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    Clinical Trial Results:
    A randomized, subjects and investigator blinded, placebo controlled parallel group study to assess the mode of action of QBW251 in patients with Chronic Obstructive Pulmonary Disease (COPD)

    Summary
    EudraCT number
    		 2019-000325-49
    Trial protocol
    		 DE   GB  
    Global end of trial date
    20 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Sep 2023
    First version publication date
    24 Sep 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CQBW251B2202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04268823
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.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
    20 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Sep 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the change in fibrinogen plasma concentration levels from baseline after 12 weeks of treatment with QBW251 compared to placebo.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Sep 2020
    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
    Austria: 12
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Switzerland: 8
    Worldwide total number of subjects
    54
    EEA total number of subjects
    42
    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)
    23
    From 65 to 84 years
    31
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 12 investigative sites in 4 countries.

    Pre-assignment
    Screening details
    		 Informed consent was obtained from each participant in writing at screening before any study specific procedure was performed. The study was explained to the participant by the investigator or designee, who answered any questions, and written information was also provided.

    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, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QBW251 300mg
    Arm description
    		 QBW251 300 mg oral dose, one capsule twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QBW251 300 mg oral twice daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo oral dose, one capsule twice daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    QBW251
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo oral twice daily

    Number of subjects in period 1
    		QBW251 300mg Placebo
    Started
    26
    28
    Completed
    24
    28
    Not completed
    2
    0
         Participant Decision
    1
    -
         Adverse Event
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QBW251 300mg
    Reporting group description
    		 QBW251 300 mg oral dose, one capsule twice daily

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo oral dose, one capsule twice daily

    Reporting group values
    		 QBW251 300mg Placebo Total
    Number of subjects
    		 26 28 54
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 12 11 23
        From 65-84 years
    		 14 17 31
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.7 ( 7.13 ) 67.3 ( 8.37 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 16 11 27
        Male
    		 10 17 27
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 26 28 54

    End points

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    End points reporting groups
    Reporting group title
    QBW251 300mg
    Reporting group description
    		 QBW251 300 mg oral dose, one capsule twice daily

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo oral dose, one capsule twice daily

    Primary: Change from baseline in fibrinogen plasma concentrations after 12 weeks of treatment

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    End point title
    		 Change from baseline in fibrinogen plasma concentrations after 12 weeks of treatment
    End point description
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on fibrinogen. The least-squares means for change from baseline in fibrinogen plasma concentrations after 12 weeks visits for each individual dose group were obtained from a linear mixed effects model for repeated measures (MMRM). A MMRM was fitted to the changes from baseline in fibrinogen for all time points until Day 84. A decrease in fibrinogen plasma concentration indicates improvement.
    End point type
    Primary
    End point timeframe
    Baseline, week 12.
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    26
    28
    Units: g/L
        least squares mean (standard error)
    -0.086 ( 0.1374 )
    0.117 ( 0.1365 )
    Statistical analysis title
    		 Fibrinogen
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.298
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    -0.203
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.524
         upper limit
    		 0.119
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1938

    Secondary: Change from baseline in total bacteria load of log10 colony forming units (CFU) after 12 weeks of treatment

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    End point title
    		 Change from baseline in total bacteria load of log10 colony forming units (CFU) after 12 weeks of treatment
    End point description
    Change from baseline in total bacteria load of colony forming units of potentially pathogenic microorganisms in sputum. A decrease in airway bacterial colonization as detected in the sputum is considered improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12.
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    26
    28
    Units: log10 CFU/mL
        least squares mean (standard error)
    -0.2 ( 0.30 )
    0.0 ( 0.32 )
    Statistical analysis title
    		 Colony forming units
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.651
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    -0.2
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.44

    Secondary: Change from baseline in Euro Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) questionnaire after 12 weeks of treatment

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    End point title
    		 Change from baseline in Euro Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) questionnaire after 12 weeks of treatment
    End point description
    The EQ-5D-3L questionnaire is a general health status and health utility measure which captures 5 dimensions of health state: mobility, self-care, usual activities, pain/discomfort and anxiety/depression and visual analog has a scale 0 to 100 (0=worst imaginable health state, 100=best imaginable health state).
    End point type
    Secondary
    End point timeframe
    Baseline, week 12.
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    26
    28
    Units: Score on a scale
        least squares mean (standard error)
    7.63 ( 3.116 )
    3.43 ( 2.854 )
    Statistical analysis title
    		 Euro Quality of Life-5 Dimensions-3 Level
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.338
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    4.2
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -3.09
         upper limit
    		 11.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.336

    Secondary: Change from baseline in COPD Assessment Test (CAT) questionnaire after 12 weeks of treatment

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    End point title
    		 Change from baseline in COPD Assessment Test (CAT) questionnaire after 12 weeks of treatment
    End point description
    The COPD assessment test (CAT) is a short instrument which was used to quantify the symptom burden of COPD and disease severity of participants in this study. The CAT consists of 8 items, each presented as a semantic 6-point differential scale (0-5), providing a total range from 0 to 40. A higher score indicates a worse health status.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12.
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    26
    28
    Units: Score on a scale
        least squares mean (standard error)
    -3.55 ( 0.947 )
    -2.16 ( 0.874 )
    Statistical analysis title
    		 COPD Assessment Test
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.288
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    -1.39
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -3.55
         upper limit
    		 0.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.29

    Secondary: Change from baseline in St. George's Respiratory Questionnaire (SGRQ) total and domain scores after 12 weeks of treatment

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    End point title
    		 Change from baseline in St. George's Respiratory Questionnaire (SGRQ) total and domain scores after 12 weeks of treatment
    End point description
    The St. George's Respiratory questionnaire (SGRQ) was used to provide the health status measurements. The SGRQ contains 50 items divided into two parts covering three aspects of health related to COPD: Part I covers “Symptoms”, Part II covers “Activity” and “Impacts”. A score is calculated for each of these three subscales including the "Total" score. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12.
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    26
    28
    Units: Score on a scale
    least squares mean (standard error)
        Week 12- total score
    -2.99 ( 2.297 )
    -2.17 ( 2.111 )
        Week 12- Symptoms score
    -0.98 ( 3.052 )
    -6.73 ( 2.806 )
        Week 12- Activity score
    -1.96 ( 2.388 )
    -1.35 ( 2.194 )
        Week 12- Impact score
    -3.72 ( 2.944 )
    -1.65 ( 2.705 )
    Statistical analysis title
    		 St. George's Respiratory questionnaire
    Statistical analysis description
    Total score
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.795
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    -0.82
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -6.05
         upper limit
    		 4.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.147
    Statistical analysis title
    		 St. George's Respiratory questionnaire
    Statistical analysis description
    Activity score
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.851
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    -0.61
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -6.02
         upper limit
    		 4.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.259
    Statistical analysis title
    		 St. George's Respiratory questionnaire
    Statistical analysis description
    Impact score
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.61
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    -2.07
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -8.78
         upper limit
    		 4.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.035
    Statistical analysis title
    		 St. George's Respiratory questionnaire
    Statistical analysis description
    Symptoms score
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.17
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    5.75
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -1.16
         upper limit
    		 12.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.155

    Secondary: Change from baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) after 12 weeks of treatment

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    End point title
    		 Change from baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) after 12 weeks of treatment
    End point description
    The CASA-Q is a validated questionnaire used to measure cough and sputum production, and their impact in patients with COPD and/or chronic bronchitis. There are only domain scores and no overall score. The scores in each domain range from 0 to 100, with lower scores indicating more severe symptoms or a higher impact.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12.
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    26
    28
    Units: Score on a scale
    least squares mean (standard error)
        Week 12 - cough symptom score
    4.36 ( 3.339 )
    4.11 ( 3.083 )
        Week 12 - sputum symptom score
    5.00 ( 3.401 )
    0.78 ( 3.121 )
        Week 12 - cough impact score
    4.64 ( 2.936 )
    2.60 ( 2.697 )
        Week 12 - sputum impact score
    3.22 ( 3.298 )
    2.28 ( 3.017 )
    Statistical analysis title
    		 Cough and Sputum Assessment Questionnaire
    Statistical analysis description
    Cough symptom score
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.956
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    0.25
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 7.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.557
    Statistical analysis title
    		 Cough and Sputum Assessment Questionnaire
    Statistical analysis description
    Sputum impact score
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.835
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    0.94
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -6.58
         upper limit
    		 8.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.518
    Statistical analysis title
    		 Cough and Sputum Assessment Questionnaire
    Statistical analysis description
    Cough impact score
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.613
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    2.03
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -4.61
         upper limit
    		 8.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.001
    Statistical analysis title
    		 Cough and Sputum Assessment Questionnaire
    Statistical analysis description
    Sputum symptom score
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.369
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    4.22
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -3.55
         upper limit
    		 11.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.671

    Secondary: Pre-dose trough concentration (Ctrough) of QBW251

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    End point title
    		 Pre-dose trough concentration (Ctrough) of QBW251 [1]
    End point description
    Pharmacokinetic blood samples were collected and evaluated in all participants exposed to QBW251. QBW251 was analyzed by a validated Liquid Chromatography with tandem Mass Spectrometry. Concentration below the lower limit of quantification (LLOQ) was reported as zero. The Number of Subjects Analyzed differs as stated on the first column for each row.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 28, Day 56 and Day 84
    Notes
    [1] - 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: PK was not analyzed for participants receiving Placebo.
    End point values
    		 QBW251 300mg
    Number of subjects analysed
    26
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n=23)
    0.00 ( 0.00 )
        Day 28 (n=22)
    526 ( 735 )
        Day 56 (n=23)
    489 ( 540 )
        Day 84 (n=24)
    567 ( 883 )
    No statistical analyses for this end point

    Secondary: Change from baseline in trough FEV1 after 12 weeks of treatment

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    End point title
    		 Change from baseline in trough FEV1 after 12 weeks of treatment
    End point description
    FEV1 (forced expiratory volume in one second) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The least-squares means for change from baseline in FEV1 to assess the effect of QBW251 compared to placebo after 12 weeks were obtained from a linear mixed effects model for repeated measures (MMRM). A positive change from baseline in pre-dose FEV1 is considered a favourable outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12.
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    26
    28
    Units: liters (L)
        least squares mean (standard error)
    0.0 ( 0.03 )
    -0.1 ( 0.03 )
    Statistical analysis title
    		 Forced Expiratory Volume in one second
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.335
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares Mean
    Point estimate
    0
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04

    Secondary: Change from baseline in FVC after 12 weeks of treatment

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    End point title
    		 Change from baseline in FVC after 12 weeks of treatment
    End point description
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on spirometry (Forced Vital Capacity). Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    26
    28
    Units: liters (L)
        least squares mean (standard error)
    -0.1 ( 0.05 )
    -0.1 ( 0.05 )
    Statistical analysis title
    		 Forced Vital Capacity
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.645
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    0
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07

    Secondary: Change from baseline in FEV1/FVC after 12 weeks of treatment

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    End point title
    		 Change from baseline in FEV1/FVC after 12 weeks of treatment
    End point description
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on spirometry. FEV1/FVC is the percent of a person's vital capacity that they are able to expire in the first second of forced expiration (FEV1) to the full, forced vital capacity (FVC).
    End point type
    Secondary
    End point timeframe
    Baseline, week 12.
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    26
    28
    Units: percent
        least squares mean (standard error)
    1.7 ( 0.58 )
    -0.3 ( 0.55 )
    Statistical analysis title
    		 FEV1/FVC
    Comparison groups
    QBW251 300mg v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.01
    Method
    		 Mixed effects Model for Repeated Measure
    Parameter type
    		 Least Squares mean
    Point estimate
    2.1
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 3.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8

    Secondary: Area under plasma concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) of QBW251

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    End point title
    		 Area under plasma concentration-time curve from time zero to the last measurable concentration sampling time (AUClast) of QBW251 [2]
    End point description
    Pharmacokinetic blood samples were collected and evaluated in all participants exposed to QBW251. QBW251 was analyzed by a validated Liquid Chromatography with tandem Mass Spectrometry. Concentration below the lower limit of quantification was reported as zero. AUClast is the area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (tlast) of QBW251.
    End point type
    Secondary
    End point timeframe
    Pre dose, Post dose (1, 2, 3, 4, 6, and 8 hours) at Day 1 and Day 28
    Notes
    [2] - 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: PK was not analyzed for participants receiving Placebo.
    End point values
    		 QBW251 300mg
    Number of subjects analysed
    12
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Day 1
    4290 ( 3630 )
        Day 28
    7320 ( 5950 )
    No statistical analyses for this end point

    Secondary: Maximum observed plasma concentrations (Cmax) of QBW251

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    End point title
    		 Maximum observed plasma concentrations (Cmax) of QBW251 [3]
    End point description
    Cmax is the maximum (peak) observed plasma concentration of QBW251 after dose administration. QBW251 was analyzed by a validated Liquid Chromatography with tandem Mass Spectrometry. Concentration below the lower limit of quantification was reported as zero. On Day 56 and Day 84 pre-dose and 3 hour post dose sparse samples were collected from all participants. The Number of Subjects Analyzed differs as stated on the first column for each row.
    End point type
    Secondary
    End point timeframe
    Post-dose (3 hours) at Day 56 and Day 84.
    Notes
    [3] - 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: PK was not analyzed for participants receiving Placebo.
    End point values
    		 QBW251 300mg
    Number of subjects analysed
    21
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 56 (n=20)
    903 ( 648 )
        Day 84 (n=21)
    997 ( 497 )
    No statistical analyses for this end point

    Secondary: Maximum observed plasma concentrations (Cmax) of QBW251 in a subset of patient population

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    End point title
    		 Maximum observed plasma concentrations (Cmax) of QBW251 in a subset of patient population [4]
    End point description
    Cmax is the maximum (peak) observed plasma concentration of QBW251 after dose administration. QBW251 was analyzed by a validated Liquid Chromatography with tandem Mass Spectrometry. Concentration below the lower limit of quantification was reported as zero. Serial plasma PK concentrations were sampled on Day 1 and Day 28 up to 8 hours post dose in a subset of the patient population.
    End point type
    Secondary
    End point timeframe
    Pre dose, Post dose (1, 2, 3, 4, 6, and 8 hours) at Day 1 and Day 28.
    Notes
    [4] - 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: PK was not analyzed for participants receiving Placebo.
    End point values
    		 QBW251 300mg
    Number of subjects analysed
    12
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1
    1000 ( 608 )
        Day 28
    1580 ( 866 )
    No statistical analyses for this end point

    Secondary: Annualized rate of EXACT-PRO-defined exacerbations

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    End point title
    		 Annualized rate of EXACT-PRO-defined exacerbations
    End point description
    The Exacerbations of COPD Tool-Patient Reported Outcome (EXACT-PRO) is a validated 14-item electronic questionnaire designed to detect the frequency, severity, and duration of exacerbations in participants with COPD. Minimum score is 0 and Maximum score is 40 (higher scores indicate worsening indicative of an exacerbation). EXACT-PRO-defined exacerbations are defined as a persistent increase from baseline in total EXACT-PRO score of ≥9 points for 3 days or ≥12 points for 2 days. Annualized rate of exacerbations was analyzed using a generalized linear model assuming a negative binomial distribution.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment until last dose of study treatment plus 7 days, up to a maximum duration of 99 days
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    24
    28
    Units: exacerbations per participant per year
        number (confidence interval 80%)
    1.22 (0.74 to 2.03)
    1.01 (0.61 to 1.67)
    No statistical analyses for this end point

    Secondary: On-treatment analysis of time to first COPD exacerbation using Cox regression model

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    End point title
    		 On-treatment analysis of time to first COPD exacerbation using Cox regression model
    End point description
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on COPD exacerbations, exacerbations defined by EXACT-PRO questionnaire. The protocol defined that the time-to-event analyses were to be carried out only upon sufficient number of exacerbation events occur during the study to estimate the median in either of the treatment groups.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12.
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: days
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [5] - The number of exacerbations were insufficient.
    [6] - The number of exacerbations were insufficient.
    No statistical analyses for this end point

    Secondary: Proportion of patients (percentage) with exacerbations

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    End point title
    		 Proportion of patients (percentage) with exacerbations
    End point description
    The EXACT-PRO is a validated 14-item electronic questionnaire designed to detect the frequency, severity, and duration of exacerbations in participants with COPD. Minimum score is 0 and Maximum score is 40 (higher scores indicate worsening indicative of an exacerbation). EXACT-PRO-defined exacerbations are defined as a persistent increase from baseline in total EXACT-PRO score of ≥9 points for 3 days or ≥12 points for 2 days.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment until last dose of study treatment plus 7 days, up to a maximum duration of 99 days
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    26
    28
    Units: participants
    3
    3
    No statistical analyses for this end point

    Secondary: Change from baseline in airway wall and lumen

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    End point title
    		 Change from baseline in airway wall and lumen
    End point description
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on airway structure and function, measured by High Resolution Computed Tomography (HRCT). The Number of Subjects Analyzed differs as stated on the comment field for each column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    Baseline, week 12.
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    21 [7]
    18 [8]
    Units: mm
    arithmetic mean (standard deviation)
        Lung, Left, Inferior Lobe, Posterior Basal Segment
    0.01 ( 0.201 )
    0.02 ( 0.155 )
        Lung, Left, Superior Lobe, Apical Segment
    -0.01 ( 0.150 )
    0.06 ( 0.134 )
        Lung,Right,Inferior Lobe,Posterior Basal Segment
    0.08 ( 0.378 )
    -0.03 ( 0.149 )
        Lung, Right, Middle Lobe, Lateral Segment
    0.00 ( 0.145 )
    -0.06 ( 0.105 )
        Lung, Right, Superior Lobe, Apical Segment
    -0.02 ( 0.128 )
    0.02 ( 0.092 )
    Notes
    [7] - n=19(Lung,Right,Inferior Lobe,Posterior Basal Segment);n=20(Lung,Right, Middle Lobe,Lateral Segment)
    [8] - n=17(Lung,Right, Middle Lobe,Lateral Segment)
    No statistical analyses for this end point

    Secondary: Change from baseline in percent global and regional air trapping after 12 weeks of treatment

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    End point title
    		 Change from baseline in percent global and regional air trapping after 12 weeks of treatment
    End point description
    To assess the effect of QBW251 compared to placebo after 12 weeks of treatment on airway structure and functions, measured by High Resolution Computed Tomography (HRCT). Air trapping is defined as the percentage of lung voxels with mean attenuation below -856 Hounsfield units (HU).
    End point type
    Secondary
    End point timeframe
    Baseline, week 12.
    End point values
    		 QBW251 300mg Placebo
    Number of subjects analysed
    19
    18
    Units: percent air trapping
    arithmetic mean (standard deviation)
        Lung
    -3.53 ( 7.534 )
    -0.95 ( 7.733 )
        Lung, Left
    -3.93 ( 7.176 )
    -0.89 ( 7.248 )
        Lung, Left Lower Lobe
    -4.27 ( 9.708 )
    -1.55 ( 7.486 )
        Lung, Left Upper Lobe
    -3.83 ( 7.220 )
    -0.78 ( 7.910 )
        Lung, Right
    -3.24 ( 8.280 )
    -0.98 ( 9.032 )
        Lung, Right Lower Lobe
    -3.57 ( 9.896 )
    -1.90 ( 11.666 )
        Lung, Right Middle Lobe
    -1.98 ( 10.362 )
    -0.80 ( 8.480 )
        Lung, Right Upper Lobe
    -2.09 ( 8.500 )
    0.27 ( 8.934 )
        Thirds, Left Lower
    -5.40 ( 10.613 )
    -1.90 ( 8.111 )
        Thirds, Left Middle
    -3.56 ( 6.803 )
    -0.76 ( 6.659 )
        Thirds, Left Upper
    -2.84 ( 7.597 )
    -0.11 ( 9.272 )
        Thirds, Right Lower
    -4.52 ( 8.545 )
    -1.70 ( 10.890 )
        Thirds, Right Middle
    -3.28 ( 9.116 )
    -1.09 ( 8.218 )
        Thirds, Right Upper
    -1.84 ( 8.956 )
    0.18 ( 10.107 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until last dose of study treatment plus 7 days, up to a maximum duration of 99 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    QBW251 300 mg b.i.d
    Reporting group description
    		 QBW251 300 mg b.i.d

    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 QBW251 300 mg b.i.d Total Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 54 (3.70%)
    0 / 28 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 54 (1.85%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 54 (1.85%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 54 (1.85%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 QBW251 300 mg b.i.d Total Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 26 (46.15%)
    17 / 54 (31.48%)
    5 / 28 (17.86%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 26 (15.38%)
    4 / 54 (7.41%)
    0 / 28 (0.00%)
         occurrences all number
    4
    4
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary mass
         subjects affected / exposed
    3 / 26 (11.54%)
    4 / 54 (7.41%)
    1 / 28 (3.57%)
         occurrences all number
    4
    5
    1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    4 / 26 (15.38%)
    7 / 54 (12.96%)
    3 / 28 (10.71%)
         occurrences all number
    4
    7
    3
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 26 (3.85%)
    3 / 54 (5.56%)
    2 / 28 (7.14%)
         occurrences all number
    1
    3
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 26 (11.54%)
    4 / 54 (7.41%)
    1 / 28 (3.57%)
         occurrences all number
    3
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Apr 2021
    The protocol was amended: 1. to clarify that the dose to be used in the study is 300 mg and the respective dose rationale, 2. to update and clarification to the inclusion and exclusion criteria to enable recruitment more aligned with clinical expectations of this subject population, 3. to permit subjects with documented 2 moderate exacerbations or 1 severe exacerbation between January 2019 and study screening, 4. to remove GOLD Stage 4 criteria from the inclusion criteria, 5. to include a statement that any restart following a temporary hold due to stopping rules being met will require the Competent Authorities and Ethic Committees approval, as required per country regulations, 6. On section 8.4.4 COPD Exacerbation - to update to reflect the instructions provided in the Note to File given to sites 17Dec2020 on what assessments are needed for COPD exacerbations.
    25 Aug 2021
    The protocol was amended to change the requirement for screening sputum samples from having a minimum of 80,000 CFU pathogenic bacteria, to require screening sputum samples to be positive for any pathogenic bacteria at any level >0. This amendment removes mucolytics from the prohibited medication list. The study drug has a different mechanism of action compared to mucolytics, so use of mucolytics is permitted as it will not interfere with assessment of the study drug.

    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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