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    Clinical Trial Results:
    A two part, double blind, placebo controlled, study to assess the safety, tolerability, pharmacokinetics and pharmacodynamic effects of multiple doses of QBM076 in patients with Chronic Obstructive Pulmonary Disease (COPD)

    Summary
    EudraCT number
    		 2012-005615-92
    Trial protocol
    		 DE   GB   BE   NL   HU  
    Global end of trial date
    12 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 May 2016
    First version publication date
    29 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CQBM076X2203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01972776
    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
    12 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Part 1: To evaluate the safety and tolerability of multiple ascending doses of QBM076 in current or ex-smoking patients with stable chronic bronchitis COPD with spirometry grades I-III (according to the current GOLD strategy(GOLD 2013)) for 14 consecutive days of treatment Part 2: To evaluate the preliminary efficacy of 8 consecutive weeks of QBM076 in current or ex-smoking patients with stable chronic bronchitis COPD with spirometry grades I-III (according to the current GOLD strategy (GOLD 2013)): Lung Clearance Index (LCI); absolute neutrophil count in sputum ; spirometry FEV1; TDI.
    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
    27 Nov 2013
    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
    Germany: 37
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Romania: 4
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    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)
    26
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 In part 1, participants were randomly assigned to one of two treatment arms in a ratio of 3:1 for each cohort. In part 2, participants were stratified by smoking status (current versus ex-smoker) and randomized in a ratio of 2:1 into one of two treatments.

    Period 1
    Period 1 title
    Part 1 and Part 2 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QBM076 Part 1 Cohort 1
    Arm description
    		 Participants received QBM076 25 mg bid for 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBM076
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg twice daily (bid) for 14 days.

    Arm title
    		 QBM076 Part 1 Cohort 2
    Arm description
    		 Participants received QBM076 75 mg bid for 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBM076
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg bid for 14 days

    Arm title
    		 QBM076 Part 1 Cohort 3
    Arm description
    		 Participants received QBM076 150 mg bid for 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBM076
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg bid for 14 days

    Arm title
    		 Placebo Part 1
    Arm description
    		 Participants in each cohort received matching placebo bid for 14 days.
    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 in each cohort received matching placebo bid for 14 days.

    Arm title
    		 QBM076 Part 2
    Arm description
    		 Participants received QBM076 150 mg bid for 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    QBM076
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received QBM076 150 mg bid for 8 weeks.

    Arm title
    		 Placebo Part 2
    Arm description
    		 Participants received matching placebo bid for 8 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 bid for 8 weeks.

    Number of subjects in period 1
    		QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3 Placebo Part 1 QBM076 Part 2 Placebo Part 2
    Started
    6
    6
    8
    7
    14
    7
    Completed
    6
    6
    6
    6
    1
    0
    Not completed
    0
    0
    2
    1
    13
    7
         Consent withdrawn by subject
    -
    -
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    1
    1
    3
    -
         Administrative problems
    -
    -
    -
    -
    10
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QBM076 Part 1 Cohort 1
    Reporting group description
    		 Participants received QBM076 25 mg bid for 14 days.

    Reporting group title
    QBM076 Part 1 Cohort 2
    Reporting group description
    		 Participants received QBM076 75 mg bid for 14 days.

    Reporting group title
    QBM076 Part 1 Cohort 3
    Reporting group description
    		 Participants received QBM076 150 mg bid for 14 days.

    Reporting group title
    Placebo Part 1
    Reporting group description
    		 Participants in each cohort received matching placebo bid for 14 days.

    Reporting group title
    QBM076 Part 2
    Reporting group description
    		 Participants received QBM076 150 mg bid for 8 weeks.

    Reporting group title
    Placebo Part 2
    Reporting group description
    		 Participants received matching placebo bid for 8 weeks.

    Reporting group values
    		 QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3 Placebo Part 1 QBM076 Part 2 Placebo Part 2 Total
    Number of subjects
    		 6 6 8 7 14 7 48
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 4 3 3 6 7 3 26
        From 65-84 years
    		 2 3 5 1 7 4 22
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 63 ( 5.6 ) 64 ( 7.5 ) 65 ( 4.5 ) 61 ( 2.9 ) 64 ( 5.5 ) 66 ( 5.6 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 2 2 4 4 7 5 24
        Male
    		 4 4 4 3 7 2 24

    End points

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    End points reporting groups
    Reporting group title
    QBM076 Part 1 Cohort 1
    Reporting group description
    		 Participants received QBM076 25 mg bid for 14 days.

    Reporting group title
    QBM076 Part 1 Cohort 2
    Reporting group description
    		 Participants received QBM076 75 mg bid for 14 days.

    Reporting group title
    QBM076 Part 1 Cohort 3
    Reporting group description
    		 Participants received QBM076 150 mg bid for 14 days.

    Reporting group title
    Placebo Part 1
    Reporting group description
    		 Participants in each cohort received matching placebo bid for 14 days.

    Reporting group title
    QBM076 Part 2
    Reporting group description
    		 Participants received QBM076 150 mg bid for 8 weeks.

    Reporting group title
    Placebo Part 2
    Reporting group description
    		 Participants received matching placebo bid for 8 weeks.

    Primary: Percentage of participants with adverse events (Part 1)

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    End point title
    		 Percentage of participants with adverse events (Part 1) [1] [2]
    End point description
    Adverse events were counted and corresponding percentages were tabulated.
    End point type
    Primary
    End point timeframe
    14 days
    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 performed for this end point.
    [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: Part 1 placebo arm and Part 2 arms do not apply to this analysis.
    End point values
    		 QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3 Placebo Part 1
    Number of subjects analysed
    6
    6
    8
    7
    Units: percentage of participants
    33
    50
    63
    71
    No statistical analyses for this end point

    Primary: Change from baseline in Lung Clearance Index (LCI) (Part 2)

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    End point title
    		 Change from baseline in Lung Clearance Index (LCI) (Part 2) [3] [4]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, 8 weeks
    Notes
    [3] - 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 performed for this end point.
    [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: End point pertains to Part 2 arms only.
    End point values
    		 QBM076 Part 2 Placebo Part 2
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: units on a scale
    Notes
    [5] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    [6] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    No statistical analyses for this end point

    Primary: Change from baseline in absolute number of sputum neutrophils (Part 2)

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    End point title
    		 Change from baseline in absolute number of sputum neutrophils (Part 2) [7] [8]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, 8 weeks
    Notes
    [7] - 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 performed for this end point.
    [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: End point pertains to Part 2 arms only.
    End point values
    		 QBM076 Part 2 Placebo Part 2
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: number of sputum neutrophils
    Notes
    [9] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    [10] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    No statistical analyses for this end point

    Primary: Change from baseline in Transition Dyspnea Index (TDI) (Part 2)

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    End point title
    		 Change from baseline in Transition Dyspnea Index (TDI) (Part 2) [11] [12]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, 8 weeks
    Notes
    [11] - 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 performed for this end point.
    [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: End point pertains to Part 2 arms only.
    End point values
    		 QBM076 Part 2 Placebo Part 2
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: units on a scale
    Notes
    [13] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    [14] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    No statistical analyses for this end point

    Primary: Change From baseline in Forced Expiratory Volume in 1 Second (FEV1) (Part 2)

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    End point title
    		 Change From baseline in Forced Expiratory Volume in 1 Second (FEV1) (Part 2) [15] [16]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline, 8 weeks
    Notes
    [15] - 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 performed for this end point.
    [16] - 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: End point pertains to Part 2 only.
    End point values
    		 QBM076 Part 2 Placebo Part 2
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: liters
    Notes
    [17] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    [18] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-time curve from time zero to the end of the dosing interval, tau (AUCtau) (Part 1)

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    End point title
    		 Area under the plasma concentration-time curve from time zero to the end of the dosing interval, tau (AUCtau) (Part 1) [19]
    End point description
    Venous blood samples were collected for concentration-time profiles.
    End point type
    Secondary
    End point timeframe
    day 1 (from pre-dose to 12 hours post dose)
    Notes
    [19] - 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: Part 1 placebo arm and Part 2 arms do not apply to this analysis.
    End point values
    		 QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3
    Number of subjects analysed
    6
    6
    8
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    431 ( 158 )
    2060 ( 829 )
    7640 ( 6770 )
    No statistical analyses for this end point

    Secondary: AUCtau, steady state (AUCtau,ss) (Part 1)

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    End point title
    		 AUCtau, steady state (AUCtau,ss) (Part 1) [20]
    End point description
    Venous blood samples were collected for concentration-time profiles.
    End point type
    Secondary
    End point timeframe
    day 14 (from pre-dose to 72 hours post dose)
    Notes
    [20] - 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: Part 1 placebo arm and Part 2 arms do not apply to this analysis.
    End point values
    		 QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3
    Number of subjects analysed
    6
    6
    8
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    601 ( 112 )
    2220 ( 787 )
    6660 ( 4320 )
    No statistical analyses for this end point

    Secondary: Observed maximum plasma concentration following drug administration (Cmax) (Part 1)

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    End point title
    		 Observed maximum plasma concentration following drug administration (Cmax) (Part 1) [21]
    End point description
    Venous blood samples were collected for concentration-time profiles.
    End point type
    Secondary
    End point timeframe
    day 1 (from pre-dose to 12 hours post dose)
    Notes
    [21] - 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: Part 1 placebo arm and Part 2 arms do not apply to this analysis.
    End point values
    		 QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3
    Number of subjects analysed
    6
    6
    8
    Units: ng/mL
        arithmetic mean (standard deviation)
    69.5 ( 28.8 )
    366 ( 192 )
    1810 ( 1790 )
    No statistical analyses for this end point

    Secondary: Cmax,ss (Part 1)

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    End point title
    		 Cmax,ss (Part 1) [22]
    End point description
    Venous blood samples were collected for concentration-time profiles.
    End point type
    Secondary
    End point timeframe
    day 14 (from pre-dose to 72 hours post dose)
    Notes
    [22] - 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: Part 1 placebo arm and Part 2 arms do not apply to this analysis.
    End point values
    		 QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3
    Number of subjects analysed
    6
    6
    8
    Units: ng/mL
        arithmetic mean (standard deviation)
    91 ( 13.9 )
    338 ( 123 )
    2380 ( 2680 )
    No statistical analyses for this end point

    Secondary: Time to reach the maximum concentration after drug administration (Tmax) (Part 1)

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    End point title
    		 Time to reach the maximum concentration after drug administration (Tmax) (Part 1) [23]
    End point description
    Venous blood samples were collected for concentration-time profiles.
    End point type
    Secondary
    End point timeframe
    day 1 (from pre-dose to 12 hours post dose)
    Notes
    [23] - 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: Part 1 placebo arm and Part 2 arms do not apply to this analysis.
    End point values
    		 QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3
    Number of subjects analysed
    6
    6
    8
    Units: hours
        median (full range (min-max))
    3.05 (2 to 6)
    3.01 (2 to 8)
    3.04 (2.02 to 10.1)
    No statistical analyses for this end point

    Secondary: Tmax,ss (Part 1)

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    End point title
    		 Tmax,ss (Part 1) [24]
    End point description
    Venous blood samples were collected for concentration-time profiles.
    End point type
    Secondary
    End point timeframe
    day 14 (from pre-dose to 72 hours post dose)
    Notes
    [24] - 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: Part 1 placebo arm and Part 2 arms do not apply to this analysis.
    End point values
    		 QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3
    Number of subjects analysed
    6
    6
    8
    Units: hours
        median (full range (min-max))
    2 (2 to 4)
    2 (2 to 6.02)
    2.05 (0.5 to 6.02)
    No statistical analyses for this end point

    Secondary: Change from baseline in cluster of differentiation 11b (CD11b) (Part 1)

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    End point title
    		 Change from baseline in cluster of differentiation 11b (CD11b) (Part 1) [25]
    End point description
    Whole blood samples were taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein in order to measure CD11b expression on neutrophils. A negative change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, day 14
    Notes
    [25] - 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: Part 1 placebo arm and Part 2 arms do not apply to this analysis.
    End point values
    		 QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3 Placebo Part 1
    Number of subjects analysed
    6
    6
    6
    5
    Units: percentage change
        number (not applicable)
    -69
    -89
    -75
    -37
    No statistical analyses for this end point

    Secondary: Change from baseline in Chemokine (C-X-C motif) receptor 2 (CXCR2) receptor occupancy (Part 1)

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    End point title
    		 Change from baseline in Chemokine (C-X-C motif) receptor 2 (CXCR2) receptor occupancy (Part 1) [26]
    End point description
    Whole blood samples were taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein in order to measure CXCR2 receptor occupancy on neutrophils. A positive change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, day 14
    Notes
    [26] - 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: Part 1 placebo arm and Part 2 arms do not apply to this analysis.
    End point values
    		 QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3 Placebo Part 1
    Number of subjects analysed
    6
    6
    6
    6
    Units: percent change
    98
    104
    129
    37
    No statistical analyses for this end point

    Secondary: Change from baseline in Forced expiratory volume in one second (FEV1) (Part 1)

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    End point title
    		 Change from baseline in Forced expiratory volume in one second (FEV1) (Part 1) [27]
    End point description
    FEV1 is the amount of air that can be exhaled in one second. FEV1 will be measured by spirometry and performed at approximately the same time of day on each visit to avoid diurnal variation. All spirometry calibrations and evaluations followed the recommendations of the American Thoracic Society / European Respiratory Society guidelines for acceptability. A positive change from baseline in FEV1 indicates improvement in lung function.
    End point type
    Secondary
    End point timeframe
    baseline, day 14 pre-dose
    Notes
    [27] - 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: Part 1 placebo arm and Part 2 arms do not apply to this analysis.
    End point values
    		 QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3 Placebo Part 1
    Number of subjects analysed
    6
    6
    6
    6
    Units: mL
        arithmetic mean (standard error)
    -0.116 ( 0.05 )
    -0.008 ( 0.05 )
    0.117 ( 0.05 )
    0.039 ( 0.05 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Lung Clearance Index 2.5 (LCI2.5) (Part 1)

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    End point title
    		 Change from baseline in Lung Clearance Index 2.5 (LCI2.5) (Part 1) [28]
    End point description
    Lung clearance index (LCI) is a measure of abnormal ventilation distribution derived from the multiple breath inert gas washout (MBW) technique. LCI is equal to the cumulative expired volume/functional residual capacity. LCI was measured at baseline and day 14. LCI was analyzed using a Bayesian model for repeated measurements. The model may investigate effects for pre-dose baseline, treatment, time, age, COPD class, treatment by time interaction, and baseline by time interaction. A positive change from baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    baseline, day 14 pre-dose
    Notes
    [28] - 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: Part 1 placebo arm and Part 2 arms do not apply to this analysis.
    End point values
    		 QBM076 Part 1 Cohort 1 QBM076 Part 1 Cohort 2 QBM076 Part 1 Cohort 3 Placebo Part 1
    Number of subjects analysed
    6
    6
    6
    6
    Units: index score
        arithmetic mean (standard error)
    1.145 ( 0.42 )
    0.136 ( 0.42 )
    0.66 ( 0.42 )
    0.063 ( 0.42 )
    No statistical analyses for this end point

    Secondary: Change from baseline in forced expirtory flow 25-75 (FEF25-75), forced expiratory volume 3 (FEV3)/forced vital capacity (FVC), 1-(FEV3/FVC), FEV6, FEV1/FEV6 and post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (Part 2)

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    End point title
    		 Change from baseline in forced expirtory flow 25-75 (FEF25-75), forced expiratory volume 3 (FEV3)/forced vital capacity (FVC), 1-(FEV3/FVC), FEV6, FEV1/FEV6 and post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) (Part 2) [29]
    End point description
    End point type
    Secondary
    End point timeframe
    baseline, day 56
    Notes
    [29] - 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: End point pertains to Part 2 arms only.
    End point values
    		 QBM076 Part 2 Placebo Part 2
    Number of subjects analysed
    0 [30]
    0 [31]
    Units: liters
    Notes
    [30] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    [31] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    No statistical analyses for this end point

    Secondary: AUC0-24 (Part 2)

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    End point title
    		 AUC0-24 (Part 2) [32]
    End point description
    End point type
    Secondary
    End point timeframe
    day 1, day 56
    Notes
    [32] - 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: End point pertains to Part 2 only.
    End point values
    		 QBM076 Part 2 Placebo Part 2
    Number of subjects analysed
    0 [33]
    0 [34]
    Units: ng*hours/mL
    Notes
    [33] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    [34] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    No statistical analyses for this end point

    Secondary: Cmax between 0h and 24h (Part 2)

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    End point title
    		 Cmax between 0h and 24h (Part 2)
    End point description
    End point type
    Secondary
    End point timeframe
    day 1, day 56
    End point values
    Number of subjects analysed
    Units: ng/mL
    No statistical analyses for this end point

    Secondary: Tmax between 0h and 24h (Part 2)

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    End point title
    		 Tmax between 0h and 24h (Part 2) [35]
    End point description
    End point type
    Secondary
    End point timeframe
    day 1, day 56
    Notes
    [35] - 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: End point pertains to Part 2 only.
    End point values
    		 QBM076 Part 2 Placebo Part 2
    Number of subjects analysed
    0 [36]
    0 [37]
    Units: hours
    Notes
    [36] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    [37] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    No statistical analyses for this end point

    Secondary: Change from baseline in percentage sputum neutrophils (Part 2)

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    End point title
    		 Change from baseline in percentage sputum neutrophils (Part 2) [38]
    End point description
    End point type
    Secondary
    End point timeframe
    baseline, day 56
    Notes
    [38] - 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: End point pertains to Part 2 only.
    End point values
    		 QBM076 Part 2 Placebo Part 2
    Number of subjects analysed
    0 [39]
    0 [40]
    Units: percentage sputum neutrophils
    Notes
    [39] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    [40] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    No statistical analyses for this end point

    Secondary: Change from baseline in diffusing capacity of the lung for carbon monoxide (DLco) (Part 2)

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    End point title
    		 Change from baseline in diffusing capacity of the lung for carbon monoxide (DLco) (Part 2) [41]
    End point description
    End point type
    Secondary
    End point timeframe
    baseline, day 56
    Notes
    [41] - 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: End point pertains to part 2 only.
    End point values
    		 QBM076 Part 2 Placebo Part 2
    Number of subjects analysed
    0 [42]
    0 [43]
    Units: liters
    Notes
    [42] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    [43] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    No statistical analyses for this end point

    Secondary: Change from baseline in Scond/Sacin as measured by multiple breath nitrogen washout (MBNW) (Part 2)

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    End point title
    		 Change from baseline in Scond/Sacin as measured by multiple breath nitrogen washout (MBNW) (Part 2) [44]
    End point description
    End point type
    Secondary
    End point timeframe
    baseline, day 56
    Notes
    [44] - 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: End point pertains to Part 2 only.
    End point values
    		 QBM076 Part 2 Placebo Part 2
    Number of subjects analysed
    0 [45]
    0 [46]
    Units: liters
    Notes
    [45] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    [46] - Part 2 was terminated for safety reasons. The Part 2 efficacy outcomes were not assessed.
    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
    16.0
    Reporting groups
    Reporting group title
    Part 1 QBM076 25 mg bid
    Reporting group description
    		 Part 1 QBM076 25 mg bid

    Reporting group title
    Part 1 QBM076 75 mg bid
    Reporting group description
    		 Part 1 QBM076 75 mg bid

    Reporting group title
    Part 1 QBM076 150 mg bid
    Reporting group description
    		 Part 1 QBM076 150 mg bid

    Reporting group title
    Part 1 Placebo
    Reporting group description
    		 Part 1 Placebo

    Reporting group title
    Part 2 QBM076 150 mg bid
    Reporting group description
    		 Part 2 QBM076 150 mg bid

    Reporting group title
    Part 2 Placebo
    Reporting group description
    		 Part 2 Placebo

    Serious adverse events
    		 Part 1 QBM076 25 mg bid Part 1 QBM076 75 mg bid Part 1 QBM076 150 mg bid Part 1 Placebo Part 2 QBM076 150 mg bid Part 2 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    2 / 14 (14.29%)
    0 / 7 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1 QBM076 25 mg bid Part 1 QBM076 75 mg bid Part 1 QBM076 150 mg bid Part 1 Placebo Part 2 QBM076 150 mg bid Part 2 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    5 / 8 (62.50%)
    4 / 7 (57.14%)
    8 / 14 (57.14%)
    3 / 7 (42.86%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Eyelid injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Procedural complication
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Headache
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    1
    0
    1
    2
    Lethargy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Catheter site eczema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Catheter site erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Therapeutic response unexpected
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vessel puncture site haematoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Abdominal tenderness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dry mouth
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Increased upper airway secretion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    0
    2
    1
    Rhinitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2013
    Amendment 1, issued before the first patient was screened, introduced the following changes: clarified that the dose chosen for Part 2 did not exceed the MTD determined from Part 1; male contraceptive requirements were revised; exclusion criteria for tuberculosis was added; clarified that repeated administration of a dose level was only permitted as long as no stopping criteria were met in the previous cohort; and clarified that for individual patient withdrawal, investigator discretion was no longer permitted.
    20 Nov 2013
    Amendment 2 issued before the first patient was screened, introduced the following change(s): Sample logs were removed from the protocol and were included in the study reference manual, this resulted in updates to the assessment schedule. The deviation window for the MRI scan at baseline was increased to within 14 days prior to baseline visit. Caffeine restrictions for 4 hours prior to the start of lung function testing were added in on days the patient attended the clinic. All meal time data were to be entered into the eCRF following collection on the patient diary. Clarified that waist and hip circumference was measured in centimeters. Clarified that glucose was fasted when performed as part of safety laboratory tests. Clarified that urine albumin was measured at screening as per exclusion criteria. Clarified that FEV1 and FVC did not need to be repeated by whole body plethysmography, because they were measured during spirometry. Clarified that a second set of spirometry measurements for reversibility was only applicable at the screening visit. Other minor corrections and correction of typographical errors.
    05 Mar 2014
    Amendment 3, issued when Cohort 1 had completed and 6 patients were ongoing in Cohort 2, introduced the following changes: Stopping criteria specific to COPD were added as requested by BfArM during review of the protocol. Inclusion of smokers into Part 2 to more closely reflect the population of patients that required treatment for COPD. Revisions were also made to the inclusion and exclusion criteria. Creatinine clearance was lowered because neither the drug nor the metabolites have shown evidence of renal clearance. Further, the target patient population is likely to have mild to moderate renal insufficiency. Hence we would like to examine the safety, tolerability and efficacy of the drug on in patients with creatinine clearance ≥ 30mL/min. The list of potentially excluded medications was revised to focus on strong inhibitors and inducers of cytochrome 3A4 (CYP3A4).
    07 Jul 2014
    Amendment 4 was issued after all patients had started Cohort 3. The main purpose of this amendment was to remove the use of hyperpolarized helium-3 MRI and to provide the maximum proposed QBM076 dose intended for Part 2. Following feedback from the FDA, it was recognized that there was insufficient justification to conduct this exploratory assessment (hyperpolarized helium-3 MRI) in the setting of an exploratory clinical trial. Revisions were also made to clarify the use of fed state vs. fasted state in earlier and ongoing clinical trials.
    23 Oct 2014
    Amendment 5 was issued after the completion of Part 1. The main purpose of this amendment was to include data from pivotal embryo-fetal toxicity studies which allowed women of child bearing potential to participate in the study as long as they used effective contraception methods (with the exception of hormonal contraceptives, due to the risk of drug-drug interaction with QBM076) as defined in the protocol. In addition, the dose QBM076 to be tested in Part 2 of the study was confirmed as 150 mg bid x 8 weeks. Revisions were also made to clarify the term “chronic bronchitis" based on investigator feedback that the term could be misleading since there are no criteria requiring a level of cough & sputum production. This was revised to require GOLD I-III based on spirometry criteria. Changes were also made to the PD and PK assessment based on results from Part 1; and to study assessments to reduce the overall protocol burden in Part 2.

    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.
    Part 2 was terminated after 21 patients were enrolled. Three of the 21 patients experienced moderate to severe (up to 17-fold) asymptomatic and reversible elevation of liver transaminase levels after 3 weeks of treatment with QBM076 150 mg bid.
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