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    Clinical Trial Results:
    A randomized, double blind, placebo controlled study to assess the safety, tolerability, pharmacokinetics and efficacy of multiple doses of QBW251 in patients with COPD

    Summary
    EudraCT number
    		 2014-001530-28
    Trial protocol
    		 PL  
    Global end of trial date
    23 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Feb 2018
    First version publication date
    03 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CQBW251X2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02449018
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    23 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of a 28-day QBW251 treatment course on small airway function in current and prior smokers with chronic bronchitis and COPD
    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
    30 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    United States: 89
    Worldwide total number of subjects
    92
    EEA total number of subjects
    3
    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)
    47
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients completed a single-blind placebo controlled Run-in period (14 days: Day −14 to Day −1) after confirmation of eligibility, which included visits at Day −14 and at Baseline (Day −1).

    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
    Arm description
    		 QBW251 (28 day treatment period) and placebo (42 days, run-in and wash-out periods)
    Arm type
    		 Experimental

    Investigational medicinal product name
    CQBW251
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg hard gelatin capsule

    Investigational medicinal product name
    QBW251X
    Investigational medicinal product code
    QBW251
    Other name
    QBW251
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg hard gelatin capsule

    Arm title
    		 Placebo
    Arm description
    		 Placebo (70 days, run-in, treatment and wash-out periods)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo 0mg

    Number of subjects in period 1
    		QBW251 Placebo
    Started
    64
    28
    Completed
    52
    26
    Not completed
    12
    2
         Patient decision
    2
    -
         Adverse event, non-fatal
    5
    1
         Protocol deviation
    4
    -
         Administrative problems
    1
    -
         Abnormal laboratory value
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QBW251
    Reporting group description
    		 QBW251 (28 day treatment period) and placebo (42 days, run-in and wash-out periods)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (70 days, run-in, treatment and wash-out periods)

    Reporting group values
    		 QBW251 Placebo Total
    Number of subjects
    		 64 28 92
    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)
    		 34 13 47
        From 65-84 years
    		 30 15 45
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 63.6 ± 6.61 64.9 ± 7.55 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 31 9 40
        Male
    		 33 19 52

    End points

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    End points reporting groups
    Reporting group title
    QBW251
    Reporting group description
    		 QBW251 (28 day treatment period) and placebo (42 days, run-in and wash-out periods)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (70 days, run-in, treatment and wash-out periods)

    Primary: Change from Baseline in Lung Clearance Index (LCI)

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    End point title
    		 Change from Baseline in Lung Clearance Index (LCI)
    End point description
    Change from baseline to Day 29 in LCI as measured by multiple breath nitrogen washout (MBNW) technique. MBNW is the time taken to wash out nitrogen while breathing 100% oxygen.
    End point type
    Primary
    End point timeframe
    Day 29
    End point values
    		 QBW251 Placebo
    Number of subjects analysed
    50
    24
    Units: Participants
        arithmetic mean (standard deviation)
    -0.03 ± 1.28
    -0.16 ± 1.15
    Statistical analysis title
    		 Absolute change from baseline
    Comparison groups
    QBW251 v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.28
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.79
    Variability estimate
    Standard deviation
    Dispersion value
    0.31

    Secondary: Change From Baseline in FEV1 pre-bronchodilator

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    End point title
    		 Change From Baseline in FEV1 pre-bronchodilator
    End point description
    Change From Baseline to Day 29 in FEV1 will be measured by spirometer before bronchodilator administration. Forced Expiratory Volume in 1 Second (FEV1) is the amount of air that can be exhaled in 1 second. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 QBW251 Placebo
    Number of subjects analysed
    51
    23
    Units: Liters
        arithmetic mean (standard deviation)
    0.04 ± 0.24
    -0.02 ± 0.23
    No statistical analyses for this end point

    Secondary: Change From Baseline in FEV1 post-bronchodilator

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    End point title
    		 Change From Baseline in FEV1 post-bronchodilator
    End point description
    Change From Baseline to Day 29 in FEV1 will be measured by spirometer after bronchodilator administration. Forced Expiratory Volume in 1 Second (FEV1) is the amount of air that can be exhaled in 1 second. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 QBW251 Placebo
    Number of subjects analysed
    51
    24
    Units: Liters
        arithmetic mean (standard deviation)
    0.05 ± 0.21
    -0.02 ± 0.16
    No statistical analyses for this end point

    Secondary: Change From Baseline in FVC pre bronchodilator

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    End point title
    		 Change From Baseline in FVC pre bronchodilator
    End point description
    Change From Baseline to Day 29 in FVC will be measured by spirometer before bronchodilator administration. Forced Vital Capacity (FVC) is the maximum amount of air a person can expel from the lungs after a maximum inhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. Forced vital capacity (FVC) as a measure of lung function, measured before bronchodilator
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 QBW251 Placebo
    Number of subjects analysed
    51
    23
    Units: Liters
        least squares mean (standard deviation)
    0.07 ± 0.05
    0.01 ± 0.07
    No statistical analyses for this end point

    Secondary: Change From Baseline in FVC post- bronchodilator

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    End point title
    		 Change From Baseline in FVC post- bronchodilator
    End point description
    Change From Baseline to Day 29 in FVC will be measured by spirometer after bronchodilator administration. Forced Vital Capacity (FVC) is the maximum amount of air a person can expel from the lungs after a maximum inhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. Forced vital capacity (FVC) as a measure of lung function, measured after bronchodilator
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 QBW251 Placebo
    Number of subjects analysed
    51
    24
    Units: Liters
        least squares mean (standard deviation)
    0.03 ± 0.04
    0.01 ± 0.05
    No statistical analyses for this end point

    Secondary: Change From Baseline in TLC

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    End point title
    		 Change From Baseline in TLC
    End point description
    Change From Baseline to Day 29 in TLC will be measured by spirometry. Total lung capacity (TLC) is the volume in the lungs at maximal inflation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 QBW251 Placebo
    Number of subjects analysed
    50
    24
    Units: Liters
        least squares mean (standard deviation)
    0.01 ± 0.07
    -0.07 ± 0.10
    No statistical analyses for this end point

    Secondary: Change From Baseline in RV

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    End point title
    		 Change From Baseline in RV
    End point description
    Change From Baseline to Day 29 in RV will be measured by spirometry. Residual volume (RV) is the volume of air remaining in the lungs after a maximal exhalation. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 QBW251 Placebo
    Number of subjects analysed
    48
    24
    Units: Liters
        least squares mean (standard deviation)
    0.03 ± 0.07
    -0.02 ± 0.10
    No statistical analyses for this end point

    Secondary: Change From Baseline in FRC

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    End point title
    		 Change From Baseline in FRC
    End point description
    Change From Baseline to Day 29 in FRC will be measured by spirometry. Functional residual capacity (FRC) is the volume in the lungs at the end-expiratory position. All spirometry calibrations and evaluations will follow the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability.
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 QBW251 Placebo
    Number of subjects analysed
    50
    24
    Units: Liters
        least squares mean (standard deviation)
    0.01 ± 0.07
    -0.02 ± 0.09
    No statistical analyses for this end point

    Secondary: Change From Baseline in DLCO

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    End point title
    		 Change From Baseline in DLCO
    End point description
    Diffusing capacity of the lung for carbon monoxide (DLCO) is the extent to which oxygen passes from the lung to the blood.
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 QBW251 Placebo
    Number of subjects analysed
    42
    22
    Units: ml/min/mmHg
        least squares mean (standard deviation)
    -0.91 ± 0.24
    -0.25 ± 0.34
    No statistical analyses for this end point

    Secondary: Plasma concentration of QBW251 by TMax

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    End point title
    		 Plasma concentration of QBW251 by TMax [1]
    End point description
    Tmax is the time to reach the maximum concentration after drug administration.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 28
    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: No stats analysis for this outcome measure
    End point values
    		 QBW251
    Number of subjects analysed
    62
    Units: hr
    median (full range (min-max))
        Day 1 (n=57)|
    1.27 (0.983 to 8.03)
        Day 28 (n=53)|
    1.98 (0.933 to 7.97)
    No statistical analyses for this end point

    Secondary: Plasma concentration of QBW251 by CMax

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    End point title
    		 Plasma concentration of QBW251 by CMax [2]
    End point description
    Cmax is the observed maximum plasma concentration following drug administration.
    End point type
    Secondary
    End point timeframe
    Day 1, 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: No stats analysis for this outcome measure
    End point values
    		 QBW251
    Number of subjects analysed
    62
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n=57)|
    1250 ± 840
        Day 28 (n=53)|
    1640 ± 916
    No statistical analyses for this end point

    Secondary: Plasma concentration of QBW251 by AUClast

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    End point title
    		 Plasma concentration of QBW251 by AUClast [3]
    End point description
    AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 28
    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: No stats analysis for this outcome measure
    End point values
    		 QBW251
    Number of subjects analysed
    62
    Units: hr×ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n=57)|
    3830 ± 3280
        Day 28 (n=53)|
    6840 ± 4490
    No statistical analyses for this end point

    Secondary: Plasma concentration of QBW251 by AUC0-12h

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    End point title
    		 Plasma concentration of QBW251 by AUC0-12h
    End point description
    AUC 0-12h is the area under the plasma concentration-time curve from time zero to 12 hours.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 28
    End point values
    		 QBW251 Placebo
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: hr×ng/mL
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [4] - analysis AUClast was not calculated up to 12 hours after dosing So this data is not available.
    [5] - analysis AUClast was not calculated up to 12 hours after dosing So this data is not available.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    QBW251 300 mg bid
    Reporting group description
    		 QBW251 300 mg bid

    Serious adverse events
    		 Placebo QBW251 300 mg bid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 28 (0.00%)
    4 / 64 (6.25%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo QBW251 300 mg bid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 28 (17.86%)
    6 / 64 (9.38%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 64 (3.13%)
         occurrences all number
    2
    2
    Nausea
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 64 (1.56%)
         occurrences all number
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 28 (7.14%)
    3 / 64 (4.69%)
         occurrences all number
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2015
    The purpose was to clarify multiple requirements related to the chest HRCT study component. HRCT was utilized as a screening measurement as well as a mechanism to quantify air trapping for comparative efficacy purposes in this study. Experience in ongoing sponsor trials revealed that historical scans are unlikely to adhere to the imaging requirements of this study. Therefore, the use of historical HRCT scans for the purpose of air trapping quantification was removed, except in the instance that a patient was re-screened for this study. The specific quantitative thresholds used to determine evidence of air trapping and emphysema extent was removed from the radiologic eligibility criteria and only a qualitative description remained.
    01 Jul 2015
    The purpose was to modify the dose of QBW251, changing from the original dose of 450 mg bid to 300 mg bid. At the time of the protocol amendment, 4 patients were randomized to 450 mg bid (drug/placebo).
    01 Feb 2016
    The purpose was to discontinue the collection and analysis of EPCs. EPC cellular biomarkers were collected as an exploratory objective to evaluate vascular remodeling in COPD patients. Results from the analysis of 136 EPC samples from a total of 44 patients showed that blood leukocyte populations and EPCs could not be identified properly because of staining failure and quality issue of the reagents. Based on this data, cellular biomarkers were removed as an exploratory biomarker assessment

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

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

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