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    Clinical Trial Results:
    A 52-Week Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of Reslizumab 110 mg Fixed, Subcutaneous Dosing in Patients with Uncontrolled Asthma and Elevated Blood Eosinophils

    Summary
    EudraCT number
    2015-000865-29
    Trial protocol
    CZ   ES   HU   BE   PL   DE  
    Global end of trial date
    31 Jan 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Dec 2018
    First version publication date
    16 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C38072-AS-30025
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02452190
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products, R&D Inc
    Sponsor organisation address
    41 Moores Road, Frazer, United States, 19355
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, 001 2155913000, ustevatrials@tevapharm.com
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, 001 2155913000, ustevatrials@tevapharm.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001202-PIP02-13
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study was to establish the safety and efficacy of the subcutaneous formulation of reslizumab in participants with uncontrolled asthma and elevated blood eosinophils.
    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 Title 21, Parts 11, 50, 54, 56, 312, and 314; European Union Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical studies on medicinal products for human use). Written and/or oral information about the study was provided to all participants in a language understandable by the participants. 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 participant before any study procedures or assessments were done. It was explained to the participants 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
    12 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 12
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Turkey: 4
    Country: Number of subjects enrolled
    Ukraine: 76
    Country: Number of subjects enrolled
    United States: 105
    Country: Number of subjects enrolled
    Argentina: 27
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Hungary: 35
    Country: Number of subjects enrolled
    Israel: 34
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Romania: 18
    Country: Number of subjects enrolled
    Russian Federation: 45
    Worldwide total number of subjects
    468
    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)
    53
    Adults (18-64 years)
    348
    From 65 to 84 years
    67
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 1159 participants were screened, of whom 468 participants were eligible and enrolled in a 3-week run-in period for self-monitoring. All 468 enrolled participants were then randomized at 201 centers in 20 countries.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Matching placebo administered subcutaneously 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 injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo administered once every 4 weeks (+/-7 days)

    Arm title
    Reslizumab 110 mg
    Arm description
    Reslizumab 110 milligrams (mg) administered subcutaneously once every 4 weeks (+/-7 days) for a total of 13 doses.
    Arm type
    Experimental

    Investigational medicinal product name
    Resizumab
    Investigational medicinal product code
    CEP-38072
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Reslizumab 110 mg once every 4 weeks (+/-7 days)

    Number of subjects in period 1
    Placebo Reslizumab 110 mg
    Started
    232
    236
    Intent to Treat (ITT) Population
    230
    234
    Completed
    197
    212
    Not completed
    35
    24
         Death
    -
    1
         Noncompliance with study drug
    1
    -
         Participant traveled abroad
    1
    -
         Adverse event (non-fatal)
    2
    5
         Lack of efficacy
    3
    1
         Withdrawal by Sponsor
    1
    3
         Investigator's Decision
    2
    -
         Pregnancy
    1
    -
         Consent withdrawn by subject
    20
    11
         Lost to follow-up
    4
    3

    Baseline characteristics

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

    Reporting group title
    Reslizumab 110 mg
    Reporting group description
    Reslizumab 110 milligrams (mg) administered subcutaneously once every 4 weeks (+/-7 days) for a total of 13 doses.

    Reporting group values
    Placebo Reslizumab 110 mg Total
    Number of subjects
    232 236 468
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    25 28 53
        Adults (18-64 years)
    176 172 348
        From 65-84 years
    31 36 67
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    45.03 ± 17.748 47.08 ± 17.695 -
    Sex: Female, Male
    Units: Subjects
        Female
    130 145 275
        Male
    102 91 193
    Region of Enrollment
    Units: Subjects
        United States and Canada|
    58 52 110
        Europe|
    127 137 264
        Rest of World|
    47 47 94
    Race/Ethnicity, Customized
    Units: Subjects
        Not Hispanic or Latino|
    203 218 421
        Hispanic or Latino|
    26 17 43
        Unknown|
    3 1 4
    Blood Eosinophil Category at Baseline
    Units: Subjects
        less than (<)300 per (/) microliter (mcl)|
    0 1 1
        300 to <400/mcl
    42 48 90
        greater than or equal to (≥)400/mcl
    190 187 377
    Race/Ethnicity, Customized
    Units: Subjects
        White
    201 207 408
        Black or African American
    11 15 26
        Asian
    11 6 17
        American Indian or Alaska Native
    1 0 1
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Other
    8 8 16
    Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1)
    Number of participants analyzed N=Participants in the ITT population with pre-bronchodilator FEV1 at baseline measures available. (N=229 and 234 for Placebo and Reslizumab arm, respectively)
    Units: liters
        arithmetic mean (standard deviation)
    2.102 ± 0.870 1.988 ± 0.780 -
    Asthma Quality of Life Questionnaire for Participants 12 Years and Older (AQLQ+12) Score
    AQLQ is a 32-item self-assessment. AQLQ+12 is modified version of AQLQ to measure functional impairments of participants 12-70 years. It is divided into 4 domains: activity limitation, symptoms, emotional function, environmental stimuli. Participants were asked to recall experiences during the last 2 weeks and respond to each question on a 7-point scale (1=severe impairment, 7=no impairment), where higher scores indicate better quality of life. Overall AQLQ+12 score is the mean of all 32 responses. N=ITT population with baseline AQLQ+12 scores available. N=215, 217 for Pla, Res, respectively
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.39 ± 0.995 4.28 ± 1.048 -
    Asthma Control Questionnaire (ACQ-6) Score
    The ACQ-6 is a validated 6-item asthma assessment tool that has been widely used. Six questions are self-assessments (completed by the participant), 5 questions assessing asthma symptoms: night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing, and 1 question for short-acting bronchodilator use. Each item on the ACQ has a possible score ranging from 0 to 6, and the total score is the mean of all responses. The total score ranging from 0-6 (0=totally controlled and 6=severely uncontrolled). ITT population (N= 230 and 234 for Pla and Res, respectively)
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.42 ± 0.812 2.48 ± 0.88 -
    Total Asthma Symptom Scores
    Asthma symptoms were recorded by participants in an asthma control diary. Night score was assessed on a 5-point scale where 0=no symptoms, slept through night, to 4=bad night, no sleep. Day score was assessed on a 6-point scale where 0=very well, no symptoms, to 5=asthma very severe, unable to carry out daily activities. Total asthma symptom score was calculated by taking the sum of the night and day asthma symptom scores recorded each day, ranging from 0 (no symptom) to 9 (severe symptom). N=ITT population with asthma symptom scores at baseline. (N= 222 and 224 for Pla and Res, respectively)
    Units: units on a scale
        arithmetic mean (standard deviation)
    2.6 ± 1.62 2.5 ± 1.53 -
    Number of Clinical Asthma Exacerbation (CAE) Events in the Previous 12 Months
    CAE at baseline were defined as asthma exacerbations requiring systemic corticosteroids within last 12 months. ITT population N=230 and 234 for placebo and reslizumab arms, respectively.
    Units: Count of Events
        arithmetic mean (standard deviation)
    2.30 ± 0.843 2.35 ± 1.043 -

    End points

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

    Reporting group title
    Reslizumab 110 mg
    Reporting group description
    Reslizumab 110 milligrams (mg) administered subcutaneously once every 4 weeks (+/-7 days) for a total of 13 doses.

    Primary: Frequency of Clinical Asthma Exacerbations (CAEs) During 52 Weeks of Treatment

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    End point title
    Frequency of Clinical Asthma Exacerbations (CAEs) During 52 Weeks of Treatment
    End point description
    CAE is deterioration in asthma control, determined by investigator and evidenced by new/worsening symptoms based on history, asthma control diary, physical examination, and/or ambulatory or clinic visit assessment of lung function and that resulted in a medical intervention, including at least 1 of the following: use of systemic corticosteroids or at least a doubling from a stable maintenance oral corticosteroid dose for at least 3 days; asthma-specific hospital admission; asthma-specific ER department visit. Adjusted CAE rate and CIs were based on Negative Binomial regression model adjusted for stratification factors. Offset variable calculated as the logarithm of treatment duration minus the summed duration of exacerbations during treatment period. ITT population included all randomized participants, excluding participants from the site terminated due to GCP issues. Treatment based on to which participants were randomized, regardless of which treatment they received
    End point type
    Primary
    End point timeframe
    Day 1 to Week 52
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    230
    234
    Units: CAEs in 52 weeks
        number (confidence interval 95%)
    0.52 (0.347 to 0.773)
    0.41 (0.279 to 0.607)
    Statistical analysis title
    Difference between Reslizumab and Placebo
    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, randomization stratification factors, and number of prior exacerbations as model factors and the logarithm of treatment duration excluding the summed duration of exacerbations in the treatment period as an offset variable.
    Comparison groups
    Placebo v Reslizumab 110 mg
    Number of subjects included in analysis
    464
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.194 [2]
    Method
    Chi-squared
    Parameter type
    CAE rate ratio (reslizumab vs placebo)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.562
         upper limit
    1.124
    Notes
    [1] - A fixed-sequence multiple testing procedure was implemented to test the primary and 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.
    [2] - The treatment effect was tested using the likelihood based Chi-square test at the 0.05 significance level.

    Secondary: Change from Baseline to Week 52 in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1)

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    End point title
    Change from Baseline to Week 52 in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1)
    End point description
    Change in pre-bronchodilator FEV1 from baseline to week 52 is presented. FEV1 is a standard measurement of air movement in the lungs of participants 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. Analysis of the change from baseline to each visit was performed using a mixed effect model for repeated measures (MMRM) including fixed effects for treatment, visit, treatment by visit interaction, age group, blood eosinophil counts at enrollment, and sex, height and baseline value as covariates, and participant as a random effect. ITT includes all randomized participants, excluding participants from the site terminated due to GCP issues. Treatment was based on the treatment to which participants were randomized, regardless of which treatment they received. Overall number of participants analyzed=participants with both baseline and Week 52 FEV1 values available.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    193
    211
    Units: liters
        least squares mean (standard error)
    0.225 ± 0.040
    0.368 ± 0.039
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in Asthma Quality of Life Questionnaire for Participants 12 Years and Older (AQLQ+12) Score

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    End point title
    Change from Baseline to Week 52 in Asthma Quality of Life Questionnaire for Participants 12 Years and Older (AQLQ+12) Score
    End point description
    AQLQ is a 32-item instrument administered as a self-assessment. AQLQ+12 is a modified version of AQLQ developed to measure functional impairments of participants aged 12-70 years. It is divided into 4 domains: activity limitation, symptoms, emotional function, and environmental stimuli. Participants were asked to recall their experiences during the last 2 weeks and respond to each question on a 7-point scale (1=severe impairment, 7=no impairment), where higher scores indicated "better quality of life." Overall AQLQ+12 score is the mean of all 32 responses. Analysis of the change from baseline to each visit was performed using a MMRM including fixed effects for treatment, visit, treatment by visit interaction, age group, blood eosinophil counts at enrollment, and sex, height and baseline value as covariates, and participant as a random effect. ITT population aged 12-70 years. Overall number of participants analyzed=participants with both baseline and Week 52 AQLQ+12 score available.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    188
    197
    Units: units on a scale
        least squares mean (standard error)
    1.06 ± 0.089
    1.14 ± 0.087
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in 6-item Asthma Control Questionnaire (ACQ-6) Score

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    End point title
    Change from Baseline to Week 52 in 6-item Asthma Control Questionnaire (ACQ-6) Score
    End point description
    ACQ-6 is a 6-item asthma assessment tool. 6 questions are self-assessments, 5 assessing asthma symptoms: night waking, symptoms on waking, activity limits, shortness of breath, wheezing, and 1 question for short-acting bronchodilator use. Each item has possible score ranges from 0-6, and total score is mean of all responses. Total score range from 0-6 (0=totally controlled, 6=severely uncontrolled). Higher score=poorer asthma control. Analysis of change from baseline to each visit performed using a MMRM including fixed effects for treatment, visit, treatment by visit interaction, age group, eosinophil count at enrollment, and sex, height and baseline value as covariates, and participant as a random effect. ITT includes all randomized participants, excluding the site terminated due to GCP issues. Treatment based on what participants were randomized to, regardless of which they received. Number of participants analyzed=participants with both baseline and Week 52 ACQ-6 score available.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    197
    212
    Units: units on a scale
        least squares mean (standard error)
    -1.14 ± 0.080
    -1.22 ± 0.078
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in Total Asthma Symptom Scores (Day and Night)

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    End point title
    Change from Baseline to Week 52 in Total Asthma Symptom Scores (Day and Night)
    End point description
    Asthma symptoms recorded by participant each day and night in an asthma diary. Night score assessed on 5-point scale: 0=no symptoms to 4=bad night. Day score assessed on 6-point scale where 0=very well to 5=asthma very severe. Total symptom score calculated by taking the sum of the night and day symptom scores recorded ranging from 0 (no symptom) to 9 (severe symptom). Lower symptom score indicated better outcome. Analysis of the change from baseline to each visit was performed using a MMRM including fixed effects for treatment, visit, treatment by visit interaction, age group, eosinophil count at enrollment, and sex, height and baseline value as covariate, and participant as a random effect. ITT=all randomized participants, excluding from site terminated due to GCP issues. Treatment based on treatment to which participants were randomized, regardless of treatment received. Overall number of participants analyzed=participants with both baseline and Week 52 total asthma symptom score.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    128
    143
    Units: units on a scale
        least squares mean (standard error)
    -1.4 ± 0.12
    -1.5 ± 0.12
    No statistical analyses for this end point

    Secondary: Change from Baseline in Percentage of Asthma Control Days

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    End point title
    Change from Baseline in Percentage of Asthma Control Days
    End point description
    The percentage of asthma control days over 52 weeks of treatment is presented. An asthma control day was defined as a day on which the participant used less than or equal to 2 puffs of inhaled short-acting beta-agonist, had no nighttime awakenings, and experienced no asthma exacerbations. Analysis of the change from baseline to each visit was performed using a mixed effect MMRM including fixed effects for treatment, visit, treatment by visit interaction, age group, blood eosinophil counts at enrollment, and sex, height and baseline value as covariates, and participant as a random effect. ITT population includes all randomized participants, excluding participants from the site terminated due to GCP issues. Treatment was based on the treatment to which participants were randomized, regardless of which treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 52
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    230
    234
    Units: percentage of days
        least squares mean (standard error)
    7.1 ± 1.27
    8.0 ± 1.24
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 32 in St. George’s Respiratory Questionnaire (SGRQ) Total Score

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    End point title
    Change from Baseline to Week 32 in St. George’s Respiratory Questionnaire (SGRQ) Total Score
    End point description
    SGRQ is 17-item questionnaire with 50 weighted responses that provides total score and 3 component scores: Symptoms (distress caused by respiratory symptoms), Activity (physical activities cause/limited by breathlessness), and Impacts (social/psychological effects). Total score and each of the SGRQ subscores are from 0-100 where 0=best, 100=worst health. Increase in score indicates worsening health. Analysis of the change from baseline to each visit was performed using a MMRM including fixed effects for treatment, visit, treatment by visit interaction, age group, eosinophil counts at enrollment, and sex, height and baseline value as covariates, and participant as a random effect. ITT=all randomized participants, excluding site terminated due to GCP issues. Treatment was based on treatment to which participants were randomized, regardless of which treatment they received. Overall number of participants analyzed=participants with both baseline and Week 32 SGRQ total scores available.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 32
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    199
    222
    Units: units on a scale
        least squares mean (standard error)
    -13.1 ± 1.38
    -16.4 ± 1.32
    No statistical analyses for this end point

    Secondary: Kaplan-Meier (K-M) Estimate of Probability (Percent [%]) of Not Experiencing a CAE by Week 52

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    End point title
    Kaplan-Meier (K-M) Estimate of Probability (Percent [%]) of Not Experiencing a CAE by Week 52
    End point description
    CAE defined as deterioration in asthma control, as determined by investigator and new or worsening asthma symptoms based on history, asthma control diary, physical examination, and/or ambulatory/clinic visit assessment of lung function and that resulted in a medical intervention, including 1 of the following: use of systemic corticosteroids or at least a doubling from a stable maintenance oral corticosteroid dose for at least 3 days; asthma-specific hospital admission; asthma-specific ER visit. KM method used to estimate/compare the distributions of time to first CAE between groups. Participants without event during treatment period were censored at either the date of the end of treatment visit for participants who completed treatment or at date of last dose for participants who discontinued. ITT=all randomized participants, excluding site terminated due to GCP issues. Treatment based on treatment to which participants were randomized regardless of which treatment they received.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 52
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    230
    234
    Units: percent probability
        number (confidence interval 95%)
    0.66 (0.59 to 0.72)
    0.66 (0.59 to 0.71)
    No statistical analyses for this end point

    Secondary: Frequency of CAEs Requiring Hospitalization and/or Emergency Department Visits During 52 weeks of Treatment

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    End point title
    Frequency of CAEs Requiring Hospitalization and/or Emergency Department Visits During 52 weeks of Treatment
    End point description
    CAE defined as deterioration in asthma control, as determined by investigator and new or worsening asthma symptoms based on history, asthma control diary, physical examination, and/or ambulatory/clinic visit assessment of lung function and that resulted in a medical intervention, including 1 of the following: use of systemic corticosteroids or at least a doubling from a stable maintenance oral corticosteroid dose for at least 3 days; asthma-specific hospital admission; asthma-specific ER visit. Frequency of CAEs over treatment period expressed as adjusted CAEs rate in 52 weeks. Adjusted CAE rate and CIs based on Negative Binomial regression model adjusted for stratification factors (age group, blood eosinophil group) and number of prior exacerbations, and an offset variable. ITT=all randomized participants, excluding site terminated due to GCP issues. Treatment based on treatment to which participants were randomized regardless of which treatment they received.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 52
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    230
    234
    Units: CAEs in 52 weeks
        number (confidence interval 95%)
    0.05 (0.016 to 0.169)
    0.05 (0.015 to 0.158)
    No statistical analyses for this end point

    Secondary: Frequency of Moderate Exacerbations During 52 Weeks of Treatment

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    End point title
    Frequency of Moderate Exacerbations During 52 Weeks of Treatment
    End point description
    Moderate exacerbation defined as deterioration in asthma control determined by investigator and new/worsening symptoms based on history, asthma diary, physical exam, and/or ambulatory or clinic visit assessment of lung function and that resulted in a medical intervention requiring additional asthma controller medication that was not a systemic corticosteroid and did not result in an asthma-specific hospitalization or ER visit (that is, a medical intervention that did not meet criteria for primary endpoint). Frequency of moderate exacerbations over treatment period expressed as adjusted exacerbation rate in 52 weeks. Adjusted exacerbation rate and CIs based on Negative Binomial regression model adjusted for stratification factors (age group, eosinophil group) and number of prior exacerbations, and offset variable. ITT=all randomized participants, excluding site terminated due to GCP issues. Treatment based on treatment participants were randomized to, regardless of what was received.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 52
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    230
    234
    Units: Number of moderate exacerbations
        number (confidence interval 95%)
    0.15 (0.082 to 0.290)
    0.14 (0.074 to 0.250)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug to the end of treatment visit (Week 52) for completed participants and between the first dose of study drug and 4 weeks after the last dose of study drug for participants who discontinued treatment early.
    Adverse event reporting additional description
    1 participant randomized to the placebo group was treated with reslizumab 110 mg at 1 study visit and counted in the reslizumab 110 mg arm for safety.There were no deaths during the treatment period. 1 death in the reslizumab group occurred 48 days after the participant's last dose.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Reslizumab 110 mg
    Reporting group description
    Reslizumab 110 milligrams (mg) administered subcutaneously once every 4 weeks (+/-7 days) for a total of 13 doses.

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo administered subcutaneously once every 4 weeks (+/-7 days) for a total of 13 doses.

    Serious adverse events
    Reslizumab 110 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 237 (8.02%)
    19 / 231 (8.23%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign tracheal neoplasm
    Additional description: The events of Bronchial neoplasm benign and Benign tracheal neoplasm were reported for the same participant.
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial neoplasm benign
    Additional description: The events of Bronchial neoplasm benign and Benign tracheal neoplasm were reported for the same participant.
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 237 (0.42%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    4 / 237 (1.69%)
    5 / 231 (2.16%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophilic pneumonia
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 237 (0.42%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis noninfective
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reaction to food colouring
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary cirrhosis primary
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 237 (0.00%)
    4 / 231 (1.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 231 (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
    Appendicitis
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 237 (0.42%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 237 (0.84%)
    4 / 231 (1.73%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Reslizumab 110 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    102 / 237 (43.04%)
    97 / 231 (41.99%)
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    9 / 237 (3.80%)
    18 / 231 (7.79%)
         occurrences all number
    15
    25
    Rhinitis allergic
         subjects affected / exposed
    16 / 237 (6.75%)
    12 / 231 (5.19%)
         occurrences all number
    16
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 237 (5.91%)
    10 / 231 (4.33%)
         occurrences all number
    28
    19
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    13 / 237 (5.49%)
    7 / 231 (3.03%)
         occurrences all number
    35
    13
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    14 / 237 (5.91%)
    15 / 231 (6.49%)
         occurrences all number
    16
    19
    Bronchitis
         subjects affected / exposed
    13 / 237 (5.49%)
    17 / 231 (7.36%)
         occurrences all number
    14
    23
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 237 (11.81%)
    19 / 231 (8.23%)
         occurrences all number
    37
    26
    Viral upper respiratory tract infection
         subjects affected / exposed
    27 / 237 (11.39%)
    31 / 231 (13.42%)
         occurrences all number
    45
    42

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2015
    Amendment 1 (04 May 2015) was issued before any participants were enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: 1) The total blood volume was corrected. 2) The AQLQ questionnaire was replaced by the AQLQ+12 Questionnaire.
    25 Jan 2016
    Amendment 2 (25 January 2016) to the protocol was issued after 24 participants were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of the participants already enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: 1) Methods of recording adverse events on the CRF were clarified. 2) SABA therapy was changed to asthma rescue medication. 3) Procedures on discontinuation of study treatment were clarified. 4) The inclusion criteria were amended to encompass a medium and higher daily dose range of ICS per GINA 2015.
    25 Jul 2016
    Amendment 3 (25 July 2016) to the protocol was issued after 368 participants were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of the participants already enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: 1) The total enrollment of the study was increased in order to ensure adequate adolescent enrollment. 2) CPK assessments were added based on a request by Health Authorities. 3) Opportunistic infections were added to the list of protocol-defined adverse events for expedited reporting to Teva; an appendix on opportunistic infections was added.
    24 Oct 2016
    Amendment 4 (24 October 2016) to the protocol was issued after 468 participants were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of the participants already enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: 1) The follow-up visit was changed from 8 to 12 weeks after the EOT as requested by the European Medicines Agency. 2) Adolescents were required to complete the early follow-up visit before starting an open-label extension study.

    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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