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    Clinical Trial Results:
    A randomized, double blind, parallel-group study with use of budesonide/formoterol “as needed”, or terbutaline “as needed” or regular use of budesonide + terbutaline “as needed”, in patients mild intermittent asthma and exercise induced bronchoconstriction.

    Summary
    EudraCT number
    		 2009-012805-20
    Trial protocol
    		 SE  
    Global end of trial date
    03 May 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Feb 2017
    First version publication date
    31 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5890L00032
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    AstraZeneca R&D, S-221 87 Lund, Sweden,
    Public contact
    Lars - Göran Carlsson, MD, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Lars - Göran Carlsson, MD, 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
    03 May 2011
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 May 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    03 May 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the protective effect of the combination of budesonide and formoterol on an as needed basis compared to as needed use of terbutaline on EIB in adults and adolescents with mild intermittent asthma. This was evaluated by measuring maximum post-exercise fall in FEV1 before and after 6 weeks of treatment.
    Protection of trial subjects
    The final Study Protocol, including the final version of the Master Informed Consent Form, was approved or given a favourable opinion in writing by an Independent Ethics Committee (IEC). The participating physicians were to submit written approval to AstraZeneca before they enrolled any patient into the Study, as local regulations require. The participating physician at each centre ensured that the patient and, if applicable, parent/legal guardian was given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the Patient Follow-up Programme. They were notified that it was possible to discontinue from the programme at any time and were given the opportunity to ask questions and allowed time to consider the information provided. The participating physician obtained and documented the patient’s or the legal guardians signed and dated informed consent before conducting any procedure specifically for the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Sep 2009
    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
    Norway: 7
    Country: Number of subjects enrolled
    Sweden: 59
    Worldwide total number of subjects
    66
    EEA total number of subjects
    66
    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)
    13
    Adults (18-64 years)
    51
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 On Visit 1, a total of 189 patients, aged 12-67, were enrolled at 10 study sites in 2 countries: Sweden and Norway. Of 189 enrolled patients, 66 patients were randomized and allocated to study treatment on Visit 3 (7 patients in Norway and 59 patients in Sweden).

    Pre-assignment
    Screening details
    		 A standardized exercise test (ECT) with duration of 6 minutes, at approximately 90% of maximal aerobic capacity (as defined on Visit 1) was performed on a treadmill while breathing dry air on Visit 2. Patients with exercised induced bronchoconstriction (defined as fall in FEV1 ≥ 10% ) could be randomized on Visit 3.

    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
    		 Budesonide/terbutaline
    Arm description
    		 Budesonide once daily and terbutaline before exercise and as needed
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide 400 + terbutaline 0.4 mg as needed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Budesonide 400 + terbutaline 0.4 mg as needed

    Arm title
    		 Terbutaline
    Arm description
    		 Placebo budesonide once daily and terbutaline before exercise and as needed
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Terbutaline 0.4 mg as needed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Terbutaline 0.4 mg as needed

    Arm title
    		 Budesonide/formoterol
    Arm description
    		 Placebo budesonide once daily and budesonide/formoterol before exercise and as needed
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide/formoterol 160/4.5 ug mg as needed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Budesonide/formoterol 160/4.5 ug mg as needed

    Number of subjects in period 1
    		Budesonide/terbutaline Terbutaline Budesonide/formoterol
    Started
    21
    22
    23
    Completed
    19
    19
    21
    Not completed
    2
    3
    2
         Consent withdrawn by subject
    -
    -
    1
         Incorrectly randomized
    1
    -
    -
         Lost to follow-up
    -
    1
    -
         Protocol deviation
    1
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Budesonide/terbutaline
    Reporting group description
    		 Budesonide once daily and terbutaline before exercise and as needed

    Reporting group title
    Terbutaline
    Reporting group description
    		 Placebo budesonide once daily and terbutaline before exercise and as needed

    Reporting group title
    Budesonide/formoterol
    Reporting group description
    		 Placebo budesonide once daily and budesonide/formoterol before exercise and as needed

    Reporting group values
    		 Budesonide/terbutaline Terbutaline Budesonide/formoterol Total
    Number of subjects
    		 21 22 23 66
    Age Categorical
    Units: Participants
        <=18 years
    		 6 4 3 13
        Between 18 and 65 years
    		 15 17 19 51
        >=65 years
    		 0 1 1 2
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 25.9 (12.3 to 47.1) 28 (15.7 to 66.6) 30.8 (13.4 to 67.5) -
    Gender, Male/Female
    Units: Participants
        Female
    		 11 16 9 36
        Male
    		 10 6 14 30

    End points

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    End points reporting groups
    Reporting group title
    Budesonide/terbutaline
    Reporting group description
    		 Budesonide once daily and terbutaline before exercise and as needed

    Reporting group title
    Terbutaline
    Reporting group description
    		 Placebo budesonide once daily and terbutaline before exercise and as needed

    Reporting group title
    Budesonide/formoterol
    Reporting group description
    		 Placebo budesonide once daily and budesonide/formoterol before exercise and as needed

    Primary: Percent change in maximum post-exercise forced expiratory volume in one second (FEV1) fall after 6 weeks

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    End point title
    		 Percent change in maximum post-exercise forced expiratory volume in one second (FEV1) fall after 6 weeks
    End point description
    FEV1
    End point type
    Primary
    End point timeframe
    Baseline and Visit 6
    End point values
    		 Budesonide/terbutaline Terbutaline Budesonide/formoterol
    Number of subjects analysed
    20
    21
    21
    Units: Percent change
        arithmetic mean (standard deviation)
    -5.85 ( 6.5 )
    0.61 ( 10.92 )
    -5.24 ( 9.64 )
    Statistical analysis title
    		 Change in FEV1
    Comparison groups
    Budesonide/terbutaline v Budesonide/formoterol
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 ANCOVA
    Parameter type
    		 LSMean Difference
    Point estimate
    -1.24
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -5.95
         upper limit
    		 -
    Notes
    [1] - The pre-defined non-inferiority limit was specified to be 7.28%
    Statistical analysis title
    		 Change in FEV1
    Comparison groups
    Terbutaline v Budesonide/formoterol
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.017
    Method
    		 ANCOVA
    Parameter type
    		 LSMean difference
    Point estimate
    6.9278
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.31
         upper limit
    		 12.55
    Statistical analysis title
    		 Change in FEV1
    Comparison groups
    Budesonide/terbutaline v Terbutaline
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0026
    Method
    		 ANCOVA
    Parameter type
    		 LSMean difference
    Point estimate
    8.0994
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.953
         upper limit
    		 13.25

    Secondary: Percent change in maximum post-exercise FEV1 fall after 3 weeks

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    End point title
    		 Percent change in maximum post-exercise FEV1 fall after 3 weeks
    End point description
    FEV1
    End point type
    Secondary
    End point timeframe
    Baseline and 3 weeks
    End point values
    		 Budesonide/terbutaline Terbutaline Budesonide/formoterol
    Number of subjects analysed
    20
    21
    21
    Units: Percent change
        arithmetic mean (standard deviation)
    -4.07 ( 5.56 )
    -1.19 ( 8.03 )
    -3.81 ( 8.68 )
    Statistical analysis title
    		 Percent change in max post-exercise FEV1
    Comparison groups
    Terbutaline v Budesonide/formoterol
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1131
    Method
    		 ANCOVA
    Parameter type
    		 LSMean Difference
    Point estimate
    3.5528
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.88
         upper limit
    		 7.986
    Statistical analysis title
    		 Percent change in max post-exercise FEV1
    Comparison groups
    Budesonide/terbutaline v Terbutaline
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0509
    Method
    		 ANCOVA
    Parameter type
    		 LSMean Difference
    Point estimate
    4.0277
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 8.433

    Secondary: Bronchial responsiveness to mannitol

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    End point title
    		 Bronchial responsiveness to mannitol
    End point description
    Change in cumulative Mannitol dose in mg in patients with a positive mannitol provocation test at baseline (PD15)
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks
    End point values
    		 Budesonide/terbutaline Terbutaline Budesonide/formoterol
    Number of subjects analysed
    11
    6
    5
    Units: mg
        arithmetic mean (standard deviation)
    67.26 ( 141.98 )
    -6.15 ( 95.1 )
    151.87 ( 141.09 )
    No statistical analyses for this end point

    Secondary: Concentration of exhaled nitric oxide

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    End point title
    		 Concentration of exhaled nitric oxide
    End point description
    Fraction of exhaled nitric oxide at 6 weeks. 3 attempts are made by the patient and the mean of these values is recorded.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Budesonide/terbutaline Terbutaline Budesonide/formoterol
    Number of subjects analysed
    19
    18
    21
    Units: ppb
        arithmetic mean (standard deviation)
    25.9 ( 20.1 )
    35.5 ( 36.6 )
    24.4 ( 22.4 )
    No statistical analyses for this end point

    Secondary: Use of as-needed medication before exercise and as-needed

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    End point title
    		 Use of as-needed medication before exercise and as-needed
    End point description
    Mean number of as needed inhalations taken before exercise and as needed.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Budesonide/terbutaline Terbutaline Budesonide/formoterol
    Number of subjects analysed
    20
    20
    21
    Units: number of inhalations per day
        arithmetic mean (standard deviation)
    0.8 ( 0.7 )
    0.9 ( 0.5 )
    0.8 ( 0.5 )
    No statistical analyses for this end point

    Secondary: Asthma control measured by a 5-item asthma control questionnaire (ACQ5)

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    End point title
    		 Asthma control measured by a 5-item asthma control questionnaire (ACQ5)
    End point description
    Change in overall ACQ5. ACQ5 measures asthma control and a lower values shows a better asthma control, a higher value is worse. A decrease in the ACQ5 shows an improvement during the treatment period. Range of ACQ5 is 0-5, with 0 as the best value and 5 as the worst value. Further information at www.qoltech.co.uk.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks
    End point values
    		 Budesonide/terbutaline Terbutaline Budesonide/formoterol
    Number of subjects analysed
    20
    21
    22
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.3 ( 0.7 )
    -0.2 ( 0.8 )
    -0.4 ( 0.7 )
    Statistical analysis title
    		 Change in ACQ5
    Comparison groups
    Terbutaline v Budesonide/formoterol
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3724
    Method
    		 ANCOVA
    Parameter type
    		 LSMean differnce
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.55
    Statistical analysis title
    		 change in ACQ5
    Comparison groups
    Budesonide/terbutaline v Terbutaline
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3623
    Method
    		 ANCOVA
    Parameter type
    		 LSMean difference
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.56

    Secondary: Diary recording of asthma symptoms

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    End point title
    		 Diary recording of asthma symptoms
    End point description
    Asthma symptoms during days with exercise
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Budesonide/terbutaline Terbutaline Budesonide/formoterol
    Number of subjects analysed
    20
    20
    21
    Units: Percent of exercise days
        arithmetic mean (standard deviation)
    51.1 ( 30.5 )
    50.9 ( 36.6 )
    49.8 ( 26.1 )
    Statistical analysis title
    		 Diary recording of asthma symptoms
    Statistical analysis description
    Asthma symptoms during days with exercise
    Comparison groups
    Terbutaline v Budesonide/formoterol
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9078
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    1.112
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18
         upper limit
    		 20.3
    Statistical analysis title
    		 Diary recordings of asthma symptoms
    Statistical analysis description
    Asthma symptoms during days with exercise
    Comparison groups
    Budesonide/terbutaline v Terbutaline
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9844
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20
         upper limit
    		 19.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the enrolment visit (visit 1) until visit 6 (42 days after randomisation). Only AEs occuring on or after first dose of study medication are inluded in the summaries below.
    Adverse event reporting additional description
    A total of 27 patients reported non-serious adverse events; 8 on Budesonide/terbutaline, 9 on Terbutaline, 10 on Budesonide/formoterol. Numbers for non-serious AEs in the reporting group table are based on the 5% threshold frequency.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Budesonide/terbutaline
    Reporting group description
    		 Budesonide once daily and terbutaline before exercise and as needed

    Reporting group title
    Terbutaline
    Reporting group description
    		 Placebo budesonide once daily and terbutaline before exercise and as needed

    Reporting group title
    Budesonide/formoterol
    Reporting group description
    		 Placebo budesonide once daily and budesonide/formoterol before exercise and as needed

    Serious adverse events
    		 Budesonide/terbutaline Terbutaline Budesonide/formoterol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    0 / 23 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Budesonide/terbutaline Terbutaline Budesonide/formoterol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 21 (28.57%)
    10 / 22 (45.45%)
    10 / 23 (43.48%)
    Injury, poisoning and procedural complications
    Fall
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    1 / 23 (4.35%)
         occurrences all number
    0
    0
    2
    General disorders and administration site conditions
    Headache
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 22 (9.09%)
    0 / 23 (0.00%)
         occurrences all number
    1
    2
    0
    Slight Fever
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 22 (4.55%)
    0 / 23 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrointestinal disorders
    Gastroenteritis
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 22 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    1
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 22 (13.64%)
    1 / 23 (4.35%)
         occurrences all number
    0
    3
    1
    Sore throat
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 22 (0.00%)
    4 / 23 (17.39%)
         occurrences all number
    0
    0
    4
    Infections and infestations
    Common cold
    alternative dictionary used: MedDRA 10.0
         subjects affected / exposed
    5 / 21 (23.81%)
    7 / 22 (31.82%)
    4 / 23 (17.39%)
         occurrences all number
    5
    7
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jul 2009
    Further explanations/ changes regarding the Maximal exercise test, ECT and Mannitol challenge. The leaning would not be more then up to 10% during the aximal exercise test. The standardized exercise test would be at 90% of maximal aerobic capacity instead of 80%, since this were active patients and well trained. The measurement of FEV1 at baseline (pre test) would always be 3, but during a test this was too much for the patient, and therefore we made these changes. ATS had new guidelines regarding FENO - measurement. It was enough with 2 measurements instead of 3. Clarification regarding leukotriene antagonists taken before randomisation was needed
    11 Dec 2009
    Clarification regarding coffee and other drinks with caffeine before visits. A clarification regarding which reference value should be used for children since European Community for Steel and Coal is limited to adults. A reversibility test will be allowed at visit 1 for those patients with FEV1 ≥75.0% but <80.0% of predicted normal value. Since most of the sites are using NIOX MINO, the text regarding the service is not applicable.

    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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    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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