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    Clinical Trial Results:
    A Phase IIb, Randomized (Stratified), Double-Blind (Sponsor Open), Parallel-Group, Placebo-Controlled, Dose-Finding Study of Nemiralisib (GSK2269557) Added to Standard of Care (SoC) Versus SoC Alone in Participants Diagnosed with an Acute Moderate or Severe Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)

    Summary
    EudraCT number
    		 2017-001074-42
    Trial protocol
    		 NL   SE   GB   PL   DE   ES   IT   RO  
    Global end of trial date
    10 Jan 2019

    Results information
    Results version number
    		 v1
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    200879
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom, TW8 9GS
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterize the dose response of nemiralisib administered in addition to SoC compared with placebo and SoC in participants diagnosed with an acute moderate or severe exacerbation of COPD
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 103
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 84
    Country: Number of subjects enrolled
    Italy: 43
    Country: Number of subjects enrolled
    Korea, Republic of: 68
    Country: Number of subjects enrolled
    Mexico: 16
    Country: Number of subjects enrolled
    Netherlands: 27
    Country: Number of subjects enrolled
    Poland: 89
    Country: Number of subjects enrolled
    Romania: 88
    Country: Number of subjects enrolled
    Russian Federation: 101
    Country: Number of subjects enrolled
    Spain: 114
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    United States: 126
    Worldwide total number of subjects
    943
    EEA total number of subjects
    484
    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)
    430
    From 65 to 84 years
    513
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a Phase IIb, multicenter, randomized, stratified, double-blind (sponsor open), placebo controlled parallel-group study in participants who presented with an acute moderate or severe exacerbation of chronic obstructive pulmonary disease (COPD) requiring Standard of Care (SoC).

    Pre-assignment
    Screening details
    		 A total of 943 participants were randomized, and 938 participants who received at least one dose of study treatment were included in the modified intent to treat (MITT) Population. The study included participants enrolled from 16 countries.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Carer, Data analyst, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants were administered a single oral inhalation of placebo via ELLIPTA dry powder inhaler (DPI) once daily in the morning for 12 weeks. Albuterol (salbutamol) metered-dose inhaler (MDI) or nebules were also provided to all participants as rescue medication.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received placebo as dry powder inhalation once in the morning.

    Arm title
    		 Nemiralisib 12.5 mcg
    Arm description
    		 Participants were administered a single oral inhalation of 12.5 micrograms (mcg) nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nemiralisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received Nemiralisib at concentration of 12.5 micrograms (mcg) as dry powder inhalation once in the morning.

    Arm title
    		 Nemiralisib 50 mcg
    Arm description
    		 Participants were administered a single oral inhalation of 50 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nemiralisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received Nemiralisib at concentration of 50 mcg as dry powder inhalation once in the morning.

    Arm title
    		 Nemiralisib 100 mcg
    Arm description
    		 Participants were administered a single oral inhalation of 100 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nemiralisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received Nemiralisib at concentration of 100 mcg as dry powder inhalation once in the morning.

    Arm title
    		 Nemiralisib 250 mcg
    Arm description
    		 Participants were administered a single oral inhalation of 250 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nemiralisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received Nemiralisib at concentration 250 mcg as dry powder inhalation once in the morning.

    Arm title
    		 Nemiralisib 500 mcg
    Arm description
    		 Participants were administered a single oral inhalation of 500 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nemiralisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received Nemiralisib at concentration of 500 mcg as dry powder inhalation once in the morning.

    Arm title
    		 Nemiralisib 750 mcg
    Arm description
    		 Participants were administered a single oral inhalation of 750 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nemiralisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received Nemiralisib at concentration of 750 mcg as dry powder inhalation once in the morning.

    Number of subjects in period 1 [1]
    		Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Started
    276
    22
    91
    92
    90
    89
    278
    Completed
    244
    19
    79
    81
    75
    73
    233
    Not completed
    32
    3
    12
    11
    15
    16
    45
         Consent withdrawn by subject
    11
    1
    5
    6
    3
    6
    16
         Physician decision
    3
    1
    -
    -
    1
    2
    3
         Protocol-defined stopping criteria
    9
    -
    -
    -
    2
    1
    1
         Adverse event, non-fatal
    4
    -
    5
    4
    6
    5
    16
         Lost to follow-up
    2
    -
    1
    -
    1
    2
    3
         Protocol deviation
    2
    -
    -
    -
    1
    -
    3
         Lack of efficacy
    1
    1
    1
    1
    1
    -
    3
    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: 943 participants were randomized, and 938 participants who received at least one dose of study treatment were included in the MITT Population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were administered a single oral inhalation of placebo via ELLIPTA dry powder inhaler (DPI) once daily in the morning for 12 weeks. Albuterol (salbutamol) metered-dose inhaler (MDI) or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 12.5 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 12.5 micrograms (mcg) nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 50 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 50 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 100 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 100 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 250 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 250 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 500 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 500 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 750 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 750 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg Total
    Number of subjects
    		 276 22 91 92 90 89 278 938
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 123 9 44 38 39 41 134 428
        From 65-84 years
    		 153 13 47 54 51 48 144 510
        85 years and over
    		 0 0 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 65.4 ( 7.94 ) 67.8 ( 7.20 ) 63.1 ( 7.61 ) 65.1 ( 7.43 ) 66.0 ( 6.94 ) 64.9 ( 8.04 ) 64.8 ( 7.61 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 86 6 35 29 31 22 100 309
        Male
    		 190 16 56 63 59 67 178 629
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 2 0 2 1 2 2 6 15
        Asian-East Asian Heritage
    		 18 4 7 2 9 7 19 66
        Asian-South East Asian Heritage
    		 1 0 0 1 0 1 1 4
        Black or African American
    		 2 1 2 1 0 2 6 14
        White-Arabic/North African Heritage
    		 1 0 1 1 0 1 0 4
        White-White Caucasian/European Heritage
    		 252 17 79 86 79 76 246 835

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were administered a single oral inhalation of placebo via ELLIPTA dry powder inhaler (DPI) once daily in the morning for 12 weeks. Albuterol (salbutamol) metered-dose inhaler (MDI) or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 12.5 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 12.5 micrograms (mcg) nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 50 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 50 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 100 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 100 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 250 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 250 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 500 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 500 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 750 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 750 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Primary: Change from Baseline in Clinic Visit trough forced expiratory volume in one second (FEV1) at Day 84 measured post bronchodilator

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    End point title
    		 Change from Baseline in Clinic Visit trough forced expiratory volume in one second (FEV1) at Day 84 measured post bronchodilator
    End point description
    Post-bronchodilator FEV1 was conducted approximately 10-30 minutes after administration of 4 inhalations of albuterol (salbutamol) via MDI using spacer/valved-holding chamber or via 1 nebulized treatment. Post-bronchodilator Baseline FEV1 is latest FEV1 measured prior to first dose of study treatment and post-bronchodilator. Change from Baseline in clinic visit trough FEV1 at Day 84 measured post-bronchodilator is FEV1 measured prior to dosing and post-bronchodilator on Day 84 minus post-bronchodilator Baseline FEV1. Bayesian repeated measure model adjusted for Baseline by visit interaction, treatment by visit interaction, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in previous 12 months and gender was used. Posterior adjusted median change from Baseline and 95% highest posterior density (HPD) credible interval (CrI) was presented. Only those participants with data at specified data points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline and Day 84
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    215 [1]
    16 [2]
    72 [3]
    75 [4]
    69 [5]
    58 [6]
    216 [7]
    Units: Liters
        median (confidence interval 95%)
    0.052 (0.018 to 0.091)
    0.031 (-0.090 to 0.149)
    0.026 (-0.036 to 0.084)
    0.014 (-0.044 to 0.073)
    0.058 (-0.002 to 0.118)
    0.049 (-0.017 to 0.113)
    0.049 (0.012 to 0.086)
    Notes
    [1] - MITT Population consists of randomized participants who received atleast 1 dose of study treatment.
    [2] - MITT Population.
    [3] - MITT Population.
    [4] - MITT Population.
    [5] - MITT Population.
    [6] - MITT Population.
    [7] - MITT Population.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.022
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.143
         upper limit
    		 0.103
    Notes
    [8] - Treatment comparison (posterior adjusted median difference and 95% HPD CrI) of Nemiralisib 12.5 mcg and placebo for Day 84 change from Baseline FEV1 measured post-bronchodilator has been presented.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    287
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.098
         upper limit
    		 0.036
    Notes
    [9] - Treatment comparison (posterior adjusted median difference and 95% HPD CrI) of Nemiralisib 50 mcg and placebo for Day 84 change from Baseline FEV1 measured post-bronchodilator has been presented.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.038
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.102
         upper limit
    		 0.028
    Notes
    [10] - Treatment comparison (posterior adjusted median difference and 95% HPD CrI) of Nemiralisib 100 mcg and placebo for Day 84 change from Baseline FEV1 measured post-bronchodilator has been presented.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    0.005
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.064
         upper limit
    		 0.071
    Notes
    [11] - Treatment comparison (posterior adjusted median difference and 95% HPD CrI) of Nemiralisib 250 mcg and placebo for Day 84 change from Baseline FEV1 measured post-bronchodilator has been presented.
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.075
         upper limit
    		 0.061
    Notes
    [12] - Treatment comparison (posterior adjusted median difference and 95% HPD CrI) of Nemiralisib 500 mcg and placebo for Day 84 change from Baseline FEV1 measured post-bronchodilator has been presented.
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.051
         upper limit
    		 0.042
    Notes
    [13] - Treatment comparison (posterior adjusted median difference and 95% HPD CrI) of Nemiralisib 750 mcg and placebo for Day 84 change from Baseline FEV1 measured post-bronchodilator has been presented.

    Secondary: Rate of moderate and severe exacerbations over 12-week treatment period

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    End point title
    		 Rate of moderate and severe exacerbations over 12-week treatment period
    End point description
    Moderate COPD exacerbations are defined as worsening symptoms of COPD treated with short-acting bronchodilators (SABDs) plus antibiotics and/or oral/systemic corticosteroids. Severe COPD exacerbations are defined as worsening symptoms of COPD that require hospitalization or visit to the emergency room. Severe exacerbation may also be associated with acute respiratory failure. Rate of exacerbations was analyzed using Bayesian Poisson model adjusting for length of on-treatment follow-up, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in the previous 12 months and gender. Posterior median exacerbation rate and 95% HPD CrI has been presented. The participants randomized to Nemiralisib 12.5 mcg were excluded from this analysis due to insufficient participants with data.
    End point type
    Secondary
    End point timeframe
    Up to Week 12
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [14]
    22 [15]
    91 [16]
    92 [17]
    90 [18]
    89 [19]
    278 [20]
    Units: No.of exacerbation per 84 Days
        median (confidence interval 95%)
    0.31 (0.25 to 0.39)
    99999 (99999 to 99999)
    0.29 (0.20 to 0.39)
    0.28 (0.20 to 0.38)
    0.32 (0.23 to 0.43)
    0.20 (0.13 to 0.29)
    0.36 (0.29 to 0.43)
    Notes
    [14] - MITT Population.
    [15] - MITT Population.
    [16] - MITT Population.
    [17] - MITT Population.
    [18] - MITT Population.
    [19] - MITT Population.
    [20] - MITT Population.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    Method
    Parameter type
    		 Posterior median exacerbation rate ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.4
    Notes
    [21] - Treatment comparison (posterior median exacerbation rate ratio and 95% HPD CrI) of Nemiralisib 50 mcg and placebo for moderate/severe exacerbations has been presented.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    Method
    Parameter type
    		 Posterior median exacerbation rate ratio
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.35
    Notes
    [22] - Treatment comparison (posterior median exacerbation rate ratio and 95% HPD CrI) of Nemiralisib 100 mcg and placebo for moderate/severe exacerbations has been presented.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    Method
    Parameter type
    		 Posterior median exacerbation rate ratio
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.5
    Notes
    [23] - Treatment comparison (posterior median exacerbation rate ratio and 95% HPD CrI) of Nemiralisib 250 mcg and placebo for moderate/severe exacerbations has been presented.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    Method
    Parameter type
    		 Posterior median exacerbation rate ratio
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.02
    Notes
    [24] - Treatment comparison (posterior median exacerbation rate ratio and 95% HPD CrI) of Nemiralisib 500 mcg and placebo for moderate/severe exacerbations has been presented.
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    Method
    Parameter type
    		 Posterior median exacerbation rate ratio
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.52
    Notes
    [25] - Treatment comparison (posterior median exacerbation rate ratio and 95% HPD CrI) of Nemiralisib 750 mcg and placebo for moderate/severe exacerbations has been presented.

    Secondary: Number of participants with Time to next moderate/severe exacerbation following index exacerbation

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    End point title
    		 Number of participants with Time to next moderate/severe exacerbation following index exacerbation
    End point description
    Time to next (on-treatment) moderate/severe exacerbation following index exacerbation during the 12-Week Treatment Period was defined as time from the date of randomization until the date of onset of the first moderate/severe exacerbation whilst on study treatment. Participants who did not have an exacerbation whilst on study treatment were censored at the date of their last dose of study treatment. Time to next exacerbation was analyzed using a Bayesian Cox proportional hazards model adjusting for treatment group, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in the previous 12 months and gender.
    End point type
    Secondary
    End point timeframe
    Up to Week 12
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [26]
    22 [27]
    91 [28]
    92 [29]
    90 [30]
    89 [31]
    278 [32]
    Units: Participants
    72
    3
    24
    25
    26
    15
    80
    Notes
    [26] - MITT Population.
    [27] - MITT Population.
    [28] - MITT Population.
    [29] - MITT Population.
    [30] - MITT Population.
    [31] - MITT Population.
    [32] - MITT Population.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    Method
    Parameter type
    		 Posterior median hazard ratio
    Point estimate
    0.455
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.054
         upper limit
    		 1.103
    Notes
    [33] - Treatment comparison (Hazard Ratio and 95% HPD CrI) of Nemiralisib 12.5 mcg and placebo for time to next moderate/severe exacerbations has been presented.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    Method
    Parameter type
    		 Posterior median hazard ratio
    Point estimate
    0.991
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.5
    Notes
    [34] - Treatment comparison (Hazard Ratio and 95% HPD CrI) of Nemiralisib 50 mcg and placebo for time to next moderate/severe exacerbations has been presented.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    Method
    Parameter type
    		 Posterior median hazard ratio
    Point estimate
    0.975
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.581
         upper limit
    		 1.467
    Notes
    [35] - Treatment comparison (Hazard Ratio and 95% HPD CrI) of Nemiralisib 100 mcg and placebo for time to next moderate/severe exacerbations has been presented.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [36]
    Method
    Parameter type
    		 Posterior median hazard ratio
    Point estimate
    1.132
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.682
         upper limit
    		 1.709
    Notes
    [36] - Treatment comparison (Hazard Ratio and 95% HPD CrI) of Nemiralisib 250 mcg and placebo for time to next moderate/severe exacerbations has been presented.
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    Method
    Parameter type
    		 Posterior median hazard ratio
    Point estimate
    0.556
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.268
         upper limit
    		 0.902
    Notes
    [37] - Treatment comparison (Hazard Ratio and 95% HPD CrI) of Nemiralisib 500 mcg and placebo for time to next moderate/severe exacerbations has been presented.
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [38]
    Method
    Parameter type
    		 Posterior median hazard ratio
    Point estimate
    1.149
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.539
    Notes
    [38] - Treatment comparison (Hazard Ratio and 95% HPD CrI) of Nemiralisib 750 mcg and placebo for time to next moderate/severe exacerbations has been presented.

    Secondary: Change from Baseline in Clinic Visit trough FEV1 measured pre and post-bronchodilator

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    End point title
    		 Change from Baseline in Clinic Visit trough FEV1 measured pre and post-bronchodilator
    End point description
    Pulmonary function was measured by FEV1. Post-bronchodilator FEV1 was conducted approximately 10-30 minutes after participant was administered with 4 inhalations of albuterol via MDI using a spacer/valved-holding chamber or via 1 nebulized treatment. Pre-bronchodilator and post-bronchodilator Baseline FEV1 is latest FEV1 measured prior to first dose of study treatment and pre-bronchodilator and post-bronchodilator, respectively. Change from Baseline in clinic visit trough FEV1 at Days 14, 28, 56 and 84 measured pre-bronchodilator is defined as FEV1 measured prior to dosing and pre-bronchodilator on Days 14, 28, 56 and 84 minus pre-bronchodilator Baseline FEV1. Only those participants with data available at specified data points were analyzed (represented by n= X in category titles). 99999 indicates standard deviation could not be calculated as single participant was analyzed. 88888 indicates number of participants analyzed was zero.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 14, 28, 56 (pre and post bronchodilaor), 84 (pre-bronchodilator) and at hospital discharge (maximum 24 Weeks)
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [39]
    22 [40]
    91 [41]
    92 [42]
    90 [43]
    89 [44]
    278 [45]
    Units: Liters
    arithmetic mean (standard deviation)
        Day 14, Pre, n=240, 20, 85, 83, 76, 76, 238
    0.008 ( 0.2729 )
    0.100 ( 0.2511 )
    -0.021 ( 0.2657 )
    -0.013 ( 0.2509 )
    0.053 ( 0.2958 )
    0.041 ( 0.2738 )
    0.023 ( 0.2561 )
        Day 14, Post, n=248, 20, 86, 83, 77, 78, 241
    0.034 ( 0.2707 )
    0.075 ( 0.2425 )
    0.010 ( 0.2168 )
    -0.050 ( 0.2477 )
    0.054 ( 0.2983 )
    0.073 ( 0.2655 )
    0.044 ( 0.2216 )
        Day 28, Pre, n=239, 20, 82, 79, 75, 71, 232
    0.017 ( 0.2585 )
    0.081 ( 0.2661 )
    -0.034 ( 0.2875 )
    -0.010 ( 0.2333 )
    0.064 ( 0.2592 )
    0.016 ( 0.2713 )
    0.020 ( 0.2512 )
        Day 28, Post, n=245, 19, 83, 81, 76, 72, 232
    0.036 ( 0.2647 )
    0.059 ( 0.2575 )
    0.004 ( 0.2183 )
    -0.034 ( 0.2401 )
    0.049 ( 0.2639 )
    0.027 ( 0.2369 )
    0.029 ( 0.2307 )
        Day 56, Pre, n=230, 20, 78, 76, 73, 67, 224
    0.005 ( 0.2295 )
    -0.006 ( 0.2636 )
    -0.024 ( 0.3210 )
    0.011 ( 0.2415 )
    0.022 ( 0.2522 )
    -0.004 ( 0.2233 )
    -0.001 ( 0.2858 )
        Day 56, Post, n=237, 19, 78, 77, 74, 69, 224
    0.020 ( 0.2614 )
    -0.002 ( 0.2252 )
    -0.012 ( 0.2524 )
    0.004 ( 0.2373 )
    0.026 ( 0.2556 )
    -0.011 ( 0.2260 )
    0.011 ( 0.2470 )
        Day 84, Pre, n=210, 17, 71, 73, 66, 58, 212
    0.000 ( 0.2566 )
    0.003 ( 0.2232 )
    -0.049 ( 0.2549 )
    0.005 ( 0.2668 )
    0.015 ( 0.2739 )
    0.007 ( 0.2461 )
    0.010 ( 0.2829 )
        Hospital discharge, Pre, n=23, 2, 8, 8, 7, 3, 22
    0.071 ( 0.1586 )
    0.168 ( 0.2652 )
    0.108 ( 0.3888 )
    0.056 ( 0.1782 )
    0.052 ( 0.3481 )
    0.162 ( 0.1426 )
    0.075 ( 0.1974 )
        Hospital discharge, Post, n=8, 2, 1, 1, 1, 0, 6
    0.134 ( 0.1514 )
    0.153 ( 0.0933 )
    0.083 ( 99999 )
    -0.076 ( 99999 )
    0.094 ( 99999 )
    88888 ( 99999 )
    -0.006 ( 0.1079 )
    Notes
    [39] - MITT Population.
    [40] - MITT Population.
    [41] - MITT Population.
    [42] - MITT Population.
    [43] - MITT Population.
    [44] - MITT Population.
    [45] - MITT Population.
    No statistical analyses for this end point

    Secondary: Change from hospital discharge in Clinic Visit trough FEV1 measured pre and post-bronchodilator

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    End point title
    		 Change from hospital discharge in Clinic Visit trough FEV1 measured pre and post-bronchodilator
    End point description
    FEV1, defined as maximal amount of air exhaled forcefully from lungs in 1 second. Post-bronchodilator FEV1 was conducted approximately 10-30 minutes after administration with 4 inhalations of albuterol via MDI using a spacer/valved-holding chamber or via 1 nebulized treatment. Pre- and post-bronchodilator Baseline FEV1 is defined as latest FEV1 measured prior to first dose of study treatment and pre- and post-bronchodilator, respectively. Change from hospital discharge in clinic visit trough FEV1 at Days 14, 28, 56 and 84 measured pre- and post-bronchodilator is defined as FEV1 measured prior to dosing and pre- and post-bronchodilator on Days 14, 28, 56 and 84 minus pre and post-bronchodilator Baseline FEV1. Only those participants with data at specified data points were analyzed (represented by n= X in category titles). 99999 indicates standard deviation could not be calculated as single participant was analyzed. 88888 indicates number of participants analyzed was 0.
    End point type
    Secondary
    End point timeframe
    Baseline and pre- and post-bronchodilator on Days 14, 28, 56 and 84
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [46]
    22 [47]
    91 [48]
    92 [49]
    90 [50]
    89 [51]
    278 [52]
    Units: Liters
    arithmetic mean (standard deviation)
        Day 14, Pre, n=20, 2, 8, 8, 6, 4, 20
    0.082 ( 0.2783 )
    0.355 ( 0.4207 )
    0.069 ( 0.3012 )
    -0.049 ( 0.1882 )
    -0.069 ( 0.4905 )
    0.173 ( 0.5137 )
    0.002 ( 0.2343 )
        Day 14, Post, n=5, 2, 1, 1, 1, 0, 5
    0.056 ( 0.3372 )
    0.431 ( 0.5190 )
    0.119 ( 99999 )
    0.310 ( 99999 )
    -0.305 ( 99999 )
    88888 ( 99999 )
    -0.021 ( 0.1326 )
        Day 28, Pre, n=37, 2, 14, 8, 10, 9, 37
    0.026 ( 0.2691 )
    0.261 ( 0.5204 )
    0.012 ( 0.2910 )
    -0.085 ( 0.2072 )
    0.012 ( 0.4020 )
    0.030 ( 0.4029 )
    -0.046 ( 0.2639 )
        Day 28, Post, n=22, 2, 8, 1, 4, 4, 22
    0.034 ( 0.2779 )
    0.334 ( 0.5614 )
    0.130 ( 0.2327 )
    0.130 ( 99999 )
    0.009 ( 0.2006 )
    0.007 ( 0.3237 )
    -0.094 ( 0.2293 )
        Day 56, Pre, n=37, 2, 14, 8, 9, 10, 36
    0.019 ( 0.2282 )
    0.106 ( 0.6138 )
    0.019 ( 0.3509 )
    0.014 ( 0.1938 )
    -0.074 ( 0.3847 )
    -0.042 ( 0.1840 )
    -0.054 ( 0.2942 )
        Day 56, Post, n=22, 2, 7, 1, 4, 5, 21
    -0.014 ( 0.2896 )
    0.139 ( 0.6838 )
    0.042 ( 0.3068 )
    0.098 ( 99999 )
    -0.056 ( 0.3572 )
    -0.072 ( 0.1490 )
    -0.135 ( 0.2410 )
        Day 84, Pre, n=37, 2, 12, 8, 7, 10, 35
    0.007 ( 0.2741 )
    -0.027 ( 0.4554 )
    0.121 ( 0.2770 )
    -0.081 ( 0.1738 )
    -0.072 ( 0.4391 )
    0.043 ( 0.2511 )
    -0.062 ( 0.2816 )
        Day 84, Post, n=22, 2, 6, 1, 4, 5, 22
    -0.039 ( 0.2610 )
    0.133 ( 0.5162 )
    0.037 ( 0.3341 )
    0.108 ( 99999 )
    0.021 ( 0.3151 )
    0.006 ( 0.2180 )
    -0.106 ( 0.2956 )
    Notes
    [46] - MITT Population.
    [47] - MITT Population.
    [48] - MITT Population.
    [49] - MITT Population.
    [50] - MITT Population.
    [51] - MITT Population.
    [52] - MITT Population.
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving the exacerbations of chronic pulmonary disease tool (EXACT) definition of recovery from the index exacerbation

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    End point title
    		 Percentage of participants achieving the exacerbations of chronic pulmonary disease tool (EXACT) definition of recovery from the index exacerbation
    End point description
    EXACT patient-reported outcome (EXACT-PRO), 14-item instrument to capture occurrence, frequency, severity, and duration of exacerbations using an electronic diary (eDiary). Total score ranges from 0-100, higher score indicates more severe condition. Participants were required to complete EXACT-PRO every evening; however, on the day of randomization it was to be completed in the morning. Response was decrease in rolling average EXACT Total Score >=9 points from maximum observed value, sustained for >=7 days, with first of 7 days defined as recovery day. Analysis was performed using Bayesian Cox proportional hazards model adjusting for treatment group, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in previous 12 months and gender.
    End point type
    Secondary
    End point timeframe
    Days 14, 28, 56 and 84
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [53]
    22 [54]
    91 [55]
    92 [56]
    90 [57]
    89 [58]
    278 [59]
    Units: Percentage of participants
        Day 14
    29
    27
    37
    29
    28
    24
    32
        Day 28
    40
    41
    52
    43
    42
    27
    42
        Day 56
    49
    45
    59
    52
    50
    31
    50
        Day 84
    51
    50
    59
    54
    50
    37
    54
    Notes
    [53] - MITT Population.
    [54] - MITT Population.
    [55] - MITT Population.
    [56] - MITT Population.
    [57] - MITT Population.
    [58] - MITT Population.
    [59] - MITT Population.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [60]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 2.3
    Notes
    [60] - Treatment comparison between placebo and nemiralisib 12.5 mcg at Day 14 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [61]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 2.17
    Notes
    [61] - Treatment comparison between placebo and nemiralisib 50 mcg at Day 14 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [62]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.61
    Notes
    [62] - Treatment comparison between placebo and nemiralisib 100 mcg at Day 14 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [63]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.49
    Notes
    [63] - Treatment comparison between placebo and nemiralisib 250 mcg at Day 14 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [64]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.25
    Notes
    [64] - Treatment comparison between placebo and nemiralisib 500 mcg at Day 14 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [65]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.63
    Notes
    [65] - Treatment comparison between placebo and nemiralisib 750 mcg at Day 14 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 7
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [66]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 2.69
    Notes
    [66] - Treatment comparison between placebo and nemiralisib 12.5 mcg at Day 28 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 8
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [67]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 2.33
    Notes
    [67] - Treatment comparison between placebo and nemiralisib 50 mcg at Day 28 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 9
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [68]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.79
    Notes
    [68] - Treatment comparison between placebo and nemiralisib 100 mcg at Day 28 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 10
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [69]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.74
    Notes
    [69] - Treatment comparison between placebo and nemiralisib 250 mcg at Day 28 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 11
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [70]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 0.88
    Notes
    [70] - Treatment comparison between placebo and nemiralisib 500 mcg at Day 28 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 12
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [71]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.49
    Notes
    [71] - Treatment comparison between placebo and nemiralisib 750 mcg at Day 28 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 13
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [72]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 2.17
    Notes
    [72] - Treatment comparison between placebo and nemiralisib 12.5 mcg at Day 56 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 14
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [73]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 2.27
    Notes
    [73] - Treatment comparison between placebo and nemiralisib 50 mcg at Day 56 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 15
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [74]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.78
    Notes
    [74] - Treatment comparison between placebo and nemiralisib 100 mcg at Day 56 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 16
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [75]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.67
    Notes
    [75] - Treatment comparison between placebo and nemiralisib 250 mcg at Day 56 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 17
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [76]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 0.77
    Notes
    [76] - Treatment comparison between placebo and nemiralisib 500 mcg at Day 56 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 18
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [77]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.42
    Notes
    [77] - Treatment comparison between placebo and nemiralisib 750 mcg at Day 56 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 19
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [78]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 2.38
    Notes
    [78] - Treatment comparison between placebo and nemiralisib 12.5 mcg at Day 84 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 20
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [79]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 2
    Notes
    [79] - Treatment comparison between placebo and nemiralisib 50 mcg at Day 84 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 21
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [80]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.71
    Notes
    [80] - Treatment comparison between placebo and nemiralisib 100 mcg at Day 84 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 22
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [81]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.48
    Notes
    [81] - Treatment comparison between placebo and nemiralisib 250 mcg at Day 84 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 23
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [82]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.87
    Notes
    [82] - Treatment comparison between placebo and nemiralisib 500 mcg at Day 84 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 24
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [83]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.47
    Notes
    [83] - Treatment comparison between placebo and nemiralisib 500 mcg at Day 84 was performed and posterior median odds ratio and 95% HPD CrI has been presented.

    Secondary: Time to recovery from index exacerbation using EXACT- PRO tool

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    End point title
    		 Time to recovery from index exacerbation using EXACT- PRO tool
    End point description
    Time to EXACT-defined recovery from index exacerbation is defined as time from the date of randomization until date of the first EXACT-defined recovery day during the 12-Week Treatment Period. EXACT-defined recovery from the index exacerbation is defined as a decrease in the Rolling Average EXACT total Score >=9 points from the Maximum Observed Value, sustained for >=7 days, with the first of the 7 days defined as the recovery day. Analysis was performed using a Bayesian Cox proportional hazards model adjusting for treatment group, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in the previous 12 months and gender. Number of participants reporting events is presented.
    End point type
    Secondary
    End point timeframe
    From randomization to Week 12
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [84]
    22 [85]
    91 [86]
    92 [87]
    90 [88]
    89 [89]
    278 [90]
    Units: Participants
    141
    11
    54
    50
    45
    34
    149
    Notes
    [84] - MITT Population.
    [85] - MITT Population.
    [86] - MITT Population.
    [87] - MITT Population.
    [88] - MITT Population.
    [89] - MITT Population.
    [90] - MITT Population.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [91]
    Method
    Parameter type
    		 Posterior median hazard ratio
    Point estimate
    1.053
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.477
         upper limit
    		 1.765
    Notes
    [91] - Treatment comparison between placebo and Nemiralisib 12.5 mcg was performed and posterior median hazard ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [92]
    Method
    Parameter type
    		 Posterior median hazard ratio
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.597
    Notes
    [92] - Treatment comparison between placebo and Nemiralisib 50 mcg was performed and posterior median hazard ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [93]
    Method
    Parameter type
    		 Posterior median hazard ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.734
         upper limit
    		 1.432
    Notes
    [93] - Treatment comparison between placebo and Nemiralisib 100 mcg was performed and posterior median hazard ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [94]
    Method
    Parameter type
    		 Posterior median hazard ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.719
         upper limit
    		 1.413
    Notes
    [94] - Treatment comparison between placebo and Nemiralisib 250 mcg was performed and posterior median hazard ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [95]
    Method
    Parameter type
    		 Posterior median hazard ratio
    Point estimate
    0.751
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.487
         upper limit
    		 1.057
    Notes
    [95] - Treatment comparison between placebo and Nemiralisib 500 mcg was performed and posterior median hazard ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [96]
    Method
    Parameter type
    		 Posterior median hazard ratio
    Point estimate
    1.149
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.899
         upper limit
    		 1.426
    Notes
    [96] - Treatment comparison between placebo and Nemiralisib 750 mcg was performed and posterior median hazard ratio and 95% HPD CrI has been presented.

    Secondary: Mean severity of subsequent health care resource use (HCRU) exacerbations defined by EXACT

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    End point title
    		 Mean severity of subsequent health care resource use (HCRU) exacerbations defined by EXACT
    End point description
    Severity of subsequent HCRU-defined exacerbations defined by EXACT was defined as the highest EXACT Total Score (not using the 3-day Rolling Average) during the period from date of onset of the subsequent HCRU-exacerbation until date of EXACT-defined recovery of subsequent exacerbation. EXACT-PRO, 14-item instrument to capture occurrence, frequency, severity, and duration of exacerbations using an eDiary. Total score ranges from 0-100, higher score indicates more severe condition. For participants with more than one subsequent exacerbation, severity was calculated for each subsequent exacerbation. Only those participants with data available at specified data points were analyzed (represented by n=X in the category title). 99999 indicates standard deviation could not be calculated as only one participant was analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Week 12
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [97]
    22 [98]
    91 [99]
    92 [100]
    90 [101]
    89 [102]
    278 [103]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Moderate/Severe, n=66, 3, 23, 25, 26, 15, 78
    53.3 ( 12.16 )
    64.6 ( 25.20 )
    59.8 ( 12.82 )
    50.5 ( 10.76 )
    47.5 ( 13.95 )
    57.6 ( 10.30 )
    51.9 ( 10.78 )
        Moderate, n=55, 3, 15, 23, 17, 10, 63
    53.1 ( 11.54 )
    60.0 ( 26.56 )
    57.4 ( 11.08 )
    50.0 ( 11.15 )
    46.3 ( 14.20 )
    53.8 ( 9.28 )
    50.0 ( 10.17 )
        Severe, n=13, 1, 9, 3, 10, 6, 20
    54.0 ( 15.53 )
    83.0 ( 99999 )
    64.0 ( 15.01 )
    55.3 ( 5.69 )
    49.5 ( 13.95 )
    64.1 ( 8.99 )
    58.8 ( 10.34 )
    Notes
    [97] - Severity was derived for participants from MITT Population who had reported subsequent exacerbation.
    [98] - Severity was derived for participants from MITT Population who had reported subsequent exacerbation.
    [99] - Severity was derived for participants from MITT Population who had reported subsequent exacerbation.
    [100] - Severity was derived for participants from MITT Population who had reported subsequent exacerbation.
    [101] - Severity was derived for participants from MITT Population who had reported subsequent exacerbation.
    [102] - Severity was derived for participants from MITT Population who had reported subsequent exacerbation.
    [103] - Severity was derived for participants from MITT Population who had reported subsequent exacerbation.
    No statistical analyses for this end point

    Secondary: Percentage of responders using the COPD Assessment Test (CAT) on treatment Days 28, 56, and 84, and following EXACT defined recovery from the index exacerbation

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    End point title
    		 Percentage of responders using the COPD Assessment Test (CAT) on treatment Days 28, 56, and 84, and following EXACT defined recovery from the index exacerbation
    End point description
    The CAT is a short, self-completed, 8-item questionnaire, each item was rated on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment). The total CAT score is calculated by summing the scores of all items and ranges from 0 to 40, higher scores indicating severe condition. The percentage of responders using the CAT is defined as number of participants with a decrease from Baseline in CAT Total Score >=2 on or before Days 28, 56 and 84 divided by total number of participants in the MITT population. Percentage of responders using CAT was derived only for participants with a Baseline CAT Total Score >=2. Analysis was performed using a separate Bayesian logistic regression for each time point adjusting for treatment group, smoking status at baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in the previous 12 months and gender.
    End point type
    Secondary
    End point timeframe
    Days 28, 56 and 84
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [104]
    22 [105]
    91 [106]
    92 [107]
    90 [108]
    89 [109]
    278 [110]
    Units: Percentage of responders
        Day 28
    32
    36
    34
    39
    38
    34
    25
        Day 56
    63
    50
    73
    61
    69
    55
    61
        Day 84
    70
    55
    78
    65
    72
    60
    66
    Notes
    [104] - MITT Population.
    [105] - MITT Population.
    [106] - MITT Population.
    [107] - MITT Population.
    [108] - MITT Population.
    [109] - MITT Population.
    [110] - MITT Population.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [111]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 2.7
    Notes
    [111] - Treatment comparison between placebo and nemiralisib 12.5 mcg at Day 28 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [112]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.77
    Notes
    [112] - Treatment comparison between placebo and nemiralisib 50 mcg at Day 28 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [113]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 2.17
    Notes
    [113] - Treatment comparison between placebo and nemiralisib 100 mcg at Day 28 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [114]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 2
    Notes
    [114] - Treatment comparison between placebo and nemiralisib 250 mcg at Day 28 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [115]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.75
    Notes
    [115] - Treatment comparison between placebo and nemiralisib 500 mcg at Day 28 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Anallysis 6
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [116]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.99
    Notes
    [116] - Treatment comparison between placebo and nemiralisib 750 mcg at Day 28 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 7
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [117]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 1.41
    Notes
    [117] - Treatment comparison between placebo and nemiralisib 12.5 mcg at Day 56 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 8
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [118]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 2.46
    Notes
    [118] - Treatment comparison between placebo and nemiralisib 50 mcg at Day 56 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 9
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [119]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.48
    Notes
    [119] - Treatment comparison between placebo and nemiralisib 100 mcg at Day 56 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 10
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [120]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 2.16
    Notes
    [120] - Treatment comparison between placebo and nemiralisib 250 mcg at Day 56 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 11
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [121]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.17
    Notes
    [121] - Treatment comparison between placebo and nemiralisib 500 mcg at Day 56 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 12
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [122]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.27
    Notes
    [122] - Treatment comparison between placebo and nemiralisib 750 mcg at Day 56 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 13
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [123]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 1.2
    Notes
    [123] - Treatment comparison between placebo and nemiralisib 12.5 mcg at Day 84 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 14
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [124]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 2.56
    Notes
    [124] - Treatment comparison between placebo and nemiralisib 50 mcg at Day 84 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 15
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [125]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.3
    Notes
    [125] - Treatment comparison between placebo and nemiralisib 100 mcg at Day 84 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 16
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [126]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.86
    Notes
    [126] - Treatment comparison between placebo and nemiralisib 250 mcg at Day 84 was performed and posterior median odds ratio and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 17
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [127]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1.02
    Notes
    [127] - Treatment comparison between placebo and nemiralisib 500 mcg at Day 84 was performed and posterior median odds ratio and 95% HPD CrI has been presented
    Statistical analysis title
    		 Statistical Analysis 18
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [128]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.17
    Notes
    [128] - Treatment comparison between placebo and nemiralisib 750 mcg at Day 84 was performed and posterior median odds ratio and 95% HPD CrI has been presented.

    Secondary: Change from Baseline in CAT total score

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    End point title
    		 Change from Baseline in CAT total score
    End point description
    CAT is a short, self-completed, 8-item questionnaire, each item was rated on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment). Total CAT score was calculated by summing scores of all items and ranges from 0 to 40, higher scores indicating more severe condition. Baseline (Day 1) is latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline in CAT Total Score is CAT Total Score on Days 28, 56 and 84 minus Baseline CAT Total Score. Analysis was using Bayesian repeated measures model adjusting for Baseline by visit interaction, treatment by visit interaction, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in the previous 12 months and gender. Posterior adjusted median change from Baseline and 95% HPD CrI has been presented. Only those participants with data available at specified data points were analyzed (represented by n= X in category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and at Days 28, 56 and 84
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [129]
    22 [130]
    91 [131]
    92 [132]
    90 [133]
    89 [134]
    278 [135]
    Units: Scores on a scale
    median (confidence interval 95%)
        Day 28, n=234, 19, 86, 80, 77, 74, 229
    -4.7 (-5.6 to -3.8)
    -2.3 (-5.1 to 0.5)
    -4.0 (-5.4 to -2.7)
    -3.9 (-5.4 to -2.4)
    -5.1 (-6.5 to -3.7)
    -3.1 (-4.5 to -1.6)
    -4.7 (-5.6 to -3.8)
        Day 56, n=231, 20, 78, 77, 76, 69, 222
    -4.2 (-5.2 to -3.3)
    -1.9 (-4.7 to 1.0)
    -3.4 (-5.0 to -1.9)
    -4.5 (-6.0 to -2.9)
    -4.8 (-6.4 to -3.4)
    -3.8 (-5.5 to -2.3)
    -4.4 (-5.4 to -3.5)
        Day 84, n=218, 17, 75, 75, 69, 62, 213
    -4.6 (-5.6 to -3.6)
    -2.7 (-6.0 to 0.3)
    -3.5 (-5.0 to -1.9)
    -5.1 (-6.7 to -3.5)
    -4.7 (-6.3 to -3.1)
    -3.8 (-5.4 to -2.1)
    -4.2 (-5.2 to -3.2)
    Notes
    [129] - MITT Population.
    [130] - MITT Population.
    [131] - MITT Population.
    [132] - MITT Population.
    [133] - MITT Population.
    [134] - MITT Population.
    [135] - MITT Population.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [136]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 5.2
    Notes
    [136] - Treatment comparison between placebo and Nemiralisib 12.5 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [137]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 2.3
    Notes
    [137] - Treatment comparison between placebo and Nemiralisib 50 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [138]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 2.4
    Notes
    [138] - Treatment comparison between placebo and Nemiralisib 100 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [139]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 1.2
    Notes
    [139] - Treatment comparison between placebo and Nemiralisib 250 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [140]
    Method
    Parameter type
    		 Posterior adjacent median difference
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 3.3
    Notes
    [140] - Treatment comparison between placebo and Nemiralisib 500 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [141]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 1.1
    Notes
    [141] - Treatment comparison between placebo and Nemiralisib 750 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 7
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [142]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 5.4
    Notes
    [142] - Treatment comparison between placebo and Nemiralisib 12.5 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 8
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [143]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 2.4
    Notes
    [143] - Treatment comparison between placebo and Nemiralisib 50 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 9
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [144]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 1.4
    Notes
    [144] - Treatment comparison between placebo and Nemiralisib 100 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 10
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [145]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 1
    Notes
    [145] - Treatment comparison between placebo and Nemiralisib 250 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 11
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [146]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 2.2
    Notes
    [146] - Treatment comparison between placebo and Nemiralisib 500 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analyis 12
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [147]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 1
    Notes
    [147] - Treatment comparison between placebo and Nemiralisib 750 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 13
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [148]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 5.1
    Notes
    [148] - Treatment comparison between placebo and Nemiralisib 12.5 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 14
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [149]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 2.8
    Notes
    [149] - Treatment comparison between placebo and Nemiralisib 50 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 15
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [150]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 1.1
    Notes
    [150] - Treatment comparison between placebo and Nemiralisib 100 mcg at Day 84 was performed and posterior adjsted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 16
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [151]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 1.7
    Notes
    [151] - Treatment comparison between placebo and Nemiralisib 250 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 17
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [152]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 2.8
    Notes
    [152] - Treatment comparison between placebo and Nemiralisib 500 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 18
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [153]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 1.7
    Notes
    [153] - Treatment comparison between placebo and Nemiralisib 750 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.

    Secondary: Percentage of responders on the St. George’s Respiratory Questionnaire (SGRQ) total score as measured by the SGRQ for COPD participants (SGRQ-C) at Days 28, 56, and 84

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    End point title
    		 Percentage of responders on the St. George’s Respiratory Questionnaire (SGRQ) total score as measured by the SGRQ for COPD participants (SGRQ-C) at Days 28, 56, and 84
    End point description
    SGRQ-C is a 40-item questionnaire designed specifically to focus on COPD participants and was scored equivalent to the SGRQ Total Score, ranging from 0 to 100, where higher scores reflect worse health-related quality of life. The percentage of responders on the SGRQ Total Score was derived for participants with a Baseline SGRQ Total Score >=4. Percentage of responders on the SGRQ Total Score is defined as number of participants with a decrease from Baseline in SGRQ Total Score >=4 on or before Days 28, 56 and 84 divided by total number of participants in the MITT population. Analysis was performed using a separate Bayesian logistic regression for each time point adjusting for treatment group, smoking status at baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in the previous 12 months and gender. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Days 28, 56 and 84
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [154]
    22 [155]
    91 [156]
    92 [157]
    90 [158]
    89 [159]
    278 [160]
    Units: Percentage of responders
        Day 28
    21
    14
    19
    26
    32
    24
    21
        Day 56
    50
    36
    56
    55
    60
    49
    53
        Day 84
    61
    50
    66
    63
    68
    57
    62
    Notes
    [154] - MITT Population.
    [155] - MITT Population.
    [156] - MITT Population.
    [157] - MITT Population.
    [158] - MITT Population.
    [159] - MITT Population.
    [160] - MITT Population.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [161]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 1.41
    Notes
    [161] - Treatment comparison between placebo and Nemiralisib 12.5 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [162]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.47
    Notes
    [162] - Treatment comparison between placebo and Nemiralisib 50 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [163]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 2.24
    Notes
    [163] - Treatment comparison between placebo and Nemiralisib 100 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [164]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 2.91
    Notes
    [164] - Treatment comparison between placebo and Nemiralisib 250 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [165]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 2.08
    Notes
    [165] - Treatment comparison between placebo and Nemiralisib 500 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [166]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.4
    Notes
    [166] - Treatment comparison between placebo and Nemiralisib 750 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 7
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [167]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 1.16
    Notes
    [167] - Treatment comparison between placebo and Nemiralisib 12.5 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 8
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [168]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.98
    Notes
    [168] - Treatment comparison between placebo and Nemiralisib 50 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 9
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [169]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.97
    Notes
    [169] - Treatment comparison between placebo and Nemiralisib 100 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 10
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [170]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 2.27
    Notes
    [170] - Treatment comparison between placebo and Nemiralisib 250 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 11
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [171]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.62
    Notes
    [171] - Treatment comparison between placebo and Nemiralisib 500 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 12
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [172]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.5
    Notes
    [172] - Treatment comparison between placebo and Nemiralisib 750 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 13
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [173]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 1.39
    Notes
    [173] - Treatment comparison between placebo and Nemiralisib 12.5 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 14
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [174]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 2.01
    Notes
    [174] - Treatment comparison between placebo and Nemiralisib 50 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 15
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [175]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.79
    Notes
    [175] - Treatment comparison between placebo and Nemiralisib 100 mcg at Day 84 was performed and posterior adjsted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 16
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [176]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 2.14
    Notes
    [176] - Treatment comparison between placebo and Nemiralisib 250 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 17
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [177]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.45
    Notes
    [177] - Treatment comparison between placebo and Nemiralisib 500 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 18
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [178]
    Method
    Parameter type
    		 Posterior median odds ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.43
    Notes
    [178] - Treatment comparison between placebo and Nemiralisib 750 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.

    Secondary: Change from Baseline in SGRQ total score at Days 28, 56 and 84

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    End point title
    		 Change from Baseline in SGRQ total score at Days 28, 56 and 84
    End point description
    SGRQ-C is 40-item questionnaire was scored equivalent to SGRQ Total Score, ranging from 0-100, higher scores reflect worse health-related quality of life. Scores on a scale were calculated as 100*summed weights from positive items in questionnaire divided by sum of weights of all items in questionnaire. Baseline (Day 1) is latest pre-dose assessment with a non-missing value, including those from unscheduled visits. Change from Baseline in SGRQ Total Score is SGRQ Total Score on Days 28, 56 and 84 minus Baseline SGRQ Total Score. Analysis was using Bayesian repeated measures model adjusting for Baseline by visit interaction, treatment by visit interaction, smoking status at Baseline, region, severity of index exacerbation, number of moderate/severe exacerbations in previous 12 months and gender. Posterior adjusted median change from Baseline and 95% HPD CrI was presented. Only those participants with data at specified data points were analyzed (represented by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and Days 28, 56 and 84
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [179]
    22 [180]
    91 [181]
    92 [182]
    90 [183]
    89 [184]
    278 [185]
    Units: Scores on a scale
    median (confidence interval 95%)
        Day 28, n=232, 19, 86, 78, 77, 72, 225
    -7.7 (-9.8 to -5.7)
    -5.7 (-12.2 to 0.5)
    -8.2 (-11.4 to -5.1)
    -10.6 (-13.8 to -7.1)
    -10.9 (-14.2 to -7.6)
    -7.8 (-11.2 to -4.3)
    -7.9 (-9.9 to -5.9)
        Day 56, n=227, 20, 78, 77, 74, 68, 219
    -8.0 (-10.2 to -6.0)
    -3.9 (-10.4 to 2.8)
    -9.3 (-12.5 to -5.9)
    -10.7 (-14.1 to -7.3)
    -11.3 (-14.6 to -7.6)
    -8.9 (-12.6 to -5.5)
    -8.4 (-10.6 to -6.3)
        Day 84, n=218, 17, 74, 74, 69, 60, 209
    -9.1 (-11.3 to -6.8)
    -6.6 (-13.6 to 0.3)
    -9.3 (-12.8 to -6.0)
    -11.3 (-14.8 to -7.7)
    -10.9 (-14.4 to -7.2)
    -9.4 (-13.1 to -5.5)
    -7.9 (-10.1 to -5.7)
    Notes
    [179] - MITT Population.
    [180] - MITT Population.
    [181] - MITT Population.
    [182] - MITT Population.
    [183] - MITT Population.
    [184] - MITT Population.
    [185] - MITT Population.
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [186]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 8.3
    Notes
    [186] - Treatment comparison between placebo and Nemiralisib 12.5 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [187]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 3.1
    Notes
    [187] - Treatment comparison between placebo and Nemiralisib 50 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [188]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 1.1
    Notes
    [188] - Treatment comparison between placebo and Nemiralisib 100 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [189]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.7
         upper limit
    		 0.4
    Notes
    [189] - Treatment comparison between placebo and Nemiralisib 250 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [190]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 3.5
    Notes
    [190] - Treatment comparison between placebo and Nemiralisib 500 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 7
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [191]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 11
    Notes
    [191] - Treatment comparison between placebo and Nemiralisib 12.5 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analyais 6
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [192]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 2.3
    Notes
    [192] - Treatment comparison between placebo and Nemiralisib 750 mcg at Day 28 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 8
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [193]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 2.5
    Notes
    [193] - Treatment comparison between placebo and Nemiralisib 50 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 9
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [194]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.3
         upper limit
    		 1.1
    Notes
    [194] - Treatment comparison between placebo and Nemiralisib 100 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 10
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [195]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 0.4
    Notes
    [195] - Treatment comparison between placebo and Nemiralisib 250 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 11
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [196]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 3
    Notes
    [196] - Treatment comparison between placebo and Nemiralisib 500 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 12
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [197]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 2.5
    Notes
    [197] - Treatment comparison between placebo and Nemiralisib 750 mcg at Day 56 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 13
    Comparison groups
    Placebo v Nemiralisib 12.5 mcg
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [198]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 9.4
    Notes
    [198] - Treatment comparison between placebo and Nemiralisib 12.5 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 14
    Comparison groups
    Placebo v Nemiralisib 50 mcg
    Number of subjects included in analysis
    367
    Analysis specification
    Pre-specified
    Analysis type
    		 other [199]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 3.6
    Notes
    [199] - Treatment comparison between placebo and Nemiralisib 50 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 15
    Comparison groups
    Placebo v Nemiralisib 100 mcg
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [200]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.1
         upper limit
    		 1.8
    Notes
    [200] - Treatment comparison between placebo and Nemiralisib 100 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 16
    Comparison groups
    Placebo v Nemiralisib 250 mcg
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [201]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.7
         upper limit
    		 2.3
    Notes
    [201] - Treatment comparison between placebo and Nemiralisib 250 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 17
    Comparison groups
    Placebo v Nemiralisib 500 mcg
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    		 other [202]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 3.8
    Notes
    [202] - Treatment comparison between placebo and Nemiralisib 500 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.
    Statistical analysis title
    		 Statistical Analysis 18
    Comparison groups
    Placebo v Nemiralisib 750 mcg
    Number of subjects included in analysis
    554
    Analysis specification
    Pre-specified
    Analysis type
    		 other [203]
    Method
    Parameter type
    		 Posterior adjusted median difference
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 4
    Notes
    [203] - Treatment comparison between placebo and Nemiralisib 750 mcg at Day 84 was performed and posterior adjusted median difference and 95% HPD CrI has been presented.

    Secondary: Mean number of occasions of rescue medication use per day

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    End point title
    		 Mean number of occasions of rescue medication use per day
    End point description
    Albuterol (Salbutamol) MDI or nebules was used as a rescue medication. Rescue medication use was recorded as the number of occasions of rescue medication use each day. The mean number of occasions of rescue medication use per day is defined as sum of the number of occasions of rescue medication use each day within the time-period divided by the total number of days with non-missing values within the time-period. Over the 12-Week treatment period is defined as Day 1 to Day of last dose. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 of treatment and over the Week 12 treatment period
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [204]
    22 [205]
    91 [206]
    92 [207]
    90 [208]
    89 [209]
    278 [210]
    Units: No. of occasions of rescue use per day
    arithmetic mean (standard deviation)
        Week 1, n=254, 21, 87, 88, 80, 79, 254
    1.699 ( 1.7674 )
    2.112 ( 2.2977 )
    1.633 ( 1.4320 )
    1.926 ( 2.1569 )
    1.670 ( 1.5728 )
    1.917 ( 1.9298 )
    1.747 ( 1.7332 )
        Week 2, n=259, 21, 88, 89, 80, 82, 252
    1.650 ( 1.8711 )
    2.231 ( 2.7169 )
    1.469 ( 1.4036 )
    1.712 ( 2.0310 )
    1.497 ( 1.5700 )
    1.611 ( 1.7717 )
    1.587 ( 1.6531 )
        Week 3, n=256, 21, 90, 88, 80, 81, 245
    1.729 ( 1.8157 )
    2.021 ( 2.2926 )
    1.495 ( 1.3943 )
    1.693 ( 1.9679 )
    1.488 ( 1.6611 )
    1.742 ( 1.8380 )
    1.655 ( 1.7430 )
        Week 4, n=250, 21, 89, 87, 81, 77, 243
    1.684 ( 1.7706 )
    2.190 ( 2.3657 )
    1.514 ( 1.5022 )
    1.720 ( 2.0083 )
    1.489 ( 1.6734 )
    2.009 ( 2.0506 )
    1.707 ( 1.7512 )
        Week 5, n=251, 20, 88, 85, 78, 76, 240
    1.735 ( 1.8662 )
    2.329 ( 2.6394 )
    1.533 ( 1.5706 )
    1.750 ( 2.0380 )
    1.535 ( 1.8384 )
    1.949 ( 1.9685 )
    1.737 ( 1.8030 )
        Week 6, n=250, 20, 86, 84, 78, 72, 234
    1.741 ( 1.9543 )
    2.378 ( 2.6904 )
    1.382 ( 1.4000 )
    1.792 ( 2.0822 )
    1.636 ( 1.8042 )
    1.936 ( 2.0729 )
    1.780 ( 1.8083 )
        Week 7, n=250, 20, 85, 83, 77, 71, 231
    1.703 ( 1.9914 )
    2.479 ( 2.6976 )
    1.531 ( 1.6374 )
    1.697 ( 2.0769 )
    1.628 ( 1.8741 )
    1.899 ( 2.1694 )
    1.826 ( 1.8778 )
        Week 8, n=250, 20, 84, 83, 77, 71, 231
    1.656 ( 1.8606 )
    2.736 ( 3.1579 )
    1.553 ( 1.5884 )
    1.616 ( 1.9444 )
    1.572 ( 1.8294 )
    2.006 ( 2.2242 )
    1.824 ( 1.8397 )
        Week 9, n=244, 20, 82, 81, 76, 71, 229
    1.708 ( 1.8709 )
    2.765 ( 3.1104 )
    1.608 ( 1.7699 )
    1.658 ( 2.0646 )
    1.720 ( 1.8918 )
    1.953 ( 2.1838 )
    1.775 ( 1.8753 )
        Week 10, n=241, 20, 81, 80, 73, 71, 227
    1.698 ( 1.9023 )
    2.543 ( 2.8753 )
    1.589 ( 1.6571 )
    1.596 ( 1.9809 )
    1.546 ( 1.8824 )
    1.927 ( 2.1613 )
    1.705 ( 1.7646 )
        Week 11, n=241, 20, 79, 80, 73, 71, 226
    1.729 ( 1.9406 )
    2.164 ( 2.2504 )
    1.404 ( 1.4897 )
    1.602 ( 1.9435 )
    1.672 ( 1.9447 )
    1.926 ( 2.3243 )
    1.716 ( 1.7421 )
        Week 12, n=240, 20, 78, 80, 73, 70, 225
    1.666 ( 1.7913 )
    2.386 ( 2.8157 )
    1.414 ( 1.3920 )
    1.671 ( 1.9612 )
    1.712 ( 1.9532 )
    1.790 ( 2.1140 )
    1.731 ( 1.7245 )
        Over 12 Week, n=273, 21, 91, 91, 86, 83, 268
    1.684 ( 1.6903 )
    2.330 ( 2.4715 )
    1.553 ( 1.4044 )
    1.750 ( 1.9048 )
    1.620 ( 1.5994 )
    1.921 ( 1.9201 )
    1.733 ( 1.6618 )
    Notes
    [204] - MITT Population.
    [205] - MITT Population.
    [206] - MITT Population.
    [207] - MITT Population.
    [208] - MITT Population.
    [209] - MITT Population.
    [210] - MITT Population.
    No statistical analyses for this end point

    Secondary: Percentage of rescue-free days

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    End point title
    		 Percentage of rescue-free days
    End point description
    Albuterol (Salbutamol) MDI or nebules was used as a rescue medication. Percentage of Rescue-Free Days is defined as sum of the number of days where the number of occasions of rescue medication use is zero within the time-period divided by total number of days with non-missing values within the time-period multiplied by 100 where the time-period is defined as follows: Week 1: Day 1-7; Week 2: Day 8 - 14; Week 3: Day 15-21; Week 4: Day 22-28; Week 5: Day 29-35; Week 6: Day 36-42; Week 7: Day 43-49; Week 8: Day 50-56; Week 9: Day 57-63; Week 10: Day 64-70; Week 11: Day 71-77; Week 12: Day 78 to Day of last dose; Over the 12-Week: Day 1 to Day of last dose. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 of treatment and over the Week 12 treatment period
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [211]
    22 [212]
    91 [213]
    92 [214]
    90 [215]
    89 [216]
    278 [217]
    Units: Percentage of rescue free days
    arithmetic mean (standard deviation)
        Week 1, n=254, 21, 87, 88, 80, 79, 254
    34.898 ( 37.7118 )
    36.076 ( 44.3182 )
    29.849 ( 38.3385 )
    33.392 ( 39.7372 )
    32.583 ( 38.3577 )
    34.453 ( 35.9802 )
    29.779 ( 36.1498 )
        Week 2, n=259, 21, 88, 89, 80, 82, 252
    41.002 ( 40.9566 )
    40.819 ( 46.7899 )
    32.145 ( 41.2227 )
    43.017 ( 43.9884 )
    38.573 ( 40.3629 )
    40.595 ( 41.1717 )
    33.639 ( 38.9767 )
        Week 3, n=256, 21, 90, 88, 80, 81, 245
    38.204 ( 39.0621 )
    38.776 ( 44.0612 )
    31.643 ( 38.0943 )
    39.964 ( 40.3936 )
    41.191 ( 42.1751 )
    34.923 ( 40.4026 )
    33.006 ( 38.4986 )
        Week 4, n=250, 21, 89, 87, 81, 77, 243
    39.678 ( 40.8359 )
    35.376 ( 43.9405 )
    32.531 ( 39.0078 )
    42.202 ( 43.0692 )
    43.194 ( 41.0201 )
    30.986 ( 38.5941 )
    32.394 ( 39.0174 )
        Week 5, n=251, 20, 88, 85, 78, 76, 240
    38.262 ( 40.7807 )
    35.005 ( 41.8344 )
    35.552 ( 40.5745 )
    41.682 ( 41.3648 )
    41.026 ( 42.1584 )
    33.912 ( 37.9973 )
    33.168 ( 39.0654 )
        Week 6, n=250, 20, 86, 84, 78, 72, 234
    40.287 ( 42.2167 )
    37.870 ( 40.2125 )
    35.384 ( 40.9175 )
    41.720 ( 44.0117 )
    39.196 ( 41.6575 )
    35.519 ( 42.2122 )
    32.351 ( 39.2542 )
        Week 7, n=250, 20, 85, 83, 77, 71, 231
    41.373 ( 43.4266 )
    32.145 ( 43.1992 )
    35.634 ( 41.3319 )
    45.266 ( 43.5910 )
    40.409 ( 42.0560 )
    38.232 ( 41.0296 )
    31.975 ( 39.4910 )
        Week 8, n=250, 20, 84, 83, 77, 71, 231
    42.058 ( 41.2168 )
    34.290 ( 42.8300 )
    33.029 ( 41.0867 )
    44.118 ( 41.6682 )
    42.918 ( 42.8354 )
    34.811 ( 39.3585 )
    32.357 ( 39.9221 )
        Week 9, n=244, 20, 82, 81, 76, 71, 229
    39.268 ( 40.5300 )
    32.145 ( 44.6657 )
    32.759 ( 39.2972 )
    42.505 ( 41.2121 )
    39.476 ( 42.2376 )
    36.823 ( 42.3513 )
    33.606 ( 39.4690 )
        Week 10, n=241, 20, 81, 80, 73, 71, 227
    40.608 ( 41.0492 )
    35.000 ( 42.3430 )
    32.456 ( 40.7192 )
    43.396 ( 42.3040 )
    41.492 ( 42.1984 )
    37.024 ( 41.2291 )
    33.483 ( 40.1924 )
        Week 11, n=241, 20, 79, 80, 73, 71, 226
    39.701 ( 41.9689 )
    38.575 ( 44.2366 )
    35.624 ( 42.6625 )
    42.859 ( 41.7845 )
    39.337 ( 42.3061 )
    39.841 ( 43.7237 )
    33.127 ( 39.1842 )
        Week 12, n=240, 20, 78, 80, 73, 70, 225
    41.390 ( 40.8871 )
    39.415 ( 45.0442 )
    37.369 ( 40.2613 )
    41.300 ( 39.8199 )
    39.981 ( 40.8296 )
    42.236 ( 42.1567 )
    33.906 ( 38.4851 )
        Over 12 Week, n=273, 21, 91, 91, 86, 83, 268
    39.743 ( 36.8957 )
    35.533 ( 39.0694 )
    33.590 ( 36.6456 )
    40.441 ( 37.6285 )
    39.631 ( 36.5157 )
    35.820 ( 34.6377 )
    32.743 ( 33.9362 )
    Notes
    [211] - MITT Population.
    [212] - MITT Population.
    [213] - MITT Population.
    [214] - MITT Population.
    [215] - MITT Population.
    [216] - MITT Population.
    [217] - MITT Population.
    No statistical analyses for this end point

    Secondary: Plasma concentration of Nemiralisib

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    End point title
    		 Plasma concentration of Nemiralisib [218]
    End point description
    Plasma samples were collected at indicated time points and analyzed for concentrations of Nemiralisb. Pharmacokinetic (PK) Population consists of all participants in the Safety population who had at least 1 non-missing PK assessment (Non-quantifiable [NQ] values will be considered as non-missing values). Participants were summarized according to the treatment that they actually received. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
    Notes
    [218] - 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: Plasma concentration was analyzed for the active comparator, Nemiralisib.
    End point values
    		 Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    5 [219]
    22 [220]
    24 [221]
    19 [222]
    20 [223]
    73 [224]
    Units: Picograms per milliliter
    geometric mean (geometric coefficient of variation)
        Day 14, Pre-dose, n=2, 19, 24, 16, 18, 69
    113.6 ( 6 )
    62.0 ( 46 )
    142.8 ( 44 )
    416.0 ( 59 )
    687.3 ( 53 )
    1069.6 ( 70 )
        Day 14, 0-1 hour, n=4, 19, 24, 15, 18, 67
    54.9 ( 43 )
    109.9 ( 51 )
    253.7 ( 73 )
    767.6 ( 71 )
    1492.0 ( 59 )
    1972.0 ( 110 )
        Day 14, >1-6 hours, n=4, 20, 23, 15, 18, 65
    35.0 ( 57 )
    93.1 ( 58 )
    231.8 ( 53 )
    657.0 ( 61 )
    1146.7 ( 56 )
    1622.7 ( 90 )
        Day 28, Pre-dose, n=2, 18, 23, 16, 16, 67
    23.6 ( 24 )
    60.5 ( 45 )
    129.4 ( 46 )
    315.6 ( 85 )
    528.3 ( 110 )
    937.6 ( 101 )
        Day 28, 0-1 hour, n=3, 19, 23, 16, 15, 63
    36.2 ( 26 )
    104.9 ( 70 )
    253.3 ( 52 )
    807.0 ( 66 )
    1552.2 ( 83 )
    1717.6 ( 114 )
        Day 28, >1-6 hours, n=3, 18, 23, 16, 14, 64
    28.1 ( 15 )
    85.4 ( 40 )
    211.4 ( 41 )
    598.8 ( 39 )
    1079.5 ( 80 )
    1388.1 ( 101 )
    Notes
    [219] - PK Population.
    [220] - PK Population.
    [221] - PK Population.
    [222] - PK Population.
    [223] - PK Population.
    [224] - PK Population.
    No statistical analyses for this end point

    Secondary: Area under the concentration time curve (AUC) from time zero to 24 hours [AUC(0-24)] of nemiralisib

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    End point title
    		 Area under the concentration time curve (AUC) from time zero to 24 hours [AUC(0-24)] of nemiralisib [225]
    End point description
    Plasma samples were collected at indicated time points and analyzed. 99999 indicates sparse plasma concentrations of GSK2269557 were summarized in all PK evaluable participants by time interval as stated in protocol. No subsequent population PK was conducted on these plasma data to derive PK parameters due to termination of the development of project at the end of the study. The plasma exposure summarized from all the evaluated participants over the interval of collection of these sparse samples provides adequate information on the adequacy of the doses the participants were exposed in this study.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
    Notes
    [225] - 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: Plasma concentration was analyzed for the active comparator, Nemiralisib.
    End point values
    		 Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    5 [226]
    22 [227]
    24 [228]
    19 [229]
    20 [230]
    73 [231]
    Units: Hours*picograms per milliliter
        geometric mean (geometric coefficient of variation)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    Notes
    [226] - PK Population.
    [227] - PK Population.
    [228] - PK Population.
    [229] - PK Population.
    [230] - PK Population.
    [231] - PK Population.
    No statistical analyses for this end point

    Secondary: AUC from time zero to time 't' [AUC(0-t)] of nemiralisib

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    End point title
    		 AUC from time zero to time 't' [AUC(0-t)] of nemiralisib [232]
    End point description
    Plasma samples were collected at indicated time points and analyzed. 99999 indicates sparse plasma concentrations of GSK2269557 were summarized in all PK evaluable participants by time interval as stated in protocol. No subsequent population PK was conducted on these plasma data to derive PK parameters due to termination of the development of project at the end of the study. The plasma exposure summarized from all the evaluated participants over the interval of collection of these sparse samples provides adequate information on the adequacy of the doses the participants were exposed in this study.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
    Notes
    [232] - 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: Plasma concentration was analyzed for the active comparator, Nemiralisib.
    End point values
    		 Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    5 [233]
    22 [234]
    24 [235]
    19 [236]
    20 [237]
    73 [238]
    Units: Hours*picograms per milliliter
        geometric mean (geometric coefficient of variation)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    Notes
    [233] - PK Population.
    [234] - PK Population.
    [235] - PK Population.
    [236] - PK Population.
    [237] - PK Population.
    [238] - PK Population.
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Drug Concentration (Cmax) of nemiralisib

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    End point title
    		 Maximum Observed Plasma Drug Concentration (Cmax) of nemiralisib [239]
    End point description
    Plasma samples were collected at indicated time points and analyzed. 99999 indicates sparse plasma concentrations of GSK2269557 were summarized in all PK evaluable participants by time interval as stated in protocol. No subsequent population PK was conducted on these plasma data to derive PK parameters due to termination of the development of project at the end of the study. The plasma exposure summarized from all the evaluated participants over the interval of collection of these sparse samples provides adequate information on the adequacy of the doses the participants were exposed in this study.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
    Notes
    [239] - 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: Plasma concentration was analyzed for the active comparator, Nemiralisib.
    End point values
    		 Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    5 [240]
    22 [241]
    24 [242]
    19 [243]
    20 [244]
    73 [245]
    Units: Picograms per milliliter
        geometric mean (geometric coefficient of variation)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    Notes
    [240] - PK Population.
    [241] - PK Population.
    [242] - PK Population.
    [243] - PK Population.
    [244] - PK Population.
    [245] - PK Population.
    No statistical analyses for this end point

    Secondary: Time to reach Cmax (Tmax) of nemiralisib

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    End point title
    		 Time to reach Cmax (Tmax) of nemiralisib [246]
    End point description
    Plasma samples were collected at indicated time points and analyzed. 99999 indicates sparse plasma concentrations of GSK2269557 were summarized in all PK evaluable participants by time interval as stated in protocol. No subsequent population PK was conducted on these plasma data to derive PK parameters due to termination of the development of project at the end of the study. The plasma exposure summarized from all the evaluated participants over the interval of collection of these sparse samples provides adequate information on the adequacy of the doses the participants were exposed in this study.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
    Notes
    [246] - 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: Plasma concentration was analyzed for the active comparator, Nemiralisib.
    End point values
    		 Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    5 [247]
    22 [248]
    24 [249]
    19 [250]
    20 [251]
    73 [252]
    Units: Hours
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [247] - PK Population.
    [248] - PK Population.
    [249] - PK Population.
    [250] - PK Population.
    [251] - PK Population.
    [252] - PK Population.
    No statistical analyses for this end point

    Secondary: Plasma drug concentration at pre-dose (Ctrough) of nemiralisib

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    End point title
    		 Plasma drug concentration at pre-dose (Ctrough) of nemiralisib [253]
    End point description
    Plasma samples were collected at indicated time points and analyzed. 99999 indicates sparse plasma concentrations of GSK2269557 were summarized in all PK evaluable participants by time interval as stated in protocol. No subsequent population PK was conducted on these plasma data to derive PK parameters due to termination of the development of project at the end of the study. The plasma exposure summarized from all the evaluated participants over the interval of collection of these sparse samples provides adequate information on the adequacy of the doses the participants were exposed in this study.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0-1 hour, >1-6 hours post-dose on Days 14 and 28
    Notes
    [253] - 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: Plasma concentration was analyzed for the active comparator, Nemiralisib.
    End point values
    		 Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    5 [254]
    22 [255]
    24 [256]
    19 [257]
    20 [258]
    73 [259]
    Units: Picograms per milliliter
        geometric mean (geometric coefficient of variation)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    Notes
    [254] - PK Population.
    [255] - PK Population.
    [256] - PK Population.
    [257] - PK Population.
    [258] - PK Population.
    [259] - PK Population.
    No statistical analyses for this end point

    Secondary: Number of participants reporting non-serious adverse events (non-SAEs), SAEs and AE of special interest (AESI)

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    End point title
    		 Number of participants reporting non-serious adverse events (non-SAEs), SAEs and AE of special interest (AESI)
    End point description
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth effect and other important medical events. Safety Population consists of all randomized participants who received at least one dose of study treatment. Participants were summarized according to treatment that they actually received.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [260]
    22 [261]
    91 [262]
    92 [263]
    90 [264]
    89 [265]
    278 [266]
    Units: Participants
        Any non-SAE
    31
    1
    14
    19
    25
    36
    101
        Any SAE
    23
    2
    9
    13
    16
    6
    26
        Any AESI
    9
    0
    10
    10
    21
    29
    93
    Notes
    [260] - Safety Population.
    [261] - Safety Population.
    [262] - Safety Population.
    [263] - Safety Population.
    [264] - Safety Population.
    [265] - Safety Population.
    [266] - Safety Population.
    No statistical analyses for this end point

    Secondary: Number of participants with worst case post Baseline diastolic blood pressure (DBP), systolic blood pressure (SBP) and pulse rate

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    End point title
    		 Number of participants with worst case post Baseline diastolic blood pressure (DBP), systolic blood pressure (SBP) and pulse rate
    End point description
    The DBP, SBP and pulse rate were measured with participants seated at least 5 minutes before the assessments. Participants are counted in the worst case category if their value changes to (low, within range or no change, or high). Participants whose value category was unchanged (e.g., High to High), or whose value became within range, are recorded in the "To w/in Range or No Change" category. Participants are counted twice if the participant has values that changed "To Low" and "To High", so the percentages may not add to 100%. Participants with missing baseline value are assumed to have within range value. Only those participants with data available at the specified data points were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Week 16
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    271 [267]
    21 [268]
    91 [269]
    92 [270]
    88 [271]
    88 [272]
    266 [273]
    Units: Participants
        DBP, To low
    8
    3
    3
    0
    4
    4
    7
        DBP, To within range/no change
    260
    17
    85
    91
    79
    82
    256
        DBP, To high
    3
    1
    3
    1
    5
    2
    3
        Pulse rate, To low
    1
    0
    0
    0
    0
    0
    0
        Pulse rate,To within range/no change
    265
    21
    84
    90
    82
    83
    258
        Pulse rate, To high
    5
    0
    7
    2
    6
    5
    8
        SBP, To low
    11
    1
    5
    3
    2
    3
    8
        SBP, To withinn range/no change
    250
    18
    83
    82
    79
    80
    239
        SBP, To high
    10
    2
    3
    7
    8
    6
    19
    Notes
    [267] - Safety Population.
    [268] - Safety Population.
    [269] - Safety Population.
    [270] - Safety Population.
    [271] - Safety Population.
    [272] - Safety Population.
    [273] - Safety Population.
    No statistical analyses for this end point

    Secondary: Number of participants with abnormal electrocardiogram (ECG) findings

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    End point title
    		 Number of participants with abnormal electrocardiogram (ECG) findings
    End point description
    A single 12-lead ECG with a 15-second rhythm strip was obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT and corrected QT (QTc) intervals. Abnormal ECG findings are presented.
    End point type
    Secondary
    End point timeframe
    Screening, Days 14, 84, 112 and at early withdrawal
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [274]
    22 [275]
    91 [276]
    92 [277]
    90 [278]
    89 [279]
    278 [280]
    Units: Participants
        Screening
    93
    10
    25
    37
    28
    21
    86
        Day 14
    88
    8
    24
    33
    29
    18
    74
        Day 84
    79
    8
    22
    27
    24
    18
    64
        Day 112
    77
    11
    28
    28
    25
    20
    75
        Early withdrawal
    3
    0
    2
    1
    3
    1
    4
    Notes
    [274] - Safety Population.
    [275] - Safety Population.
    [276] - Safety Population.
    [277] - Safety Population.
    [278] - Safety Population.
    [279] - Safety Population.
    [280] - Safety Population.
    No statistical analyses for this end point

    Secondary: Number of participants with worst case post Baseline clinical chemistry values

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    End point title
    		 Number of participants with worst case post Baseline clinical chemistry values
    End point description
    Blood samples were collected for the analysis of clinical chemistry parameters including: blood urea nitrogen (BUN), creatinine (Crt), glucose (Glu), potassium (Pot), sodium (Sod), calcium (Cal), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total and direct bilirubin, total protein and albumin (Alb). Participants are counted in the worst case category if their value changes to (low, within range or no change, or high). Participants whose value category was unchanged (e.g., High to High), or whose value became within range, are recorded in the "To w/in Range or No Change" category. Participants are counted twice if the participant has values that changed "To Low" and "To High", so the percentages may not add to 100%. Participants with missing baseline value are assumed to have within range value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Upto Week 16
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [281]
    22 [282]
    91 [283]
    92 [284]
    90 [285]
    89 [286]
    278 [287]
    Units: Participants
        Alb,To low, n=266, 21, 91, 90, 87, 85, 263
    2
    0
    0
    0
    1
    1
    2
        Alb,w/in range/no change,n=266,21,91,90,87,85,263
    264
    21
    90
    90
    85
    84
    261
        Alb,To high,n=266,21,91,90,87,85,263
    0
    0
    1
    0
    1
    0
    0
        Cal,To low, n=266, 21, 90, 90, 87, 85, 263
    1
    0
    0
    0
    0
    1
    1
        Cal,w/in range/no change,n=266,21,90,90,87,85,263
    265
    21
    90
    90
    87
    84
    262
        Cal,To high, n=266,21,90,90,87,85,263
    0
    0
    0
    0
    0
    0
    0
        Crt,To low, n=266, 21, 91, 90, 87, 85, 263
    27
    3
    10
    7
    4
    9
    32
        Crt,w/in range/no change,n=266,21,91,90,87,85,263
    237
    18
    81
    82
    80
    76
    231
        Crt,To high, n=266,21,91,90,87,85,263
    2
    0
    0
    1
    3
    0
    0
        Glu,To low, n=266, 21, 91, 90, 87, 85, 263
    0
    0
    0
    1
    0
    0
    0
        Glu,w/in range/no change,n=266,21,91,90,87,85,263
    266
    21
    91
    89
    87
    85
    263
        Glu,To high, n=266,21,91,90,87,85,263
    0
    0
    0
    0
    0
    0
    0
        Pot,To low, n=266, 21, 90, 90, 87, 85, 263
    0
    0
    0
    0
    0
    0
    0
        Pot,w/in range/no change,n=266,21,90,90,87,85,263
    264
    21
    90
    90
    86
    84
    262
        Pot,To high, n=266,21,90,90,87,85,263
    2
    0
    0
    0
    1
    1
    1
        Sod,To low, n=266, 21, 91, 90, 87, 85, 263
    0
    0
    0
    0
    0
    0
    0
        Sod,w/in range/no change,n=266,21,91,90,87,85,263
    266
    21
    91
    90
    87
    85
    263
        Sod,To high, n=266,21,91,90,87,85,263
    0
    0
    0
    0
    0
    0
    0
        BUN,To low, n=266, 21, 91, 90, 87, 85, 263
    7
    0
    3
    2
    2
    3
    6
        BUN,w/in range/no change,n=266,21,91,90,87,85,263
    256
    21
    88
    86
    85
    82
    253
        BUN,To high, n=266,21,91,90,87,85,263
    3
    0
    0
    2
    0
    0
    4
    Notes
    [281] - Safety Population.
    [282] - Safety Population.
    [283] - Safety Population.
    [284] - Safety Population.
    [285] - Safety Population.
    [286] - Safety Population.
    [287] - Safety Population.
    No statistical analyses for this end point

    Secondary: Number of participants with worst case post Baseline hematology values

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    End point title
    		 Number of participants with worst case post Baseline hematology values
    End point description
    Blood samples were collected for the analysis of hematology parameters including: platelets (Pla), red blood cells count, Hemoglobin (Hb), Hematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), percentage reticulocytes, neutrophils (Neu), lymphocytes (Lym), monocytes, eosinophils, leukocytes (Leu) and basophils. Participants are counted in the worst case category if their value changes to (low, within range or no change, or high). Participants whose value category was unchanged (e.g., High to High), or whose value became within range, are recorded in the "To w/in Range or No Change" category. Participants are counted twice if the participant has values that changed "To Low" and "To High", so the percentages may not add to 100%. Participants with missing baseline value are assumed to have within range value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Upto Week 16
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [288]
    22 [289]
    91 [290]
    92 [291]
    90 [292]
    89 [293]
    278 [294]
    Units: Participants
        Hb,To low, n=260, 20, 90, 90, 84, 81, 254
    0
    0
    0
    0
    0
    0
    0
        Hb,w/in range/no change,n=260,20,90,90,84,81,254
    260
    20
    90
    90
    84
    81
    253
        Hb,To high,n=260, 20, 90, 90, 84, 81, 254
    0
    0
    0
    0
    0
    0
    1
        Leu,To low,n=259, 20, 90, 90, 83, 78, 251
    0
    0
    0
    0
    0
    0
    0
        Leu,w/in range/no change,n=259,20,90,90,83,78,251
    211
    16
    81
    74
    63
    62
    201
        Leu,To high, n=259,20,90,90,83,78,251
    48
    4
    9
    16
    20
    16
    50
        Lym,To low, n=256, 20, 85, 88, 82, 77, 249
    8
    1
    6
    7
    7
    2
    11
        Lym,w/in range/no change,n=256,20,85,88,82,77,249
    239
    19
    79
    76
    70
    73
    226
        Lym,To high,n=256,20,85,88,82,77,249
    9
    0
    0
    5
    5
    2
    12
        Neu, To low, n=256,20,85,88,82,77,249
    3
    0
    1
    1
    0
    0
    2
        Neu,w/in range/no change,n=256,20,85,88,82,77,249
    215
    17
    73
    76
    68
    60
    213
        Neu,To high, n=256,20,85,88,82,77,249
    38
    3
    11
    11
    14
    17
    34
        Pla,To low, n=253, 19, 88, 90, 84, 78, 245
    0
    0
    0
    0
    0
    0
    0
        Pla,w/in range/no change,n=253,19,88,90,84,78,245
    253
    19
    88
    90
    84
    78
    245
        Pla,To high, n=253,19,88,90,84,78,245
    0
    0
    0
    0
    0
    0
    0
    Notes
    [288] - Safety Population.
    [289] - Safety Population.
    [290] - Safety Population.
    [291] - Safety Population.
    [292] - Safety Population.
    [293] - Safety Population.
    [294] - Safety Population.
    No statistical analyses for this end point

    Secondary: Number of participants reporting COPD exacerbations

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    End point title
    		 Number of participants reporting COPD exacerbations
    End point description
    Participants reporting acute COPD exacerbations during the study period has been presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 16
    End point values
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Number of subjects analysed
    276 [295]
    22 [296]
    91 [297]
    92 [298]
    90 [299]
    89 [300]
    278 [301]
    Units: Participants
    8
    1
    6
    4
    4
    3
    17
    Notes
    [295] - Safety Population.
    [296] - Safety Population.
    [297] - Safety Population.
    [298] - Safety Population.
    [299] - Safety Population.
    [300] - Safety Population.
    [301] - Safety Population.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious AEs and SAEs were collected up to Week 24
    Adverse event reporting additional description
    Non-serious AEs and SAEs were summarized for the Safety Population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants were administered a single oral inhalation of placebo via ELLIPTA dry powder inhaler (DPI) once daily in the morning for 12 weeks. Albuterol (salbutamol) metered-dose inhaler (MDI) or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 12.5 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 12.5 micrograms (mcg) nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 50 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 50 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 100 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 100 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 250 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 250 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 500 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 500 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Reporting group title
    Nemiralisib 750 mcg
    Reporting group description
    		 Participants were administered a single oral inhalation of 750 mcg nemiralisib via ELLIPTA DPI once daily in the morning for 12 weeks. Albuterol (salbutamol) MDI or nebules were also provided to all participants as rescue medication.

    Serious adverse events
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 276 (8.33%)
    2 / 22 (9.09%)
    9 / 91 (9.89%)
    13 / 92 (14.13%)
    16 / 90 (17.78%)
    6 / 89 (6.74%)
    26 / 278 (9.35%)
         number of deaths (all causes)
    1
    0
    3
    1
    0
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bronchial carcinoma
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    1 / 91 (1.10%)
    0 / 92 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arterial thrombosis
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    1 / 92 (1.09%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Swelling
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    1 / 92 (1.09%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chroni obstructive pulmonary disease
         subjects affected / exposed
    8 / 276 (2.90%)
    1 / 22 (4.55%)
    6 / 91 (6.59%)
    4 / 92 (4.35%)
    4 / 90 (4.44%)
    3 / 89 (3.37%)
    17 / 278 (6.12%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 1
    1 / 7
    0 / 4
    0 / 5
    0 / 3
    1 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    1 / 92 (1.09%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    1 / 92 (1.09%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    1 / 92 (1.09%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Conversion disorder
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    1 / 89 (1.12%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    1 / 89 (1.12%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    1 / 92 (1.09%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    1 / 92 (1.09%)
    2 / 90 (2.22%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    1 / 90 (1.11%)
    1 / 89 (1.12%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    1 / 92 (1.09%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Sinus arrhythmia
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    1 / 89 (1.12%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Intracranial hematoma
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterocele
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    1 / 89 (1.12%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    1 / 91 (1.10%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 276 (0.00%)
    1 / 22 (4.55%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    1 / 91 (1.10%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 276 (1.45%)
    0 / 22 (0.00%)
    1 / 91 (1.10%)
    2 / 92 (2.17%)
    3 / 90 (3.33%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
    0 / 2
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    1 / 91 (1.10%)
    1 / 92 (1.09%)
    1 / 90 (1.11%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    1 / 92 (1.09%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis klebsiella
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    1 / 91 (1.10%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 276 (0.36%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 276 (0.00%)
    1 / 22 (4.55%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    0 / 278 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 276 (0.00%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    0 / 92 (0.00%)
    0 / 90 (0.00%)
    0 / 89 (0.00%)
    1 / 278 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Nemiralisib 12.5 mcg Nemiralisib 50 mcg Nemiralisib 100 mcg Nemiralisib 250 mcg Nemiralisib 500 mcg Nemiralisib 750 mcg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 276 (11.23%)
    1 / 22 (4.55%)
    14 / 91 (15.38%)
    19 / 92 (20.65%)
    25 / 90 (27.78%)
    36 / 89 (40.45%)
    101 / 278 (36.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 276 (8.33%)
    1 / 22 (4.55%)
    6 / 91 (6.59%)
    8 / 92 (8.70%)
    4 / 90 (4.44%)
    2 / 89 (2.25%)
    15 / 278 (5.40%)
         occurrences all number
    41
    1
    8
    10
    5
    2
    18
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 276 (4.71%)
    0 / 22 (0.00%)
    10 / 91 (10.99%)
    11 / 92 (11.96%)
    23 / 90 (25.56%)
    31 / 89 (34.83%)
    96 / 278 (34.53%)
         occurrences all number
    13
    0
    12
    17
    27
    58
    141
    Oropharyngeal pain
         subjects affected / exposed
    2 / 276 (0.72%)
    0 / 22 (0.00%)
    0 / 91 (0.00%)
    2 / 92 (2.17%)
    3 / 90 (3.33%)
    5 / 89 (5.62%)
    2 / 278 (0.72%)
         occurrences all number
    2
    0
    0
    2
    3
    5
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2017
    Amendment 01: Updated and clarified the protocol during the Voluntary Harmonization Procedure in the European Union (EU).
    14 Dec 2017
    Amendment 02: Added the 12.5 mcg nemiralisib dose, added the provision for a 25 mcg dose to be added later, removed restrictions on theophylline use, made changes to discontinuation criteria, clarified the protocol, corrected minor discrepancies, and changed serious adverse events (SAE) recording such that SAEs prior to the start of study treatment were only collected if they were considered related to study participation or a GSK product.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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

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