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    Clinical Trial Results:
    A Randomized, Double-Blind, Parallel Group, Multi-Center 24-Week Study Comparing the Efficacy and Safety of Three Doses of PT001 to Placebo and Open-label Spiriva® Respimat® in Subjects With Persistent Asthma

    Summary
    EudraCT number
    		 2020-000532-22
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    12 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2020
    First version publication date
    29 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PT001102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03358147
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pearl Therapeutics, Inc.
    Sponsor organisation address
    200 Cardinal Way, Redwood City, California, United States, 94063
    Public contact
    Colin Reisner, Pearl Therapeutics Inc., 1 1-877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Pearl Therapeutics, Inc., Pearl Therapeutics, Inc., 1 18772409479, information.center@astrazeneca.com
    Sponsor organisation name
    Pearl Therapeutics, Inc.
    Sponsor organisation address
    200 Cardinal Way, 2nd Floor, Redwood City, California, United States, 94063
    Public contact
    Colin Reisner, Pearl Therapeutics, Inc., 1 1-877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Colin Reisner, Pearl Therapeutics, Inc., 1 1-877-240-9479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002017-PIP03-48
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Efficacy and Safety
    Protection of trial subjects
    Subjects were enrolled who were already taking background ICS/LABA therapy (with or without tiotropium) and continued background therapy of ICS/LABA therapy throughout the study. If a subject was taking ICS/LABA plus tiotropium, tiotropium was discontinued and these subjects were provided Ipratropium Bromide during the screening period. Sponsor-provided Albuterol sulfate was also dispensed to subjects as rescue medication during the study. Subjects were to be discontinued from study drug if had an asthma exacerbation requiring inpatient hospitalization or more than 2 severe asthma exacerbations requiring oral corticosteroid treatment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Dec 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 1071
    Worldwide total number of subjects
    1071
    EEA total number of subjects
    0
    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)
    35
    Adults (18-64 years)
    867
    From 65 to 84 years
    169
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study randomized subjects at 194 sites in the United States from December 2017 to September 2019. The entire study period was scheduled to take up to approximately 26 weeks for each individual subject from the time of screening through the follow up period.

    Pre-assignment
    Screening details
    		 Subjects were randomized in a 2:2:2:2:1 Scheme to follow 1 of the 5 treatment groups.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GP MDI 28.8 μg
    Arm description
    		 Glycopyrronium Metered Dose Inhalation 28.8 μg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glycopyrronium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    GP MDI 14.4 μg per actuation Taken as 2 inhalations BID

    Arm title
    		 GP MDI 14.4 μg
    Arm description
    		 Glycopyrronium Metered Dose Inhalation 14.4 μg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glycopyrronium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    GP MDI 7.2 μg per actuation Taken as 2 inhalations BID

    Arm title
    		 GP MDI 7.2 μg
    Arm description
    		 Glycopyrronium Metered Dose Inhalation 7.2μg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glycopyrronium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    GP MDI 3.6 μg per actuation Taken as 2 inhalations BID

    Arm title
    		 Placebo MDI
    Arm description
    		 Placebo Metered Dose Inhalation
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo MDI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo MDI (no active ingredient) Taken as 2 inhalations BID

    Arm title
    		 Spiriva Respimat
    Arm description
    		 Spiriva Respimat
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Spiriva® Respimat® 2.5 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    tiotropium bromide 1.25 μg per actuation Taken as 2 inhalations QD

    Number of subjects in period 1
    		GP MDI 28.8 μg GP MDI 14.4 μg GP MDI 7.2 μg Placebo MDI Spiriva Respimat
    Started
    235
    240
    240
    237
    119
    Completed
    201
    201
    206
    201
    105
    Not completed
    34
    39
    34
    36
    14
         Consent withdrawn by subject
    13
    19
    16
    10
    5
         Physician decision
    1
    -
    1
    6
    1
         Major Protocol Deviation
    11
    3
    2
    3
    1
         Adverse event, non-fatal
    3
    9
    7
    5
    2
         Protocol specified criteria
    2
    3
    -
    3
    1
         Administrative reasons
    -
    1
    -
    3
    -
         Lost to follow-up
    4
    3
    7
    6
    4
         Lack of efficacy
    -
    1
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GP MDI 28.8 μg
    Reporting group description
    		 Glycopyrronium Metered Dose Inhalation 28.8 μg

    Reporting group title
    GP MDI 14.4 μg
    Reporting group description
    		 Glycopyrronium Metered Dose Inhalation 14.4 μg

    Reporting group title
    GP MDI 7.2 μg
    Reporting group description
    		 Glycopyrronium Metered Dose Inhalation 7.2μg

    Reporting group title
    Placebo MDI
    Reporting group description
    		 Placebo Metered Dose Inhalation

    Reporting group title
    Spiriva Respimat
    Reporting group description
    		 Spiriva Respimat

    Reporting group values
    		 GP MDI 28.8 μg GP MDI 14.4 μg GP MDI 7.2 μg Placebo MDI Spiriva Respimat Total
    Number of subjects
    		 235 240 240 237 119 1071
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 5 12 7 9 2 35
        Adults (18-64 years)
    		 196 185 198 193 95 867
        From 65-84 years
    		 34 43 35 35 22 169
        85 years and over
    		 0 0 0 0 0 0
    Age Continuous
    Units: Number
        arithmetic mean (standard deviation)
    		 48.4 ± 15.1 47.7 ± 16.8 46.7 ± 15.5 47.1 ± 16.2 49.8 ± 15.3 -
    Sex: Female, Male
    Units: Participants
        Female
    		 146 153 151 134 76 660
        Male
    		 89 87 89 103 43 411
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 3 0 1 5
        Asian
    		 6 1 6 2 0 15
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 0 0 1
        Black or African American
    		 62 68 52 52 25 259
        White
    		 165 168 177 179 93 782
        More than one race
    		 0 0 0 0 0 0
        Unknown or Not Reported
    		 1 2 2 4 0 9
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 36 61 52 51 21 221
        Not Hispanic or Latino
    		 198 179 186 186 98 847
        Unknown or Not Reported
    		 1 0 2 0 0 3

    End points

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    End points reporting groups
    Reporting group title
    GP MDI 28.8 μg
    Reporting group description
    		 Glycopyrronium Metered Dose Inhalation 28.8 μg

    Reporting group title
    GP MDI 14.4 μg
    Reporting group description
    		 Glycopyrronium Metered Dose Inhalation 14.4 μg

    Reporting group title
    GP MDI 7.2 μg
    Reporting group description
    		 Glycopyrronium Metered Dose Inhalation 7.2μg

    Reporting group title
    Placebo MDI
    Reporting group description
    		 Placebo Metered Dose Inhalation

    Reporting group title
    Spiriva Respimat
    Reporting group description
    		 Spiriva Respimat

    Primary: Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 4 hours (AUC0-4)

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    End point title
    		 Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 4 hours (AUC0-4)
    End point description
    Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 4 hours (AUC0-4)AUC was normalized for length of follow up (e.g. typically 4 hours).
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 GP MDI 28.8 μg GP MDI 14.4 μg GP MDI 7.2 μg Placebo MDI Spiriva Respimat
    Number of subjects analysed
    195
    199
    205
    196
    103
    Units: Liter
        least squares mean (confidence interval 95%)
    0.294 (0.248 to 0.341)
    0.284 (0.238 to 0.331)
    0.308 (0.263 to 0.354)
    0.240 (0.194 to 0.287)
    0.347 (0.282 to 0.412)
    Statistical analysis title
    		 Change from baseline in FEV1 AUC0-4
    Statistical analysis description
    Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 4 hours (AUC0-4)
    Comparison groups
    GP MDI 28.8 μg v Placebo MDI
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.105
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.054
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 -0.011
         upper limit
    		 0.119
    Statistical analysis title
    		 Change from baseline in FEV1 AUC0-4
    Statistical analysis description
    Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 4 hours (AUC0-4)
    Comparison groups
    GP MDI 14.4 μg v Placebo MDI
    Number of subjects included in analysis
    395
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1825
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.044
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 -0.021
         upper limit
    		 0.109
    Statistical analysis title
    		 Change from baseline in FEV1 AUC0-4
    Statistical analysis description
    Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 4 hours (AUC0-4)
    Comparison groups
    GP MDI 7.2 μg v Placebo MDI
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0392
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.068
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.003
         upper limit
    		 0.133
    Statistical analysis title
    		 Change from baseline in FEV1 AUC0-4
    Statistical analysis description
    Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 4 hours (AUC0-4)
    Comparison groups
    Spiriva Respimat v Placebo MDI
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0084
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.107
    Confidence interval
         level
    		 0.95%
         sides
    2-sided
         lower limit
    		 0.027
         upper limit
    		 0.186

    Secondary: Change from baseline in morning pre-dose trough FEV1

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    End point title
    		 Change from baseline in morning pre-dose trough FEV1
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 GP MDI 28.8 μg GP MDI 14.4 μg GP MDI 7.2 μg Placebo MDI Spiriva Respimat
    Number of subjects analysed
    196
    199
    205
    198
    102
    Units: Liter
        least squares mean (confidence interval 95%)
    0.142 (0.097 to 0.188)
    0.108 (0.063 to 0.153)
    0.142 (0.098 to 0.187)
    0.129 (0.084 to 0.174)
    0.150 (0.087 to 0.213)
    No statistical analyses for this end point

    Secondary: Rate of moderate to severe Asthma exacerbations

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    End point title
    		 Rate of moderate to severe Asthma exacerbations
    End point description
    Rate of moderate to severe Asthma exacerbations (A deterioration of asthma requiring a new or increased dose of ICS for at least 3 days) or severe Asthma exacerbation (Use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days OR a hospitalization or ER visit because of asthma)
    End point type
    Secondary
    End point timeframe
    over 24 Weeks (timepoints of 4, 12 & 20 weeks)
    End point values
    		 GP MDI 28.8 μg GP MDI 14.4 μg GP MDI 7.2 μg Placebo MDI Spiriva Respimat
    Number of subjects analysed
    231
    240
    240
    237
    118
    Units: Participants per year
        arithmetic mean (standard error)
    0.43 ± 0.078
    0.44 ± 0.080
    0.41 ± 0.076
    0.55 ± 0.092
    0.50 ± 0.123
    No statistical analyses for this end point

    Secondary: Change from baseline in ACQ-7 (Asthma Control Questionnaire)

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    End point title
    		 Change from baseline in ACQ-7 (Asthma Control Questionnaire)
    End point description
    ACQ-7:ACQ questions 1 through 7, which is the ACQ-6 plus1 item that scores lung function (FEV1 percent predicted)
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 GP MDI 28.8 μg GP MDI 14.4 μg GP MDI 7.2 μg Placebo MDI Spiriva Respimat
    Number of subjects analysed
    189
    189
    194
    187
    93
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -0.78 (-0.89 to -0.66)
    -0.73 (-0.84 to -0.62)
    -0.90 (-1.01 to -0.79)
    -0.80 (-0.91 to -0.69)
    -0.90 (-1.06 to -0.74)
    No statistical analyses for this end point

    Secondary: Change from baseline in ACQ-5 (Asthma Control Questionnaire)

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    End point title
    		 Change from baseline in ACQ-5 (Asthma Control Questionnaire)
    End point description
    ACQ-5:ACQ questions 1 through 5, which measure the frequency, intensity or limitations from asthma symptoms using 1-week recall
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 GP MDI 28.8 μg GP MDI 14.4 μg GP MDI 7.2 μg Placebo MDI Spiriva Respimat
    Number of subjects analysed
    195
    198
    196
    196
    98
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -0.87 (-1.00 to -0.73)
    -0.80 (-0.93 to -0.67)
    -1.02 (-1.15 to -0.89)
    -0.93 (-1.06 to -0.80)
    -1.03 (-1.22 to -0.85)
    No statistical analyses for this end point

    Secondary: Change from baseline in Asthma Quality of Life Questionnaire for 12 years and older (AQLQ +12)

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    End point title
    		 Change from baseline in Asthma Quality of Life Questionnaire for 12 years and older (AQLQ +12)
    End point description
    AQLQ +12 - Asthma Quality of Life Questionnaire for 12 years and older
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 GP MDI 28.8 μg GP MDI 14.4 μg GP MDI 7.2 μg Placebo MDI Spiriva Respimat
    Number of subjects analysed
    191
    191
    191
    188
    94
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    0.89 (0.74 to 1.04)
    0.90 (0.75 to 1.04)
    1.02 (0.87 to 1.16)
    0.96 (0.82 to 1.11)
    1.04 (0.84 to 1.25)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse events were collected from the time subject signed Informed Consent to the time of the final follow-up telephone call. Adverse Events were collected from the time subject was randomized.
    Adverse event reporting additional description
    The safety analysis set was defined as data from all subjects who were randomized to treatment and received any amount of the study treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    GP MDI 28.8 μg
    Reporting group description
    		 Glycopyrronium Metered Dose Inhalation 28.8 μg

    Reporting group title
    GP MDI 14.4 μg
    Reporting group description
    		 Glycopyrronium Metered Dose Inhalation 14.4 μg

    Reporting group title
    GP MDI 7.2 μg
    Reporting group description
    		 Glycopyrronium Metered Dose Inhalation 7.2μg

    Reporting group title
    Placebo MDI
    Reporting group description
    		 Placebo Metered Dose Inhalation

    Reporting group title
    Spiriva Respimat
    Reporting group description
    		 Spiriva Respimat

    Serious adverse events
    		 GP MDI 28.8 μg GP MDI 14.4 μg GP MDI 7.2 μg Placebo MDI Spiriva Respimat
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 235 (3.83%)
    7 / 240 (2.92%)
    6 / 240 (2.50%)
    7 / 237 (2.95%)
    2 / 119 (1.68%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 240 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Non cardiac chest pain
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 240 (0.42%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Social circumstances
    Miscarriage of partner
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Reproductive system and breast disorders
    Adnexal torsion
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 240 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 240 (0.00%)
    2 / 240 (0.83%)
    1 / 237 (0.42%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 240 (0.42%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory failure
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Acute respiratory failure
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 240 (0.42%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Post traumatic pain
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 240 (0.42%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    Cerbrovascular accident
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Nephrolithiasis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 240 (0.42%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Influenza
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 240 (0.42%)
    0 / 240 (0.00%)
    1 / 237 (0.42%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 235 (0.85%)
    0 / 240 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 240 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Kindey infection
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 240 (0.42%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Metapneumovirus infection
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 240 (0.00%)
    1 / 240 (0.42%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia viral
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 240 (0.42%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Sepsis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 240 (0.00%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 240 (0.42%)
    0 / 240 (0.00%)
    0 / 237 (0.00%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 GP MDI 28.8 μg GP MDI 14.4 μg GP MDI 7.2 μg Placebo MDI Spiriva Respimat
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    100 / 235 (42.55%)
    106 / 240 (44.17%)
    104 / 240 (43.33%)
    110 / 237 (46.41%)
    44 / 119 (36.97%)
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 235 (5.96%)
    14 / 240 (5.83%)
    14 / 240 (5.83%)
    19 / 237 (8.02%)
    6 / 119 (5.04%)
         occurrences all number
    15
    14
    14
    20
    7
    Nasopharyngitis
         subjects affected / exposed
    11 / 235 (4.68%)
    15 / 240 (6.25%)
    17 / 240 (7.08%)
    8 / 237 (3.38%)
    2 / 119 (1.68%)
         occurrences all number
    12
    19
    19
    10
    2
    Sinusitis
         subjects affected / exposed
    10 / 235 (4.26%)
    7 / 240 (2.92%)
    4 / 240 (1.67%)
    3 / 237 (1.27%)
    7 / 119 (5.88%)
         occurrences all number
    10
    8
    4
    3
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Apr 2018
    Increased the upper limit of the pre-bronchodilator FEV1 for study inclusion, Clarified that FEV1 inclusion criterion, Revised the Schedule of Events, Changed the Fridericia-corrected QT (QTcF) interval limits for study drug discontinuation, Added the Schwartz formula for age-appropriate calculation of creatinine clearance for subjects 12 to <19 years of age,
    07 Jun 2018
    Increased the upper limit of the pre-bronchodilator FEV1 for study inclusion to <85% instead of <80% of predicted normal value for subjects 18 to 80 years of age, Decreased the minimum time on inhaled corticosteroid (ICS)/long-acting 2-agonist (LABA) from, Text regarding follow-up phone call necessity clarified, Added text to describe the analysis of the Holter Monitoring data
    22 Aug 2018
    Decreased the number of subjects required to have 24-hour Holter monitoring, Removed Visit 5 (Week 4) post-dose spirometry measurements, Added the word “heterosexual” to those females of childbearing potential and sexually active who require use of birth control, Increased number of subjects to be screenedfrom 1875 to approximately 2250, number of sites from 175 to225 to approximately 250 and removed Canada from the countries participating in the study
    08 Mar 2019
    Removed Visit 5 (Week 4) post-dose vital sign measurements, Reduced the time gaps around Visits 1, 2, and 3 by 2 days, Added height requirement at Visits 4, 5, and 7 for subjects 12 to 18 years of age, Age range for creatinine clearance equations corrected, Added wording that any clarification to the definition and analysis of consecutive asthma exacerbations will be detailed in the statistical analysis planAdded wording that any clarification to the definition and analysis of consecutive asthma exacerbations will be detailed in the statistical analysis planAdded wording that any clarification to the definition and analysis of consecutive asthma exacerbations will be detailed in the statistical analysis plan, Added wording that any clarification to the definition and analysis of consecutive asthma exacerbations will be detailed in the statistical analysis plan

    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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