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    Clinical Trial Results:
    A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Reslizumab (0.3 or 3.0 mg/kg) as Treatment for Patients (12-75 Years of Age) with Eosinophilic Asthma

    Summary
    EudraCT number
    2010-023342-67
    Trial protocol
    BE   SE   HU   NL   PL  
    Global end of trial date
    12 Sep 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    23 Jul 2016
    First version publication date
    23 Jul 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    QC'd

    Trial information

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    Trial identification
    Sponsor protocol code
    C38072/3081
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01270464
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Global Branded Pharmaceutical Products R&D, Inc.
    Sponsor organisation address
    41 Moores Road, Frazer, Pennsylvania, United States, 19355
    Public contact
    Director, Clinical Research, Teva Global Branded Pharmaceutical Products R&D, Inc., 1 215-591-3000, ustevatrials@tevapharm.com
    Scientific contact
    Director, Clinical Research, Teva Global Branded Pharmaceutical Products R&D, Inc., 1 215-591-3000, ustevatrials@tevapharm.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to determine whether reslizumab, at a dosage of 0.3 or 3.0 mg/kg administered once every 4 weeks for a total of 4 doses, is more effective than placebo in improving lung function in patients with eosinophilic asthma as assessed by the overall change from baseline in forced expiratory volume in 1 second (FEV1).
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations [CFR] Title 21, Parts 50, 54, 56, 312, and 314; EU Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical studies of medicinal products for human use). Each investigator was responsible for performing the study in accordance with the protocol, ICH guidelines, and GCP, and for collecting, recording, and reporting the data accurately and properly. Agreement of each investigator to conduct and administer this study in accordance with the protocol was documented in separate study agreements with the sponsor and other forms as required by national authorities in the country where the study center is located. Written and/or oral information about the study in a language understandable by the patient was provided to all patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each patient before any study-specific procedures or assessments were done. For patients aged 12 to 17 years, a signed and dated informed consent form was obtained from a parent/guardian. It was explained to all patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each investigator kept the original consent/assent forms, and copies were given to the patients.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Feb 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    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
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Argentina: 43
    Country: Number of subjects enrolled
    Brazil: 19
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Colombia: 6
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Mexico: 26
    Country: Number of subjects enrolled
    United States: 115
    Worldwide total number of subjects
    315
    EEA total number of subjects
    75
    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)
    15
    Adults (18-64 years)
    283
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Of the 1025 patients screened at 80 centers in 12 countries (Argentina, Belgium, Brazil, Canada, Colombia, Hungary, Israel, Mexico, Netherlands, Poland, Sweden, and the US), 315 patients met entry criteria at 68 centers and were considered to be eligible for enrollment.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer
    Blinding implementation details
    To maintain the blinding in this 3-group study, each patient was to receive a specific volume of study drug (including active or placebo) on the basis of the patient’s body weight and assigned treatment group. Interactive response technology (IRT) was used to randomly assign a patient to 1 of 3 treatment groups. To maintain blinding to eosinophil counts during the study, eosinophil count data were redacted from hematology results during the treatment period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo administered intravenously (iv) once every 4 weeks, for a total of 4 doses.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo administered by iv infusion by qualified study personnel every 4 weeks for a total of 4 doses.

    Arm title
    Reslizumab - 0.3 mg/kg
    Arm description
    0.3 mg/kg, administered intravenously (iv) once every 4 weeks, for a total of 4 doses
    Arm type
    Experimental

    Investigational medicinal product name
    Reslizumab
    Investigational medicinal product code
    Other name
    Cinquil, humanized monoclonal antibody, CEP-38072
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3.0 mg/kg or 0.3 mg/kg doses administered intravenously (iv) by qualified site personnel once every 4 weeks, for a total of 4 doses.

    Arm title
    Reslizumab - 3.0 mg/kg
    Arm description
    3.0 mg/kg, administered intravenously (iv) once every 4 weeks, for a total of 4 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    Reslizumab
    Investigational medicinal product code
    Other name
    Cinquil, humanized monoclonal antibody, CEP-38072
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3.0 mg/kg or 0.3 mg/kg doses administered intravenously (iv) by qualified site personnel once every 4 weeks, for a total of 4 doses.

    Number of subjects in period 1
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Started
    105
    104
    106
    Safety analysis set
    105
    103
    103
    Full analysis set
    105
    103
    103
    Pharmacokinetic analysis set
    105
    103
    103
    Completed
    85
    92
    88
    Not completed
    20
    12
    18
         Consent withdrawn by subject
    2
    1
    4
         Adverse event, non-fatal
    9
    1
    7
         Lost to follow-up
    2
    3
    1
         unspecified
    1
    1
    3
         Lack of efficacy
    2
    3
    1
         Protocol deviation
    4
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo administered intravenously (iv) once every 4 weeks, for a total of 4 doses.

    Reporting group title
    Reslizumab - 0.3 mg/kg
    Reporting group description
    0.3 mg/kg, administered intravenously (iv) once every 4 weeks, for a total of 4 doses

    Reporting group title
    Reslizumab - 3.0 mg/kg
    Reporting group description
    3.0 mg/kg, administered intravenously (iv) once every 4 weeks, for a total of 4 doses.

    Reporting group values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg Total
    Number of subjects
    105 104 106 315
    Age categorical
    Stratification factor with data as reported in the case report form: 1) 12-17 years 2) >= 18 years
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    5 5 5 15
        Adults (18-64 years)
    93 91 99 283
        From 65-84 years
    7 8 2 17
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    44.2 ± 14.89 44.5 ± 14.03 43 ± 14.41 -
    Gender categorical
    Units: Subjects
        Female
    62 59 62 183
        Male
    43 45 44 132
    Race
    Units: Subjects
        White
    85 80 90 255
        Black
    7 6 5 18
        Asian
    0 2 2 4
        American Indian or Alaskan Native
    1 0 0 1
        Pacific Islander
    1 0 0 1
        Other
    11 16 9 36
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    29 29 31 89
        Non-Hispanic and non-Latino
    74 73 75 222
        Unknown
    2 2 0 4
    Asthma Exacerbation Within the Last 12 Months
    A stratification factor with data as reported in the case report form
    Units: Subjects
        Yes
    57 58 60 175
        No
    48 46 46 140
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    77 ± 20.1 75.9 ± 18.8 75.7 ± 20.3 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    166.4 ± 10.93 166.2 ± 12.21 165.9 ± 10.24 -
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    27.7 ± 6.01 27.6 ± 6.68 27.4 ± 6.87 -
    In Forced Expiratory Volume In 1 Second (FEV1)
    Respiratory baseline values offered for the Full Analysis Set (n=105, 103, 103) so that comparisons can be made with endpoint "Change from Baseline...." results.
    Units: liters
        arithmetic mean (standard deviation)
    2.222 ± 0.8125 2.157 ± 0.8506 2.169 ± 0.7815 -
    Forced Vital Capacity (FVC)
    Respiratory baseline values offered for the Full Analysis Set (n=105, 103, 103) so that comparisons can be made with endpoint "Change from Baseline...." results.
    Units: liters
        arithmetic mean (standard deviation)
    3.288 ± 1.0503 3.289 ± 1.1232 3.199 ± 1.0097 -
    Forced Expiratory Flow at 25% to 75% Forced Vital Capacity (FEF 25%-75%)
    Respiratory baseline values offered for the Full Analysis Set (n=105, 103, 103) so that comparisons can be made with endpoint "Change from Baseline...." results.
    Units: liter/second
        arithmetic mean (standard deviation)
    1.657 ± 0.9201 2.337 ± 8.9642 1.705 ± 1.5396 -
    % Predicted Expiratory Volume In 1 Second (FEV1)
    Respiratory baseline values offered for the Full Analysis Set (n=105, 103, 103) so that comparisons can be made with endpoint "Change from Baseline...." results.
    Units: % predicted FEV1
        arithmetic mean (standard deviation)
    71.1 ± 19.84 68.8 ± 18.48 70 ± 18.31 -
    Asthma Control Questionnaire (ACQ)
    Respiratory baseline values offered for the Full Analysis Set (n=105, 103, 103) so that comparisons can be made with endpoint "Change from Baseline...." results.
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.471 ± 0.8301 2.499 ± 0.8903 2.591 ± 0.8861 -
    Asthma Quality of Life Questionnaire
    Respiratory baseline values offered for the Full Analysis Set (n=105, 103, 103) so that comparisons can be made with endpoint "Change from Baseline...." results.
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.374 ± 1.2047 4.479 ± 1.2266 4.164 ± 1.2233 -
    Asthma Symptom Utility Index (ASUI)
    Respiratory baseline values offered for the Full Analysis Set (n=105, 103, 103) so that comparisons can be made with endpoint "Change from Baseline...." results.
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.674 ± 0.1897 0.675 ± 0.2061 0.657 ± 0.1913 -
    Average Daily Use of Short-Acting Beta-Agonist (SABA) Use
    SABA use values offered for the Full Analysis Set (n=104, 103, 103) so that comparisons can be made with endpoint "Change from Baseline...." results.
    Units: SABA puffs per day
        arithmetic mean (standard deviation)
    2.3 ± 2.2 1.9 ± 2.45 2.3 ± 2.58 -
    Blood Eosinophil Count
    Blood eosinophil baseline values offered for the Full Analysis Set (n=105, 103, 103) so that comparisons can be made with endpoint "Change from Baseline...." results.
    Units: 10^9 / L
        arithmetic mean (standard deviation)
    0.601 ± 0.4331 0.644 ± 0.4926 0.595 ± 0.3931 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo administered intravenously (iv) once every 4 weeks, for a total of 4 doses.

    Reporting group title
    Reslizumab - 0.3 mg/kg
    Reporting group description
    0.3 mg/kg, administered intravenously (iv) once every 4 weeks, for a total of 4 doses

    Reporting group title
    Reslizumab - 3.0 mg/kg
    Reporting group description
    3.0 mg/kg, administered intravenously (iv) once every 4 weeks, for a total of 4 doses.

    Primary: Change From Baseline In Forced Expiratory Volume In 1 Second (FEV1) over 16 weeks

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    End point title
    Change From Baseline In Forced Expiratory Volume In 1 Second (FEV1) over 16 weeks
    End point description
    FEV1 is a standard measurement of air movement in the lungs of patients with asthma obtained from pulmonary function tests. It is the volume of air expired in the first second of a forced expiration using a spirometer.
    End point type
    Primary
    End point timeframe
    Day 0 (baseline, pre-dose), Weeks 4, 8, 12 and 16
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    103 [1]
    101 [2]
    102 [3]
    Units: liters
        least squares mean (standard error)
    0.126 ± 0.0549
    0.242 ± 0.0556
    0.286 ± 0.0548
    Notes
    [1] - Full analysis set-all patients randomly assigned to treatment and treated 1+ doses of study drug
    [2] - Full analysis set
    [3] - Full analysis set
    Statistical analysis title
    Placebo to Reslizumab 3.0 mg/kg
    Statistical analysis description
    The primary variable was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 3.0 mg/kg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0018 [4]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    0.259
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0507
    Notes
    [4] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.
    Statistical analysis title
    Placebo to Reslizumab 0.3 mg/kg
    Statistical analysis description
    The primary variable was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 0.3 mg/kg
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0237 [5]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.115
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.016
         upper limit
    0.215
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0508
    Notes
    [5] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.

    Secondary: Change From Baseline in Forced Vital Capacity (FVC) over 16 Weeks

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    End point title
    Change From Baseline in Forced Vital Capacity (FVC) over 16 Weeks
    End point description
    The FVC is the volume of air that can be forcibly blown out after full inspiration, measured in liters.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    103 [6]
    101 [7]
    102 [8]
    Units: liters
        least squares mean (standard error)
    0.172 ± 0.0614
    0.22 ± 0.0623
    0.301 ± 0.0613
    Notes
    [6] - Full analysis set
    [7] - Full analysis set
    [8] - Full analysis set
    Statistical analysis title
    Placebo to Resizumab 3.0 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 3.0 mg/kg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0174 [9]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.023
         upper limit
    0.237
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0543
    Notes
    [9] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.
    Statistical analysis title
    Placebo to Resizumab 0.3 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 0.3 mg/kg
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3731 [10]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.048
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.058
         upper limit
    0.155
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0543
    Notes
    [10] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.

    Secondary: Change From Baseline in Forced Expiratory Flow at 25% to 75% Forced Vital Capacity (FEF 25%-75%) over 16 Weeks

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    End point title
    Change From Baseline in Forced Expiratory Flow at 25% to 75% Forced Vital Capacity (FEF 25%-75%) over 16 Weeks
    End point description
    The FEF 25%-75% is the force expiratory flow at 25% to 75% of the Forced Vital Capacity (FVC).
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    103 [11]
    101 [12]
    102 [13]
    Units: liters/second
        least squares mean (standard error)
    -0.145 ± 0.1342
    -0.114 ± 0.1361
    0.089 ± 0.1342
    Notes
    [11] - Full analysis set
    [12] - Full analysis set
    [13] - Full analysis set
    Statistical analysis title
    Placebo to Resizumab 3.0 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 3.0 mg/kg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0552 [14]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.233
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.005
         upper limit
    0.472
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1212
    Notes
    [14] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.
    Statistical analysis title
    Placebo to Resizumab 0.3 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 0.3 mg/kg
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.802 [15]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.209
         upper limit
    0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1215
    Notes
    [15] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.

    Secondary: Change From Baseline in % Predicted Expiratory Volume In 1 Second (FEV1) at Week 16 and at Endpoint

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    End point title
    Change From Baseline in % Predicted Expiratory Volume In 1 Second (FEV1) at Week 16 and at Endpoint
    End point description
    The % predicted FEV1 is the ratio of the volume of air expired in the first second of a forced expiration to the FVC.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Week 16, endpoint
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    105 [16]
    103 [17]
    103 [18]
    Units: % predicted FEV1
    arithmetic mean (standard deviation)
        Week 16 (n=84, 92, 91)
    0.8 ± 11.92
    4.9 ± 15.06
    7.5 ± 14.74
        Endpoint (n=103, 101, 102)
    0.8 ± 13.83
    5.5 ± 15.16
    6.7 ± 15.01
    Notes
    [16] - Full analysis set.
    [17] - Full analysis set
    [18] - Full analysis set
    No statistical analyses for this end point

    Secondary: Change From Baseline in Asthma Control Questionnaire (ACQ) over 16 Weeks

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    End point title
    Change From Baseline in Asthma Control Questionnaire (ACQ) over 16 Weeks
    End point description
    The ACQ is a 7-item instrument that measures asthma control (Juniper et al 1999). Six questions are self-assessments; the seventh item, completed by a member of the study staff, is the result of the patient’s FEV1 measurement. Each item has 7 possible answers on a scale of 0 to 6, and the total score is the mean of all responses. A higher score is an indication of poorer asthma control. Negative change from baseline scores indicate improvement.
    End point type
    Secondary
    End point timeframe
    Timeframes: Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    103 [19]
    101 [20]
    101 [21]
    Units: units on a scale
        least squares mean (standard error)
    -0.494 ± 0.1231
    -0.732 ± 0.125
    -0.853 ± 0.1233
    Notes
    [19] - Full analysis set, including patients who contributed at least once to the analysis.
    [20] - Full analysis set, including patients who contributed at least once to the analysis.
    [21] - Full analysis set, including patients who contributed at least once to the analysis.
    Statistical analysis title
    Placebo to Resizumab 3.0 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 3.0 mg/kg
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0014 [22]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.359
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.577
         upper limit
    -0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.111
    Notes
    [22] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.
    Statistical analysis title
    Copy of Placebo to Resizumab 0.3 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 0.3 mg/kg
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0329 [23]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.238
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.456
         upper limit
    -0.019
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1108
    Notes
    [23] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.

    Secondary: Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) at Week 16 or at Last Observed Value

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    End point title
    Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) at Week 16 or at Last Observed Value
    End point description
    The AQLQ is a 32-item instrument administered as a self-assessment (Juniper et al 1992). The questionnaire is divided into 4 domains: activity limitation, symptoms, emotional function, and environmental stimuli. Patients were asked to recall their experiences during the last 2 weeks and to respond to each question on a 7-point scale (1=severe impairment, 7=no impairment) for a total scale of 32-224. Five of the activity questions were “patient-specific,” which means that each patient identified and scored 5 activities in which the patient was limited by asthma; these 5 activities were identified at the first visit and retained for all subsequent follow-up visits. Positive change from baseline scores indicate improvement in quality of life. The AQLQ score was only assessed once during the study at week 16 or at early withdrawal if it met endpoint criteria for efficacy assessments: ie, last postbaseline assessment if within 3 to 5 weeks of the last dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Week 16 or last observed value
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    101 [24]
    96 [25]
    99 [26]
    Units: units on a scale
        least squares mean (standard error)
    0.779 ± 0.1817
    1.057 ± 0.1881
    1.138 ± 0.1829
    Notes
    [24] - Full analysis set, including patients who contributed at least once to the analysis.
    [25] - Full analysis set, including patients who contributed at least once to the analysis.
    [26] - Full analysis set, including patients who contributed at least once to the analysis.
    Statistical analysis title
    Placebo to Resizumab 3.0 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 3.0 mg/kg
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0241 [27]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.359
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.047
         upper limit
    0.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1582
    Notes
    [27] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.
    Statistical analysis title
    Copy of Placebo to Resizumab 0.3 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 0.3 mg/kg
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0822 [28]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.278
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.036
         upper limit
    0.591
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1591
    Notes
    [28] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.

    Secondary: Change From Baseline in Asthma Symptom Utility Index (ASUI) over 16 Weeks

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    End point title
    Change From Baseline in Asthma Symptom Utility Index (ASUI) over 16 Weeks
    End point description
    The ASUI is an 11-item instrument designed to assess the frequency and severity of asthma symptoms and side effects, weighted by patient preferences (Revicki et al 1998). ASUI is a utility score that ranges from 0 to 1, with higher values indicating better asthma control; info obtained from questionnaire about asthma symptoms.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    103 [29]
    101 [30]
    101 [31]
    Units: units on a scale
        least squares mean (standard error)
    0.082 ± 0.0218
    0.132 ± 0.0221
    0.129 ± 0.0218
    Notes
    [29] - Full analysis set, including patients who contributed at least once to the analysis.
    [30] - Full analysis set, including patients who contributed at least once to the analysis.
    [31] - Full analysis set, including patients who contributed at least once to the analysis.
    Statistical analysis title
    Placebo to Resizumab 3.0 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 3.0 mg/kg
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.016 [32]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.009
         upper limit
    0.085
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0193
    Notes
    [32] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.
    Statistical analysis title
    Copy of Placebo to Resizumab 0.3 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 0.3 mg/kg
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0094 [33]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.051
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.012
         upper limit
    0.089
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0193
    Notes
    [33] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.

    Secondary: Change From Baseline in Short-Acting Beta-Agonist (SABA) Use over 16 Weeks

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    End point title
    Change From Baseline in Short-Acting Beta-Agonist (SABA) Use over 16 Weeks
    End point description
    At each clinic visit, to measure SABA use, patients were asked to recall their usage of SABA therapy within the last 3 days of the scheduled visit. If usage was confirmed, the number of puffs used was recorded.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    102 [34]
    101 [35]
    102 [36]
    Units: SABA puffs per day
        least squares mean (standard error)
    -0.3 ± 0.28
    -1 ± 0.28
    -0.9 ± 0.27
    Notes
    [34] - Full analysis set, including patients who contributed at least once to the analysis.
    [35] - Full analysis set, including patients who contributed at least once to the analysis.
    [36] - Full analysis set, including patients who contributed at least once to the analysis.
    Statistical analysis title
    Placebo to Resizumab 3.0 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 3.0 mg/kg
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0151 [37]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.624
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.126
         upper limit
    -0.121
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2551
    Notes
    [37] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.
    Statistical analysis title
    Placebo to Resizumab 0.3 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 0.3 mg/kg
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0119 [38]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.648
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.152
         upper limit
    -0.144
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2559
    Notes
    [38] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.

    Secondary: Change From Baseline in Blood Eosinophil Count over 16 Weeks

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    End point title
    Change From Baseline in Blood Eosinophil Count over 16 Weeks
    End point description
    Blood eosinophil counts were measured using a standard CBC with differential blood test at each scheduled visit, and from all patients experiencing a serious adverse event, an adverse event leading to withdrawal, or an exacerbation of asthma symptoms.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    103 [39]
    101 [40]
    102 [41]
    Units: 10^9/L
        least squares mean (standard error)
    -0.035 ± 0.0271
    -0.358 ± 0.0277
    -0.529 ± 0.027
    Notes
    [39] - Full analysis set, including patients who contributed at least once to the analysis.
    [40] - Full analysis set, including patients who contributed at least once to the analysis.
    [41] - Full analysis set, including patients who contributed at least once to the analysis.
    Statistical analysis title
    Placebo to Resizumab 3.0 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 3.0 mg/kg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [42]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.494
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.542
         upper limit
    -0.447
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0242
    Notes
    [42] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.
    Statistical analysis title
    Copy of Placebo to Resizumab 0.3 mg/kg
    Statistical analysis description
    As with the primary outcome, this respiratory test outcome was analyzed using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements.
    Comparison groups
    Placebo v Reslizumab - 3.0 mg/kg v Reslizumab - 0.3 mg/kg
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [43]
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.323
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.37
         upper limit
    -0.275
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0243
    Notes
    [43] - The overall treatment effect for each reslizumab dose was compared to placebo using a 2-sided t-test at the a priori significance level of 0.05.

    Secondary: Participants with Adverse Events

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    End point title
    Participants with Adverse Events
    End point description
    An adverse event was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
    End point type
    Secondary
    End point timeframe
    Day 1 (post-dose) to Week 29. The last postbaseline value for approximately 10 patients in each treatment group is the 90-day follow-up visit post end-of-treatment (approx. Week 29).
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    105 [44]
    103 [45]
    103 [46]
    Units: participants
        At least 1 AE
    66
    59
    61
        Severe AE
    4
    2
    7
        Treatment-related AE
    8
    6
    12
        Withdrawn from study due to AE
    10
    1
    6
        Withdrawn from study due to treatment-related AE
    0
    0
    1
        Death
    0
    0
    0
        Serious AE without the outcome of death
    1
    0
    4
        Treatment-related serious AEs
    0
    0
    0
    Notes
    [44] - Safety analysis set
    [45] - Safety analysis set
    [46] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Participants with Treatment-Emergent Potentially Clinically Significant (PCS) Abnormal Lab Values

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    End point title
    Participants with Treatment-Emergent Potentially Clinically Significant (PCS) Abnormal Lab Values
    End point description
    Data represents participants with potentially clinically significant (PCS) abnormal serum chemistry, hematology (except for eosinophil values), and urinalysis values. Significance criteria: Blood urea nitrogen: >=10.71 mmol/L Creatinine: >=177 μmol/L Uric acid: M>=625, F>=506 μmol/L GGT = gamma-glutamyl transpeptidase: >= 3*upper limit of normal. Normal range is 5-49 U/L. Total bilirubin: >=34.2 μmol/L White blood cells: <=3.0 10^9/L Hemoglobin: M<=115, F<=95 g/dL Hematocrit: M<0.37, F<0.32 % Platelets: >=700 10^9/L Absolute neutrophil count: <=1.0 10^9/L Urinalysis: blood, glucose, ketones and total protein: >=2 unit increase from baseline Actual number of participants evaluated varies between 100-104 for each test and treatment arm.
    End point type
    Secondary
    End point timeframe
    Day 2 to Week 29. The last postbaseline hematology value for approximately 10 patients in each treatment group is the 90-day follow-up visit post end-of-treatment (approx. Week 29).
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    105 [47]
    103 [48]
    103 [49]
    Units: participants
        At least 1 PCS abnormal serum chemistry value
    1
    5
    2
        Blood urea nitrogen
    0
    0
    1
        Creatinine
    1
    0
    0
        Uric acid
    0
    0
    2
        GGT
    0
    4
    0
        Total bilirubin
    0
    1
    0
        At least 1 PCS abnormal hematology value
    4
    7
    3
        White blood cells
    0
    0
    1
        Hemoglobin
    0
    2
    0
        Hematocrit
    2
    6
    2
        Platelets
    0
    0
    1
        Absolute neutrophil count
    2
    1
    0
        At least 1 PCS abnormal urinalysis value
    21
    21
    18
        Blood in urine
    10
    11
    6
        Glucose in urine
    3
    4
    5
        Ketones in urine
    0
    1
    3
        Total protein in urine
    11
    11
    11
    Notes
    [47] - Safety analysis set
    [48] - Safety analysis set
    [49] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Participants with Treatment-Emergent Potentially Clinically Significant (PCS) Vital Signs Values

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    End point title
    Participants with Treatment-Emergent Potentially Clinically Significant (PCS) Vital Signs Values
    End point description
    Data represents participants with potentially clinically significant (PCS) vital sign values. Significance criteria Sitting pulse - high: >100 and increase of >= 30 beats/minute Sitting pulse - low: <50 and decrease of >=30 beats/minute Sitting diastolic blood pressure: >100 and increase of >=12 mmHg Respiration rate: >24 and increase of >=10 breaths/minute Body temperature: <96.5° Fahrenheit or <35.8° Celsius
    End point type
    Secondary
    End point timeframe
    Day 2 to Week 29. The last postbaseline value for approximately 10 patients in each treatment group is the 90-day follow-up visit post end-of-treatment (approx. Week 29).
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    104 [50]
    102 [51]
    103 [52]
    Units: participants
        At least 1 PCS abnormal vital sign
    12
    16
    16
        Sitting pulse - high
    0
    1
    2
        Sitting pulse - low
    0
    1
    1
        Sitting diastolic blood pressure
    0
    0
    1
        Respiration rate
    0
    2
    0
        Body temperature
    12
    13
    13
    Notes
    [50] - Safety analysis set of patients with both a baseline and postbaseline vital sign value.
    [51] - Safety analysis set of patients with both a baseline and postbaseline vital sign value.
    [52] - Safety analysis set of patients with both a baseline and postbaseline vital sign value.
    No statistical analyses for this end point

    Secondary: Shifts from Baseline to Endpoint in Electrocardiogram Findings

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    End point title
    Shifts from Baseline to Endpoint in Electrocardiogram Findings
    End point description
    Participant counts in each category of shift from baseline to endpoint of ECG finding. Findings summarized as normal or abnormal.
    End point type
    Secondary
    End point timeframe
    Weeks -4 to -2 (Screening Visit), Week 16
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    102 [53]
    99 [54]
    101 [55]
    Units: participants
        Normal to Normal
    64
    70
    63
        Normal to Abnormal
    14
    10
    15
        Abnormal to Normal
    11
    9
    13
        Abnormal to Abnormal
    13
    10
    10
    Notes
    [53] - Safety analysis set of participants with both baseline and endpoint values.
    [54] - Safety analysis set of participants with both baseline and endpoint values.
    [55] - Safety analysis set of participants with both baseline and endpoint values.
    No statistical analyses for this end point

    Secondary: Participant With a Positive Anti-Reslizumab Antibody Status at Baseline, Week 8, Week 16, Endpoint, and Overall

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    End point title
    Participant With a Positive Anti-Reslizumab Antibody Status at Baseline, Week 8, Week 16, Endpoint, and Overall
    End point description
    Counts of participants with a positive anti-drug antibody (ADA) response during treatment is offered for the two experimental treatment arms. Blood samples were collected for determination of ADAs before study drug infusion at baseline, visit 4 (week 8), and at visit 6 (week 16: EOT or early withdrawal) from patients in all 3 treatment groups (ie, placebo, 0.3 mg/kg reslizumab, and 3.0 mg/kg reslizumab); however, only the blood samples drawn from patients treated with either 0.3 mg/kg reslizumab or 3.0 mg/kg reslizumab were analyzed. Serum samples from patients who were treated with reslizumab were analyzed for ADA by Teva (Teva Biopharmaceuticals USA, Rockville, MD) using a validated homogeneous solution-based bridging enzyme-linked immunosorbent assay (ELISA).
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose), week 8, 16 and endpoint
    End point values
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Number of subjects analysed
    0 [56]
    103 [57]
    103 [58]
    Units: participants
        Overall (n=102, 103)
    12
    11
        Baseline (n=99, 98)
    8
    8
        Week 8 (n=90, 94)
    8
    10
        Week 16 (n=91, 89)
    7
    5
        Endpoint (n=101, 102)
    10
    6
    Notes
    [56] - Anti-Reslizumab antibody status was not analyzed for patients in the Placebo treatment arm.
    [57] - Pharmacokinetic analysis set
    [58] - Pharmacokinetic analysis set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Week 29. The last postbaseline value for approximately 10 patients in each treatment group is the 90-day follow-up visit post end-of-treatment (approx. Week 29). Events reported during the follow-up were treated as treatment-emergent.
    Adverse event reporting additional description
    Total subjects affected with non-serious AEs by treatment arm is consistent with the 5% threshold.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo administered intravenously (iv) once every 4 weeks, for a total of 4 doses.

    Reporting group title
    Reslizumab - 0.3 mg/kg
    Reporting group description
    0.3 mg/kg, administered intravenously (iv) once every 4 weeks, for a total of 4 doses

    Reporting group title
    Reslizumab - 3.0 mg/kg
    Reporting group description
    3.0 mg/kg, administered intravenously (iv) once every 4 weeks, for a total of 4 doses.

    Serious adverse events
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    4 / 103 (3.88%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    3 / 103 (2.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 105 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Reslizumab - 0.3 mg/kg Reslizumab - 3.0 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 105 (26.67%)
    20 / 103 (19.42%)
    28 / 103 (27.18%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 105 (5.71%)
    8 / 103 (7.77%)
    11 / 103 (10.68%)
         occurrences all number
    7
    9
    11
    Asthma
         subjects affected / exposed
    20 / 105 (19.05%)
    6 / 103 (5.83%)
    14 / 103 (13.59%)
         occurrences all number
    24
    10
    14
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 105 (3.81%)
    6 / 103 (5.83%)
    6 / 103 (5.83%)
         occurrences all number
    5
    9
    6

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2010
    Amendment 1 (dated 22 December 2010) to the protocol was issued before any patients were enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol:  Body weight was to be measured only at screening and baseline.  The requirement to document the use of the anti-IgE monoclonal antibody omalizumab (XOLAIR®) taken 12 months before study drug administration was added.  Several clarifications and corrections were made to the study design.
    14 Apr 2011
    Amendment 2 (dated 14 April 2011) to the protocol was issued after 15 of the 300 planned patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol:  - The inclusion criterion describing required asthma therapy was clarified.  - An exclusion criterion was changed to exclude patients who had other pulmonary conditions with symptoms of asthma and blood eosinophilia such as Churg-Strauss syndrome.  - Exclusion criteria were added to exclude patients who had or who were suspected of having a parasitic infestation/infection and to exclude patients who had received a live attenuated vaccine within 12-weeks before screening.  - An independent Data and Safety Monitoring Board (DSMB) was added to further ensure the safety of the patients.  - For patients who did not enroll in the open-label extension study, a 90-day follow-up evaluation was added to assess adverse events, blood eosinophils, and vital signs.
    19 Apr 2011
    Amendment 3 (dated 19 April 2011) to the protocol was issued after 17 of the 300 planned patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol:  - Country-specific changes and clarifications were made to study inclusion and exclusion criteria.  - For patients experiencing a serious adverse event, an adverse event leading to withdrawal, or an exacerbation of asthma symptoms, the collection of a blood sample was added for pharmacokinetic evaluation, eosinophil determination, and ADA assessment.  - The anti-IgE monoclonal antibody omalizumab (XOLAIR®) was added as a prohibited medication within 6 months prior to screening.  - A full physical examination was added to the end-of-treatment visit.
    29 Feb 2012
    Amendment 4 (dated 29 February 2012) to the protocol was issued after 195 of the 300 planned patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol:  - The number of patients planned to be enrolled in the study was increased from approximately 180 to approximately 300 patients, to achieve 90% power for the primary efficacy variable instead of 85% power. The increase in sample size also resulted in a lowered effect size from 0.6 to 0.47. The lowered effect size reflected an anticipated greater variability in the FEV1 change as the result of broader geographic enrollment than initially planned.
    19 Apr 2013
    Amendment 5 (dated 19 April 2013) to the protocol was issued after 315 patients were enrolled into the study, ie, patient enrollment was complete. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol:  - Text related to the timings of blood sample collection for biomarkers (ECP, EDN, and EP) and ADA was clarified and minor terminology updates related to pharmacokinetic sampling were made.  - Three new subsections (Immunogenicity, Pharmacokinetics, and Pharmacodynamics) were added to the Primary and Secondary Measures and Endpoints section for clarification.  - The exploratory objectives of biomarkers, sputum eosinophil levels, and change in presence or absence of nasal polyps were clarified.

    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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