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    Clinical Trial Results:
    Randomised Controlled Trial of the efficacy and safety of an ICS/LABA reliever therapy regimen in asthma.

    Summary
    EudraCT number
    		 2015-002384-42
    Trial protocol
    		 GB  
    Global end of trial date
    30 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Apr 2021
    First version publication date
    23 Apr 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MRINZ/15/A1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1170-2118
    Other trial identifiers
    		 Global Sponsor: MRINZ/15/A1, ANZCTR: ACTRN12615000999538
    Sponsors
    Sponsor organisation name
    (1) THE CHANCELLOR MASTERS AND SCHOLARS OF THE OXFORD OF OXFORD
    Sponsor organisation address
    Oxford Offices, Wellington Square, Oxford, United Kingdom, OX1 2JD
    Public contact
    Magda Laskawiec-Szkonter, Oxford Respiratory Trials Unit (ORTU), 44 01865225205, magda.laskawiec@ouh.nhs.uk
    Scientific contact
    Magda Laskawiec-Szkonter, Oxford Respiratory Trials Unit (ORTU), 44 01865225205, magda.laskawiec@ouh.nhs.uk
    Sponsor organisation name
    Medical Research Institute of New Zealand
    Sponsor organisation address
    Level 7 CSB Building, Wellington Hospital, Riddiford Street, Newtown, Wellington, New Zealand, 6021
    Public contact
    Richard Beasley, Medical Research Institute of New Zealand, 64 43890147, mark.holliday@mrinz.ac.nz
    Scientific contact
    Richard Beasley, Medical Research Institute of New Zealand, 64 43890147, mark.holliday@mrinz.ac.nz
    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
    31 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of ICS/LABA reliever therapy with SABA reliever therapy and with maintenance ICS and SABA reliever therapy in adult patients using SABA monotherapy (i.e. without any other asthma medication).
    Protection of trial subjects
    The Data Safety Monitoring Committee was established to ensure independent safety review during the study. Participants were withdrawn from the study after experiencing 3 asthma exacerbations or 1 severe asthma exacerbation for the purpose of safety, to ensure they were able to receive the appropriate treatment outside of the randomised regimens.
    Background therapy
    		 n/a
    Evidence for comparator
    		 Comparators were selected based on their use in clinical practice driven by international guidelines (the Global Initiative for Asthma). Short acting beta agonist (SABA) taken as required for relief of symptoms was recommended step 1 and maintenance inhaled corticosteroids plus SABA as required recommended as step 2 treatment at the time the trial was initiated.
    Actual start date of recruitment
    01 Jan 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
    United Kingdom: 52
    Country: Number of subjects enrolled
    Australia: 26
    Country: Number of subjects enrolled
    New Zealand: 553
    Country: Number of subjects enrolled
    Italy: 44
    Worldwide total number of subjects
    675
    EEA total number of subjects
    96
    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)
    641
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from sites in New Zealand, Australia, Italy and the United Kingdom. The recruitment period ran from first patient first visit (FPFV) on 17/03/2016 to last patient first visit (LPFV) on 29/08/2017 worldwide.

    Pre-assignment
    Screening details
    		 Participants were screened according to the protocol inclusion/ exclusion criteria. Participants that were randomised but subsequently were found to be ineligible (incorrectly randomised) are not included as part of the baseline or analysis sets (n=7), based on a modified intention to treat approach.

    Pre-assignment period milestones
    Number of subjects started
    		 675
    Number of subjects completed
    		 668

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 7
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    n/a

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SABA reliever therapy
    Arm description
    		 salbutamol MDI 100μg, 2 inhalations for relief of symptoms as required.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    salbutamol
    Investigational medicinal product code
    Other name
    Ventolin
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    salbutamol metered dose inhaler 100μg, 2 inhalations for relief of symptoms as required.

    Arm title
    		 ICS/LABA reliever therapy
    Arm description
    		 budesonide/formoterol Turbuhaler 200/6μg, one inhalation for relief of symptoms as required.
    Arm type
    		 Experimental

    Investigational medicinal product name
    budesonide/formoterol
    Investigational medicinal product code
    Other name
    Symbicort
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    budesonide/formoterol Turbuhaler 200/6μg, one inhalation for relief of symptoms as required.

    Arm title
    		 Maintenance ICS and SABA reliever therapy
    Arm description
    		 budesonide Turbuhaler 200μg, 1 inhalation twice daily and salbutamol MDI 100μg 2 inhalations for relief of symptoms as required.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    budesonide Turbuhaler 200μg, 1 inhalation twice daily
    Investigational medicinal product code
    Other name
    Pulmicort
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    budesonide Turbuhaler 200μg, 1 inhalation twice daily

    Investigational medicinal product name
    salbutamol MDI 100μg 2 inhalations for relief of symptoms as required.
    Investigational medicinal product code
    Other name
    Ventolin
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    salbutamol MDI 100μg 2 inhalations for relief of symptoms as required.

    Number of subjects in period 1 [1]
    		SABA reliever therapy ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy
    Started
    223
    220
    225
    Completed
    151
    163
    153
    Not completed
    72
    57
    72
         Adverse event, serious fatal
    -
    1
    1
         incorrectly withdrawn in error
    -
    1
    2
         Physician decision
    1
    1
    -
         Consent withdrawn by subject
    24
    32
    33
         randomised in error, ineligible
    3
    2
    1
         Adverse event, non-fatal
    -
    2
    10
         Pregnancy
    2
    5
    1
         Lost to follow-up
    5
    1
    2
         Lack of efficacy
    37
    12
    22
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 675 participants were randomised however 7 were found to have not met the eligibility criteria after they had been randomised (randomised in error). 668 participants were therefore included in the analysis dataset, including within the baseline reporting datataset, as part of a modified intention to treat approach.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SABA reliever therapy
    Reporting group description
    		 salbutamol MDI 100μg, 2 inhalations for relief of symptoms as required.

    Reporting group title
    ICS/LABA reliever therapy
    Reporting group description
    		 budesonide/formoterol Turbuhaler 200/6μg, one inhalation for relief of symptoms as required.

    Reporting group title
    Maintenance ICS and SABA reliever therapy
    Reporting group description
    		 budesonide Turbuhaler 200μg, 1 inhalation twice daily and salbutamol MDI 100μg 2 inhalations for relief of symptoms as required.

    Reporting group values
    		 SABA reliever therapy ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy Total
    Number of subjects
    		 223 220 225 668
    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)
    		 214 210 215 639
        From 65-84 years
    		 9 10 10 29
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 35.8 ± 14 36 ± 14.1 34.9 ± 14.3 -
    Gender categorical
    Units: Subjects
        Female
    		 113 122 129 364
        Male
    		 110 98 96 304
    Current Smoker
    Units: Subjects
        Smoker
    		 24 18 22 64
        Non-smoker
    		 199 202 203 604
    No. of severe exacerbations in the previous 12 months
    Units: Subjects
        Zero
    		 203 208 208 619
        One
    		 20 12 15 47
        Two
    		 0 0 2 2
    Patient-reported SABA use in the 4 weeks before enrollment
    Units: No. occasions per week
        arithmetic mean (standard deviation)
    		 3.4 ± 3.3 3.8 ± 3.5 3.2 ± 3.0 -
    No. of hospital admissions for asthma at any time before enrollment
    Units: Mean per participant
        arithmetic mean (standard deviation)
    		 0.3 ± 0.9 0.3 ± 1.3 0.3 ± 0.9 -
    Asthma Control Questionnaire-5 score
    Units: Score
        arithmetic mean (standard deviation)
    		 1.1 ± 0.7 1.1 ± 0.7 1.1 ± 0.7 -
    On-treatment Forced Expired Volume in 1 Second
    Units: % of predicted value
        arithmetic mean (standard deviation)
    		 89.2 ± 13.7 89.8 ± 14.1 90.3 ± 13.6 -
    Fractional Exhaled Nitric Oxide
    Units: parts per billion
        median (full range (min-max))
    		 40 (5 to 235) 37 (3 to 300) 38 (5 to 200) -
    Periostin
    Units: ng/ml
        arithmetic mean (standard deviation)
    		 69.3 ± 28.9 70.8 ± 27 70.6 ± 27.8 -
    Blood eosinophil count
    Units: x10^9 per litre
        arithmetic mean (standard deviation)
    		 0.3 ± 0.2 0.3 ± 0.2 0.3 ± 0.2 -

    End points

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    End points reporting groups
    Reporting group title
    SABA reliever therapy
    Reporting group description
    		 salbutamol MDI 100μg, 2 inhalations for relief of symptoms as required.

    Reporting group title
    ICS/LABA reliever therapy
    Reporting group description
    		 budesonide/formoterol Turbuhaler 200/6μg, one inhalation for relief of symptoms as required.

    Reporting group title
    Maintenance ICS and SABA reliever therapy
    Reporting group description
    		 budesonide Turbuhaler 200μg, 1 inhalation twice daily and salbutamol MDI 100μg 2 inhalations for relief of symptoms as required.

    Primary: Annualized rate of asthma exacerbations per patient

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    End point title
    		 Annualized rate of asthma exacerbations per patient
    End point description
    End point type
    Primary
    End point timeframe
    Overall study period
    End point values
    		 SABA reliever therapy ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy
    Number of subjects analysed
    223
    220
    225
    Units: Rate of exacerbations
        number (not applicable)
    0.40
    0.195
    0.175
    Statistical analysis title
    		 Relative rate exacerbations ICS/LABA vs SABA
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 Poisson regression
    Parameter type
    		 Relative Rate
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.72
    Notes
    [1] - Overall test for a difference in rates by treatment: Chi-square 21.1 on 2 DF; P<0.001
    Statistical analysis title
    		 Relative rate exacerbations ICS/LABA vs ICS+SABA
    Comparison groups
    Maintenance ICS and SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.65
    Method
    		 Poisson regression
    Parameter type
    		 Relative rate
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.79

    Secondary: Time to first exacerbation

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    End point title
    		 Time to first exacerbation
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study period
    End point values
    		 SABA reliever therapy ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy
    Number of subjects analysed
    223
    220
    225
    Units: Exacerbations
    74
    37
    32
    Statistical analysis title
    		 Time to first exacerbation ICS/LABA vs SABA only
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Log rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 0.73
    Statistical analysis title
    		 Time to first exacerbation ICS/LABA vs ICS+SABA
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79
    Method
    		 Log rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.57

    Secondary: Time to first severe exacerbation

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    End point title
    		 Time to first severe exacerbation
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study period
    End point values
    		 SABA reliever therapy ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy
    Number of subjects analysed
    223
    220
    225
    Units: exacerbtions
    23
    9
    21
    Statistical analysis title
    		 Time to severe exacerbation ICS/LABA vs SABA only
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 Log rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 0.82
    Statistical analysis title
    		 Time to severe exacerbation ICS/LABA vs ICS+SABA
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 Log rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.9

    Secondary: Number of severe exacerbations

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    End point title
    		 Number of severe exacerbations
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study period
    End point values
    		 SABA reliever therapy ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy
    Number of subjects analysed
    223
    220
    225
    Units: Severe Exacerbations
    23
    9
    21
    Statistical analysis title
    		 Relative risk sev. exacerbations ICS/LABA vs SABA
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.019
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 0.86
    Statistical analysis title
    		 Relative risk sev. exac ICS/LABA vs ICS+SABA
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.038
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.96

    Secondary: Asthma Control Questionnaire-5 Score

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    End point title
    		 Asthma Control Questionnaire-5 Score
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study period
    End point values
    		 SABA reliever therapy ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy
    Number of subjects analysed
    222
    220
    225
    Units: Score
    arithmetic mean (standard deviation)
        Visit 1
    1.1 ± 0.7
    1.1 ± 0.7
    1.1 ± 0.7
        Visit 2
    1.0 ± 0.7
    0.9 ± 0.6
    0.8 ± 0.7
        Visit 3
    1.0 ± 0.8
    0.8 ± 0.6
    0.7 ± 0.6
        Visit 4
    0.9 ± 0.7
    0.8 ± 0.6
    0.7 ± 0.7
        Visit 5
    0.9 ± 0.9
    0.8 ± 0.7
    0.6 ± 0.7
        Visit 6
    0.8 ± 0.8
    0.8 ± 0.7
    0.6 ± 0.8
        Visit 7
    0.9 ± 0.9
    0.8 ± 0.7
    0.7 ± 0.8
    Statistical analysis title
    		 Mean difference in ACQ-5 ICS/LABA vs SABA only
    Statistical analysis description
    main effects averaged over all visits
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    442
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 -0.06
    Notes
    [2] - Overall P<0.001 for treatment effect
    Statistical analysis title
    		 Mean difference in ACQ-5 ICS/LABA vs ICS+SABA
    Statistical analysis description
    Main effects analysis averaged over all visits
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 0.23
    Notes
    [3] - Overall P<0.001 for treatment effect

    Secondary: Forced Expired Volume in 1 second (FEV1)

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    End point title
    		 Forced Expired Volume in 1 second (FEV1)
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study period
    End point values
    		 SABA reliever therapy ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy
    Number of subjects analysed
    223
    218
    225
    Units: Litres
    arithmetic mean (standard deviation)
        Visit 1
    3.30 ± 0.76
    3.30 ± 0.87
    3.30 ± 0.87
        Visit 2
    3.33 ± 0.77
    3.37 ± 0.85
    3.36 ± 0.88
        Visit 3
    3.35 ± 0.78
    3.36 ± 0.89
    3.38 ± 0.88
        Visit 4
    3.33 ± 0.78
    3.32 ± 0.84
    3.35 ± 0.88
        Visit 5
    3.32 ± 0.74
    3.30 ± 0.85
    3.33 ± 0.88
        Visit 6
    3.30 ± 0.72
    3.30 ± 0.87
    3.34 ± 0.91
        Visit 7
    3.23 ± 0.71
    3.28 ± 0.84
    3.31 ± 0.89
    Statistical analysis title
    		 Mean difference in FEV1 (L) ICS/LABA vs SABA only
    Statistical analysis description
    Main effects analysis averaged over all visits
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.006
         upper limit
    		 0.07
    Notes
    [4] - Overall P=0.20 for treatment effect
    Statistical analysis title
    		 Mean difference in FEV1 (L) ICS/LABA vs ICS+SABA
    Statistical analysis description
    Main effects analysis averaged over all visits
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.04

    Secondary: Fraction of exhaled nitric oxide (FeNO)

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    End point title
    		 Fraction of exhaled nitric oxide (FeNO)
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study period
    End point values
    		 SABA reliever therapy ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy
    Number of subjects analysed
    223
    220
    225
    Units: parts per billion
    log mean (standard deviation)
        Visit 1
    3.69 ± 0.83
    3.56 ± 0.88
    3.66 ± 0.84
        Visit 3
    3.7 ± 0.8
    3.36 ± 0.78
    3.2 ± 0.65
        Visit 7
    3.61 ± 0.77
    3.32 ± 0.78
    3.29 ± 0.74
    Statistical analysis title
    		 Difference in log FeNO ICS/LABA vs SABA only V3
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 ratio of geometric means
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 0.87
    Statistical analysis title
    		 Difference in log FeNO ICS/LABA vs ICS+SABA V3
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 ratio of geometric means
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.15
         upper limit
    		 1.4
    Statistical analysis title
    		 Difference in log FeNO ICS/LABA vs SABA only V7
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 ratio of geometric means
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 0.91
    Statistical analysis title
    		 Difference in log FeNO ICS/LABA vs ICS+SABA V7
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.022
    Method
    		 Mixed models analysis
    Parameter type
    		 ratio of geometric means
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.25

    Secondary: Mean inhaled corticosteroid dose per day

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    End point title
    		 Mean inhaled corticosteroid dose per day [5]
    End point description
    End point type
    Secondary
    End point timeframe
    overall study period
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The SABA only arm did not take regular maintenance inhaled corticosteroid therefore no data is available for this outcome for that group.
    End point values
    		 ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy
    Number of subjects analysed
    220
    225
    Units: microgram(s)
        arithmetic mean (standard deviation)
    1.07 ± 109
    222 ± 113
    No statistical analyses for this end point

    Secondary: Total systemic corticosteroid exposure use per year

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    End point title
    		 Total systemic corticosteroid exposure use per year
    End point description
    End point type
    Secondary
    End point timeframe
    overall study period
    End point values
    		 SABA reliever therapy ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy
    Number of subjects analysed
    223
    220
    225
    Units: milligram(s)
        arithmetic mean (standard deviation)
    17.4 ± 59.8
    71.4 ± 72.1
    152.3 ± 97.1
    Statistical analysis title
    		 Total systemic steroid exposure ICS/LABA vs SABA
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimator
    Point estimate
    41.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 34.4
         upper limit
    		 48.4
    Statistical analysis title
    		 Total systemic steroid exp. ICS/LABA vs ICS+SABA
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges-Lehmann estimator
    Point estimate
    -84.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -104
         upper limit
    		 -64.8

    Secondary: Proportion of participants withdrawn due to treatment failure

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    End point title
    		 Proportion of participants withdrawn due to treatment failure
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study period
    End point values
    		 SABA reliever therapy ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy
    Number of subjects analysed
    223
    220
    225
    Units: Participants
        One Severe Exacerbation
    23
    9
    21
        Three Exacerbations
    3
    3
    1
        Randomised treatment modified by healthcare provid
    11
    0
    0
    No statistical analyses for this end point

    Secondary: Global Initiative for Asthma Question Category

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    End point title
    		 Global Initiative for Asthma Question Category
    End point description
    End point type
    Secondary
    End point timeframe
    Overall study period
    End point values
    		 SABA reliever therapy ICS/LABA reliever therapy Maintenance ICS and SABA reliever therapy
    Number of subjects analysed
    223
    220
    225
    Units: GINA Category
        Visit 1 Well controlled
    54
    44
    54
        Visit 1 Partly controlled
    121
    123
    108
        Visit 1 Uncontrolled
    48
    53
    63
        Visit 2 Well controlled
    60
    38
    79
        Visit 2 Partly controlled
    95
    127
    101
        Visit 2 Uncontrolled
    50
    43
    26
        Visit 3 Well controlled
    57
    53
    95
        Visit 3 Partly controlled
    95
    109
    82
        Visit 3 Uncontrolled
    49
    25
    26
        Visit 4 Well controlled
    53
    58
    85
        Visit 4 Partly controlled
    90
    95
    78
        Visit 4 Uncontrolled
    39
    30
    19
        Visit 5 Well controlled
    71
    56
    82
        Visit 5 Partly controlled
    68
    87
    69
        Visit 5 Uncontrolled
    35
    31
    20
        Visit 6 Well controlled
    58
    62
    74
        Visit 6 Partly controlled
    77
    78
    56
        Visit 6 Uncontrolled
    28
    30
    25
        Visit 7 Well controlled
    72
    69
    87
        Visit 7 Partly controlled
    77
    97
    74
        Visit 7 Uncontrolled
    48
    31
    36
    Statistical analysis title
    		 GINA level of control ICS/LABA vs SABA Visit 2
    Statistical analysis description
    Comparison of ordinal odds of association with GINA overall level of control (generalized linear mixed model) without baseline GINA control as a co-variate and with a time by treatment interaction, at Visit 2
    Comparison groups
    ICS/LABA reliever therapy v SABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.32
    Notes
    [6] - Time by treatment interaction not statistically significant, P=0.23
    Statistical analysis title
    		 GINA level of control ICS/LABA vs SABA Visit 3
    Statistical analysis description
    Comparison of ordinal odds of association with GINA overall level of control (generalized linear mixed model) without baseline GINA control as a co-variate and with a time by treatment interaction, at Visit 3
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.67 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.78
    Notes
    [7] - Time by treatment interaction not statistically significant, P=0.23
    Statistical analysis title
    		 GINA level of control ICS/LABA vs SABA Visit 4
    Statistical analysis description
    Comparison of ordinal odds of association with GINA overall level of control (generalized linear mixed model) without baseline GINA control as a co-variate and with a time by treatment interaction, at Visit 4
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.24 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 2.2
    Notes
    [8] - Time by treatment interaction not statistically significant, P=0.23
    Statistical analysis title
    		 GINA level of control ICS/LABA vs SABA Visit 5
    Statistical analysis description
    Comparison of ordinal odds of association with GINA overall level of control (generalized linear mixed model) without baseline GINA control as a co-variate and with a time by treatment interaction, at Visit 5
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.39
    Notes
    [9] - Time by treatment interaction not statistically significant, P=0.23
    Statistical analysis title
    		 GINA level of control ICS/LABA vs SABA Visit 6
    Statistical analysis description
    Comparison of ordinal odds of association with GINA overall level of control (generalized linear mixed model) without baseline GINA control as a co-variate and with a time by treatment interaction, at Visit 6
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.68 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.86
    Notes
    [10] - Time by treatment interaction not statistically significant, P=0.23
    Statistical analysis title
    		 GINA level of control ICS/LABA vs SABA Visit 7
    Statistical analysis description
    Comparison of ordinal odds of association with GINA overall level of control (generalized linear mixed model) without baseline GINA control as a co-variate and with a time by treatment interaction, at Visit 7
    Comparison groups
    SABA reliever therapy v ICS/LABA reliever therapy
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 2.05
    Notes
    [11] - Time by treatment interaction not statistically significant, P=0.23
    Statistical analysis title
    		 GINA level of control ICS/LABA vs ICS+SABA Visit 2
    Statistical analysis description
    Comparison of ordinal odds of association with GINA overall level of control (generalized linear mixed model) without baseline GINA control as a co-variate and with a time by treatment interaction, at Visit 2
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 0.65
    Notes
    [12] - Time by treatment interaction not statistically significant, P=0.23
    Statistical analysis title
    		 GINA level of control ICS/LABA vs ICS+SABA Visit 3
    Statistical analysis description
    Comparison of ordinal odds of association with GINA overall level of control (generalized linear mixed model) without baseline GINA control as a co-variate and with a time by treatment interaction, at Visit 3
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.64
    Notes
    [13] - Time by treatment interaction not statistically significant, P=0.23
    Statistical analysis title
    		 GINA level of control ICS/LABA vs ICS+SABA Visit 4
    Statistical analysis description
    Comparison of ordinal odds of association with GINA overall level of control (generalized linear mixed model) without baseline GINA control as a co-variate and with a time by treatment interaction, at Visit 4
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 0.79
    Notes
    [14] - Time by treatment interaction not statistically significant, P=0.23
    Statistical analysis title
    		 GINA level of control ICS/LABA vs ICS+SABA Visit 5
    Statistical analysis description
    Comparison of ordinal odds of association with GINA overall level of control (generalized linear mixed model) without baseline GINA control as a co-variate and with a time by treatment interaction, at Visit 5
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003 [15]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 0.77
    Notes
    [15] - Time by treatment interaction not statistically significant, P=0.23
    Statistical analysis title
    		 GINA level of control ICS/LABA vs ICS+SABA Visit 6
    Statistical analysis description
    Comparison of ordinal odds of association with GINA overall level of control (generalized linear mixed model) without baseline GINA control as a co-variate and with a time by treatment interaction, at Visit 6
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.09
    Notes
    [16] - Time by treatment interaction not statistically significant, P=0.23
    Statistical analysis title
    		 GINA level of control ICS/LABA vs ICS+SABA Visit 7
    Statistical analysis description
    Comparison of ordinal odds of association with GINA overall level of control (generalized linear mixed model) without baseline GINA control as a co-variate and with a time by treatment interaction, at Visit 7
    Comparison groups
    ICS/LABA reliever therapy v Maintenance ICS and SABA reliever therapy
    Number of subjects included in analysis
    445
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28 [17]
    Method
    		 Mixed models analysis
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.24
    Notes
    [17] - Time by treatment interaction not statistically significant, P=0.23

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall study period
    Adverse event reporting additional description
    Adverse events were collected at each visit via participant self-report, investigator assessment and investigator review of the participant completed asthma management plans/ logbooks containing healthcare utilisation and asthma related events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Safety Analysis Dataset
    Reporting group description
    		 Dataset includes all participants that were randomised, including those who were randomised incorrectly (those who were randomised and subsequently found to not meet the eligibility criteria).

    Serious adverse events
    		 Safety Analysis Dataset
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 675 (3.41%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery dissection
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    2 / 675 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eating disorder
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 675 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    2 / 675 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Safety Analysis Dataset
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    549 / 675 (81.33%)
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    21 / 675 (3.11%)
         occurrences all number
    23
    Nervous system disorders
    Headache
         subjects affected / exposed
    38 / 675 (5.63%)
         occurrences all number
    49
    Migraine
         subjects affected / exposed
    14 / 675 (2.07%)
         occurrences all number
    14
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    27 / 675 (4.00%)
         occurrences all number
    28
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    14 / 675 (2.07%)
         occurrences all number
    14
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    89 / 675 (13.19%)
         occurrences all number
    99
    Cough
         subjects affected / exposed
    36 / 675 (5.33%)
         occurrences all number
    37
    Oropharyngeal pain
         subjects affected / exposed
    22 / 675 (3.26%)
         occurrences all number
    23
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    19 / 675 (2.81%)
         occurrences all number
    19
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    23 / 675 (3.41%)
         occurrences all number
    24
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    221 / 675 (32.74%)
         occurrences all number
    305
    Nasopharyngitis
         subjects affected / exposed
    128 / 675 (18.96%)
         occurrences all number
    163
    Influenza
         subjects affected / exposed
    62 / 675 (9.19%)
         occurrences all number
    72
    Lower respiratory tract infection
         subjects affected / exposed
    52 / 675 (7.70%)
         occurrences all number
    57
    Respiratory tract infection
         subjects affected / exposed
    28 / 675 (4.15%)
         occurrences all number
    33
    Sinusitis
         subjects affected / exposed
    26 / 675 (3.85%)
         occurrences all number
    35
    Gastroenteritis
         subjects affected / exposed
    20 / 675 (2.96%)
         occurrences all number
    25
    Viral upper respiratory tract infection
         subjects affected / exposed
    19 / 675 (2.81%)
         occurrences all number
    22

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Oct 2016
    Protocol Amendment v3.0 to v4.0 due to request by MHRA: Addition of exclusion criterion 14; 14. Any known or suspected contraindications to the Investigational Medicinal Products or excipients Update to wording in 7.2.3.; 7.2.3. In the case of safety concerns arising during the study, the Sponsor and Investigators may deviate from the protocol only in cases where appropriate urgent safety measures are warranted to protect the trial participants against any immediate hazard to their health or safety. The Global Sponsor must be informed of any cases where the protocol is not adhered to and the reasons for non-adherence, as soon as possible. Non-adherence will be reported to the appropriate ethics committees and regulatory authorities in line with local requirements.
    30 Aug 2018
    Protocol Amendment v4.0 to v5.0. The MHRA approval date for this amendment was 13/09/2018 however this cannot be entered into the system as it prevents form validation due to approval date being subsequent to global end date. Change of definition for exacerbation of asthma (removal of "use" and replacement with "prescription"): Exacerbation of Asthma: Worsening asthma resulting in the prescription of systemic corticosteroids, such as a course of oral prednisone for any duration and/or… Severe Asthma Exacerbation: a. The prescription of systemic corticosteroids for at least 3 days because of asthma, or… Addition of sensitivity analysis: Severe exacerbation sensitivity analysis Wherever severe exacerbations are analysed a separate sensitivity analysis will be performed using the interpretation of the definition of a severe exacerbation that has been used in the PRACTICAL41 study; i.e.: self-reported use of corticosteroids for 3 or more days because of asthma, rather than prescription of systemic corticosteroid for at least 3 days because of asthma. Addition of reference to the PRACTICAL trial: 41. Fingleton J, et al. Description of the protocol for the PRACTICAL study: a randomised controlled trial of the efficacy and safety of ICS/LABA reliever therapy in asthma. BMJ Open Respiratory Research 2017;4:e000217. DOI: 10.1136/bmjresp-2017-000217

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31112386
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