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    Clinical Trial Results:
    A randomized, subject- and investigator-blinded, placebo-controlled, parallel group study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of QBW251 in patients with bronchiectasis

    Summary
    EudraCT number
    		 2019-002840-26
    Trial protocol
    		 GB   DE  
    Global end of trial date
    21 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2024
    First version publication date
    07 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CQBW251C12201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04396366
    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
    21 Jun 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jun 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the change on sputum bacterial colonization. Note: Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    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
    02 Feb 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    China: 21
    Worldwide total number of subjects
    42
    EEA total number of subjects
    7
    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)
    28
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All inclusion and exclusion criteria were checked at screening.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QBW251 300 mg b.i.d
    Arm description
    		 Participants received QBW251 300 mg orally, twice daily (b.i.d.), for 12 weeks.
    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
    Participants received QBW251 300 mg orally, twice daily (b.i.d.), for 12 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching placebo, b.i.d., for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received matching placebo, b.i.d., for 12 weeks.

    Number of subjects in period 1
    		QBW251 300 mg b.i.d Placebo
    Started
    21
    21
    Completed
    20
    21
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QBW251 300 mg b.i.d
    Reporting group description
    		 Participants received QBW251 300 mg orally, twice daily (b.i.d.), for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo, b.i.d., for 12 weeks.

    Reporting group values
    		 QBW251 300 mg b.i.d Placebo Total
    Number of subjects
    		 21 21 42
    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)
    		 14 14 28
        From 65-84 years
    		 7 7 14
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.8 ( 15.80 ) 56.2 ( 12.96 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 11 10 21
        Male
    		 10 11 21
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 11 10 21
        White
    		 10 11 21

    End points

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    End points reporting groups
    Reporting group title
    QBW251 300 mg b.i.d
    Reporting group description
    		 Participants received QBW251 300 mg orally, twice daily (b.i.d.), for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo, b.i.d., for 12 weeks.

    Primary: Change from Baseline In Bacterial Load Colony-forming Units of Potentially Pathogenic Microorganisms in Sputum at Week 12

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    End point title
    		 Change from Baseline In Bacterial Load Colony-forming Units of Potentially Pathogenic Microorganisms in Sputum at Week 12 [1]
    End point description
    No statistical analysis was planned for this primary outcome.
    End point type
    Primary
    End point timeframe
    Baseline, 12 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary outcome measure.
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    13
    19
    Units: CFU/mL
        arithmetic mean (standard deviation)
    -0.192 ( 1.4621 )
    0.340 ( 1.6476 )
    No statistical analyses for this end point

    Secondary: Proportion of Participants with Absence of any Colony-forming Units of Potentially Pathogenic Bacteria Sputum

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    End point title
    		 Proportion of Participants with Absence of any Colony-forming Units of Potentially Pathogenic Bacteria Sputum
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: participants
    0
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fibrinogen Plasma Concentration

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    End point title
    		 Change from Baseline in Fibrinogen Plasma Concentration
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    19
    19
    Units: g/L
        arithmetic mean (standard deviation)
    -0.193 ( 0.6278 )
    -0.127 ( 0.4828 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B) (Respiratory Symptoms Domain)

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    End point title
    		 Change from baseline in Quality of Life Questionnaire for Bronchiectasis (QOL-B) (Respiratory Symptoms Domain)
    End point description
    The Quality of Life Questionnaire for Bronchiectasis (QOL-B) is a disease-specific questionnaire developed for non-cystic fibrosis bronchiectasis. It covers 8 dimensions: physical functioning, role functioning, emotional functioning, social functioning, vitality, treatment burden, health perceptions, and respiratory symptoms. Each dimension is scored separately on a scale of 0 to 100, and higher scores represent better outcomes. Only the respiratory symptoms domain score will be reported for this outcome measure. Errors have been identified for the Quality of Life Questionnaire for Bronchiectasis (QOL-B) outcome measure in the final CSR, which don´t allow us to report results at this time. The CSR is currently being amended, and results will be provided by November 2024.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: score
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [2] - Data to be provided by November 2024.
    [3] - Data to be provided by November 2024.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Rescue Medication Use (Salbutamol/Albuterol)

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    End point title
    		 Change from Baseline in Rescue Medication Use (Salbutamol/Albuterol)
    End point description
    Data were collected as the number of puffs taken at every 12-hour window. The first 12 hours of the day were categorized as “Morning” and the next 12 hours as “Evening”. Total daily number of puffs was derived for each 24-hour window (per day), which was then used to calculate weekly and monthly average number of puffs taken. Baseline rescue medication use was defined as the average number of puffs per day in the screening period and the morning record at Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    16
    20
    Units: number of puffs
        arithmetic mean (standard deviation)
    -0.37 ( 1.069 )
    0.14 ( 0.895 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pre-bronchodilator Forced Exploratory Volume in the First Second (FEV1)

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    End point title
    		 Change from Baseline in Pre-bronchodilator Forced Exploratory Volume in the First Second (FEV1)
    End point description
    Errors have been identified for the Quality of Life Questionnaire for Bronchiectasis (QOL-B) outcome measure in the final CSR, which don´t allow us to report results at this time. The CSR is currently being amended, and results will be provided by November 2024.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: liters
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [4] - Data to be provided by November 2024.
    [5] - Data to be provided by November 2024.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pre-bronchodilator Forced Vital Capacity (FVC)

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    End point title
    		 Change from Baseline in Pre-bronchodilator Forced Vital Capacity (FVC)
    End point description
    Errors have been identified for the Quality of Life Questionnaire for Bronchiectasis (QOL-B) outcome measure in the final CSR, which don´t allow us to report results at this time. The CSR is currently being amended, and results will be provided by November 2024.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: liters
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [6] - Data to be provided by November 2024.
    [7] - Data to be provided by November 2024.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Bronchus Area with Perimeter of 10 Millimeters

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    End point title
    		 Change from Baseline in Bronchus Area with Perimeter of 10 Millimeters
    End point description
    Measured by high resolution computed tomography (HRCT)
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: mm
    arithmetic mean (standard deviation)
        Left Inferior Lobe Posterior Basal Segment n=21,21
    -0.072 ( 0.3592 )
    -0.029 ( 1456 )
        Left Superior Lobe Apical Segment n=16,18
    -0.063 ( 0.4140 )
    0.029 ( 0.1600 )
        Right Inferior Lobe Post. Basal Segment n=14,18
    0.001 ( 0.1999 )
    -0.015 ( 0.1071 )
        Right Middle Lobe Lateral Segment n=16,19
    0.074 ( 0.1867 )
    0.039 ( 0.1471 )
        Right Superior Lobe Apical Segment n=15,19
    -0.037 ( 0.1990 )
    -0.026 ( 0.0991 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mucus Score

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    End point title
    		 Change from Baseline in Mucus Score
    End point description
    Measured by HRCT
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: score
    arithmetic mean (standard deviation)
        Lower Lobe Bronchus, Left n=15,17
    -0.9 ( 3.13 )
    -0.8 ( 1.68 )
        Lung, Left Upper Lobe n=15,18
    -0.9 ( 3.13 )
    -0.8 ( 1.63 )
        Lung, Right Lower Lobe n=16,19
    -0.9 ( 3.03 )
    -1.6 ( 3.83 )
        Lung, Right Upper Lobe n=16,19
    -0.9 ( 3.03 )
    -1.6 ( 3.83 )
        Lung, Right, Middle Lobe, Lateral Segment n=16,19
    -0.9 ( 3.03 )
    -1.6 ( 3.83 )
        Lung, Right, Middle Lobe, Medial Segment n=16,19
    -0.9 ( 3.03 )
    -1.6 ( 3.83 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Region Percent Below or Equal to -856 Hounsfield units (HU)

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    End point title
    		 Change from Baseline in Region Percent Below or Equal to -856 Hounsfield units (HU)
    End point description
    The region percent below or equal to -856 HU represents air trapping, which was evaluated by HRCT in the whole lung and in the regions (thirds, lobes).
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: change from baseline in % </= -856 HU
    arithmetic mean (standard deviation)
        Lung n=15,17
    -0.284 ( 9.2755 )
    -1.074 ( 8.7794 )
        Lung, Left n=15,17
    -1.659 ( 8.5613 )
    -1.095 ( 7.2200 )
        Lung, Left Lower Lobe n=15,17
    -3.582 ( 8.4976 )
    -2.975 ( 7.8007 )
        Lung, Left Upper Lobe n=15,17
    0.002 ( 10.3698 )
    1.946 ( 10.7307 )
        Lung, Right n=15,17
    1.410 ( 10.8421 )
    -1.552 ( 10.1631 )
        Lung, Right Lower Lobe n=15,17
    0.303 ( 7.9933 )
    -2.193 ( 10.7784 )
        Lung, Right Middle Lobe n=15,17
    2.877 ( 10.3635 )
    0.502 ( 9.3885 )
        Lung, Right Upper Lobe n=15,17
    1.513 ( 13.1404 )
    -2.105 ( 11.4788 )
        Thirds, Left Lower n=15,17
    -2.726 ( 9.4063 )
    -1.109 ( 4.8754 )
        Thirds, Left Middle n=15,17
    -2.319 ( 8.3145 )
    -0.892 ( 8.0664 )
        Thirds, Left Upper n=15,17
    0.940 ( 10.8083 )
    -1.056 ( 9.7966 )
        Thirds, Right Lower n=15,17
    0.394 ( 9.2444 )
    -2.214 ( 9.6626 )
        Thirds, Right Middle n=15,17
    1.563 ( 11.7119 )
    -0.804 ( 10.4909 )
        Thirds, Right Upper n=15,17
    1.905 ( 12.7615 )
    -2.052 ( 11.7677 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Region Air Volume

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    End point title
    		 Change from Baseline in Region Air Volume
    End point description
    Measured by HRCT
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: liters
    arithmetic mean (standard deviation)
        Lung n=16,19
    7.588 ( 362.231 )
    -4.667 ( 323.292 )
        Lung, Left n=16,19
    6.719 ( 188.304 )
    -7.304 ( 144.047 )
        Lung, Left Lower Lobe n=15,19
    22.142 ( 125.643 )
    -14.848 ( 84.4328 )
        Lung, Left Upper Lobe n=16,19
    -14.039 ( 82.9500 )
    7.545 ( 69.1768 )
        Lung, Right n=16,19
    0.869 ( 179.912 )
    2.637 ( 190.892 )
        Lung, Right Lower Lobe n=16,19
    9.886 ( 95.0629 )
    -5.435 ( 105.079 )
        Lung, Right Middle Lobe n=16,19
    -3.233 ( 20.4193 )
    1.242 ( 13.5834 )
        Lung, Right Upper Lobe n=16,19
    -5.784 ( 78.3195 )
    6.830 ( 81.4095 )
        Thirds, Left Lower n=16,19
    -3.409 ( 82.0621 )
    -5.155 ( 50.2945 )
        Thirds, Left Middle n=16,19
    -1.319 ( 76.6437 )
    -1.992 ( 63.8795 )
        Thirds, Left Upper n=16,19
    11.444 ( 73.0426 )
    -0.432 ( 41.7288 )
        Thirds, Right Lower n=16,19
    -20.490 ( 122.493 )
    -7.548 ( 76.9902 )
        Thirds, Right Middle n=16,19
    8.762 ( 98.3416 )
    2.994 ( 93.2434 )
        Thirds, Right Upper n=16,19
    12.574 ( 84.6939 )
    5.327 ( 60.5143 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Segment Average Inner Area

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    End point title
    		 Change from Baseline in Segment Average Inner Area
    End point description
    Measured by HRCT
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: mm^2
    arithmetic mean (standard deviation)
        Lower Lobe Bronchus, Left n=15,17
    2.009 ( 10.4977 )
    -1.376 ( 6.5410 )
        Lung, Left Upper Lobe n=15,18
    1.106 ( 11.1387 )
    1.506 ( 7.5668 )
        Lung, Right Lower Lobe n=16,19
    -0.677 ( 7.9904 )
    -2.119 ( 6.7263 )
        Lung, Right Upper Lobe n=16,19
    0.667 ( 4.9950 )
    -2.653 ( 14.9922 )
        Lung, Right, Middle Lobe, Lateral Segment n=16,19
    0.138 ( 4.8198 )
    -0.379 ( 2.8929 )
        Lung, Right, Middle Lobe, Medial Segment n=16,19
    -0.502 ( 5.2215 )
    1.828 ( 5.5992 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Segment Average Major Inner Diameter

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    End point title
    		 Change from Baseline in Segment Average Major Inner Diameter
    End point description
    Measured by HRCT
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: mm
    arithmetic mean (standard deviation)
        Lower Lobe Bronchus, Left n=15,17
    0.364 ( 1.0234 )
    -0.128 ( 0.5242 )
        Lung, Left Upper Lobe n=15,18
    -0.095 ( 0.7972 )
    -0.116 ( 0.7192 )
        Lung, Right Lower Lobe n=16,19
    -0.040 ( 0.7883 )
    -0.207 ( 0.7876 )
        Lung, Right Upper Lobe n=16,19
    0.081 ( 0.7149 )
    -0.525 ( 1.9690 )
        Lung, Right, Middle Lobe, Lateral Segment n=16,19
    0.075 ( 0.9001 )
    -0.066 ( 0.5419 )
        Lung, Right, Middle Lobe, Medial Segment n=16,19
    0.046 ( 0.8759 )
    0.336 ( 1.2354 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Segment Average Minor Inner Diameter

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    End point title
    		 Change from Baseline in Segment Average Minor Inner Diameter
    End point description
    Measured by HRCT
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: mm
    arithmetic mean (standard deviation)
        Lower Lobe Bronchus, Left n=15,17
    0.080 ( 0.8100 )
    -0.204 ( 0.7995 )
        Lung, Left Upper Lobe n=15,18
    0.160 ( 0.7449 )
    0.120 ( 0.5935 )
        Lung, Right Lower Lobe n=16,19
    -0.011 ( 0.6186 )
    -0.220 ( 0.6556 )
        Lung, Right Upper Lobe n=16,19
    0.034 ( 0.4546 )
    0.127 ( 0.5699 )
        Lung, Right, Middle Lobe, Lateral Segment n=16,19
    -0.037 ( 0.5225 )
    -0.058 ( 0.4702 )
        Lung, Right, Middle Lobe, Medial Segment n=16,19
    -0.309 ( 0.7621 )
    0.065 ( 0.5016 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Segment Average Outer Area

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    End point title
    		 Change from Baseline in Segment Average Outer Area
    End point description
    Measured by HRCT
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: mm^2
    arithmetic mean (standard deviation)
        Lower Lobe Bronchus, Left n=15,17
    3.805 ( 15.3509 )
    -3.575 ( 9.6603 )
        Lung, Left Upper Lobe n=15,18
    2.527 ( 25.2783 )
    6.387 ( 15.1487 )
        Lung, Right Lower Lobe n=16,19
    -0.887 ( 13.2296 )
    -2.439 ( 10.4313 )
        Lung, Right Upper Lobe n=16,19
    3.054 ( 11.6503 )
    -6.171 ( 35.7465 )
        Lung, Right, Middle Lobe, Lateral Segment n=16,19
    0.011 ( 8.9779 )
    -0.574 ( 6.6601 )
        Lung, Right, Middle Lobe, Medial Segment n=16,19
    -1.929 ( 12.3065 )
    3.655 ( 9.0492 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Segment Average Wall Area Fraction

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    End point title
    		 Change from Baseline in Segment Average Wall Area Fraction
    End point description
    Measured by HRCT
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: percent
    arithmetic mean (standard deviation)
        Lower Lobe Bronchus, Left n=15,17
    -0.009 ( 0.0515 )
    -0.002 ( 0.0310 )
        Lung, Left Upper Lobe n=15,18
    0.002 ( 0.0553 )
    0.013 ( 0.0436 )
        Lung, Right Lower Lobe n=16,19
    0.001 ( 0.0377 )
    0.011 ( 0.0277 )
        Lung, Right Upper Lobe n=16,19
    0.007 ( 0.0392 )
    0.001 ( 0.0347 )
        Lung, Right, Middle Lobe, Lateral Segment n=16,19
    -0.002 ( 0.0414 )
    0.006 ( 0.0262 )
        Lung, Right, Middle Lobe, Medial Segment n=16,19
    0.007 ( 0.0281 )
    0.002 ( 0.0347 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Segment Average Wall Thickness

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    End point title
    		 Change from Baseline in Segment Average Wall Thickness
    End point description
    Measured by HRCT
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: mm
    arithmetic mean (standard deviation)
        Lower Lobe Bronchus, Left n=15,17
    0.001 ( 0.1680 )
    -0.042 ( 0.0987 )
        Lung, Left Upper Lobe n=15,18
    0.014 ( 0.3422 )
    0.081 ( 0.2417 )
        Lung, Right Lower Lobe n=16,19
    0.001 ( 0.1691 )
    0.021 ( 0.0900 )
        Lung, Right Upper Lobe n=16,19
    0.054 ( 0.2231 )
    -0.030 ( 0.2941 )
        Lung, Right, Middle Lobe, Lateral Segment n=16,19
    -0.014 ( 0.0828 )
    -0.004 ( 0.0968 )
        Lung, Right, Middle Lobe, Medial Segment n=16,19
    -0.040 ( 0.1606 )
    0.057 ( 0.0766 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Segment Wall Area Percent

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    End point title
    		 Change from Baseline in Segment Wall Area Percent
    End point description
    Measured by HRCT
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: percent
    arithmetic mean (standard deviation)
        Lower Lobe Bronchus, Left n=15,17
    -0.009 ( 0.0515 )
    -0.002 ( 0.0305 )
        Lung, Left Upper Lobe n=15,18
    0.002 ( 0.0553 )
    0.013 ( 0.0437 )
        Lung, Right Lower Lobe n=16,19
    0.001 ( 0.0376 )
    0.011 ( 0.0276 )
        Lung, Right Upper Lobe n=16,19
    0.007 ( 0.0394 )
    0.002 ( 0.0337 )
        Lung, Right, Middle Lobe, Lateral Segment n=16,19
    -0.003 ( 0.0411 )
    0.006 ( 0.0261 )
        Lung, Right, Middle Lobe, Medial Segment n=16,19
    0.007 ( 0.0282 )
    0.002 ( 0.0347 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Segment Wall Area

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    End point title
    		 Change from Baseline in Segment Wall Area
    End point description
    Measured by HRCT
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks
    End point values
    		 QBW251 300 mg b.i.d Placebo
    Number of subjects analysed
    21
    21
    Units: mm^2
    arithmetic mean (standard deviation)
        Lower Lobe Bronchus, Left n=15,17
    1.796 ( 6.6301 )
    -2.199 ( 4.3938 )
        Lung, Left Upper Lobe n=15,18
    1.421 ( 18.5698 )
    4.881 ( 12.4380 )
        Lung, Right Lower Lobe n=16,19
    -0.209 ( 6.9730 )
    -0.320 ( 4.5446 )
        Lung, Right Upper Lobe n=16,19
    2.388 ( 9.7223 )
    -3.518 ( 21.8864 )
        Lung, Right, Middle Lobe, Lateral Segment n=16,19
    -0.127 ( 4.6312 )
    -0.194 ( 4.0452 )
        Lung, Right, Middle Lobe, Medial Segment n=16,19
    -1.427 ( 7.3051 )
    1.827 ( 3.8885 )
    No statistical analyses for this end point

    Secondary: Cmax of QBW251

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    End point title
    		 Cmax of QBW251 [8]
    End point description
    Maximum (peak) plasma concentration of QBW251
    End point type
    Secondary
    End point timeframe
    1h, 2h, 3h, 4h, 6h and 8h post-dose on Days 1 and 28, and 3h post-dose on Day 56 and Day 84
    Notes
    [8] - 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: Pharmacokinetic parameters were only analyzed for the QBW251 arm.
    End point values
    		 QBW251 300 mg b.i.d
    Number of subjects analysed
    21
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 n=19
    1120 ( 913 )
        Day 28 n=19
    1520 ( 951 )
        Day 56 n=19
    1190 ( 578 )
        Day 84 n=18
    1460 ( 947 )
    No statistical analyses for this end point

    Secondary: Ctrough of QBW251

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    End point title
    		 Ctrough of QBW251 [9]
    End point description
    Trough (pre-dose) plasma concentration of QBW251
    End point type
    Secondary
    End point timeframe
    Pre-dose Day 1, Day 28, Day 56, Day 84
    Notes
    [9] - 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: Pharmacokinetic parameters were only analyzed for the QBW251 arm.
    End point values
    		 QBW251 300 mg b.i.d
    Number of subjects analysed
    21
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 n=21
    0.00 ( 0.00 )
        Day 28 n=20
    489 ( 371 )
        Day 56 n=19
    483 ( 395 )
        Day 84 n=18
    498 ( 416 )
    No statistical analyses for this end point

    Secondary: Ctrough of QBW251 for a Serial PK Set

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    End point title
    		 Ctrough of QBW251 for a Serial PK Set [10]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28
    Notes
    [10] - 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: Pharmacokinetic parameters were only analyzed for the QBW251 arm.
    End point values
    		 QBW251 300 mg b.i.d
    Number of subjects analysed
    3
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1
    0.00 ( 0.00 )
        Day 28
    603 ( 142 )
    No statistical analyses for this end point

    Secondary: Cmax of QBW251 for a Serial PK Set

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    End point title
    		 Cmax of QBW251 for a Serial PK Set [11]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28
    Notes
    [11] - 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: Pharmacokinetic parameters were only analyzed for the QBW251 arm.
    End point values
    		 QBW251 300 mg b.i.d
    Number of subjects analysed
    3
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1
    2470 ( 787 )
        Day 28
    3000 ( 1390 )
    No statistical analyses for this end point

    Secondary: AUClast of QBW251 for a Serial PK Set

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    End point title
    		 AUClast of QBW251 for a Serial PK Set [12]
    End point description
    Area under the concentration-time curve up to the last measurable concentration of QBW251 (AUClast)
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28
    Notes
    [12] - 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: Pharmacokinetic parameters were only analyzed for the QBW251 arm.
    End point values
    		 QBW251 300 mg b.i.d
    Number of subjects analysed
    3
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Day 1
    6100 ( 2340 )
        Day 28
    10300 ( 3100 )
    No statistical analyses for this end point

    Secondary: Tmax of QBW251 for a Serial PK Set

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    End point title
    		 Tmax of QBW251 for a Serial PK Set [13]
    End point description
    Time to reach maximum (peak) plasma concentration after single-dose administration
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28
    Notes
    [13] - 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: Pharmacokinetic parameters were only analyzed for the QBW251 arm.
    End point values
    		 QBW251 300 mg b.i.d
    Number of subjects analysed
    3
    Units: hours
    median (full range (min-max))
        Day 1
    1.00 (1.00 to 4.00)
        Day 28
    2.00 (1.00 to 3.08)
    No statistical analyses for this end point

    Secondary: AUC0-12h of QBW251 for a Serial PK Set

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    End point title
    		 AUC0-12h of QBW251 for a Serial PK Set [14]
    End point description
    Twelve-hour AUC
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28
    Notes
    [14] - 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: Pharmacokinetic parameters were only analyzed for the QBW251 arm.
    End point values
    		 QBW251 300 mg b.i.d
    Number of subjects analysed
    3
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Day 1 n=2
    5260 ( 1780 )
        Day 28 n=1
    15400 ( 999 )
    No statistical analyses for this end point

    Secondary: Tlast of QBW251 for a Serial PK Set

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    End point title
    		 Tlast of QBW251 for a Serial PK Set [15]
    End point description
    Tlast is the last measurable concentration sampling time.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1h, 2h, 3h, 4h, 6h and 8h post-dose on Day 1 and Day 28
    Notes
    [15] - 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: Pharmacokinetic parameters were only analyzed for the QBW251 arm.
    End point values
    		 QBW251 300 mg b.i.d
    Number of subjects analysed
    3
    Units: hours
    arithmetic mean (standard deviation)
        Day 1
    7.99 ( 0.00962 )
        Day 28
    8.00 ( 0.00 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events
    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 / 21 (9.52%)
    2 / 42 (4.76%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Renal and urinary disorders
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 42 (2.38%)
    0 / 21 (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
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 42 (2.38%)
    0 / 21 (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
    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
    14 / 21 (66.67%)
    27 / 42 (64.29%)
    13 / 21 (61.90%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 42 (7.14%)
    0 / 21 (0.00%)
         occurrences all number
    3
    3
    0
    Headache
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 42 (9.52%)
    2 / 21 (9.52%)
         occurrences all number
    2
    4
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 21 (14.29%)
    8 / 42 (19.05%)
    5 / 21 (23.81%)
         occurrences all number
    3
    8
    5
    Peripheral swelling
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 42 (4.76%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Pyrexia
         subjects affected / exposed
    3 / 21 (14.29%)
    4 / 42 (9.52%)
    1 / 21 (4.76%)
         occurrences all number
    3
    4
    1
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 42 (4.76%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    8 / 21 (38.10%)
    12 / 42 (28.57%)
    4 / 21 (19.05%)
         occurrences all number
    8
    12
    4
    Cough
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 42 (4.76%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 42 (4.76%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    3
    Rhinorrhoea
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 42 (7.14%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    3 / 21 (14.29%)
    4 / 42 (9.52%)
    1 / 21 (4.76%)
         occurrences all number
    3
    4
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 21 (9.52%)
    4 / 42 (9.52%)
    2 / 21 (9.52%)
         occurrences all number
    2
    4
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2021
    This protocol amendment: Clarified that the dose to be used in the study was 300 mg b.i.d, as well as the respective dose rationale; Removed the requirement for the serious adverse reactions to be similar in nature as a pre-requisite to put the study on hold; Included a statement that any restart following a temporary hold due to stopping rules being met would require the competent authorities and ethic committees’ approval; Clarified the primary analysis strategy.
    04 Nov 2021
    This protocol amendment addressed the following changes: two inclusion and one exclusion criteria were amended to improve study feasibility and recruitment. These changes expanded the number of eligible participants but did not change the overall patient profile for the study.
    02 Dec 2022
    This protocol amendment: Removed the stopping rules for NOAEL threshold limits; Discontinued the DMC involvement in the trial; Clarified the requirement of participant’s completion of the exacerbations of COPD Tool - Patient Reported Outcome (EXACT-PRO) during screening/baseline period for the purpose of EXACT-PRO baseline score calculation to correctly set up EXACT-PRO alert after patient’s being randomized; Updated the exploratory objective and endpoints related to mucus burden to be more specific; Reduced the number of ECGs to one per visit; Updated the co-medication lists to include the most updated drug-drug interaction (DDI) information based on clinical DDI study (CQBW251A2107) and in vitro data; Clarified the inclusion/exclusion criteria, allowing patients with primary ciliary dyskinesia (PCD) to participate; Clarified inclusion criteria, including the use of screening HRCT to satisfy inclusion in the study and clarified that Haemophilus parainfluenzae alone was not permitted for inclusion as a pathogenic organism; Introduced flexibility in the number of attempts for spontaneous sputum collection for each visit before attempting induced sputum collection; Allowed participants at selected sites, upon approval of the sponsor, to forgo HRCT scanning.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    For support, Contact us.
    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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