Safety) comprised of all participants who received mepolizumab.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Lyophilized vial
    Reporting group description
    		 Participants were administered 100 milligram per milliliter (mg/mL) subcutaneous (SC) dose of mepolizumab as lyophilized powder reconstituted with sterile water for injection from vial. Participants were administered a single SC dose in upper arm, abdomen or thigh.

    Reporting group title
    Liquid autoinjector
    Reporting group description
    		 Participants were administered 100 mg/mL SC dose of mepolizumab liquid formulation via disposable pre-filled autoinjector. Participants were administered a single SC dose in upper arm, abdomen or thigh.

    Reporting group title
    Liquid safety syringe
    Reporting group description
    		 Participants were administered 100 mg/mL SC dose of mepolizumab liquid formulation via disposable pre-filled safety syringe. Participants were administered a single SC dose in upper arm, abdomen or thigh.

    Serious adverse events
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 79 (0.00%)
    0 / 80 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Lyophilized vial Liquid autoinjector Liquid safety syringe
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 85 (12.94%)
    13 / 79 (16.46%)
    14 / 80 (17.50%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 85 (7.06%)
    9 / 79 (11.39%)
    8 / 80 (10.00%)
         occurrences all number
    6
    9
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 85 (5.88%)
    2 / 79 (2.53%)
    1 / 80 (1.25%)
         occurrences all number
    5
    2
    1
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 85 (2.35%)
    3 / 79 (3.80%)
    6 / 80 (7.50%)
         occurrences all number
    2
    3
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2016
    Amendment No. 1: Update to the content of the Device error forms to reflect consistency with other data captured in similar studies. Updated withdrawal wording in Section 5.4.1. Removal of Cardiovascular and deaths events in Section 7.3.1.4.
    17 Nov 2016
    Amendment No. 2: Minor changes incorporated throughout the document as part of the QC step
    10 Jul 2017
    Amendment No. 3: In Section 7.3.1.4 Cardiovascular and Death Events section has been removed. In subsequent Section 7.3.1.5 “Regulatory reporting requirements for SAE’s” is assigned and section number 7.3.1.4 to maintain numerical sequence.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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