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    Clinical Trial Results:
    Does a low exhaled Nitric Oxide level exclude a clinical benefit from inhaled corticosteroids in suspected asthma; a double-blind, randomised, placebo controlled trial.

    Summary
    EudraCT number
    		 2016-000338-23
    Trial protocol
    		 GB  
    Global end of trial date
    22 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Nov 2019
    First version publication date
    17 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    16013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02771717
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Nottingham
    Sponsor organisation address
    Jubilee Campus, Triumph Road, Nottingham, United Kingdom, NG8 1DH
    Public contact
    Angela Shone, University of Nottingham, +44 1158467906, sponsor@nottingham.ac.uk
    Scientific contact
    Angela Shone, University of Nottingham, +44 1158467906, sponsor@nottingham.ac.uk
    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 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the study is to determine if a low exhaled nitric oxide level (<27ppb) is a good predictor of a negative clinical benefit from inhaled corticosteroids in patients with suspected asthma? The primary objective is to determine if asthma symptoms, using the 7 point ACQ (Asthma Control Questionnaire), differ between the low dose inhaled steroid and placebo groups.
    Protection of trial subjects
    None applicable
    Background therapy
    		 None
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    22 Feb 2016
    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
    United Kingdom: 180
    Worldwide total number of subjects
    180
    EEA total number of subjects
    180
    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)
    156
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from 47 primary care practices across Nottinghamshire, Leicestershire and Derbyshire as well as from the Nottingham Respiratory Research database and from advertisements in the University of Nottingham and Nottingham University Hospitals between May 2016 and March 2018.

    Pre-assignment
    Screening details
    		 236 patients were screened for entry, 180 were randomised. 56 participants failed screening; 45 patients were denied entry into the study due to FeNO levels greater than 27, 4 due to FEV1 less than 70%, 1 due to insufficient short-acting bronchodilator use,2 due to spirometry contraindications and 4 who withdrew consent prior to randomisation.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    Patients were randomized to treatment groups in blocks of eight with stratification according to their smoking status; current (or smoked within 12 months) or never/ex (never or quit more than one year ago). Allocation sequences were generated using a pseudo-random number generator (sealedenvelop.com). This sequence was linked to an electronic case report form (eCRF) where the participants’ study data was recorded. If the participants' study data was recorded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Budesonide
    Arm description
    		 Participants received200 mcg Budesonide (Pulmicort) via a Turbuhaler or placebo one puff twice daily. The total daily dose of budesonide was therefore 400 mcg per day.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide (Pulmicort)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    200 micrograms per inhalation

    Arm title
    		 Placebo
    Arm description
    		 Placebo 200 mcg via a Turbuhaler or placebo one puff twice daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    na
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    200mcg per inhalation one puff twice daily

    Number of subjects in period 1
    		Budesonide Placebo
    Started
    91
    89
    Completed
    68
    66
    Not completed
    23
    23
         Consent withdrawn by subject
    9
    11
         unknown reason
    3
    4
         Lost to follow-up
    10
    7
         Protocol deviation
    1
    1
    Period 2
    Period 2 title
    End of Trial (12 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    Patients were randomized to treatment groups in blocks of eight with stratification according to their smoking status; current (or smoked within 12 months) or never/ex (never or quit more than one year ago). Allocation sequences were generated by the Respiratory Research Unit’s database manager using a pseudo-random number generator (sealedenvelop.com). This sequence was linked to an electronic case report form (eCRF) where the participants’ study data was recorded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Budesonide
    Arm description
    		 Participants received200 mcg Budesonide (Pulmicort) via a Turbuhaler or placebo one puff twice daily. The total daily dose of budesonide was therefore 400 mcg per day.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide (Pulmicort)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    200 micrograms per inhalation

    Arm title
    		 Placebo
    Arm description
    		 Placebo 200 mcg via a Turbuhaler or placebo one puff twice daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Budesonide (Pulmicort)
    Investigational medicinal product code
    19162
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    200 mcg per inhalation one puff twice daily

    Number of subjects in period 2
    		Budesonide Placebo
    Started
    68
    66
    Completed
    68
    66

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Budesonide
    Reporting group description
    		 Participants received200 mcg Budesonide (Pulmicort) via a Turbuhaler or placebo one puff twice daily. The total daily dose of budesonide was therefore 400 mcg per day.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo 200 mcg via a Turbuhaler or placebo one puff twice daily.

    Reporting group values
    		 Budesonide Placebo Total
    Number of subjects
    		 91 89 180
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age at Baseline
    Units: years
        arithmetic mean (standard deviation)
    		 42.49 ± 18.76 45.38 ± 18.31 -
    Gender categorical
    Units: Subjects
        Female
    		 64 66 130
        Male
    		 27 23 50
    Cough
    Cough
    Units: Subjects
        Yes
    		 74 69 143
        No
    		 17 20 37
    Wheeze
    Wheeze
    Units: Subjects
        Yes
    		 58 62 120
        No
    		 33 27 60
    SOB
    Shortness of Breath
    Units: Subjects
        Yes
    		 65 69 134
        No
    		 26 20 46
    Smoking status
    Cigarette smoking status
    Units: Subjects
        Never
    		 71 72 143
        Current
    		 20 17 37
    Ethnicity
    Ethnicity
    Units: Subjects
        Caucasian
    		 80 78 158
        Asian
    		 2 3 5
        Black
    		 2 5 7
        Other
    		 7 3 10
    ACQ7
    Asthma Control Questionnaire
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 1.28 (0.85 to 2.00) 1.28 (0.57 to 1.86) -
    FEV1
    Forced Expiratory Volume Over One Second
    Units: Liters
        arithmetic mean (standard deviation)
    		 3.02 ± 0.78 2.73 ± 0.72 -
    LCQ
    Leicester Cough Questionnaire
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 17.46 (12.93 to 20.07) 17.36 (13.43 to 19.96) -
    MRC
    Medical Research Council Dyspnea Questionnaire
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 2.00 (1.00 to 2.00) 2.00 (1.00 to 2.00) -
    FEV1 percent predicted
    Forced Expiratory Volume Over One Second percent predicted
    Units: Liters
        arithmetic mean (standard deviation)
    		 95.00 ± 13.79 93.11 ± 14.74 -
    FVC
    Full Vital Capacity
    Units: Liters
        arithmetic mean (standard deviation)
    		 3.81 ± 20.91 3.52 ± 0.87 -
    FEV1/FVC
    ratio of forced expiratory volume over one second to the full vital capacity
    Units: ratio
        arithmetic mean (standard deviation)
    		 79.24 ± 8.20 77.41 ± 8.50 -
    FeNO
    Fractional Exhaled Nitric Oxide
    Units: Parts per billion
        arithmetic mean (standard deviation)
    		 16.31 ± 6.24 16.46 ± 6.75 -
    Blood Eosinophils
    Blood Eosinophils
    Units: cells x10^9
        median (inter-quartile range (Q1-Q3))
    		 0.16 (0.10 to 0.24) 0.20 (0.10 to 0.30) -
    ACQ6
    Asthma Control Questionnaire 6
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 1.33 (0.83 to 2.17) 1.17 (0.67 to 1.83) -
    Duration of Asthma
    Length of diagnosis
    Units: Months
        median (inter-quartile range (Q1-Q3))
    		 1.30 (0.20 to 84.00) 2.00 (0.20 to 89.00) -
    BMI
    Body Mass Index
    Units: Kg/m^2
        median (inter-quartile range (Q1-Q3))
    		 28.20 (23.53 to 33.80) 26.67 (23.32 to 31.60) -

    End points

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    End points reporting groups
    Reporting group title
    Budesonide
    Reporting group description
    		 Participants received200 mcg Budesonide (Pulmicort) via a Turbuhaler or placebo one puff twice daily. The total daily dose of budesonide was therefore 400 mcg per day.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo 200 mcg via a Turbuhaler or placebo one puff twice daily.
    Reporting group title
    Budesonide
    Reporting group description
    		 Participants received200 mcg Budesonide (Pulmicort) via a Turbuhaler or placebo one puff twice daily. The total daily dose of budesonide was therefore 400 mcg per day.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo 200 mcg via a Turbuhaler or placebo one puff twice daily.

    Primary: ACQ7

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    End point title
    		 ACQ7
    End point description
    Statistical analysis of the primary outcome was assessed using a two one-sided equivalence test (TOST) conducted with a delta of 0.5, the widely validated minimal clinical difference in ACQ score, and a type 1 error rate of 0.05 (5 %).
    End point type
    Primary
    End point timeframe
    Baseline to end of study (12 weeks)
    End point values
    		 Budesonide Placebo Budesonide Placebo
    Number of subjects analysed
    91
    89
    68
    66
    Units: Points
        median (inter-quartile range (Q1-Q3))
    1.28 (0.85 to 2.00)
    1.28 (0.57 to 1.86)
    0.85 (0.28 to 1.42)
    0.71 (0.42 to 1.71)
    Statistical analysis title
    		 Equivalence
    Statistical analysis description
    Two One Sided Equivalence Test (TOST)
    Comparison groups
    Budesonide v Placebo v Budesonide v Placebo
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 TOST
    Parameter type
    		 TOST
    Confidence interval
    Notes
    [1] - Difference baseline to 12 weeks between active and placebo
    [2] - P values : <0.001, 0.0462 CI: -0.004 to 0.49 around the equivalence margin of -0.5 to 0.5

    Secondary: FEV1

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    End point title
    		 FEV1
    End point description
    Lung function as assessed by forced expiratory volume over one second where the minimum clinically significant improvement was 02 L from baseline to 12 weeks.
    End point type
    Secondary
    End point timeframe
    Baseline to end of study (12 weeks)
    End point values
    		 Budesonide Placebo Budesonide Placebo
    Number of subjects analysed
    91
    89
    68
    66
    Units: Liters
        arithmetic mean (standard deviation)
    3.02 ± 0.78
    2.73 ± 0.72
    2.92 ± 0.77
    2.69 ± 0.66
    Statistical analysis title
    		 TOST
    Statistical analysis description
    Two One-Sided T-Test (TOST)
    Comparison groups
    Budesonide v Budesonide v Placebo v Placebo
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 < 0.001 [4]
    Method
    		 TOST
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.06
    Notes
    [3] - TOST for equivalence -0.2 to 0.2
    [4] - P values: <0.0001, <0.0001 CI: -.0.6 to 0.06

    Secondary: LCQ

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    End point title
    		 LCQ
    End point description
    LCQ possible scores ranged from 3-21 where 3 represented the worst cough and 21 was no cough. An increase of ≥ 1.3 was required for the difference to be considered clinically significant
    End point type
    Secondary
    End point timeframe
    Baseline to end of study ( 12 weeks)
    End point values
    		 Budesonide Placebo Budesonide Placebo
    Number of subjects analysed
    91
    89
    68
    66
    Units: points
        median (inter-quartile range (Q1-Q3))
    17.46 (12.93 to 20.07)
    17.36 (13.43 to 19.96)
    19.65 (18.03 to 20.69)
    19.04 (15.95 to 20.5)
    Statistical analysis title
    		 TOST
    Statistical analysis description
    two one-sides t-test (TOST)
    Comparison groups
    Budesonide v Placebo v Budesonide v Placebo
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    P-value
    		 = 0.0501 [6]
    Method
    		 TOST
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.06
         upper limit
    		 1.31
    Notes
    [5] - equivalnce with delta -1.3 to 1.3
    [6] - P values: =0.0235, =0.0501 CI: -1.06 to 1.31

    Secondary: MRC

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    End point title
    		 MRC
    End point description
    MRC assessed the level of perceived breathlessness on a 1-5 stage scale where any decrease in points was considered a clinically significant improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to end of study ( 12 weeks)
    End point values
    		 Budesonide Placebo Budesonide Placebo
    Number of subjects analysed
    91
    89
    68
    66
    Units: points
        median (inter-quartile range (Q1-Q3))
    2.00 (1.00 to 2.00)
    2.00 (1.00 to 2.00)
    1.00 (1.00 to 2.00)
    2.00 (1.00 to 2.00)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Regular monitoring took place throughout the trial by the CI.
    Adverse event reporting additional description
    The stopping rules and discontinuation from the study were an increase in ACQ7 of > 0.5 points or a fall in FEV1 of 20% from baseline. Discontinuation was assessed on an individual basis by the CI
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 no dictionary used
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Control treatment with placebo

    Reporting group title
    Budesonide
    Reporting group description
    		 Active treatment with budesonide

    Serious adverse events
    		 Placebo Budesonide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 91 (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: 0%
    Non-serious adverse events
    		 Placebo Budesonide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 89 (0.00%)
    0 / 91 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Budesonide is routinely prescribed with a high safety profile and within the short time frame of the study, no new unexpected adverse events were expected.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
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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
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