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    Clinical Trial Results:
    A Phase 3, 24-Week Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and Safety Study of Reslizumab Subcutaneous Dosing (110 mg Every 4 weeks) in Patients with Oral Corticosteroid Dependent Asthma and Elevated Blood Eosinophils

    Summary
    EudraCT number
    2015-001580-39
    Trial protocol
    CZ   HU   BE   ES   IT   NL   PL   DE  
    Global end of trial date
    04 Dec 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    C38072-AS-30027
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02501629
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Global Branded Pharmaceutical Products R&D, Inc
    Sponsor organisation address
    41 Moores Road, Frazer, Pennsylvania, United States, 19355
    Public contact
    Director, Clinical Research, Teva Global Branded Products R&D, Inc., 01 888-483-8279, info.era-clinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Global Branded Products R&D, Inc., 01 888-483-8279, info.era-clinical@teva.de
    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
    11 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Dec 2017
    Was the trial ended prematurely?
    No
    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 (sc) formulation of reslizumab in patients with oral corticosteroid (OCS) dependent asthma and elevated blood eosinophils. The primary objective of this study is to determine the ability of reslizumab (110 mg) administered subcutaneously (sc) once every 4 weeks to produce a corticosteroid-sparing effect (as demonstrated by percent reduction in daily OCS use) in patients with OCS-dependent asthma and elevated blood eosinophils, without loss of asthma control.
    Protection of trial subjects
    This study was conducted in full accordance with the International Council for Harmonisation’s (ICH) Consolidated Guideline for Good Clinical Practice (GCP) (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 GCP in the conduct of clinical trials on medicinal products for human use). Each investigator was responsible for performing the study in accordance with the protocol, ICH guidelines, and GCP and for collecting, recording, and reporting the data accurately and properly. 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. Written informed consent was obtained from each patient before any study procedures or assessments were done. It was 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. Each patient’s willingness to participate in the study was documented in writing in a consent form that was signed by the patient with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the patients.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Sep 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
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 5
    Country: Number of subjects enrolled
    Mexico: 24
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Ukraine: 47
    Country: Number of subjects enrolled
    United States: 19
    Country: Number of subjects enrolled
    Argentina: 11
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Israel: 11
    Worldwide total number of subjects
    177
    EEA total number of subjects
    48
    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)
    1
    Adults (18-64 years)
    137
    From 65 to 84 years
    39
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 273 patients with OCS-dependent severe eosinophilic asthma were screened, and 180 of these patients (at 78 centers) were considered eligible for enrollment. Three of the eligible patients were not randomized due to failure to meet randomization criteria.

    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, Data analyst
    Blinding implementation details
    Patients were randomly assigned to treatment through an 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. Eosinophils and monocytes were redacted from the post baseline differential cell count reports.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six 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
    Placebo was administered by qualified study personnel as subcutaneous injections in the upper arm(s) once every 4 weeks for a total of 6 doses. Drug was supplied in pre-filled syringes.

    Arm title
    Reslizumab 110 mg
    Arm description
    Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.
    Arm type
    Experimental

    Investigational medicinal product name
    Reslizumab
    Investigational medicinal product code
    Other name
    CEP38072, Cinqair, Cinqaero
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Reslizumab 110 mg was administered by qualified study personnel as subcutaneous injections in the upper arm(s) once every 4 weeks for a total of 6 doses. Drug was supplied in pre-filledsyringes.

    Number of subjects in period 1
    Placebo Reslizumab 110 mg
    Started
    89
    88
    Safety Population
    89
    88
    Intent to Treat (ITT) population
    89
    88
    Completed
    84
    81
    Not completed
    5
    7
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    3
    5
         At request of sponsor
    2
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.

    Reporting group title
    Reslizumab 110 mg
    Reporting group description
    Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.

    Reporting group values
    Placebo Reslizumab 110 mg Total
    Number of subjects
    89 88 177
    Age categorical
    Units: Subjects
        12-<18 years
    1 0 1
        18 to <65 years
    74 63 137
        >=65 years
    14 25 39
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.1 ( 11.99 ) 55.5 ( 12.72 ) -
    Gender categorical
    Units: Subjects
        Female
    57 60 117
        Male
    32 28 60
    Race
    Units: Subjects
        White
    80 72 152
        Black or African American
    1 3 4
        Asian
    3 2 5
        American Indian or Alaska Native
    1 3 4
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Other
    4 8 12
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    72 65 137
        Hispanic or Latino
    16 22 38
        Unknown
    1 1 2
    Geographic Region Group
    Units: Subjects
        U.S. / Canada
    10 9 19
        Europe
    58 47 105
        Other
    21 32 53
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    82.69 ( 18.949 ) 79.58 ( 21.390 ) -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    29.859 ( 6.3499 ) 29.389 ( 8.0105 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.

    Reporting group title
    Reslizumab 110 mg
    Reporting group description
    Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.

    Primary: Categorized Percent Reduction In Daily Oral Corticosteroid (OCS) Dose During Weeks 20-24 As Compared to the Optimized Dose At Baseline

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    End point title
    Categorized Percent Reduction In Daily Oral Corticosteroid (OCS) Dose During Weeks 20-24 As Compared to the Optimized Dose At Baseline
    End point description
    The primary endpoint was the 5-level categorized percent reduction in OCS dose during weeks 20 to 24 compared with the optimized dose at baseline. The primary analysis incorporated data from all randomized patients. Analysis of the primary and secondary variables related to categorical OCS dose reduction incorporated missing data as non-responders. No decrease indicates there was no decrease in OCS, loss of baseline asthma control during weeks 20 to 24, or discontinuation from study drug.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Weeks 20-24
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    89 [1]
    88 [2]
    Units: participants
        90% - 100%
    20
    18
        75% - <90%
    4
    8
        50% - <75%
    8
    13
        >0% - <50%
    9
    7
        No decrease
    48
    42
    Notes
    [1] - ITT
    [2] - ITT
    Statistical analysis title
    OCS Dose Reduction
    Statistical analysis description
    The proportional odds ratio (reslizumab/placebo) was estimated from this model, representing the ratio of the odds of a patient outcome being in a higher OCS dose reduction category for reslizumab compared to placebo.
    Comparison groups
    Placebo v Reslizumab 110 mg
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.468 [3]
    Method
    proportional odds model
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.702
         upper limit
    2.157
    Notes
    [3] - Significance at 0.05. Factors for treatment group and randomization strata (age and OCS dose); baseline OCS dose and duration of OCS use prior to study were covariates.

    Secondary: Percentage of Participants Achieving a >=50% Reduction in OCS dose at Weeks 20-24 Compared to Baseline While Maintaining Asthma Control

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    End point title
    Percentage of Participants Achieving a >=50% Reduction in OCS dose at Weeks 20-24 Compared to Baseline While Maintaining Asthma Control
    End point description
    Percentage of patients whose OCS dose at weeks 20-24 was reduced >=50% compared to baseline while maintaining asthma control. Patients listed as “no” did not achieve the 50% reduction in baseline OCS dose goal, or did achieve that goal but lost asthma control during weeks 20 to 24, or discontinued from study drug.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 20-24
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    89 [4]
    88 [5]
    Units: percentage of participants
    number (not applicable)
        Yes
    36
    44
        No
    64
    56
    Notes
    [4] - ITT
    [5] - ITT
    Statistical analysis title
    OCS Dose Reduction: >=50% from Baseline
    Statistical analysis description
    As the analysis of the primary efficacy endpoint did not meet criteria for statistical significance (p≤0.05), the secondary efficacy endpoints were not interpreted inferentially according to the pre-defined hierarchy. P-values are nominal, meaning they were obtained from the analysis without adjustments to protect family-wise errors and should be interpreted with caution. Nominal p-values do not indicate treatment differences.
    Comparison groups
    Placebo v Reslizumab 110 mg
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.596 [6]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.786
         upper limit
    2.683
    Notes
    [6] - Significance of 0.05. Logistic regression model adjusted for treatment, stratification factors (age group and OCS dose group), duration of OCS use, and baseline value.

    Secondary: Percentage of Participants Achieving an OCS dose of <=5 mg at Weeks 20-24 While Maintaining Asthma Contro

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    End point title
    Percentage of Participants Achieving an OCS dose of <=5 mg at Weeks 20-24 While Maintaining Asthma Contro
    End point description
    Percentage of participants whose OCS dose at weeks 20-24 was <=5 mg and they maintained asthma control. Patients listed as “no” had a week 20-24 OCS dose > 5 mg, or whose OCS dose was <=5 mg at weeks 20-24 but did not maintain asthma control, or they discontinued from study drug.
    End point type
    Secondary
    End point timeframe
    Week 20 - 24
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    89 [7]
    88 [8]
    Units: percentage of participants
    number (not applicable)
        YES
    38
    42
        NO
    62
    58
    Notes
    [7] - ITT
    [8] - ITT
    Statistical analysis title
    OCS Dose <=5 mg
    Statistical analysis description
    As the analysis of the primary efficacy endpoint did not meet criteria for statistical significance (p≤0.05), the secondary efficacy endpoints were not interpreted inferentially according to the pre-defined hierarchy. P-values are nominal, meaning they were obtained from the analysis without adjustments to protect family-wise errors and should be interpreted with caution. Nominal p-values do not indicate treatment differences.
    Comparison groups
    Placebo v Reslizumab 110 mg
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.596 [9]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.631
         upper limit
    2.229
    Notes
    [9] - Significance of 0.05. Logistic regression model adjusted for treatment, stratification factors (age group and OCS dose group), duration of OCS use, and baseline value.

    Secondary: Percentage of Participants Achieving an OCS dose of 0 mg at Weeks 20-24 While Maintaining Asthma Control

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    End point title
    Percentage of Participants Achieving an OCS dose of 0 mg at Weeks 20-24 While Maintaining Asthma Control
    End point description
    Percentage of participants who discontinue use of OCS during weeks 20-24 while maintaining asthma control. Patients listed as “no” continued to use OCS during weeks 20-24, or who discontinued use of OCS during weeks 20-24 but lost control of their asthma, or discontinued from study drug.
    End point type
    Secondary
    End point timeframe
    Weeks 24-26
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    89 [10]
    88 [11]
    Units: percentage of participants
    number (not applicable)
        YES
    22
    20
        NO
    78
    80
    Notes
    [10] - ITT
    [11] - ITT
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving a >=5 mg Reduction in OCS dose at Weeks 20-24 Compared to Baseline While Maintaining Asthma Control

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    End point title
    Percentage of Participants Achieving a >=5 mg Reduction in OCS dose at Weeks 20-24 Compared to Baseline While Maintaining Asthma Control
    End point description
    Percentage of participants whose OCS dose at weeks 20-24 was reduced by at least 5mg from baseline and maintained asthma control. Patients listed as "no" had a week 20-24 OCS dose that did not meet the threshold of a 5mg reduction, or whose OCS dose met the threshold but did not maintain asthma control, or discontinued from study drug.
    End point type
    Secondary
    End point timeframe
    Week 20-24
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    89 [12]
    88 [13]
    Units: percentage of participants
    number (not applicable)
        YES
    35
    41
        NO
    65
    59
    Notes
    [12] - ITT
    [13] - ITT
    Statistical analysis title
    >=5 mg Reduction From Baseline
    Statistical analysis description
    As the analysis of the primary efficacy endpoint did not meet criteria for statistical significance (p≤0.05), the secondary efficacy endpoints were not interpreted inferentially according to the pre-defined hierarchy. P-values are nominal, meaning they were obtained from the analysis without adjustments to protect family-wise errors and should be interpreted with caution. Nominal p-values do not indicate treatment differences.
    Comparison groups
    Placebo v Reslizumab 110 mg
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.341 [14]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.722
         upper limit
    2.562
    Notes
    [14] - Significance at 0.05. Logistic regression model adjusted for treatment, stratification factors (age group and OCS dose group), duration of OCS use, and baseline value.

    Secondary: Annualized Rate of Clinical Asthma Exacerbations (CAEs)

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    End point title
    Annualized Rate of Clinical Asthma Exacerbations (CAEs)
    End point description
    The annual exacerbation rate is based on clinical asthma exacerbations reported by the investigator in the eCRF.
    End point type
    Secondary
    End point timeframe
    Day 1 through Week 24
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    89 [15]
    88 [16]
    Units: CAEs / year
        number (confidence interval 95%)
    1.86 (1.283 to 2.682)
    1.51 (1.052 to 2.177)
    Notes
    [15] - ITT
    [16] - ITT
    Statistical analysis title
    Adjusted CAE Rate
    Comparison groups
    Placebo v Reslizumab 110 mg
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.407 [17]
    Method
    Negative binomial regression model
    Parameter type
    CAE rate ratio
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.504
         upper limit
    1.321
    Notes
    [17] - significance at 0.05. Negative binomial regression model adjusted for stratification factors (OCS dose group), age, number of prior exacerbations, and an offset variable.

    Secondary: Participants with Treatment-Emergent Anti-Drug Antibody (ADA) Responses

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    End point title
    Participants with Treatment-Emergent Anti-Drug Antibody (ADA) Responses
    End point description
    Treatment-emergent responses were defined as a positive sample post-baseline (negative baseline) OR a titer increase of >=4-fold relative to a positive baseline sample. Two types of antibody assay were performed, an immunogenicity status assay (ADA) and neutralizing assay (NAb). The ADA assay produces a positive or negative result. For samples with a positive result, a neutralizing assay was performed, which also produces a positive or negative result.
    End point type
    Secondary
    End point timeframe
    before the administration of study drug at baseline (Day 1), weeks 4, 8, 12, 24 or early withdrawal.
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    89 [18]
    88 [19]
    Units: participants
        Positive ADA samples
    0
    11
        Positive Nab samples
    0
    0
    Notes
    [18] - ITT
    [19] - ITT
    No statistical analyses for this end point

    Secondary: Participants With Adverse Events

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    End point title
    Participants With Adverse Events
    End point description
    An adverse event was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. 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. Treatment-related adverse events or adverse events related to OCS use included events with missing relationship to study drug or OCS use, respectively.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 24 (end of treatment visit); Data were included between Day 1 and Week 24 for completed patients, and Day 1 and 4 weeks after the last dose of study drug for patients who discontinued treatment early.
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    89 [20]
    88 [21]
    Units: participants
        Any treatment-emergent AE
    47
    57
        Treatment-related AE
    3
    7
        Serious AE (SAE)
    4
    10
        Treatment-related SAE
    0
    0
        SAE resulting in death
    0
    1
        AE leading to treatment discontinuation
    1
    0
        AE related to OCS withdrawal
    2
    3
        AE related to OCS use
    2
    5
    Notes
    [20] - Safety analysis set
    [21] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Daily Oral Corticosteroid (OCS) Dose During Weeks 20-24 Using a Mixed Model for Repeated Measures

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    End point title
    Percent Change from Baseline in Daily Oral Corticosteroid (OCS) Dose During Weeks 20-24 Using a Mixed Model for Repeated Measures
    End point description
    The baseline OCS dose is the prescribed optimized OCS dose following the OCS optimization period. Endpoint data are presented using an on-treatment approach. In this context, ‘endpoint’ was defined as the last observation obtained at a scheduled or qualified early termination visit during the treatment period. Weeks 20-24 data is included between the Week 20 dose and Week 24 for completed patients; last dose of study drug to 4 weeks after the last dose of study drug for patients who discontinued treatment early. Measurements collected outside of these defined timeframes are excluded from the analyses. The mixed model repeated measures (MMRM) included fixed effects for treatment, visit, treatment by visit interaction, age group, and OCS dose group, duration of OCS use and baseline value as covariates, and patient as a random effect. Unstructured covariance was assumed for the repeated measures.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 20-24
    End point values
    Placebo Reslizumab 110 mg
    Number of subjects analysed
    83 [22]
    84 [23]
    Units: percent change from baseline
        least squares mean (standard error)
    -40.34 ( 17.318 )
    -58.08 ( 17.633 )
    Notes
    [22] - ITT analysis population with available data using the on-treatment approach.
    [23] - ITT analysis population with available data using the on-treatment approach.
    Statistical analysis title
    % Change OCS
    Statistical analysis description
    Mixed model repeated measures (MMRM) with fixed effects for treatment, visit, treatment by visit interaction, age group, and OCS dose group, duration of OCS use and baseline value as covariates, and patient as a random effect. Unstructured covariance was assumed for the repeated measures.
    Comparison groups
    Reslizumab 110 mg v Placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.101
    Method
    mixed model for repeated measures
    Parameter type
    Mean difference (final values)
    Point estimate
    -17.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -38.986
         upper limit
    3.494
    Variability estimate
    Standard error of the mean
    Dispersion value
    10.759

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Week 24
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.

    Reporting group title
    Reslizumab 110 mg
    Reporting group description
    Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses.

    Serious adverse events
    Placebo Reslizumab 110 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 89 (4.49%)
    10 / 88 (11.36%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (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
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         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
    2 / 89 (2.25%)
    3 / 88 (3.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia bacterial
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 88 (1.14%)
         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 110 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 89 (22.47%)
    20 / 88 (22.73%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 89 (5.62%)
    1 / 88 (1.14%)
         occurrences all number
    5
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    4 / 89 (4.49%)
    5 / 88 (5.68%)
         occurrences all number
    6
    6
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    5 / 89 (5.62%)
    11 / 88 (12.50%)
         occurrences all number
    5
    13
    Bronchitis
         subjects affected / exposed
    4 / 89 (4.49%)
    6 / 88 (6.82%)
         occurrences all number
    4
    6
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 89 (5.62%)
    1 / 88 (1.14%)
         occurrences all number
    5
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2016
    Amendment 1 to the protocol was issued after 2 patients had been enrolled in the study under the original protocol. • The wording for adverse drug reactions, malignancy risk, pregnancy, immunogenicity, and risks of reslizumab was updated based on the most recent data. • The population to be studied was updated to clarify the exclusion of pediatric patients in the Netherlands. • Other pre-specified efficacy endpoints were updated to accommodate inhaled rescue medications other than SABA. • The number of nighttime awakenings due to asthma was updated to make this endpoint more general. • Other pre-specified efficacy measures and time points were revised to clarify that the asthma control diary will measure asthma symptoms, reliever bronchodilator inhalation use, and nighttime awakenings due to asthma on a daily basis. • The table of study procedures and assessments was updated for clarity. • Time of study drug administration was updated because the exact hour is not critical; the study drug is an anti inflammatory drug with a long half-life. • Procedures/assessments to be performed during and after administration of study drug were updated to capture events that occurred during or after study drug administration. • Inclusion criteria were updated to encompass the medium (and higher) daily dose range for a given ICS formulation. • Section 4.5.1 (Discontinuation of Study Treatment) and Section 4.5.2 (Complete Withdrawal from Study) were inserted to clarify discontinuation of study treatment and complete withdrawal from the study. • Section 7.1.7.3.1 (Anaphylaxis/Hypersensitivity Reactions CRF) and Section 7.1.7.3.2 (Creatine Phosphokinase/Muscular Adverse Events CRF) were added to address the reporting of anaphylaxis/hypersensitivity and muscular adverse events, respectively. • An additional blood sample collection to measure serum reslizumab concentrations was added for patients who experienced a serious adverse event... others.....
    18 Jul 2016
    Amendment 2 to the protocol was issued after 44 patients had been enrolled in the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled in the study. • The text for OCS medication in run-in period and eligibility criteria with respect to asthma control was revised. • Information regarding the natural rubber component of the prefilled syringe was added for transparency. • Stopping rules and discontinuation criteria were revised with regard to pregnancy, specifying that the administration of study drug should be discontinued, but the patient does not need to be withdrawn from the study for being pregnant. • Additional language was added to describe reasons for patient withdrawal. • Time points for CPK assessments were added at weeks 4, 8, 16, and 20 to address requests from the Health Authorities. • The inclusion criteria were revised to encompass the medium (and higher) daily dose range for a given ICS formulation (as per GINA 2015). • The schedule of assessments was updated. • Total blood volume was increased to account for additional CPK draws. • Text was added for the reporting of the disease under study as an adverse event. • Serious adverse event definition was updated for alignment between protocol language, adverse event reporting instructions, and processes. • A list of opportunistic infections was included in the protocol to aid in the accurate reporting of potential opportunistic infection adverse events. • Text for CPK/muscular adverse events CSR was updated per request of Health Authority and for overall clarity. • Immunogenicity analysis was updated to accommodate baseline ADA testing in previous placebo patients. • Appendix I (Opportunistic Infections) was added per request of Health Authority

    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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