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    Clinical Trial Results:
    A 12-Month, Double-Blind, Placebo-Controlled, Parallel-Group Study to evaluate the Efficacy and Safety of Reslizumab (3.0 mg/kg) in the reduction of Clinical Asthma Exacerbations in Patients (12-75 years of age) with Eosinophilic Asthma

    Summary
    EudraCT number
    2010-024006-35
    Trial protocol
    SK   DE   GR  
    Global end of trial date
    03 Apr 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Jul 2016
    First version publication date
    09 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C38072/3083
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01285323
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products, R&D Inc.
    Sponsor organisation address
    41 Moores Road, Frazer, Pennsylvania, United States, 19355
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.com
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, 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
    24 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2014
    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 dose of 3 mg/kg administered intravenously (iv) every 4 weeks over 12 months, is more effective than placebo in reducing the number of clinical asthma exacerbations (CAEs) in patients with eosinophilic asthma as assessed by the frequency of CAEs. A CAE is defined by 1 of the following: 1) a hospitalization because of asthma, 2) emergency treatment because of asthma, 3) a decrease in forced expiratory volume in 1 second (FEV1) by 20% or more from baseline, or 4) If the peak expiratory flow rate (PEFR) drops below 30% from baseline on 2 consecutive days worsening of asthma will be assessed. If there is a prescribed increase in baseline oral corticosteroid (OCS) or inhaled corticosteroid (ICS) or if the symptoms warrant additional asthma treatment (OCS) this would be considered a CAE.
    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; European Union (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 trials on medicinal products for human use). Information regarding any investigational study centers participating in this study that could not comply with these standards was documented. Written and/or oral information about the study was provided to all patients in a language understandable by the patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. For patients aged 12 through 17, a signed and dated informed consent form (ICF) was obtained from each parent/guardian and a signed and dated assent form was obtained from each patient before any study specific procedures or assessments are done and after the aims, methods, anticipated benefits, and potential hazards were explained, according to local IEC/IRB requirements. The patient’s willingness to participate in the study was documented in the assent form, which was signed by the patient with the date of that signature indicated. Each investigator kept the original consent/assent forms and copies were given to the patients. It was also explained to the 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.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 18
    Country: Number of subjects enrolled
    Slovakia: 30
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 64
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Argentina: 14
    Country: Number of subjects enrolled
    Brazil: 21
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 34
    Country: Number of subjects enrolled
    Mexico: 12
    Country: Number of subjects enrolled
    Peru: 68
    Country: Number of subjects enrolled
    Russian Federation: 40
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Ukraine: 107
    Country: Number of subjects enrolled
    United States: 31
    Worldwide total number of subjects
    464
    EEA total number of subjects
    130
    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)
    12
    Adults (18-64 years)
    415
    From 65 to 84 years
    37
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 1111 patients were screened for this study. Of the 1111 patients screened, 464 patients at 82 centers in 15 countries were randomly assigned to double-blind treatment.

    Pre-assignment
    Screening details
    Patients who continued to meet inclusion/exclusion criteria and who enrolled in the study were randomly assigned in a blinded fashion (1:1) to 1 of the following 2 treatment groups: reslizumab at 3 mg/kg or placebo, stratified by OCS use (yes or no) at study enrollment and by region (US or other).

    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, Monitor
    Blinding implementation details
    Patients were randomly assigned to treatment through an Interactive Response Technology (IRT). Using this system ensured a balance across treatment groups; no effort was made to maintain a balance among treatment groups, within a study center. To maintain the blinding to study drug in this 2 treatment group study, the volume of study drug (including active or placebo treatment) to be taken from each vial was assigned by IRT on the basis of the patient’s body weight and assigned treatment group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 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
    Matching placebo (acetate sucrose buffer), administered intravenously (iv) once every 4 weeks for a total of 13 doses.

    Arm title
    Reslizumab 3.0 mg/kg
    Arm description
    Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 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
    Patients were administered intravenously over 15 to 30 minutes reslizumab at a dosage of 3.0 mg/kg at baseline and once every 4 weeks relative to baseline over 48 weeks for a total of 13 doses.

    Number of subjects in period 1
    Placebo Reslizumab 3.0 mg/kg
    Started
    232
    232
    Full Analysis Set
    232
    232
    Safety Analysis Set
    232
    232
    Completed
    199
    202
    Not completed
    33
    30
         Consent withdrawn by subject
    15
    11
         Adverse event, non-fatal
    9
    8
         Not specified
    1
    3
         Lost to follow-up
    1
    1
         Lack of efficacy
    4
    2
         Protocol deviation
    1
    2
         Non-compliance with study procedures
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.

    Reporting group title
    Reslizumab 3.0 mg/kg
    Reporting group description
    Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.

    Reporting group values
    Placebo Reslizumab 3.0 mg/kg Total
    Number of subjects
    232 232 464
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    47.5 ± 13.75 46.4 ± 13.79 -
    Gender categorical
    Units: Subjects
        Female
    150 144 294
        Male
    82 88 170
    Race
    Units: Subjects
        White
    169 168 337
        Black
    4 6 10
        Asian
    21 16 37
        American Indian or Alaskan Native
    4 7 11
        Pacific Islander
    1 0 1
        Other
    33 35 68
    Oral Corticosteroid Use at Baseline
    Participants who were taking oral corticosteroids at baseline as recorded by interactive response technology. This was a stratification factor.
    Units: Subjects
        Yes
    27 27 54
        No
    205 205 410
    Participants in the United States
    This was a stratification factor as reported by the interactive response technology (IRT).
    Units: Subjects
        Yes
    15 16 31
        No
    217 216 433
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    73.9 ± 15.93 74.7 ± 15.72 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    165.2 ± 9.81 166.4 ± 9.56 -
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    27 ± 5.05 27 ± 5.26 -
    Asthma exacerbations in the previous 12 months
    One Reslizumab participant reported no asthma exacerbations in the past 12 months.
    Units: exacerbations
        arithmetic mean (standard deviation)
    2 ± 1.78 1.9 ± 1.58 -
    Forced Expiratory Volume in 1 second (FEV1)
    Units: liters
        arithmetic mean (standard deviation)
    2.004 ± 0.6682 2.129 ± 0.7848 -
    Asthma Control Questionnaire (ACQ)
    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 overall score is the mean of all responses. A higher score is an indication of poorer asthma control.
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.605 ± 0.79 2.57 ± 0.89 -
    Asthma Quality of Life Questionnaire (AQLQ)
    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). The overall AQLQ score is the mean of all 32 responses.
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.223 ± 1.0794 4.352 ± 1.0229 -
    Asthma Symptom Utility Index (ASUI)
    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.
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.649 ± 0.1919 0.664 ± 0.2005 -
    Blood Eosinophil Count
    Units: 10^9 blood eosinophil /L
        arithmetic mean (standard deviation)
    0.688 ± 0.6824 0.61 ± 0.4115 -
    Number of Short-Acting Beta-Agonist Puffs (SABA) Daily
    Based on patient-reported total number of SABA puffs over the past 3 days. N=201, 204
    Units: puffs/day
        arithmetic mean (standard deviation)
    2.7 ± 2.41 2.9 ± 2.82 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.

    Reporting group title
    Reslizumab 3.0 mg/kg
    Reporting group description
    Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.

    Primary: Frequency of Clinical Asthma Exacerbations (CAEs) During 12 Months of Treatment

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    End point title
    Frequency of Clinical Asthma Exacerbations (CAEs) During 12 Months of Treatment
    End point description
    An exacerbation event was considered a CAE if the patient met either or both of the criteria listed below and this was corroborated with at least 1 other measurement to indicate the worsening of clinical signs and symptoms of asthma: • use of systemic, or an increase in the use of inhaled, corticosteroid treatment for 3 or more days; or an increased 2 or more fold for at least 3 or more days for patient's already on corticosteroids. • asthma-related emergency treatment, such as an unscheduled visit to the physician's office or emergency room for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms, or an asthma-related hospitalization. CAEs were adjudicated by committee to assure consistency. Adjusted CAE rate and confidence intervals were based on Negative Binomial regression model adjusted for stratification factors. Results are offered as adjusted means.
    End point type
    Primary
    End point timeframe
    Day 1 to Month 12
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    232 [1]
    232 [2]
    Units: CAEs in 52 weeks
        arithmetic mean (confidence interval 95%)
    2.115 (1.329 to 3.365)
    0.859 (0.549 to 1.345)
    Notes
    [1] - Randomized set - patients assigned to a treatment group, regardless if they took study drug
    [2] - Randomized set - patients assigned to a treatment group, regardless if they took study drug
    Statistical analysis title
    CAEs During 12 Months
    Statistical analysis description
    The frequency of CAEs was analyzed using the generalized linear model (GLM) for data from the negative binomial distributions that is commonly referred to as the negative binomial (NB) regression model. The primary NB model included the treatment group and randomization stratification factors as model factors and the logarithm of follow up time excluding the summed duration of exacerbations in the treatment period as an offset variable.
    Comparison groups
    Reslizumab 3.0 mg/kg v Placebo
    Number of subjects included in analysis
    464
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Chi-squared
    Parameter type
    CAE rate ratio (reslizumab vs placebo
    Point estimate
    0.4063
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2819
         upper limit
    0.5855
    Notes
    [3] - The treatment effect was tested using the likelihood based Chi-square test at the 0.05 significance level.

    Primary: Frequency of Each of the Two Criteria for Clinical Asthma Exacerbations (CAEs)

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    End point title
    Frequency of Each of the Two Criteria for Clinical Asthma Exacerbations (CAEs)
    End point description
    An exacerbation event was considered a CAE if the patient met either or both of the criteria listed below and this was corroborated with at least 1 other measurement to indicate the worsening of clinical signs and symptoms of asthma: • use of systemic, or an increase in the use of inhaled, corticosteroid treatment for 3 or more days; or an increased 2 or more fold for at least 3 or more days for patient's already on corticosteroids. • asthma-related emergency treatment, such as an unscheduled visit to the physician's office or emergency room for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms, or an asthma-related hospitalization CAEs were adjudicated by committee to assure consistency. Adjusted CAE rate and confidence intervals for the two criteria were based on Negative Binomial regression model adjusted for stratification factors. Results are offered as adjusted means.
    End point type
    Primary
    End point timeframe
    Day 1 to Month 12
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    232 [4]
    232 [5]
    Units: CAEs in 52 weeks
    arithmetic mean (confidence interval 95%)
        Requiring systemic corticosteroids >3 days
    1.66 (1.0005 to 2.744)
    0.646 (0.397 to 1.053)
        Requiring hospitalization or ER visit
    0.047 (0.013 to 0.168)
    0.033 (0.009 to 0.12)
    Notes
    [4] - Randomized set - patients assigned to a treatment group, regardless if they took study drug
    [5] - Randomized set - patients assigned to a treatment group, regardless if they took study drug
    Statistical analysis title
    CAEs requiring systemic corticosteroids >3 days
    Statistical analysis description
    The frequency of CAEs was analyzed using the generalized linear model (GLM) for data from the negative binomial distributions that is commonly referred to as the negative binomial (NB) regression model. The primary NB model included the treatment group and randomization stratification factors as model factors and the logarithm of follow up time excluding the summed duration of exacerbations in the treatment period as an offset variable.
    Comparison groups
    Reslizumab 3.0 mg/kg v Placebo
    Number of subjects included in analysis
    464
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Chi-squared
    Parameter type
    CAE rate ratio (reslizumab vs placebo)
    Point estimate
    0.3893
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2621
         upper limit
    0.5782
    Notes
    [6] - The treatment effect was tested using the likelihood based Chi-square test at the 0.05 significance level.
    Statistical analysis title
    CAEs requiring hospitalization or ER visit
    Statistical analysis description
    The frequency of CAEs was analyzed using the generalized linear model (GLM) for data from the negative binomial distributions that is commonly referred to as the negative binomial (NB) regression model. The primary NB model included the treatment group and randomization stratification factors as model factors and the logarithm of follow up time excluding the summed duration of exacerbations in the treatment period as an offset variable.
    Comparison groups
    Reslizumab 3.0 mg/kg v Placebo
    Number of subjects included in analysis
    464
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.402 [7]
    Method
    Chi-squared
    Parameter type
    CAE rate ratio (reslizumab vs placebo)
    Point estimate
    0.6686
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2878
         upper limit
    1.6479
    Notes
    [7] - The treatment effect was tested using the likelihood based Chi-square test at the 0.05 significance level.

    Secondary: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) At Week 16

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    End point title
    Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) At Week 16
    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. Positive change from baseline scores indicate improvement in asthma control.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Week 16
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    214 [8]
    214 [9]
    Units: liters
        least squares mean (standard error)
    0.122 ± 0.0447
    0.223 ± 0.0445
    Notes
    [8] - Randomized set Number analyzed reflects participants with both baseline and Week 16 assessments.
    [9] - Randomized set Number analyzed reflects participants with both baseline and Week 16 assessments.
    Statistical analysis title
    Change From Baseline FEV1 to Week 16
    Statistical analysis description
    A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially
    Comparison groups
    Reslizumab 3.0 mg/kg v Placebo
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0109 [10]
    Method
    Mixed model repeated measures (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    0.101
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.023
         upper limit
    0.179
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0397
    Notes
    [10] - Statistical significance at <=0.05. Fixed Factors: treatment, visit, trt by visit interaction, region, OCS at enrollment, sex. Random: covariates for height, baseline value and patient

    Secondary: 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. During study values used a mixed effect model for repeated measures (MMRM) with treatment group, visit, treatment and visit interaction, and stratification factors as fixed effects and participant as a random effect. Covariates for baseline values were also included in the model; for pulmonary function test analyses, covariates for height and sex were included as well. Positive change from baseline scores indicate improvement in asthma control.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Weeks 4, 8, 12 and 16
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    227 [11]
    230 [12]
    Units: liters
        least squares mean (standard error)
    0.094 ± 0.041
    0.187 ± 0.041
    Notes
    [11] - Randomized set. Includes participants who contributed at least once to the analysis.
    [12] - Randomized set. Includes participants who contributed at least once to the analysis.
    Statistical analysis title
    Change From Baseline FEV1 over 16 Weeks
    Statistical analysis description
    A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.
    Comparison groups
    Reslizumab 3.0 mg/kg v Placebo
    Number of subjects included in analysis
    457
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0037 [13]
    Method
    Mixed model repeated measures (MMRM
    Parameter type
    Mean difference (final values)
    Point estimate
    0.093
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.03
         upper limit
    0.155
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0317
    Notes
    [13] - Statistical significance at <=0.05. Fixed Factors: treatment, visit, trt by visit interaction, region, OCS at enrollment, sex. Random: covariates for height, baseline value and patient

    Secondary: Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) to Week 16

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    End point title
    Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) to Week 16
    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). The overall AQLQ score is the mean of all 32 responses. 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.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Week 16
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    216 [14]
    213 [15]
    Units: units on a scale
        least squares mean (standard error)
    0.777 ± 0.1152
    0.987 ± 0.1158
    Notes
    [14] - Randomized set of participants with assessments at each timepoint.
    [15] - Randomized set of participants with assessments at each timepoint.
    Statistical analysis title
    Change From Baseline in AQLQ to Week 16
    Statistical analysis description
    A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.
    Comparison groups
    Reslizumab 3.0 mg/kg v Placebo
    Number of subjects included in analysis
    429
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0259 [16]
    Method
    Mixed model repeated measures (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    0.209
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.025
         upper limit
    0.393
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.937
    Notes
    [16] - Statistical significance at <=0.05. Fixed Factors: treatment, visit, trt by visit interaction, region, OCS at enrollment, sex. Random: covariates for height, baseline value and patient.

    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 (the total scale is therefore 0-6). A higher score is an indication of poorer asthma control. The during treatment average ACQ was estimated 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. Negative change from baseline scores indicate improvement in asthma control.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    228 [17]
    230 [18]
    Units: units on a scale
        least squares mean (standard error)
    -0.66 ± 0.0875
    -0.857 ± 0.0872
    Notes
    [17] - Randomized set, including participants who contributed at least once to the analysis.
    [18] - Randomized set, including participants who contributed at least once to the analysis.
    Statistical analysis title
    Change From Baseline in ACQ Over 16 Weeks
    Statistical analysis description
    A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.
    Comparison groups
    Reslizumab 3.0 mg/kg v Placebo
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0032 [19]
    Method
    Mixed model repeated measures (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.196
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.327
         upper limit
    -0.066
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0664
    Notes
    [19] - Statistical significance at <=0.05. Fixed Factors: treatment, visit, trt by visit interaction, region, OCS at enrollment, sex. Random: covariates for height, baseline value and patient

    Secondary: Kaplan-Meier Estimates for Time to First Clinical Asthma Exacerbation (CAE)

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    End point title
    Kaplan-Meier Estimates for Time to First Clinical Asthma Exacerbation (CAE)
    End point description
    An exacerbation event was considered a CAE if the patient met either or both of the criteria listed below and this was corroborated with at least 1 other measurement to indicate the worsening of clinical signs and symptoms of asthma: • use of systemic, or an increase in the use of inhaled, corticosteroid treatment for 3 or more days; or an increased 2 or more fold for at least 3 or more days for patient's already on corticosteroids. • asthma-related emergency treatment, such as an unscheduled visit to the physician's office or emergency room for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms, or an asthma-related hospitalization. CAEs were adjudicated by committee to assure consistency. The distributions were compared by a log rank test stratified by baseline usage of oral corticosteroid (yes or no) and geographical region (U.S. or other). Values of 9999 = Insufficient data to estimate time.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 526 (longest treatment time plus 2 weeks)
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    232 [20]
    232 [21]
    Units: weeks
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [20] - Randomized set
    [21] - Randomized set
    Statistical analysis title
    Time to First CAE
    Statistical analysis description
    Kaplan-Meier estimate of probability (%) of not experiencing a CAE by week 52. The first CAEs for each patient occurring after randomization and up to 2 weeks after the end of treatment period were analyzed. Patients without a CAE within this time frame were censored at two weeks after the treatment completion date or study discontinuation, whichever came first.
    Comparison groups
    Reslizumab 3.0 mg/kg v Placebo
    Number of subjects included in analysis
    464
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [22]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.486
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.353
         upper limit
    0.67
    Notes
    [22] - Stratified by baseline usage of oral corticosteroid (yes or no) and geographical region (U.S. or other).

    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. The during treatment average ASUI was estimated 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. Positive change from baseline values indicate improvement in asthma symptoms. Information was 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 3.0 mg/kg
    Number of subjects analysed
    224 [23]
    227 [24]
    Units: units on a scale
        least squares mean (standard error)
    0.08 ± 0.0161
    0.115 ± 0.0161
    Notes
    [23] - Randomized set, including participants who contributed at least once to the analysis.
    [24] - Randomized set, including participants who contributed at least once to the analysis.
    Statistical analysis title
    Change from Baseline in ASUI Over 16 Weeks
    Statistical analysis description
    A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.
    Comparison groups
    Reslizumab 3.0 mg/kg v Placebo
    Number of subjects included in analysis
    451
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0037 [25]
    Method
    Mixed model repeated measures (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    0.035
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.011
         upper limit
    0.059
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Notes
    [25] - Statistical significance at <=0.05. Fixed Factors: treatment, visit, trt by visit interaction, region, OCS at enrollment, sex. Random: covariates for height, baseline value and patient

    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
    SABA are used for quick relief of asthma symptoms. To measure SABA use, at each clinical visit 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. For the purpose of summaries, an average daily usage was evaluated by dividing the total number of puffs recorded over 3 days by 3. The during treatment SABA use was estimated 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. Negative change from baseline scores indicate improvement in asthma control.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    188 [26]
    180 [27]
    Units: SABA puffs per day
        least squares mean (standard error)
    -0.44 ± 0.233
    -0.5 ± 0.23
    Notes
    [26] - Randomized set including patients who contributed at least once to the analysis.
    [27] - Randomized set including patients who contributed at least once to the analysis.
    Statistical analysis title
    Change from Baseline in SABA use
    Statistical analysis description
    A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.
    Comparison groups
    Reslizumab 3.0 mg/kg v Placebo
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7263 [28]
    Method
    Mixed model repeated measures (MMRM)
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.062
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.411
         upper limit
    0.287
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1775
    Notes
    [28] - Statistical significance at <=0.05. Fixed Factors: treatment, visit, trt by visit interaction, region, OCS at enrollment, sex. Random: covariates for height, baseline value and patient

    Secondary: Change From Baseline in Blood Eosinophil Count Over 16 Weeks and 52 Weeks

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    End point title
    Change From Baseline in Blood Eosinophil Count Over 16 Weeks and 52 Weeks
    End point description
    The blood eosinophil counts were measured using a standard complete blood count (CBC) with differential blood test. Results of all differential blood tests conducted after randomization were blinded. The during-treatment average eosinophil count was estimated 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. Negative change from baseline values correlate to reduced asthma severity.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 or early withdrawal
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    226 [29]
    230 [30]
    Units: 10^9/L
    least squares mean (standard error)
        Over first 16 weeks
    -0.076 ± 0.0268
    -0.555 ± 0.0266
        Over 52 weeks
    -0.076 ± 0.0233
    -0.565 ± 0.0231
    Notes
    [29] - Randomized set including patients who contributed at least once to the analysis.
    [30] - Randomized set including patients who contributed at least once to the analysis.
    No statistical analyses for this end point

    Secondary: Participants With Treatment-Emergent Adverse Events TEAE)

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    End point title
    Participants With Treatment-Emergent Adverse Events TEAE)
    End point description
    An adverse event (AE) 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 65. The endpoint for adverse events was the last postbaseline observation, which included the 90 day follow-up visit.
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    232 [31]
    232 [32]
    Units: participants
        Any TEAE
    201
    177
        Mild TEAE
    36
    67
        Moderate TEAE
    140
    98
        Severe TEAE
    25
    12
        Treatment-related AE
    27
    34
        Mild treatment-related AE
    14
    22
        Moderate treatment-related AE
    13
    11
        Severe treatment-related AE
    0
    1
        TEAE causing patient discontinuation
    9
    8
        Deaths
    0
    0
        Serious AEs
    23
    18
    Notes
    [31] - Safety analysis set
    [32] - 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 • Urate: M>=625, F>=506 μmol/L • Aspartate aminotransferase (AST): >=3*upper limit of normal (ULN) • Alanine aminotransferase (ALT): >=3*ULN • GGT = gamma-glutamyl transpeptidase: >= 3*ULN • Total bilirubin: >=34.2 μmol/L • White blood cells (low): <=3.0*10^9/L • White blood cells (high): >=20*10^9/L • Hemoglobin (age >=18 years): M<=115, F<=95 g/dL • Hematocrit (age >=18 years): M<0.37, F<0.32 L/L • Eosinophils/leukocytes: >=10.0% • Platelets: <=75*10^9/L • Neutrophils: <=1.0*10^9/L • Urinalysis: blood, ketones, glucose, and protein: >=2 unit increase from baseline
    End point type
    Secondary
    End point timeframe
    Week 4 to Week 52
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    227 [33]
    230 [34]
    Units: participants
        Blood urea nitrogen
    5
    4
        Creatinine
    0
    1
        Urate
    5
    2
        AST
    3
    2
        ALT
    7
    3
        GGT
    11
    9
        Bilirubin
    3
    3
        Leukocytes (low)
    3
    10
        Leukocytes (high)
    0
    1
        Hemoglobin
    5
    6
        Hematocrit
    10
    8
        Eosinophils/leukocytes
    168
    10
        Platelets
    1
    1
        Neutrophils
    14
    9
        Urine blood (hemoglobin)
    28
    12
        Urine ketones
    6
    1
        Urine glucose
    9
    7
        Urine protein
    28
    28
    Notes
    [33] - Safety analysis set, including participants who contributed to the analysis
    [34] - Safety analysis set, including participants who contributed to the analysis
    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 systolic blood pressure (low): <90 and decrease of >= 30 mmHg • Sitting systolic blood pressure (high): >160 and increase of >= 30 mmHg • Sitting diastolic blood pressure (low): <50 and decrease of >=12 mmHg (if 12-17 years old: <55 and decrease of >=12 mmHg 0 • Sitting diastolic blood pressure (high): >100 and increase of >=12 mmHg • Respiratory rate (low): <6 breaths/minute • Respiratory rate (high): >24 and increase of >=10 breaths/minute • Body temperature (low): <35.8° Celsius • Body temperature (high): >=38.1 and increase of >=1.1° Celsius
    End point type
    Secondary
    End point timeframe
    Week 4 to Week 52
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    230 [35]
    230 [36]
    Units: participants
        >=1 postbaseline vital sign abnormality
    58
    49
        Sitting pulse (high)
    6
    6
        Sitting systolic blood pressure (low)
    2
    1
        Sitting systolic blood pressure (high)
    0
    1
        Sitting diastolic blood pressure (low)
    4
    3
        Sitting diastolic blood pressure (high)
    3
    4
        Respiratory rate (low)
    0
    1
        Respiratory rate (high)
    4
    5
        Body temperature (low)
    50
    39
        Body temperature (high)
    1
    0
    Notes
    [35] - Safety analysis set including participants who contributed data to the analysis
    [36] - Safety analysis set including participants who contributed data to the analysis
    No statistical analyses for this end point

    Secondary: Participants With a Positive Anti-Reslizumab Antibody Status During Study

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    End point title
    Participants With a Positive Anti-Reslizumab Antibody Status During Study
    End point description
    Counts of participants with a positive anti-drug antibody (ADA) response during treatment is offered for the experimental treatment arm. Blood samples were collected for determination of ADAs before study drug infusion.
    End point type
    Secondary
    End point timeframe
    Baseline visit (prior to reslizumab exposure), Weeks 16, 32, 48 and 52
    End point values
    Placebo Reslizumab 3.0 mg/kg
    Number of subjects analysed
    0 [37]
    232 [38]
    Units: participants
        Baseline
    10
        Week 16
    10
        Week 32
    10
        Week 48
    10
        Week 52
    10
        >=1 positive test result
    15
    Notes
    [37] - Test not reported for placebo arm
    [38] - Safety Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 (post-dose) to Week 65. The endpoint for adverse events was the last postbaseline observation, which included the 90 day follow-up visit.
    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 once every 4 weeks ( +-7 days) for a total of 13 doses.

    Reporting group title
    Reslizumab 3.0 mg/kg
    Reporting group description
    Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for a total of 13 doses.

    Serious adverse events
    Placebo Reslizumab 3.0 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 232 (9.91%)
    18 / 232 (7.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasmacytoma
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    3 / 232 (1.29%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    2 / 232 (0.86%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brachial plexus injury
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post concussion syndrome
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Extrasystoles
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 232 (0.00%)
    2 / 232 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    6 / 232 (2.59%)
    3 / 232 (1.29%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status asthmaticus
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Allergic sinusitis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot deformity
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 232 (2.59%)
    2 / 232 (0.86%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 232 (0.43%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterium fortuitum infection
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    1 / 232 (0.43%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 232 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Reslizumab 3.0 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    160 / 232 (68.97%)
    123 / 232 (53.02%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 232 (6.90%)
    33 / 232 (14.22%)
         occurrences all number
    20
    55
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    118 / 232 (50.86%)
    66 / 232 (28.45%)
         occurrences all number
    293
    133
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 232 (3.45%)
    12 / 232 (5.17%)
         occurrences all number
    8
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    56 / 232 (24.14%)
    45 / 232 (19.40%)
         occurrences all number
    88
    71
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 232 (6.90%)
    8 / 232 (3.45%)
         occurrences all number
    27
    16
    Bronchitis
         subjects affected / exposed
    14 / 232 (6.03%)
    2 / 232 (0.86%)
         occurrences all number
    15
    5

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Apr 2011
    Amendment 1 (dated 14 April 2011) to the protocol was issued when 1 patient had been enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: • change in sponsor’s medical expert and pharmacovigilance representative • text was added to the study objectives to clarify the definition of emergency treatment for asthma • inclusion criterion (f) was revised to clearly state that baseline asthma therapy must be stable for 30 days prior to screening and continue without dosage changes throughout the study • exclusion criterion (c) was revised to clearly state that patients with pulmonary conditions with symptoms of asthma and blood eosinophilia (eg, Churg Strauss syndrome, allergic bronchopulmonary aspergillosis) were also to be excluded • exclusion criterion (n) was added to exclude patients who had the presence of or suspected parasitic infestation/infection • exclusion criterion (o) was added to exclude patients who have received any live attenuated vaccine within the 12 week period prior to screening • a 90-day follow-up evaluation was added for assessment of adverse events, blood eosinophils, and vital signs for patients who did not enroll in the available open-label extension study
    19 Apr 2011
    Amendment 2 (dated 19 April 2011) to the protocol was issued after 1 patient was 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: • a change was made to stipulate that blood samples were to be collected for pharmacokinetics evaluation, blood eosinophil determination, and anti reslizumab antibody assessment each time a patient experienced a serious adverse event, an adverse event leading to withdrawal, or an exacerbation of asthma symptoms • inclusion criterion (h) was revised to clarify acceptable contraceptive methods to be used during the study • exclusion criterion (e) was revised to include other prohibited biologics (ie, interferon-α and anti-TNF) • exclusion criterion (f) was revised to specifically exclude patients who had previously received anti IL 5 mAbs, whether within or outside of a clinical study • exclusion criterion (i) was revised to clarify that patients may not have participated in any investigative biologics study within 90 days prior to screening
    11 Aug 2011
    Amendment 3 (dated 11 August 2011) to the protocol was issued after 8 patients had been enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: • change in sponsor’s authorized representative and therapeutic area head • the definition of CAE was changed: the criterion capturing a fall in peak expiratory flow was modified to mandate associated asthma symptomatology • the assessment of CAEs was changed to only the treatment period of the study • inclusion criterion (b) requiring use of corticosteroids for the treatmeant of a CAE within the previous 12 months was changed to include use of intramuscular corticosteroids • exclusion criterion (p) was added and stated: The patient has a history of allergic reactions to or hypersensitivity to any component of the study drug • the procedures for diagnosing a CAE were changed to agree with the new definition of a CAE • the exclusion of a patient using OCSs greater than 10 mg/day was removed as part of an administrative letter dated 26 July 2011 and was presented in revised exclusion criterion (e2). As a result of this revision, inclusion criterion (f2) was amended so that a patient’s baseline asthma therapy regimen could now include OCSs up to a maximum dose of prednisone daily, or equivalent, and that they would be allowed into the study as long as they were stable for 30 days prior to screening and continued without dosage changes throughout the study.
    16 Aug 2012
    Amendment 4 (dated 16 August 2012) to the protocol was issued after 328 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: • change in sponsor, medical expert, pharmacovigilance representative, and contact information • assessments at the time of 1st CAE was removed based on United States Food and Drug Administration (FDA) input • revisions were made to include language regarding withholding of SABAs before lung function testing because of their impact on spirometry • additional assessments performed at screening were added (12 lead ECG, physical examination, urinalysis, vital signs measurements, β-HCG serum pregnancy test for all females of childbearing potential) • independent DSMB information was added • revision was made to ensure that the study blind was maintained when pharmacokinetic analysis was performed during the study • the study sample size was increased and the expected study completion date, study duration, and number of study centers were revised because of the change in sample size • 2 ACQ scores required prior to randomization, both had to be 1.5 or greater • patients with recent infections requiring hospitalization or oral/iv antibiotic were excluded from entering the study • benralizumab was added as an excluded prior medication • the use of an adjudication committee to assess CAEs was added • a 48-hour window was added for evaluating patients with a CAE
    19 Apr 2013
    Amendment 5 (dated 19 April 2013) to the protocol was issued after 464 patients were enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: • change in sponsor’s authorized representative, medical expert, pharmacovigilance representative, and contact information for serious adverse event reporting • pharmacokinetic and immunogenicity information was updated • the sample size was revised using an annualized exacerbation rate of 1.2, from more current global data • additional ECG assessments incorporated into the study • clarification of sampling times and assessments • clarification of exploratory endpoints and secondary endpoints
    24 Jan 2014
    Amendment 6 (dated 24 January 2014) to the protocol was issued after 464 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: • change in sponsor’s authorized representative and medical expert • the definition of a CAE was changed to the current, more stringent definition such that a decease in lung function (ie, a CRF decrease in FEV1 or PEFR) was now designated as supportive of a medical intervention for worsening asthma, and not definitive in an of itself. • secondary objectives were revised to more clearly define the variables to be analyzed and OCS use was deleted as a secondary variable because this is a subset of the primary objective • evaluation of sputum eosinophils and potential asthma biomarkers in sputum supernatants were added as exploratory objective • the filter size was changed to 0.20-micron size • statistical analyses were changed to agree with the new efficacy variables

    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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