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    Clinical Trial Results:
    A randomised, double-blind, placebo-controlled and parallel group trial to evaluate efficacy and safety of twice daily inhaled doses of BI 1265162 delivered by Respimat® inhaler as add-on therapy to standard of care over 4 weeks in patients with cystic fibrosis – BALANCE – CFTM 1

    Summary
    EudraCT number
    		 2019-000261-21
    Trial protocol
    		 SE   DE   FR   BE   IE   GB   ES  
    Global end of trial date
    24 Apr 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    27 May 2021
    First version publication date
    01 May 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1399-0003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04059094
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim Call Center, Boehringer Ingelheim, +1 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim Call Center, Boehringer Ingelheim, +1 18002430127, clintriage.rdg@boehringer-ingelheim.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
    18 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Apr 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to assess the efficacy, safety, and pharmacokinetics of different dose regimens of BI 1265162 versus placebo in adult and adolescent patients with cystic fibrosis. This trial examined twice daily inhaled doses of 20 microgram, 50 microgram, 100 microgram, and 200 microgram of BI 1265162 delivered by the Respimat® inhaler as an add-on to standard-of-care treatment for cystic fibrosis.
    Protection of trial subjects
    All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Sep 2019
    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
    Canada: 3
    Country: Number of subjects enrolled
    United States: 16
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    United Kingdom: 1
    Worldwide total number of subjects
    74
    EEA total number of subjects
    54
    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)
    73
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This trial aimed to assess the efficacy, safety, and pharmacokinetics of different dose regimens of BI 1265162 taken twice daily by the Respimat® inhaler versus placebo in adult and adolescent patients with cystic fibrosis for a 4-week treatment period. Study was terminated without recruiting any adolescent patients.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 2 puffs of matching placebo were inhaled orally via the Respimat® inhaler twice daily for a treatment period of 4 weeks in patients with cystic fibrosis.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    2 puffs of matching placebo were inhaled orally via the Respimat® inhaler twice daily for a treatment period of 4 weeks in patients with cystic fibrosis.

    Arm title
    		 BI 1265162 20μg b.i.d.
    Arm description
    		 2 puffs of 10 micrograms (μg) BI 1265162 (Total: 20μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 40μg) for a treatment period of 4 weeks in patients with cystic fibrosis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 1265162 20μg b.i.d.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    2 puffs of 10 micrograms (μg) BI 1265162 (Total: 20μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 40μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Arm title
    		 BI 1265162 50μg b.i.d.
    Arm description
    		 2 puffs of 25 micrograms (μg) BI 1265162 (Total: 50μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 100μg) for a treatment period of 4 weeks in patients with cystic fibrosis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 1265162 50μg b.i.d.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    2 puffs of 25 micrograms (μg) BI 1265162 (Total: 50μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 100μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Arm title
    		 BI 1265162 100μg b.i.d.
    Arm description
    		 2 puffs of 50 micrograms (μg) BI 1265162 (Total: 100μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 200μg) for a treatment period of 4 weeks in patients with cystic fibrosis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 1265162 100μg b.i.d.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    2 puffs of 50 micrograms (μg) BI 1265162 (Total: 100μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 200μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Arm title
    		 BI 1265162 200μg b.i.d.
    Arm description
    		 2 puffs of 100 micrograms (μg) BI 1265162 (Total: 200μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 400μg) for a treatment period of 4 weeks in patients with cystic fibrosis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 1265162 200μg b.i.d.
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    2 puffs of 100 micrograms (μg) BI 1265162 (Total: 200μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 400μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Number of subjects in period 1 [1]
    		Placebo BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Started
    18
    6
    5
    5
    18
    Completed
    18
    4
    5
    5
    17
    Not completed
    0
    2
    0
    0
    1
         Not willing to travel due to COVID-19 pandemic
    -
    2
    -
    -
    -
         Adverse event, non-fatal
    -
    -
    -
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 2 puffs of matching placebo were inhaled orally via the Respimat® inhaler twice daily for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group title
    BI 1265162 20μg b.i.d.
    Reporting group description
    		 2 puffs of 10 micrograms (μg) BI 1265162 (Total: 20μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 40μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group title
    BI 1265162 50μg b.i.d.
    Reporting group description
    		 2 puffs of 25 micrograms (μg) BI 1265162 (Total: 50μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 100μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group title
    BI 1265162 100μg b.i.d.
    Reporting group description
    		 2 puffs of 50 micrograms (μg) BI 1265162 (Total: 100μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 200μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group title
    BI 1265162 200μg b.i.d.
    Reporting group description
    		 2 puffs of 100 micrograms (μg) BI 1265162 (Total: 200μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 400μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group values
    		 Placebo BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d. Total
    Number of subjects
    		 18 6 5 5 18 52
    Age categorical
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 18 6 5 5 18 52
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
    Age Continuous
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
    Units: years
        arithmetic mean (standard deviation)
    		 29.3 ( 10.1 ) 26.8 ( 5.8 ) 31.2 ( 8.6 ) 36.8 ( 4.2 ) 33.4 ( 10.2 ) -
    Sex: Female, Male
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
    Units: Participants
        Female
    		 2 1 3 1 3 10
        Male
    		 16 5 2 4 15 42
    Race (NIH/OMB)
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 1 0 0 0 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 0 0 0 1 0 1
        White
    		 17 6 5 4 18 50
        More than one race
    		 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
    Units: Subjects
        Hispanic or Latino
    		 1 0 0 0 0 1
        Not Hispanic or Latino
    		 17 6 5 5 18 51
        Unknown or Not Reported
    		 0 0 0 0 0 0
    Trough forced expiratory volume in one second (FEV1) percent predicted
    Baseline trough FEV1 percent (%) predicted was defined as the last measurement taken on day 1 before first study drug administration and was measured within 30 minutes prior to dosing. Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received. One participant in the BI 1265162 200 microgram group did not have valid baseline trough FEV1 percent predicted value measured.
    Units: Percentage of predicted trough FEV1
        arithmetic mean (standard deviation)
    		 59.40 ( 11.29 ) 69.93 ( 15.99 ) 63.02 ( 14.40 ) 65.50 ( 7.00 ) 57.94 ( 13.76 ) -
    Subject analysis sets

    Subject analysis set title
    Total with baseline FEV1 measures
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received. One participant in the BI 1265162 200 microgram group did not have valid baseline trough forced expiratory volume in one second (FEV1) percent predicted value measured.

    Subject analysis sets values
    		 Total with baseline FEV1 measures
    Number of subjects
    51
    Age categorical
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
    Units: years
        arithmetic mean (standard deviation)
    ( )
    Sex: Female, Male
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
    Units: Participants
        Female
        Male
    Race (NIH/OMB)
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported
    Ethnicity (NIH/OMB)
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Trough forced expiratory volume in one second (FEV1) percent predicted
    Baseline trough FEV1 percent (%) predicted was defined as the last measurement taken on day 1 before first study drug administration and was measured within 30 minutes prior to dosing. Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received. One participant in the BI 1265162 200 microgram group did not have valid baseline trough FEV1 percent predicted value measured.
    Units: Percentage of predicted trough FEV1
        arithmetic mean (standard deviation)
    61.11 ( 12.89 )

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 2 puffs of matching placebo were inhaled orally via the Respimat® inhaler twice daily for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group title
    BI 1265162 20μg b.i.d.
    Reporting group description
    		 2 puffs of 10 micrograms (μg) BI 1265162 (Total: 20μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 40μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group title
    BI 1265162 50μg b.i.d.
    Reporting group description
    		 2 puffs of 25 micrograms (μg) BI 1265162 (Total: 50μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 100μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group title
    BI 1265162 100μg b.i.d.
    Reporting group description
    		 2 puffs of 50 micrograms (μg) BI 1265162 (Total: 100μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 200μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group title
    BI 1265162 200μg b.i.d.
    Reporting group description
    		 2 puffs of 100 micrograms (μg) BI 1265162 (Total: 200μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 400μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Subject analysis set title
    Total with baseline FEV1 measures
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received. One participant in the BI 1265162 200 microgram group did not have valid baseline trough forced expiratory volume in one second (FEV1) percent predicted value measured.

    Primary: Change from baseline in percent predicted trough Forced Expiratory Volume in 1 Second (FEV1) after 4 weeks of treatment

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    End point title
    		 Change from baseline in percent predicted trough Forced Expiratory Volume in 1 Second (FEV1) after 4 weeks of treatment
    End point description
    Trough FEV1 was measured within 30 minutes prior to dosing of study medication. Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received. Only participants with non-missing outcome measured were included in the analysis.
    End point type
    Primary
    End point timeframe
    At 30 minutes prior to dosing in Day 1 (baseline) and Day 29 (end of 4-week treatment period).
    End point values
    		 Placebo BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Number of subjects analysed
    17
    4
    5
    5
    16
    Units: Percentage of predicted trough FEV1
        arithmetic mean (standard deviation)
    -0.6 ( 8.03 )
    -0.5 ( 2.82 )
    -0.22 ( 2.62 )
    2.82 ( 3.57 )
    0.45 ( 5.42 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM) with fixed effects for baseline, visit, treatment, treatment-by-visit interaction, baseline-by-visit interaction, and random effect for patient was applied. No hypothesis testing was performed, as this trial was prematurely discontinued. MMRM only included data from 200µg BI and placebo, as the sample size of the BI 20µg, BI 50µg and BI 100µg dose levels was limited because of the premature discontinuation of the trial.
    Comparison groups
    Placebo v BI 1265162 200μg b.i.d.
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5468
    Method
    		 Mixed model with repeated measurements
    Parameter type
    		 Adjusted means difference
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 6.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.45

    Secondary: Change from baseline in Lung Clearance Index (LCI) assessed by N2 Multiple Breath Washout (N2MBW) procedure after 4 weeks of treatment

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    End point title
    		 Change from baseline in Lung Clearance Index (LCI) assessed by N2 Multiple Breath Washout (N2MBW) procedure after 4 weeks of treatment
    End point description
    Change from baseline in Lung Clearance Index (LCI) assessed by N2 Multiple Breath Washout (N2MBW) procedure after 4 weeks of treatment was reported. LCI was calculated as the ratio of cumulative expired volume (CEV) to functional residual capacity (FRC), which was LCI = CEV (milliliter/kilogram) / FRC (milliliter/kilogram) and hence, LCI was "Unitless". The change from baseline after 4 weeks of treatment in LCI was then calculated as the LCI value measured after 4 weeks of treatment at Day 29 minus the LCI value measured at baseline on Day 1. Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received. Only participants with non-missing outcome measured were included in the analysis. '99999' stands for 'not available' since data from only one patient was available and no standard deviation could be calculated.
    End point type
    Secondary
    End point timeframe
    At pre-dose in Day 1 (baseline) and Day 29 (end of 4-week treatment period).
    End point values
    		 Placebo BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Number of subjects analysed
    6
    0 [1]
    1 [2]
    1 [3]
    3
    Units: Unitless
        arithmetic mean (standard deviation)
    -0.824 ( 3.312 )
    ( )
    -0.238 ( 99999 )
    -2.547 ( 99999 )
    -0.081 ( 1.001 )
    Notes
    [1] - No outcome data were collected for this group.
    [2] - '99999' stands for 'not available'.
    [3] - '99999' stands for 'not available'.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    ANCOVA based on analysis of covariance with fixed effects for baseline and treatment was applied. Statistical analysis was performed for 200μg BI and placebo groups only. No hypothesis testing was performed, as this trial was prematurely discontinued. ANCOVA only included data from 200µg BI and placebo, as the sample size of the BI 20µg, BI 50µg and BI 100µg dose levels was limited because of the premature discontinuation of the trial.
    Comparison groups
    Placebo v BI 1265162 200μg b.i.d.
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3039
    Method
    		 ANCOVA
    Parameter type
    		 Adjuste means difference
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 6.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.83

    Secondary: Change from baseline in Cystic Fibrosis Questionnaire Revised (CFQ-R) total score after 4 weeks of treatment

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    End point title
    		 Change from baseline in Cystic Fibrosis Questionnaire Revised (CFQ-R) total score after 4 weeks of treatment
    End point description
    The adult/adolescent format of the CFQ-R consists of 50 questions (qts) dividing into 12 domains: Physical functioning(8 qts), role limitations(4 qts), vitality(4 qts), emotional functioning(5 qts), social functioning(6 qts), body image(3 qts), eating disturbance(3 qts), treatment burden(3 qts), health perceptions(3 qts), weight(1 qts), respiratory symptoms(7 qts), and digestive system(3 qts). The score of some qts is first reversed if reversed coded, so that the score for each of the 50 qts ranges from 1 to 4 points (less symptoms). Then, a domain score for a domain with N qts is calculated as (sum of the scores of the N qts - N)/(N ✕ 4 – N) ✕ 100. Each domain score ranges from 0 to 100 (better health). The CFQ-R total score is summing up the domain scores and ranges from 0 to 1200 (better quality of life). Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. Only patients with non-missing outcomes were included.
    End point type
    Secondary
    End point timeframe
    At Day 1 (baseline) and Day 29 (end of 4-week treatment period).
    End point values
    		 Placebo BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Number of subjects analysed
    18
    6
    5
    5
    16
    Units: Score on a scale
        arithmetic mean (standard deviation)
    5.941 ( 76.669 )
    27.083 ( 61.626 )
    11.167 ( 33.968 )
    -15.611 ( 62.167 )
    24.236 ( 58.290 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) (4 separate sub-scores) after 4 weeks of treatment

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    End point title
    		 Change from baseline in Cough and Sputum Assessment Questionnaire (CASA-Q) (4 separate sub-scores) after 4 weeks of treatment
    End point description
    The 20-item Sputum Assessment Questionnaire (CASA-Q) consisted of 4 domains: Cough Symptoms Domain (3 items), Cough Impact Domain (8 items), Sputum Symptoms Domain (3 items), and Sputum Impact Domain (6 items). Score of each item has been reversed such that better responses have higher score, which ranges from 1 (worse) to 5 (better health). For each domain, the domain score was calculated by summing up the scores of the respective items and scaling to a score ranging from 0 to 100, with higher score associated with fewer symptoms/less impact due to cough or sputum. Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received. Only participants with non-missing outcome measured were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At Day 1 (baseline) and Day 29 (end of 4-week treatment period).
    End point values
    		 Placebo BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Number of subjects analysed
    18
    4
    5
    5
    17
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Cough Symptom Domain Score
    4.167 ( 18.798 )
    10.417 ( 17.180 )
    8.333 ( 8.333 )
    3.333 ( 24.008 )
    5.392 ( 15.574 )
        Cough Impact Domain Score
    -0.521 ( 16.648 )
    -6.250 ( 12.758 )
    -0.625 ( 12.771 )
    1.250 ( 14.757 )
    0.735 ( 11.187 )
        Sputum Symptom Domain Score
    5.093 ( 15.950 )
    4.167 ( 8.333 )
    10.000 ( 14.907 )
    3.333 ( 16.245 )
    5.392 ( 19.530 )
        Sputum Impact Domain Score
    -0.694 ( 16.497 )
    -4.167 ( 3.402 )
    5.000 ( 11.562 )
    -0.833 ( 13.944 )
    0.490 ( 11.110 )
    No statistical analyses for this end point

    Secondary: Percentage of patients with treatment-emergent Adverse Events (AE) up to day 36

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    End point title
    		 Percentage of patients with treatment-emergent Adverse Events (AE) up to day 36
    End point description
    Percentage of patients with any treatment-emergent Adverse Events (AE) up to day 36 was reported. Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
    End point type
    Secondary
    End point timeframe
    From Day 1 (baseline) until end of 4 weeks of treatment period (Day 29) plus 7 days of follow-up, up to 36 days.
    End point values
    		 Placebo BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Number of subjects analysed
    18
    6
    5
    5
    18
    Units: Percentage of participants
        number (not applicable)
    66.7
    0
    40.0
    40.0
    83.3
    No statistical analyses for this end point

    Secondary: Concentration of BI 1265162 in plasma at 0.083 hour at steady state following dose 15 (C0.083,ss,15)

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    End point title
    		 Concentration of BI 1265162 in plasma at 0.083 hour at steady state following dose 15 (C0.083,ss,15) [4]
    End point description
    Concentration of BI 1265162 in plasma at 0.083 hour at steady state following dose 15 (C0.083,ss,15) was reported. Pharmacokinetic set (PKS): The PKS included all patients in the treated set who provided at least one pharmacokinetic parameter. Only participants with non-missing outcome measured were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At 5 minutes (around 0.083 hours) post dosing at steady state on Day 8 for dose 15 (morning dose on Day 8).
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Number of subjects analysed
    3
    4
    4
    16
    Units: picomole/liter (pmol/L)
        geometric mean (geometric coefficient of variation)
    207 ( 59.9 )
    471 ( 30.0 )
    1010 ( 20.1 )
    1110 ( 84.8 )
    No statistical analyses for this end point

    Secondary: Concentration of BI 1265162 in plasma at 0.083 hour at steady state following dose 57 (C0.083,ss,57)

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    End point title
    		 Concentration of BI 1265162 in plasma at 0.083 hour at steady state following dose 57 (C0.083,ss,57) [5]
    End point description
    Concentration of BI 1265162 in plasma at 0.083 hour at steady state following dose 57 (C0.083,ss,57) was reported. Pharmacokinetic set (PKS): The PKS included all patients in the treated set who provided at least one pharmacokinetic parameter. Only participants with non-missing outcome measured were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At 5 minutes (around 0.083 hours) post dosing at steady state on Day 29 for dose 57 (morning dose on Day 29).
    Notes
    [5] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Number of subjects analysed
    3
    3
    5
    14
    Units: picomole/liter (pmol/L)
        geometric mean (geometric coefficient of variation)
    162 ( 76.3 )
    463 ( 15.4 )
    573 ( 94.0 )
    1080 ( 165 )
    No statistical analyses for this end point

    Secondary: Pre-dose concentration measured of BI 1265162 in plasma at steady state after dose 15 (Cpre,ss, 15)

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    End point title
    		 Pre-dose concentration measured of BI 1265162 in plasma at steady state after dose 15 (Cpre,ss, 15) [6]
    End point description
    Pre-dose concentration measured of BI 1265162 in plasma at steady state after dose 15 (Cpre,ss, 15) was reported. Pharmacokinetic set (PKS): The PKS included all patients in the treated set who provided at least one pharmacokinetic parameter. Only participants with non-missing outcome measured were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At pre-dose (taken within 60 minutes prior to dosing) at steady state on Day 8 for dose 15 (morning dose on Day 8).
    Notes
    [6] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Number of subjects analysed
    3
    4
    5
    14
    Units: picomole/liter (pmol/L)
        geometric mean (geometric coefficient of variation)
    7.82 ( 28.0 )
    24.3 ( 31.8 )
    38.4 ( 292 )
    43.8 ( 95.6 )
    No statistical analyses for this end point

    Secondary: Pre-dose concentration measured of BI 1265162 in plasma at steady state after dose 57 (Cpre,ss, 57)

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    End point title
    		 Pre-dose concentration measured of BI 1265162 in plasma at steady state after dose 57 (Cpre,ss, 57) [7]
    End point description
    Pre-dose concentration measured of BI 1265162 in plasma at steady state after dose 57 (Cpre,ss, 57) was reported. Pharmacokinetic set (PKS): The PKS included all patients in the treated set who provided at least one pharmacokinetic parameter. Only participants with non-missing outcome measured were included in the analysis. '99999' stands for 'not available' since no descriptive statistics calculated since not enough data as only 1 patient was analyzed.
    End point type
    Secondary
    End point timeframe
    At pre-dose (taken within 60 minutes prior to dosing) at steady state on Day 29 for dose 57 (morning dose on Day 29).
    Notes
    [7] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Number of subjects analysed
    1 [8]
    3
    3
    12
    Units: picomole/liter (pmol/L)
        geometric mean (geometric coefficient of variation)
    99999 ( 99999 )
    13.0 ( 80.8 )
    22.3 ( 48.3 )
    37.2 ( 56.9 )
    Notes
    [8] - '99999' stands for 'not available'.
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve of BI 1265162 in plasma from 0 to 4 hours at steady state after dose 15 (AUC0-4,ss,15)

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    End point title
    		 Area under the concentration-time curve of BI 1265162 in plasma from 0 to 4 hours at steady state after dose 15 (AUC0-4,ss,15) [9]
    End point description
    Area under the concentration-time curve of BI 1265162 in plasma from 0 to 4 hours at steady state after dose 15 (AUC0-4,ss,15) was reported. Pharmacokinetic set (PKS): The PKS included all patients in the treated set who provided at least one pharmacokinetic parameter. Only participants with non-missing outcome measured were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At pre-dose (taken within 60 minutes prior to dosing) and 5 minutes (min), 30 min, 1 hour, and 4 hours post dosing at steady state on Day 8 for dose 15 (morning dose on Day 8).
    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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    		 BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Number of subjects analysed
    5
    4
    4
    17
    Units: hours * picomole/liter (h*pmol/L)
        geometric mean (geometric coefficient of variation)
    192 ( 45.3 )
    541 ( 19.1 )
    1020 ( 8.93 )
    1380 ( 71.0 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 (baseline) until end of 4 weeks of treatment period (Day 29) plus 7 days of follow-up, up to 36 days.
    Adverse event reporting additional description
    Treated set (TS): The TS included all patients who were randomized and treated with at least one dose of study drug. The treatment assignment was determined based on the first treatment the subjects received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 2 puffs of matching placebo were inhaled orally via the Respimat® inhaler twice daily for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group title
    BI 1265162 20μg b.i.d.
    Reporting group description
    		 2 puffs of 10 micrograms (μg) BI 1265162 (Total: 20μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 40μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group title
    BI 1265162 50μg b.i.d.
    Reporting group description
    		 2 puffs of 25 micrograms (μg) BI 1265162 (Total: 50μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 100μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group title
    BI 1265162 100μg b.i.d.
    Reporting group description
    		 2 puffs of 50 micrograms (μg) BI 1265162 (Total: 100μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 200μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Reporting group title
    BI 1265162 200μg b.i.d.
    Reporting group description
    		 2 puffs of 100 micrograms (μg) BI 1265162 (Total: 200μg) were inhaled orally via the Respimat® inhaler twice daily (b.i.d., daily dose: 400μg) for a treatment period of 4 weeks in patients with cystic fibrosis.

    Serious adverse events
    		 Placebo BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         number of deaths (all causes)
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary congestion
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo BI 1265162 20μg b.i.d. BI 1265162 50μg b.i.d. BI 1265162 100μg b.i.d. BI 1265162 200μg b.i.d.
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 18 (61.11%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
    2 / 5 (40.00%)
    15 / 18 (83.33%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pulmonary function test decreased
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
    1 / 5 (20.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    2
    2
    2
    Hypoaesthesia
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Migraine
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    0
    0
    2
    Fatigue
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    2
    Vessel puncture site haematoma
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    0
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Bronchial obstruction
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 5 (20.00%)
    3 / 18 (16.67%)
         occurrences all number
    1
    0
    0
    1
    3
    Dyspnoea
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Haemoptysis
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    Lower respiratory tract congestion
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    Nasal polyps
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Sputum increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    Back pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    0
    1
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    0
    1
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    2
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 18 (22.22%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    4
    0
    0
    0
    2
    Pneumonia bacterial
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    0
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 5 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    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
    18 Nov 2019
    introduced administrative changes, provided additional clarification, removed inconsistencies, introduced flexibility, and corrected errors in the original protocol. - Changed the secondary pharmacokinetic endpoint from Cmax,N to Ct,N; Ct,N was more in-line with the sparse sampling plan for pharmacokinetics - Adapted inclusion criterion 5 and exclusion criterion 15; these changes removed the requirement of the use of birth control for males able to father a child and simultaneously allowed the recruitment of women of child-bearing potential who used adequate contraception - Added pregnancy testing for the women of child-bearing potential who were allowed into the trial based on Global Amendment 1 - Added a description of procedures that would have to be followed in the event that a woman of child-bearing potential became pregnant during the trial, and - Added chloride, inorganic phosphorus, and calcium to the list of electrolytes to be analysed as part of safety laboratory tests - Required that each result of elevated serum potassium levels be confirmed by either a second measurement or by the presence of clinical symptoms.

    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.
    This trial was prematurely discontinued with only adult patients being recruited based on the results of a pre-specified interim futility analysis that indicated insufficient efficacy.
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    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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