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    Clinical Trial Results:
    A randomised, double-blind, placebo-controlled, parallel group study to evaluate the efficacy and safety of two doses of nebulised budesonide delivered by the VR475 Inhalation System, with an open-label comparison to conventionally nebulised budesonide, in subjects with uncontrolled asthma despite treatment with high dose inhaled corticosteroid and at least a second controller (GINA Step 4) and those receiving oral corticosteroid (GINA Step 5).

    Summary
    EudraCT number
    		 2015-000353-20
    Trial protocol
    		 DE   HU   BG   PL   Outside EU/EEA  
    Global end of trial date
    27 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Apr 2019
    First version publication date
    10 Apr 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    VR475/3/001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vectura Limited
    Sponsor organisation address
    1 Prospect West, Chippenham, United Kingdom, SN14 6FH
    Public contact
    Clinical Trials Information, Vectura Limited, +44 1249667700, clinical.enquiries@vectura.com
    Scientific contact
    Clinical Trials Information, Vectura Limited, +44 1249667700, clinical.enquiries@vectura.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001087-PIP02-12
    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
    27 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical efficacy, safety and tolerability of VR475 1 mg/2 ml twice daily given for 52 weeks compared to placebo.
    Protection of trial subjects
    All subjects had the right to withdraw from the study at any time and for any reason, without having to give their reason and without any disadvantages for their subsequent care.
    Background therapy
    		 For background therapy, subjects were required to be on high dose inhaled corticosteroids (ICS) plus at least a second asthma controller medication. During the study, for any subject that was on oral corticosteroids (OCS) at randomisation, consideration was made to reduce the OCS dose, depending on clinical response and in line with the investigator’s judgement; all other existing asthma therapy (including ICS) remained unchanged, with study medication provided as add-on therapy.
    Evidence for comparator
    		 This Phase 3, randomised, double-blind, placebo-controlled, parallel group study evaluated the efficacy and safety of two doses of nebulised budesonide delivered by the VR475 Inhalation System, with an open-label comparison to conventionally nebulised budesonide, in subjects with severe uncontrolled asthma.
    Actual start date of recruitment
    28 Oct 2015
    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
    Philippines: 69
    Country: Number of subjects enrolled
    Serbia: 16
    Country: Number of subjects enrolled
    Ukraine: 166
    Country: Number of subjects enrolled
    Poland: 86
    Country: Number of subjects enrolled
    Romania: 74
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Bulgaria: 129
    Country: Number of subjects enrolled
    Germany: 62
    Country: Number of subjects enrolled
    Hungary: 98
    Worldwide total number of subjects
    711
    EEA total number of subjects
    460
    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)
    75
    Adults (18-64 years)
    514
    From 65 to 84 years
    122
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted between 28 October 2015 (first subject, Screening visit) and 27 September 2018 (last subject, final study visit) at 96 sites (Bulgaria, Germany, Hungary, Poland, Romania, Serbia, Ukraine, United Kingdom and Philippines).

    Pre-assignment
    Screening details
    		 A total of 816 subjects were screened, of whom 103 were screen failures. Of the 713 subjects who were randomised, 711 subjects were treated. The 2 subjects (from Germany) who were not treated withdrew consent prior to treatment and have therefore been omitted from the analyses presented herein. Of the 711 treated subjects, 615 completed the study.

    Period 1
    Period 1 title
    Treated (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    Due to the unblinded nature of the conventionally nebulised budesonide group, subjects and site staff knew whether they were randomised to that group or to one of the three blinded groups (placebo or either of the two doses of VR475 Nebuliser Suspension via the VR475 Inhalation System). The foil pouches containing each of the two doses of VR475 Nebuliser Suspension and placebo were identical. Any in-clinic administration of VR475 Nebuliser Suspension/placebo was supervised by unblinded staff.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 VR475 1 mg
    Arm description
    		 VR475 1 mg delivered by the VR475 Inhalation System twice per day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VR475 (budesonide) 1 mg delivered by the VR475 Inhalation System
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    VR475 Nebuliser Suspension (budesonide) delivered by the VR475 Inhalation System (1 mg twice daily, at least 8 hours apart, for 52 weeks).

    Arm title
    		 VR475 0.5 mg
    Arm description
    		 VR475 0.5 mg delivered by the VR475 Inhalation System twice per day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VR475 (budesonide) 0.5 mg delivered by the VR475 Inhalation System
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    VR475 Nebuliser Suspension (budesonide) delivered by the VR475 Inhalation System (0.5 mg twice daily, at least 8 hours apart, for 52 weeks).

    Arm title
    		 VR475 Placebo
    Arm description
    		 VR475 Placebo delivered by the VR475 Inhalation System twice per day.
    Arm type
    		 Placebo

    Investigational medicinal product name
    VR475 Placebo delivered by the VR475 Inhalation System
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    VR475 Placebo (saline solution) delivered by the VR475 Inhalation System (twice daily, at least 8 hours apart, for 52 weeks).

    Arm title
    		 CN-BUD 1 mg
    Arm description
    		 Budesonide 1 mg delivered by conventional nebuliser twice per day.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide 1 mg delivered by conventional nebuliser
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Budesonide nebuliser suspension delivered by conventional nebuliser (PARI BOY® SX Inhalation System; 1 mg twice daily, at least 8 hours apart, for 52 weeks).

    Number of subjects in period 1
    		VR475 1 mg VR475 0.5 mg VR475 Placebo CN-BUD 1 mg
    Started
    237
    119
    119
    236
    Completed
    196
    95
    103
    221
    Not completed
    41
    24
    16
    15
         Previous AE
    1
    -
    -
    -
         Adverse event, serious fatal
    -
    2
    -
    -
         Consent withdrawn by subject
    30
    18
    14
    8
         Physician decision
    -
    -
    -
    1
         Adverse event, non-fatal
    7
    1
    1
    3
         Non-compliance with study medication
    1
    -
    -
    -
         Decision of medical monitor
    1
    -
    -
    -
         Change of residence
    -
    1
    -
    -
         Lost to follow-up
    1
    -
    -
    2
         Sponsor decision
    -
    2
    1
    -
         Protocol deviation
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    VR475 1 mg
    Reporting group description
    		 VR475 1 mg delivered by the VR475 Inhalation System twice per day.

    Reporting group title
    VR475 0.5 mg
    Reporting group description
    		 VR475 0.5 mg delivered by the VR475 Inhalation System twice per day.

    Reporting group title
    VR475 Placebo
    Reporting group description
    		 VR475 Placebo delivered by the VR475 Inhalation System twice per day.

    Reporting group title
    CN-BUD 1 mg
    Reporting group description
    		 Budesonide 1 mg delivered by conventional nebuliser twice per day.

    Reporting group values
    		 VR475 1 mg VR475 0.5 mg VR475 Placebo CN-BUD 1 mg Total
    Number of subjects
    		 237 119 119 236 711
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 26 13 11 25 75
        Adults (18-64 years)
    		 179 84 86 165 514
        From 65-84 years
    		 32 22 22 46 122
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.5 ± 16.75 49.2 ± 17.57 50.0 ± 16.94 49.1 ± 16.81 -
    Gender categorical
    Units: Subjects
        Female
    		 141 59 74 145 419
        Male
    		 96 60 45 91 292

    End points

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    End points reporting groups
    Reporting group title
    VR475 1 mg
    Reporting group description
    		 VR475 1 mg delivered by the VR475 Inhalation System twice per day.

    Reporting group title
    VR475 0.5 mg
    Reporting group description
    		 VR475 0.5 mg delivered by the VR475 Inhalation System twice per day.

    Reporting group title
    VR475 Placebo
    Reporting group description
    		 VR475 Placebo delivered by the VR475 Inhalation System twice per day.

    Reporting group title
    CN-BUD 1 mg
    Reporting group description
    		 Budesonide 1 mg delivered by conventional nebuliser twice per day.

    Primary: The annualised rate of clinically significant exacerbations (CSEs) during the 52-week treatment period

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    End point title
    		 The annualised rate of clinically significant exacerbations (CSEs) during the 52-week treatment period
    End point description
    End point type
    Primary
    End point timeframe
    During the 52-week treatment period.
    End point values
    		 VR475 1 mg VR475 0.5 mg VR475 Placebo CN-BUD 1 mg
    Number of subjects analysed
    227
    111
    114
    231
    Units: Annualised CSE rate (adjusted)
        number (confidence interval 95%)
    0.23 (0.13 to 0.41)
    0.22 (0.12 to 0.43)
    0.28 (0.15 to 0.52)
    0.20 (0.11 to 0.36)
    Statistical analysis title
    		 Ratio of CSEs (VR475 1 mg versus Placebo)
    Statistical analysis description
    Primary analysis. The observed CSE rates were calculated based on the number of exacerbations during time on treatment. Ratios of CSEs (VR475 1 mg versus placebo) were calculated.
    Comparison groups
    VR475 1 mg v VR475 Placebo
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3909
    Method
    		 Regression, Linear
    Parameter type
    		 Negative binomial regression
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.29
    Statistical analysis title
    		 Ratio of CSEs (VR475 0.5 mg versus Placebo)
    Comparison groups
    VR475 0.5 mg v VR475 Placebo
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.4028
    Method
    		 Regression, Linear
    Parameter type
    		 Negative binomial regression
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.35
    Notes
    [1] - Secondary analysis.

    Secondary: Change in in-clinic pre-bronchodilator forced expiratory volume in one second (FEV1) from baseline during the treatment period

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    End point title
    		 Change in in-clinic pre-bronchodilator forced expiratory volume in one second (FEV1) from baseline during the treatment period
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline at Weeks 24 and 52.
    End point values
    		 VR475 1 mg VR475 0.5 mg VR475 Placebo CN-BUD 1 mg
    Number of subjects analysed
    227 [2]
    111 [3]
    114 [4]
    231 [5]
    Units: litre(s)
    arithmetic mean (standard deviation)
        Change from baseline to Week 24
    0.240 ± 0.508
    0.198 ± 0.455
    0.117 ± 0.393
    0.147 ± 0.380
        Change from baseline to Week 52
    0.241 ± 0.515
    0.198 ± 0.460
    0.150 ± 0.439
    0.155 ± 0.421
    Notes
    [2] - N=210 at Week 24; N=195 at Week 52.
    [3] - N=101 at Week 24; N=95 at Week 52.
    [4] - N=108 at Week 24; N=102 at Week 52.
    [5] - N=226 at Week 24; N=220 at Week 52.
    Statistical analysis title
    		 Mean difference at Wk 24 (VR475 1 mg vs Placebo)
    Statistical analysis description
    Mean difference in FEV1 from baseline to Week 24. N=318.
    Comparison groups
    VR475 1 mg v VR475 Placebo
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0081
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    0.128
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.033
         upper limit
    		 0.222
    Statistical analysis title
    		 Mean difference at Wk 24 (VR475 0.5 mg vs Placebo)
    Statistical analysis description
    Mean difference in FEV1 from baseline to Week 24. N=209.
    Comparison groups
    VR475 0.5 mg v VR475 Placebo
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2074
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    0.071
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.182
    Statistical analysis title
    		 Mean difference at Wk 52 (VR475 1 mg vs Placebo)
    Statistical analysis description
    Mean difference in FEV1 from baseline to Week 52. N=297.
    Comparison groups
    VR475 1 mg v VR475 Placebo
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0641
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    0.094
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.006
         upper limit
    		 0.195
    Statistical analysis title
    		 Mean difference at Wk 52 (VR475 0.5 mg vs Placebo)
    Statistical analysis description
    Mean difference in FEV1 from baseline to Week 52. N=197.
    Comparison groups
    VR475 0.5 mg v VR475 Placebo
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.575
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    0.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.084
         upper limit
    		 0.151

    Secondary: Change in Asthma Control Questionnaire (ACQ-5) scores from baseline during the treatment period

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    End point title
    		 Change in Asthma Control Questionnaire (ACQ-5) scores from baseline during the treatment period
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to Weeks 24 and 52.
    End point values
    		 VR475 1 mg VR475 0.5 mg VR475 Placebo CN-BUD 1 mg
    Number of subjects analysed
    227 [6]
    111 [7]
    114 [8]
    231 [9]
    Units: Change from baseline in ACQ-5 score
    arithmetic mean (standard deviation)
        Change from baseline to Week 24
    -0.98 ± 1.067
    -1.04 ± 1.033
    -0.80 ± 0.936
    -0.92 ± 1.024
        Change from baseline to Week 52
    -1.08 ± 1.085
    -0.94 ± 1.040
    -0.91 ± 0.996
    -0.98 ± 1.093
    Notes
    [6] - N=207 at Week 24; N=212 at Week 52.
    [7] - N=97 at Week 24; N=100 at Week 52.
    [8] - N=106 at Week 24; N=105 at Week 52.
    [9] - N=221 at Week 24; N=226 at Week 52.
    Statistical analysis title
    		 Difference at Wk 24 (VR475 1 mg vs Placebo)
    Statistical analysis description
    Mean difference in ACQ-5 score from baseline to Week 24. N=313.
    Comparison groups
    VR475 1 mg v VR475 Placebo
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1768
    Method
    		 Repeated measures mixed effect model
    Parameter type
    		 LS Mean
    Point estimate
    -0.151
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.369
         upper limit
    		 0.068
    Statistical analysis title
    		 Difference at Wk 24 (VR475 0.5 mg vs Placebo)
    Statistical analysis description
    Mean difference in ACQ-5 score from baseline to Week 24. N=203.
    Comparison groups
    VR475 0.5 mg v VR475 Placebo
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1657
    Method
    		 Repeated measures mixed effect model
    Parameter type
    		 LS Mean
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.436
         upper limit
    		 0.075
    Statistical analysis title
    		 Difference at Wk 52 (VR475 1 mg vs Placebo)
    Statistical analysis description
    Mean difference in ACQ-5 score from baseline to Week 52. N=317.
    Comparison groups
    VR475 1 mg v VR475 Placebo
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.122
    Method
    		 Repeated measures mixed effects model
    Parameter type
    		 LS Mean
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.408
         upper limit
    		 0.048
    Statistical analysis title
    		 Difference at Wk 52 (VR475 0.5 mg vs Placebo)
    Statistical analysis description
    Mean difference in ACQ-5 score from baseline to Week 52. N=205.
    Comparison groups
    VR475 0.5 mg v VR475 Placebo
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9481
    Method
    		 Repeated measures mixed effects model
    Parameter type
    		 LS Mean
    Point estimate
    0.009
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.258
         upper limit
    		 0.275

    Secondary: Change in number of puffs of reliever medication use from baseline during the treatment period

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    End point title
    		 Change in number of puffs of reliever medication use from baseline during the treatment period
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline in mean number of puffs per day of reliever medication at Weeks 24 and 52 .
    End point values
    		 VR475 1 mg VR475 0.5 mg VR475 Placebo CN-BUD 1 mg
    Number of subjects analysed
    227 [10]
    111 [11]
    114 [12]
    231 [13]
    Units: Puffs
    arithmetic mean (standard deviation)
        Change from baseline to Week 24
    -0.93 ± 1.97
    -1.06 ± 1.97
    -0.73 ± 2.12
    -0.71 ± 1.83
        Change from baseline to Week 52
    -1.09 ± 2.26
    -0.92 ± 1.88
    -0.84 ± 1.77
    -0.92 ± 1.98
    Notes
    [10] - N=209 at Week 24; N=189 at Week 52.
    [11] - N=100 at Week 24; N=90 at Week 52.
    [12] - N=104 at Week 24; N=94 at Week 52.
    [13] - N=220 at Week 24; N=212 at Week 52.
    Statistical analysis title
    		 Mean difference at Wk 24 (VR475 1 mg vs Placebo)
    Statistical analysis description
    Mean difference in rescue medication use (number of puffs) from baseline to Week 24. N=313.
    Comparison groups
    VR475 1 mg v VR475 Placebo
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2522
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.233
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.633
         upper limit
    		 0.166
    Statistical analysis title
    		 Mean difference at Wk 24 (VR475 0.5 mg vs Placebo)
    Statistical analysis description
    Mean difference in rescue medication use (number of puffs) from baseline to Week 24. N=204.
    Comparison groups
    VR475 0.5 mg v VR475 Placebo
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1673
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.329
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.796
         upper limit
    		 0.138
    Statistical analysis title
    		 Mean difference at Wk 52 (VR475 1 mg vs Placebo)
    Statistical analysis description
    Mean difference in rescue medication use (number of puffs) from baseline to Week 52. N=283.
    Comparison groups
    VR475 1 mg v VR475 Placebo
    Number of subjects included in analysis
    341
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4802
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.151
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.569
         upper limit
    		 0.268
    Statistical analysis title
    		 Mean difference at Wk 52 (VR475 0.5 mg vs Placebo)
    Statistical analysis description
    Mean difference in rescue medication use (number of puffs) from baseline to Week 52. N=184.
    Comparison groups
    VR475 0.5 mg v VR475 Placebo
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9416
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.018
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.472
         upper limit
    		 0.509

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events that occurred during the study period, from the date of consent to the Follow-up Visit, were recorded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    VR475 1 mg
    Reporting group description
    		 VR475 1 mg delivered by the VR475 Inhalation System twice per day.

    Reporting group title
    VR475 0.5 mg
    Reporting group description
    		 VR475 0.5 mg delivered by the VR475 Inhalation System twice per day.

    Reporting group title
    VR475 Placebo
    Reporting group description
    		 VR475 Placebo delivered by the VR475 Inhalation System twice per day.

    Reporting group title
    CN-BUD 1 mg
    Reporting group description
    		 Budesonide 1 mg delivered by conventional nebuliser twice per day.

    Serious adverse events
    		 VR475 1 mg VR475 0.5 mg VR475 Placebo CN-BUD 1 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 237 (5.91%)
    11 / 119 (9.24%)
    7 / 119 (5.88%)
    9 / 236 (3.81%)
         number of deaths (all causes)
    0
    2
    0
    0
         number of deaths resulting from adverse events
    0
    2
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Rectal cancer
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 119 (0.84%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism arterial
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 119 (0.84%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 119 (0.00%)
    1 / 119 (0.84%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    7 / 237 (2.95%)
    2 / 119 (1.68%)
    4 / 119 (3.36%)
    4 / 236 (1.69%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 3
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood cortisol decreased
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stab wound
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 119 (0.84%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 119 (0.00%)
    1 / 119 (0.84%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 119 (0.84%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 119 (0.84%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Neurodegenerative disorder
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 119 (0.84%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinsonism
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 119 (0.84%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculitis cervical
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    1 / 119 (0.84%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    1 / 236 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal cyst
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephritis
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 119 (0.84%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 119 (0.84%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 237 (0.42%)
    1 / 119 (0.84%)
    1 / 119 (0.84%)
    2 / 236 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 119 (0.00%)
    1 / 119 (0.84%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superinfection bacterial
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 119 (0.00%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 119 (0.84%)
    0 / 119 (0.00%)
    0 / 236 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 VR475 1 mg VR475 0.5 mg VR475 Placebo CN-BUD 1 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    152 / 237 (64.14%)
    68 / 119 (57.14%)
    76 / 119 (63.87%)
    149 / 236 (63.14%)
    Investigations
    Blood cortisol decreased
         subjects affected / exposed
    27 / 237 (11.39%)
    5 / 119 (4.20%)
    2 / 119 (1.68%)
    14 / 236 (5.93%)
         occurrences all number
    28
    5
    2
    14
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 237 (7.59%)
    6 / 119 (5.04%)
    7 / 119 (5.88%)
    21 / 236 (8.90%)
         occurrences all number
    26
    7
    8
    24
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    6 / 237 (2.53%)
    6 / 119 (5.04%)
    0 / 119 (0.00%)
    3 / 236 (1.27%)
         occurrences all number
    7
    7
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    64 / 237 (27.00%)
    30 / 119 (25.21%)
    39 / 119 (32.77%)
    64 / 236 (27.12%)
         occurrences all number
    103
    48
    74
    108
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 237 (5.06%)
    10 / 119 (8.40%)
    13 / 119 (10.92%)
    28 / 236 (11.86%)
         occurrences all number
    17
    15
    17
    37
    Bronchitis
         subjects affected / exposed
    12 / 237 (5.06%)
    12 / 119 (10.08%)
    9 / 119 (7.56%)
    5 / 236 (2.12%)
         occurrences all number
    14
    13
    11
    7
    Respiratory tract infection
         subjects affected / exposed
    13 / 237 (5.49%)
    3 / 119 (2.52%)
    5 / 119 (4.20%)
    10 / 236 (4.24%)
         occurrences all number
    16
    4
    10
    15
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 237 (4.22%)
    2 / 119 (1.68%)
    8 / 119 (6.72%)
    9 / 236 (3.81%)
         occurrences all number
    11
    9
    11
    12
    Pharyngitis
         subjects affected / exposed
    9 / 237 (3.80%)
    6 / 119 (5.04%)
    2 / 119 (1.68%)
    9 / 236 (3.81%)
         occurrences all number
    12
    9
    3
    14

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Apr 2016
    The following substantial amendments were made in protocol version 2 (dated 07 April 2016); however, as further minor updates were required, this version was not submitted. The submitted version of the protocol that contained these substantial amendments was therefore protocol version 3 (dated 15 April 2016). • 24-hour serum cortisol levels were no longer assessed. Morning cortisol or adrenocorticotropic hormone (ACTH) stimulation testing was included. • The serum budesonide analysis in a sub-group of subjects was considered better suited to a specialist unit. An exploratory population pharmacokinetic analysis was incorporated. • The Week 54 Follow-up call was changed to a clinic visit at Week 56; the Treatment Period Follow-up was extended to 4 weeks. • Study visits were not limited to take place in the morning. Within-subject assessments were performed at approximately the same time of day. • An additional exploratory endpoint (CompEx) was added to inform future studies. • A Data Monitoring Committee (with access to both blinded and unblinded data) was set up to assess the quality of the study as well as ensure subject safety in the study.
    22 Mar 2017
    • The sample size was increased to a total of 702 subjects due to continued overall low rate of CSEs and higher than projected early withdrawals.

    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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