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    Clinical Trial Results:
    A Phase 2 Placebo-Controlled, Randomized, Double-Blind, Adaptive Dose Trial of the Safety and Efficacy of Inhaled AZD1419 in Adults With Eosinophilic, Moderate to Severe Asthma

    Summary
    EudraCT number
    2016-000977-19
    Trial protocol
    DK   SE   HU   PL  
    Global end of trial date
    25 Sep 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Oct 2019
    First version publication date
    11 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D2500C00003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02898662
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Research and Development, Södertälje, Sweden, SE-151 85
    Public contact
    Global Clinical Lead, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, ClinicalTrialTransparency@astrazeneca.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
    25 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test the hypothesis that inhaled AZD1419 provided sustained asthma control in eosinophilic asthma participants after removal of inhaled corticosteroids (ICS) + long-acting β2 agonist (LABA) medication.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation / Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Oct 2016
    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
    Hungary: 37
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Denmark: 18
    Country: Number of subjects enrolled
    Sweden: 5
    Worldwide total number of subjects
    81
    EEA total number of subjects
    81
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    54
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 16 centers in 4 countries (Hungary, Poland, Denmark and Sweden) between 12 October 2016 and 25 September 2018. Participants with eosinophilic moderate to severe asthma on a maintenance treatment of controller ICS + LABA and no other controller medication were recruited.

    Pre-assignment
    Screening details
    The study had a screening period (2-4 weeks), a 12-week dosing period and an observation period (up to 40 weeks). 81 participants were randomized. Treatment was started at 4 milligram (mg)/week AZD1419 or matching placebo and based on occurrence of flu-like symptoms in the individual participant, the dose was maintained or adapted up or down.

    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
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    AZD1419
    Arm description
    Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.
    Arm type
    Experimental

    Investigational medicinal product name
    AZD1419
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Inhaled AZD1419 once weekly for a 12-week dosing period.

    Arm title
    Placebo
    Arm description
    Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Inhaled placebo once weekly for a 12-week dosing period.

    Number of subjects in period 1
    AZD1419 Placebo
    Started
    40
    41
    Completed Treatment
    25
    29
    Completed
    11
    13
    Not completed
    29
    28
         Subject decision
    1
    -
         Loss of asthma control
    23
    24
         Technical issue
    -
    1
         Adverse event, non-fatal
    1
    -
         Unspecified
    -
    1
         Randomized in error
    -
    1
         Consent withdrawn by subject
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AZD1419
    Reporting group description
    Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.

    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

    Reporting group values
    AZD1419 Placebo Total
    Number of subjects
    40 41 81
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    25 29 54
        From 65-84 years
    15 12 27
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    57.4 ± 13.3 53.3 ± 15.4 -
    Sex: Female, Male
    Units: Subjects
        Female
    22 24 46
        Male
    18 17 35
    Race/Ethnicity, Customized
    Units: Subjects
        White
    40 40 80
        Other
    0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 1 1
        Not Hispanic or Latino
    40 40 80
        Unknown or Not Reported
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    AZD1419
    Reporting group description
    Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.

    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

    Primary: Number of Participants With Events for Time to Loss of Asthma Control (LOAC) up to Week 52 - Cox Regression Analysis

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    End point title
    Number of Participants With Events for Time to Loss of Asthma Control (LOAC) up to Week 52 - Cox Regression Analysis
    End point description
    LOAC was defined as any of the following: • Increase of asthma control questionnaire-5 (ACQ-5) to ≥ 1.5. • ≥ 30% reduction in morning peak expiratory flow (PEF) from baseline on 2 consecutive days. • ≥ 6 additional reliever inhalations of short-acting β agonist (SABA) in a 24-hour period relative to baseline on 2 consecutive days. • Exacerbation requiring systemic corticosteroids as decided by Investigator. Time to LOAC was calculated as start date of first LOAC – date of randomization + 1. Start date of LOAC was latest date that 1 of the 4 criteria were satisfied immediately prior to exacerbation start date, provided no more than 7 days between LOAC and exacerbation start date. Time to LOAC was displayed using a Kaplan-Meier plot and endpoint is presented as number of participants with events, analyzed using the full analysis set (FAS) which included all randomized participants who received any investigational product (IP). Cox regression analysis used to compare treatments.
    End point type
    Primary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    AZD1419 Placebo
    Number of subjects analysed
    40
    41
    Units: participants
    24
    24
    Statistical analysis title
    Time to LOAC
    Statistical analysis description
    Comparison between groups. Cox regression model analysis with age and gender included as covariates.
    Comparison groups
    AZD1419 v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.5722 [2]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    1.87
    Notes
    [1] - The null hypothesis was that during the 52-week double-blind treatment period, the time to LOAC in the AZD1419 arm was equal to the corresponding time to LOAC in the placebo arm. Hazard ratio < 1 favours AZD1419 over placebo.
    [2] - 1-sided p-value

    Secondary: Number of Participants Experiencing LOAC up to Week 52 - Generalized Estimating Equation Analysis

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    End point title
    Number of Participants Experiencing LOAC up to Week 52 - Generalized Estimating Equation Analysis
    End point description
    LOAC was defined as any of the following: • An increase of ACQ-5 to ≥ 1.5. • A ≥ 30% reduction in morning PEF from baseline on 2 consecutive days. • At least 6 additional reliever inhalations of SABA in a 24-hour period relative to baseline on 2 consecutive days. • An exacerbation requiring systemic corticosteroids. Number of participants experiencing LOAC up to Week 52 is presented for the FAS which included all randomized participants who received any IP. A generalized linear model based on a generalized estimating equation was used to compare treatments.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    AZD1419 Placebo
    Number of subjects analysed
    40
    41
    Units: participants
    24
    24
    Statistical analysis title
    Participants with LOAC
    Statistical analysis description
    Comparison between groups. Odds ratio was estimated using a generalized linear model based on a generalized estimating equation approach fitting treatment, visit and age and gender as covariates.
    Comparison groups
    AZD1419 v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2006 [3]
    Method
    Generalized estimating equation analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    4.79
    Notes
    [3] - 2-sided p-value

    Secondary: Least Squares (LS) Mean ACQ-5 Score Over 52 Weeks

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    End point title
    Least Squares (LS) Mean ACQ-5 Score Over 52 Weeks
    End point description
    ACQ-5 questionnaire: participants were asked to recall status of their asthma during the previous week with regards to symptoms for the items: • Awoken at night by asthma symptoms. • Severity of asthma symptoms in the morning. • Limitation of daily activities due to asthma. • Shortness of breath. • Wheeze. ACQ-5 score was computed as unweighted mean of responses to the 5 items, measured on a 7-point scale from 0 (totally controlled) to 6 (severely uncontrolled). A lower score indicated a better outcome. If ACQ-5 reached ≥ 1.5, the participant was reported as having LOAC. Estimates of the LS mean over 52 weeks were analyzed using a repeated measures analysis with treatment, baseline ACQ-5, week and treatment-by-week with participant as random effects, and age and gender as covariates. Baseline was average of non-missing daily measures/scores over last 5 days prior to and including the morning of randomization. The FAS included all randomized participants who received any IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    AZD1419 Placebo
    Number of subjects analysed
    37
    41
    Units: scores on a scale
        least squares mean (standard error)
    0.56 ± 0.07
    0.59 ± 0.07
    Statistical analysis title
    ACQ-5 score
    Statistical analysis description
    Comparison between groups. Repeated measures analysis.
    Comparison groups
    AZD1419 v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8166 [4]
    Method
    Repeated measures analysis
    Parameter type
    LS Mean difference
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.22
         upper limit
    0.17
    Notes
    [4] - 2-sided p-value

    Secondary: LS Mean Asthma Daily Diary Score (Weekly Total) Over 52 Weeks

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    End point title
    LS Mean Asthma Daily Diary Score (Weekly Total) Over 52 Weeks
    End point description
    Asthma symptoms during night-time and daytime were recorded by the participant each morning and evening in the Asthma Daily Diary using a 4-point scale, ranging from 0 to 3, where 0 indicated no asthma symptoms. Asthma symptom daytime score (recorded in evening), night-time score (recorded in morning), and total score were calculated separately. Daily asthma symptom total score was calculated by taking sum of the night-time and daytime asthma symptom scores recorded each day, ranging from 0 to 6. A lower symptom score indicated a better outcome. Estimates of the LS mean over 52 weeks were analyzed using a repeated measures analysis with treatment, baseline asthma daily diary weekly average, week and treatment-by-week with participant as random effects, and age and gender as covariates. Baseline was the average of non-missing daily measures/scores over the last 5 days prior to and including the morning of randomization. The FAS included all randomized participants who received any IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    AZD1419 Placebo
    Number of subjects analysed
    38
    41
    Units: scores on a scale
        least squares mean (standard error)
    0.79 ± 0.10
    0.82 ± 0.10
    Statistical analysis title
    Asthma daily diary score
    Statistical analysis description
    Comparison between groups. Repeated measures analysis.
    Comparison groups
    AZD1419 v Placebo
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8412 [5]
    Method
    Repeated measures analysis
    Parameter type
    LS Mean difference
    Point estimate
    -0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.32
         upper limit
    0.26
    Notes
    [5] - 2-sided p-value

    Secondary: Number of Participants With Events for Time to Moderate Or Severe Exacerbation up to Week 52

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    End point title
    Number of Participants With Events for Time to Moderate Or Severe Exacerbation up to Week 52
    End point description
    Moderate exacerbation was defined as a temporary increase in maintenance therapy to prevent a severe event supported by sustained (≥ 2 day) worsening in at least 1 key control metric ie, asthma score, reliever medication use, night time awakening or morning PEF. Severe exacerbation was defined as a worsening in asthma symptoms and: • Use of systemic corticosteroids for at least 3 days and/or • An unscheduled or emergency room visit due to asthma symptoms requiring systemic corticosteroids and/or • An in-patient hospitalization due to asthma requiring systemic corticosteroids. Time to moderate or severe asthma exacerbation was calculated as start date of first moderate or severe exacerbation – date of randomization + 1. Time to moderate or severe asthma exacerbation was displayed using a Kaplan-Meier plot and the endpoint is presented as number of participants with events, analysed using the FAS which included all randomized participants who received any IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    AZD1419 Placebo
    Number of subjects analysed
    40
    41
    Units: participants
    13
    16
    Statistical analysis title
    Time to moderate or severe exacerbation
    Statistical analysis description
    Comparison between groups. Cox regression model analysis with age and gender included as covariates.
    Comparison groups
    AZD1419 v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    = 0.5477 [7]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    1.67
    Notes
    [6] - The null hypothesis was that the time to moderate or severe exacerbation was not different between AZD1419 and placebo. Hazard ratio < 1 favours AZD1419 over placebo.
    [7] - 2-sided p-value
    Statistical analysis title
    Participants with moderate or severe exacerbation
    Statistical analysis description
    Comparison between groups. Odds ratio was estimated using a generalized linear model based on a generalized estimating equation approach fitting treatment and visit as covariates.
    Comparison groups
    AZD1419 v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7294 [8]
    Method
    Generalized estimating equation analysis
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    1.86
    Notes
    [8] - 2-sided p-value

    Secondary: Percentage of Participants Using Reliever Medication up to Week 52

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    End point title
    Percentage of Participants Using Reliever Medication up to Week 52
    End point description
    The use of SABAs was allowed as rescue medication (reliever bronchodilator) throughout the study. Reliever medication use was captured in the Asthma Daily Diary twice daily (morning and evening), recorded as the number of inhaler puffs. The number of inhalations (puffs) per day was calculated as: number of night inhaler puffs + number of day inhaler puffs. Percentage of participants using reliever medication (SABA) up to Week 52 is presented for the FAS which included all randomized participants who received any IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    AZD1419 Placebo
    Number of subjects analysed
    40
    41
    Units: percentage of participants
    100
    100
    No statistical analyses for this end point

    Secondary: LS Mean Pre- and Post-Bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1) Over 52 Weeks

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    End point title
    LS Mean Pre- and Post-Bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1) Over 52 Weeks
    End point description
    Lung function was assessed by pre- and post-BD FEV1 which was measured by spirometry. To ensure quality control, all spirometry measurements were reviewed to ensure that they met American Thoracic Society / European Respiratory Society criteria for acceptability. Estimates of the LS mean over 52 weeks were analyzed using a repeated measures analysis with treatment, baseline FEV1 (pre- or post-BD, as applicable), visit and treatment-by-visit with participant as random effects, and age and gender as covariates. Baseline was the last non-missing measurement recorded prior to randomization. The FAS included all randomized participants who received any IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    AZD1419 Placebo
    Number of subjects analysed
    37
    39
    Units: Liters
    least squares mean (standard error)
        pre-BD FEV1
    2.24 ± 0.05
    2.18 ± 0.05
        post-BD FEV1
    2.36 ± 0.05
    2.39 ± 0.05
    Statistical analysis title
    Post-BD FEV1
    Statistical analysis description
    Comparison between groups. Repeated measures analysis.
    Comparison groups
    AZD1419 v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7013 [9]
    Method
    Repeated measures analysis
    Parameter type
    LS Mean difference
    Point estimate
    -0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.17
         upper limit
    0.11
    Notes
    [9] - 2-sided p-value
    Statistical analysis title
    Pre-BD FEV1
    Statistical analysis description
    Comparison between groups. Repeated measures analysis.
    Comparison groups
    AZD1419 v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3764 [10]
    Method
    Repeated measures analysis
    Parameter type
    LS Mean difference
    Point estimate
    0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.08
         upper limit
    0.2
    Notes
    [10] - 2-sided p-value

    Secondary: LS Mean Total PEF (Weekly) Over 52 Weeks

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    End point title
    LS Mean Total PEF (Weekly) Over 52 Weeks
    End point description
    Morning and evening PEF measurements were recorded by the participant on a daily basis and then averaged over the week. The weekly average total PEF was calculated by taking the sum of the average of the weekly morning mean and weekly evening mean. Estimates of the LS mean over 52 weeks were analyzed using a repeated measures analysis with treatment, baseline PEF, week and treatment-by-week with participant as random effects, and age and gender as covariates. Baseline was the average of non-missing daily measures/scores over the last 5 days prior to and including the morning of randomization. The FAS included all randomized participants who received any IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    AZD1419 Placebo
    Number of subjects analysed
    38
    41
    Units: Liters/minute
        least squares mean (standard error)
    325.33 ± 5.77
    325.65 ± 5.79
    Statistical analysis title
    Total PEF
    Statistical analysis description
    Comparison between groups. Repeated measures analysis.
    Comparison groups
    AZD1419 v Placebo
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9686 [11]
    Method
    Repeated measures analysis
    Parameter type
    LS Mean difference
    Point estimate
    -0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.54
         upper limit
    15.9
    Notes
    [11] - 2-sided p-value

    Secondary: LS Mean Fractional Exhaled Nitric Oxide (FeNO) (Weekly) Over 52 Weeks

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    End point title
    LS Mean Fractional Exhaled Nitric Oxide (FeNO) (Weekly) Over 52 Weeks
    End point description
    FeNO measurements were taken at home by participants every second day. The weekly average FeNO was based on the average of measurements taken at home for a specific week. Estimates of the LS mean over 52 weeks were analyzed using a repeated measures analysis with treatment, baseline FeNO, week and treatment-by-week with participant as random effects, and age and gender as covariates. Baseline was the average of non-missing daily measures/scores over the last 5 days prior to and including the morning of randomization. The FAS included all randomized participants who received any IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    AZD1419 Placebo
    Number of subjects analysed
    35
    38
    Units: parts per billion
        least squares mean (standard error)
    33.26 ± 2.33
    35.28 ± 2.33
    Statistical analysis title
    FeNO
    Statistical analysis description
    Comparison between groups. Repeated measures analysis.
    Comparison groups
    AZD1419 v Placebo
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5403 [12]
    Method
    Repeated measures analysis
    Parameter type
    LS Mean difference
    Point estimate
    -2.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.55
         upper limit
    4.52
    Notes
    [12] - 2-sided p-value

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of IP (Week 0) up to Week 52.
    Adverse event reporting additional description
    The safety analysis set included all participants who received any IP.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received placebo for inhalation via nebuliser solution (up to 13 doses). All participants received placebo to match 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of placebo on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving placebo dose 10.

    Reporting group title
    AZD1419
    Reporting group description
    Participants received AZD1419 for inhalation via nebuliser solution (up to 13 doses). All participants received 4 mg AZD1419 once weekly for 4 doses. The following 9 doses were adapted based on tolerability (severity of flu-like symptoms). Participants were prescribed their usual controller medication (ICS + LABA) in separate inhalers. During the dosing period, controller medications were gradually reduced and discontinued. Treatment was initiated with 6 doses of AZD1419 on top of the participant's controller medication, LABA was then stopped on the evening prior to receiving dose 7, and ICS was gradually tapered down and discontinued during the next 3 weeks before being discontinued in the evening prior to receiving AZD1419 dose 10.

    Serious adverse events
    Placebo AZD1419
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 40 (7.50%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Pulmonary eosinophilia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigger finger
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         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 AZD1419
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 41 (26.83%)
    22 / 40 (55.00%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 41 (0.00%)
    5 / 40 (12.50%)
         occurrences all number
    0
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 41 (9.76%)
    6 / 40 (15.00%)
         occurrences all number
    10
    9
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 41 (2.44%)
    6 / 40 (15.00%)
         occurrences all number
    1
    13
    Pyrexia
         subjects affected / exposed
    1 / 41 (2.44%)
    10 / 40 (25.00%)
         occurrences all number
    1
    22
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 40 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 41 (2.44%)
    6 / 40 (15.00%)
         occurrences all number
    2
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 41 (14.63%)
    5 / 40 (12.50%)
         occurrences all number
    8
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Oct 2016
    Reasons for amendment: • To include additional study background information in the section for benefit/risk analysis. • To modify visit windows within the study design figure. • Inclusion criterion 3: controller medication clarified. • Exclusion criterion 2: clarification of the timing of the last dose of immunotherapy. • ICS, LABA and SABA restrictions were added to list of restrictions. • Clarification of timing of FEV1 measurement to schedule of events table. • Clarification regarding the timing of influenza vaccination for the dose adaption procedure. • Clarification to the timing of FEV1 measurements for the composite endpoint for exacerbations. • Clarification of urinalysis parameters to be measured for laboratory safety 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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