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    Clinical Trial Results:
    A Randomized, Open-Label, Two Period Crossover, Chronic Dosing, 1-Week, Pilot Study to Assess the Efficacy and Safety of Budesonide and Formoterol Fumarate Inhalation Aerosol Administered with a Spacer Compared with Symbicort® Turbuhaler® in Subjects with Severe to Very Severe Chronic Obstructive Pulmonary Disease and Low Peak Inspiratory Flow

    Summary
    EudraCT number
    		 2019-001801-26
    Trial protocol
    		 DE  
    Global end of trial date
    30 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5980C00023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04078126
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Pepparedsleden 1, Molndal, Sweden,
    Public contact
    AstraZeneca AB, AstraZeneca AB, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    AstraZeneca AB, AstraZeneca AB, +1 8772409479, information.center@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
    18 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effects of Budesonide/ Formoterol Fumarate (BFF) MDI administered with a spacer relative to Symbicort Turbuhaler on lung function.
    Protection of trial subjects
    Ventolin HFA was provided throughout the study for subjects to take as needed for relief of symptoms.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Sep 2019
    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
    Germany: 35
    Worldwide total number of subjects
    35
    EEA total number of subjects
    35
    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)
    11
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study randomized 35 subjects at 4 study centers from Jan 2020 to Dec 2020.

    Pre-assignment
    Screening details
    		 Subjects were randomized to an open-label, 2 period crossover study comparing BFF MDI administered with a spacer BID with Symbicort Turbuhaler BID. The subjects underwent an intervening two-week washout period where they used Berodual and budesonide MDI BID.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    All subjects randomized

    Arms
    Arm title
    		 Overall Study
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Symbicort Turbohaler
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Symbicord Turbohaler 320/9 µg

    Investigational medicinal product name
    Budesonide and Formoterol Fumarate Metered Dose Inhalation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    BFF MDI 320/9.6 µg

    Number of subjects in period 1
    		Overall Study
    Started
    35
    Completed
    31
    Not completed
    4
         Study put on hold due to COVID-19
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 35 35
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 11 11
        From 65-84 years
    		 24 24
        85 years and over
    		 0 0
    Age Continuous
    ITT Population; mean age in years
    Units: Years
        arithmetic mean (standard deviation)
    		 65.8 ± 5.5 -
    Sex: Female, Male
    ITT Population; Gender Distribution
    Units: Participants
        Female
    		 19 19
        Male
    		 16 16
    Race (NIH/OMB)
    ITT Population; Race distribution
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 35 35
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0
    Subject analysis sets

    Subject analysis set title
    BFF MDI - mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the ITT Population with post-baseline spirometry data from both treatment periods at Visits 4 and 6.

    Subject analysis set title
    Symbicort Turbuhaler - mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the ITT Population with post-baseline spirometry data from both treatment periods at Visits 4 and 6.

    Subject analysis set title
    BFF MDI - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who were randomised to treatment and received at least one dose of study treatment

    Subject analysis set title
    Symbicort Turbuhaler - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who were randomised to treatment and received at least one dose of study treatment

    Subject analysis sets values
    		 BFF MDI - mITT Symbicort Turbuhaler - mITT BFF MDI - ITT Symbicort Turbuhaler - ITT
    Number of subjects
    30
    30
    33
    35
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    6
    6
    9
    11
        From 65-84 years
    24
    24
    24
    24
        85 years and over
    0
    0
    0
    0
    Age Continuous
    ITT Population; mean age in years
    Units: Years
        arithmetic mean (standard deviation)
    66.5 ± 4.7
    65.8 ± 5.5
    66.9 ± 4.8
    66.9 ± 4.8
    Sex: Female, Male
    ITT Population; Gender Distribution
    Units: Participants
        Female
    15
    15
    17
    19
        Male
    15
    15
    16
    16
    Race (NIH/OMB)
    ITT Population; Race distribution
    Units: Subjects
        American Indian or Alaska Native
    0
    0
    0
    0
        Asian
    0
    0
    0
    0
        Native Hawaiian or Other Pacific Islander
    0
    0
    0
    0
        Black or African American
    0
    0
    0
    0
        White
    30
    30
    33
    35
        More than one race
    0
    0
    0
    0
        Unknown or Not Reported
    0
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Subject analysis set title
    BFF MDI - mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the ITT Population with post-baseline spirometry data from both treatment periods at Visits 4 and 6.

    Subject analysis set title
    Symbicort Turbuhaler - mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects in the ITT Population with post-baseline spirometry data from both treatment periods at Visits 4 and 6.

    Subject analysis set title
    BFF MDI - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who were randomised to treatment and received at least one dose of study treatment

    Subject analysis set title
    Symbicort Turbuhaler - ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who were randomised to treatment and received at least one dose of study treatment

    Primary: Peak change from baseline in FEV1 within 4 hours post-dose following 1 week of treatment

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    End point title
    		 Peak change from baseline in FEV1 within 4 hours post-dose following 1 week of treatment [1]
    End point description
    Peak change from baseline in FEV1 within 4 hours post-dose was defined as the maximum of the FEV1 assessments within 4 hours post-dosing at each visit minus baseline, provided that there were at least 2 non-missing values during the first 4 hours post dose.
    End point type
    Primary
    End point timeframe
    4 hours post dose after 1 week of treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This was a pilot study with no formal statistical hypothesis tests. It was to further inform the design and sample size of potential future studies. Improvements due to each treatment relative to baseline were interpreted using the confidence intervals reported.
    End point values
    		 BFF MDI - mITT Symbicort Turbuhaler - mITT
    Number of subjects analysed
    30 [2]
    30 [3]
    Units: Litre
        least squares mean (confidence interval 95%)
    0.256 (0.190 to 0.322)
    0.274 (0.208 to 0.340)
    Notes
    [2] - mITT used for analysis
    [3] - mITT used for analysis
    No statistical analyses for this end point

    Secondary: Area under the curve for change from baseline in FEV1 from 0 to 4 hours (AUC0-4 h) following 1 week of treatment

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    End point title
    		 Area under the curve for change from baseline in FEV1 from 0 to 4 hours (AUC0-4 h) following 1 week of treatment
    End point description
    FEV1 AUC0-4 was calculated using the trapezoidal rule and was normalized by dividing by the time in hours from dosing to the last measurement included (typically 4 hours).
    End point type
    Secondary
    End point timeframe
    0 to 4 hours post dose after 1 week of treatment
    End point values
    		 BFF MDI - mITT Symbicort Turbuhaler - mITT
    Number of subjects analysed
    30 [4]
    30 [5]
    Units: Litre
        least squares mean (confidence interval 95%)
    0.194 (0.133 to 0.254)
    0.210 (0.149 to 0.271)
    Notes
    [4] - mITT used for analysis
    [5] - mITT used for analysis
    No statistical analyses for this end point

    Secondary: Change from baseline in pre-dose FEV1 following 1 week of treatment

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    End point title
    		 Change from baseline in pre-dose FEV1 following 1 week of treatment
    End point description
    Change from baseline in pre-dose FEV1 following 1 week of treatment was defined as the 45-minute pre-dose value following 1 week of treatment minus baseline.
    End point type
    Secondary
    End point timeframe
    1 week of treatment
    End point values
    		 BFF MDI - mITT Symbicort Turbuhaler - mITT
    Number of subjects analysed
    30 [6]
    30 [7]
    Units: Litre
        least squares mean (confidence interval 95%)
    0.081 (0.030 to 0.131)
    0.087 (0.037 to 0.137)
    Notes
    [6] - mITT used for analysis
    [7] - mITT used for analysis
    No statistical analyses for this end point

    Secondary: Change from baseline in 2-hour post-dose inspiratory capacity (IC) following 1 week of treatment

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    End point title
    		 Change from baseline in 2-hour post-dose inspiratory capacity (IC) following 1 week of treatment
    End point description
    Change from baseline in 2-hour post-dose IC following 1 week of treatment was defined as the 2-hour post-dose assessment of IC following 1 week of treatment minus baseline IC.
    End point type
    Secondary
    End point timeframe
    2 hours post dose after 1 week of treatment
    End point values
    		 BFF MDI - mITT Symbicort Turbuhaler - mITT
    Number of subjects analysed
    30 [8]
    30 [9]
    Units: Litre
        least squares mean (confidence interval 95%)
    0.379 (0.242 to 0.517)
    0.411 (0.275 to 0.548)
    Notes
    [8] - mITT used for analysis
    [9] - mITT used for analysis
    No statistical analyses for this end point

    Secondary: Change from baseline in pre-dose PIF (InCheck device set to no resistance) following 1 week of treatment

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    End point title
    		 Change from baseline in pre-dose PIF (InCheck device set to no resistance) following 1 week of treatment
    End point description
    Change from baseline in pre-dose PIF (InCheck device set to no resistance) following 1 week of treatment was defined as the pre-dose PIF (InCheck device set to no resistance) following 1 week of treatment minus baseline PIF.
    End point type
    Secondary
    End point timeframe
    1 week of treatment
    End point values
    		 BFF MDI - mITT Symbicort Turbuhaler - mITT
    Number of subjects analysed
    30 [10]
    30 [11]
    Units: Litre/min
        least squares mean (confidence interval 95%)
    1.50 (-2.26 to 5.27)
    5.11 (1.34 to 8.88)
    Notes
    [10] - mITT used for analysis
    [11] - mITT used for analysis
    No statistical analyses for this end point

    Secondary: Change from baseline in pre-dose PIF (resistance set equal to Turbohaler S) following 1 week of treatment

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    End point title
    		 Change from baseline in pre-dose PIF (resistance set equal to Turbohaler S) following 1 week of treatment
    End point description
    Change from baseline in pre-dose PIF (resistance set equal to Turbohaler S) following 1 week of treatment was defined as the pre-dose PIF (resistance set equal to Turbohaler S) following 1 week of treatment minus baseline PIF.
    End point type
    Secondary
    End point timeframe
    1 week of treatment
    End point values
    		 BFF MDI - mITT Symbicort Turbuhaler - mITT
    Number of subjects analysed
    30 [12]
    30 [13]
    Units: Litre/min
        least squares mean (confidence interval 95%)
    1.13 (-0.78 to 3.03)
    3.82 (1.91 to 5.72)
    Notes
    [12] - mITT used for analysis
    [13] - mITT used for analysis
    No statistical analyses for this end point

    Secondary: Change from baseline in pre-dose PIF (resistance set equal to ELLIPTA) following 1 week of treatment

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    End point title
    		 Change from baseline in pre-dose PIF (resistance set equal to ELLIPTA) following 1 week of treatment
    End point description
    Change from baseline in pre-dose PIF (resistance set equal to ELLIPTA) following 1 week of treatment was defined as the pre-dose PIF (resistance set equal to ELLIPTA) following 1 week of treatment minus baseline PIF.
    End point type
    Secondary
    End point timeframe
    1 week of treatment
    End point values
    		 BFF MDI - mITT Symbicort Turbuhaler - mITT
    Number of subjects analysed
    30 [14]
    30 [15]
    Units: Litre/min
        least squares mean (confidence interval 95%)
    1.21 (-1.15 to 3.56)
    2.74 (0.39 to 5.09)
    Notes
    [14] - mITT used for analysis
    [15] - mITT used for analysis
    No statistical analyses for this end point

    Secondary: Change from baseline in 2-hour post-dose FEV1 following the first dose

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    End point title
    		 Change from baseline in 2-hour post-dose FEV1 following the first dose
    End point description
    Change from baseline in 2-hour post-dose FEV1 following the 1st dose of treatment was defined as the 2-hour post-dose assessment of FEV1 following the 1st dose of treatment (Visit 3 or 5) minus baseline FEV1.
    End point type
    Secondary
    End point timeframe
    1 day (2 hours)
    End point values
    		 BFF MDI - mITT Symbicort Turbuhaler - mITT
    Number of subjects analysed
    30 [16]
    30 [17]
    Units: Litre
        least squares mean (confidence interval 95%)
    0.136 (0.100 to 0.173)
    0.093 (0.057 to 0.130)
    Notes
    [16] - mITT used for analysis
    [17] - mITT used for analysis
    No statistical analyses for this end point

    Secondary: Change from baseline in 2-hour post-dose IC following the first dose

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    End point title
    		 Change from baseline in 2-hour post-dose IC following the first dose
    End point description
    Change from baseline in 2-hour post-dose IC following the 1st dose of treatment was defined as the 2-hour post-dose assessment of IC following the 1st dose of treatment (Visit 3 or 5) minus baseline IC.
    End point type
    Secondary
    End point timeframe
    1 day (2 hours)
    End point values
    		 BFF MDI - mITT Symbicort Turbuhaler - mITT
    Number of subjects analysed
    30 [18]
    30 [19]
    Units: Litre
        least squares mean (confidence interval 95%)
    0.264 (0.164 to 0.363)
    0.258 (0.161 to 0.356)
    Notes
    [18] - mITT used for analysis
    [19] - mITT used for analysis
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious adverse events were collected from Randomization throughout the Treatment Period and including the washout and follow-up periods.
    Adverse event reporting additional description
    The Safety Population was defined as all subjects who were randomized to treatment and received at least one dose of study treatment. Subjects were analyzed according to the treatment actually received. Serious adverse events were recorded from the time of signing of the informed consent form.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Symbicort Turbuhaler
    Reporting group description
    		 Subject treated with Symbicort Turbuhaler

    Reporting group title
    BFF MDI
    Reporting group description
    		 Subject treated with BFF MDI

    Serious adverse events
    		 Symbicort Turbuhaler BFF MDI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 33 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Symbicort Turbuhaler BFF MDI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 33 (3.03%)
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Aug 2020
    Most revisions in the amendment address the impact of study hold and re-start during the COVID-19 pandemic and related local advisories.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Mar 2020
    COVID-19 pandemic-related events
    17 Sep 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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