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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-Center Study to Assess the Efficacy, Safety and Tolerability, and Pharmacokinetics of INS1007 Administered Once Daily for 24 Weeks in Subjects with Non-Cystic Fibrosis Bronchiectasis - The Willow Study

    Summary
    EudraCT number
    		 2017-002533-32
    Trial protocol
    		 GB   DE   DK   SE   ES   NL   BG   PL   BE   IT  
    Global end of trial date
    12 Dec 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Apr 2023
    First version publication date
    23 Dec 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    INS1007-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03218917
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Insmed Incorporated
    Sponsor organisation address
    700 US Highway 202/206, Bridgewater, United States, 08807-1704
    Public contact
    Insmed Medical Information, Insmed Incorporated, medicalinformation@Insmed.com
    Scientific contact
    Insmed Medical Information, Insmed Incorporated, medicalinformation@Insmed.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
    08 Jul 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to evaluate the effect of brensocatib compared with placebo on time to first pulmonary exacerbation over the 24-week treatment period.
    Protection of trial subjects
    This trial was performed in compliance with Good Clinical Practice (GCP), including the archiving of essential documents, the International Council for Harmonisation (ICH) Guidelines, and is consistent with the ethical principles of the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Oct 2017
    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
    Netherlands: 7
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Bulgaria: 17
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Australia: 49
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    New Zealand: 29
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    United States: 67
    Worldwide total number of subjects
    256
    EEA total number of subjects
    86
    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)
    106
    From 65 to 84 years
    150
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the trial at 116 sites in 14 countries from 31 October 2017 to 12 December 2019.

    Pre-assignment
    Screening details
    		 416 subjects were screened with 160 subjects resulting in a screen failure. A total of 256 subjects were randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brensocatib 10 mg
    Arm description
    		 Subjects received brensocatib 10 mg once daily before breakfast, for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brensocatib
    Investigational medicinal product code
    Other name
    INS1007
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets administered orally.

    Arm title
    		 Brensocatib 25 mg
    Arm description
    		 Subjects received brensocatib 25 mg once daily before breakfast, for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brensocatib
    Investigational medicinal product code
    Other name
    INS1007
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets administered orally.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received the matching placebo once daily before breakfast, for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo tablet administered orally.

    Number of subjects in period 1
    		Brensocatib 10 mg Brensocatib 25 mg Placebo
    Started
    82
    87
    87
    Completed
    76
    75
    74
    Not completed
    6
    12
    13
         Adverse event, serious fatal
    -
    1
    -
         Reason Missing
    -
    2
    -
         Consent withdrawn by subject
    2
    4
    10
         Physician decision
    -
    1
    1
         Adverse event, non-fatal
    3
    3
    2
         Non-compliance of study drug
    -
    1
    -
         Lost to follow-up
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brensocatib 10 mg
    Reporting group description
    		 Subjects received brensocatib 10 mg once daily before breakfast, for 24 weeks.

    Reporting group title
    Brensocatib 25 mg
    Reporting group description
    		 Subjects received brensocatib 25 mg once daily before breakfast, for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received the matching placebo once daily before breakfast, for 24 weeks.

    Reporting group values
    		 Brensocatib 10 mg Brensocatib 25 mg Placebo Total
    Number of subjects
    		 82 87 87 256
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.6 ± 12.42 63.7 ± 12.67 64.0 ± 11.86 -
    Gender categorical
    Units: Subjects
        Female
    		 57 62 55 174
        Male
    		 25 25 32 82
    Race
    Units: Subjects
        Caucasian (White)
    		 76 78 71 225
        African American/Black of African origin
    		 0 2 2 4
        Asian
    		 5 5 13 23
        American Indian or Alaska Native
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 1 1 1 3
        Other
    		 0 1 0 1
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 80 83 87 250
        Hispanic or Latino
    		 2 4 0 6

    End points

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    End points reporting groups
    Reporting group title
    Brensocatib 10 mg
    Reporting group description
    		 Subjects received brensocatib 10 mg once daily before breakfast, for 24 weeks.

    Reporting group title
    Brensocatib 25 mg
    Reporting group description
    		 Subjects received brensocatib 25 mg once daily before breakfast, for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received the matching placebo once daily before breakfast, for 24 weeks.

    Subject analysis set title
    Brensocatib 10 mg (Pharmacodynamic [PD] population)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received brensocatib 10 mg once daily before breakfast for 24 weeks. PD population: All subjects who received at least 1 dose of study treatment, had at least 1 predose and 1 postdose measurement for neutrophil elastase (NE), or proteinase 3, or cathepsin G, or other biomarkers, and had no major protocol deviations considered to impact the analysis of PD data. 1 subject who was randomized to received brensocatib 10 mg also received brensocatib 25 mg. This subject is excluded from the brensocatib 10 mg PD population and included in brensocatib 25 mg PD population.

    Subject analysis set title
    Brensocatib 25 mg (Pharmacodynamic [PD] population)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received brensocatib 25 mg once daily before breakfast for 24 weeks. PD population: All subjects who received at least 1 dose of study treatment, had at least 1 predose and 1 postdose measurement for neutrophil elastase (NE), or proteinase 3, or cathepsin G, or other biomarkers, and had no major protocol deviations considered to impact the analysis of PD data. 1 subject who was randomized to receive brensocatib 10 mg and 1 subject who was randomized to received placebo, also received brensocatib 25 mg. Both subjects are included in brensocatib 25 mg PD population and are excluded from brensocatib 10 mg and placebo PD populations.

    Subject analysis set title
    Placebo (Pharmacodynamic [PD] population)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received the matching placebo once daily before breakfast for 24 weeks. PD population: All subjects who received at least 1 dose of study treatment, had at least 1 predose and 1 postdose measurement for neutrophil elastase (NE), or proteinase 3, or cathepsin G, or other biomarkers, and had no major protocol deviations considered to impact the analysis of PD data. 1 subject who was randomized to received placebo also received brensocatib 25 mg. The subject is excluded from the placebo PD population and included in brensocatib 25 mg PD population.

    Primary: Time to the first pulmonary exacerbation over 24-week treatment period

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    End point title
    		 Time to the first pulmonary exacerbation over 24-week treatment period
    End point description
    Pulmonary exacerbation was defined as having 3 or more of the following symptoms for at least 48 hours resulting in a physician’s decision to prescribe antibiotics: 1. Increased cough 2. Increased sputum volume or change in sputum consistency 3. Increased sputum purulence 4. Increased breathlessness and/or decreased exercise tolerance 5. Fatigue and/or malaise 6. Hemoptysis A minimum of 4 weeks must have occurred between one exacerbation onset and the next. Any exacerbation that occurred less than 4 weeks from the prior exacerbation was not considered a new exacerbation. The median time to first exacerbation could not be estimated for brensocatib 10 mg or brensocatib 25 mg. 99999 = The median, upper and lower limit of confidence interval (CI) was not estimated due to insufficient number of participants with exacerbations in the groups.
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Brensocatib 10 mg Brensocatib 25 mg Placebo
    Number of subjects analysed
    26 [1]
    29 [2]
    42 [3]
    Units: Days
        median (confidence interval 90%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    189.0 (141.0 to 99999)
    Notes
    [1] - Subjects with at least one exacerbation.
    [2] - Subjects with at least one exacerbation.
    [3] - Subjects with at least one exacerbation.
    Statistical analysis title
    		 Brensocatib 10 mg vs Placebo
    Comparison groups
    Brensocatib 10 mg v Placebo
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 Stratified Log-rank test
    Confidence interval
    Statistical analysis title
    		 Brensocatib 25 mg vs Placebo
    Comparison groups
    Brensocatib 25 mg v Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.022
    Method
    		 Stratified Log-rank test
    Confidence interval

    Secondary: Change from baseline in Quality of Life Questionnaire – Bronchiectasis (QOL-B) respiratory symptoms domain score over 24 week treatment period

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    End point title
    		 Change from baseline in Quality of Life Questionnaire – Bronchiectasis (QOL-B) respiratory symptoms domain score over 24 week treatment period
    End point description
    The QOL-B is a validated, self-administered patient reported outcome (PRO) that assesses symptoms, functioning, and health-related (HR) QOL for subjects with non-cystic fibrosis bronchiectasis (NCFBE). The QOL-B contains 37 items in 8 domains (Respiratory Symptoms, Physical Functioning, Role Functioning, Emotional Functioning, Social Functioning, Vitality, Health Perceptions and Treatment Burden). Each of the 37 items is scored from 1 to 4, and each of the 8 domains scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning and HR QoL. A positive change from baseline indicates improvement in symptoms. For this outcome measure, the respiratory symptoms domain score was reported. The analysis was based on mixed model for repeated measures (MMRM) approach. Number of subjects analysed are the number of subjects with data available for analyses at the latest assessment visit over the 24-week treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Brensocatib 10 mg Brensocatib 25 mg Placebo
    Number of subjects analysed
    75
    77
    72
    Units: Score on a scale
        least squares mean (standard error)
    3.8 ± 0.78
    5.9 ± 0.76
    5.7 ± 0.77
    No statistical analyses for this end point

    Secondary: Change from screening in post-bronchodilator percent predicted forced expiratory volume in 1 second (ppFEV1) over 24-week treatment period

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    End point title
    		 Change from screening in post-bronchodilator percent predicted forced expiratory volume in 1 second (ppFEV1) over 24-week treatment period
    End point description
    FEV1 was used to assess lung function and is the maximum amount of air that can be forced out in one second after taking a deep breath. The percent predicted FEV1 was calculated by converting the spirometer reading to a percentage of what would be predicted as normal FEV1 based on a several personal factors (e.g. sex, age, etc.). Change from screening in percent predicted FEV1 to Week 24 was calculated as: percent predicted FEV1 value at Week 24 and percent predicted FEV1 value at screening. A positive percent change from screening indicates an improvement in lung function. The analysis was done using analysis of covariance (ANCOVA) with Pa colonization status and maintenance macrolide antibiotic use at Baseline as covariates. Number of subjects analysed are the number of subjects with data available for analyses over the 24-week treatment period.
    End point type
    Secondary
    End point timeframe
    Screening to Week 24
    End point values
    		 Brensocatib 10 mg Brensocatib 25 mg Placebo
    Number of subjects analysed
    77
    77
    73
    Units: percent predicted FEV1
        least squares mean (standard error)
    -0.3 ± 0.88
    -0.3 ± 0.85
    -1.8 ± 0.87
    No statistical analyses for this end point

    Secondary: Change from baseline in concentration of active neutrophil elastase (NE) in sputum

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    End point title
    		 Change from baseline in concentration of active neutrophil elastase (NE) in sputum
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Brensocatib 10 mg (Pharmacodynamic [PD] population) Brensocatib 25 mg (Pharmacodynamic [PD] population) Placebo (Pharmacodynamic [PD] population)
    Number of subjects analysed
    80
    89
    84
    Units: µg/mL
        least squares mean (standard error)
    -2.928 ± 0.351
    -4.117 ± 0.322
    -1.409 ± 0.313
    No statistical analyses for this end point

    Secondary: Number of subjects who experienced a pulmonary exacerbation

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    End point title
    		 Number of subjects who experienced a pulmonary exacerbation
    End point description
    Pulmonary exacerbation was defined as having 3 or more of the following symptoms for at least 48 hours resulting in a physician’s decision to prescribe antibiotics. 1. Increased cough 2. Increased sputum volume or change in sputum consistency 3. Increased sputum purulence 4. Increased breathlessness and/or decreased exercise tolerance 5. Fatigue and/or malaise 6. Hemoptysis A minimum of 4 weeks must of occurred between one exacerbation onset and the next. Any exacerbation that occurred less than 4 weeks from the prior exacerbation was not considered a new exacerbation.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Brensocatib 10 mg Brensocatib 25 mg Placebo
    Number of subjects analysed
    82
    87
    87
    Units: Subjects
    26
    29
    42
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to Week 28 (End of study visit)
    Adverse event reporting additional description
    Safety population included all subjects who received at least one dose of study treatment. 2 subjects who were randomised to placebo and Brensocatib 10 mg group received Brensocatib 25 mg and hence were included in the Brensocatib 25 mg group in the Safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Brensocatib 10 mg (Safety population)
    Reporting group description
    		 Subjects received brensocatib 10 mg once daily before breakfast for 24 weeks. Safety population: All subjects who received at least one dose of study treatment. 1 subject who was randomized to receive brensocatib 10 mg also received brensocatib 25 mg. This subject is excluded from the brensocatib 10 mg safety population and included in brensocatib 25 mg safety population.

    Reporting group title
    Placebo (Safety population)
    Reporting group description
    		 Subjects received the matching placebo once daily before breakfast, for 24 weeks. Safety population: All subjects who received at least one dose of study treatment. 1 subject who was randomized to receive placebo also received brensocatib 25 mg. The subject is excluded from the placebo safety population and included in brensocatib 25 mg safety population. 1 subject who was randomized to receive placebo left the trial before receiving study treatment and is also excluded from the placebo safety population.

    Reporting group title
    Brensocatib 25 mg (Safety population)
    Reporting group description
    		 Subjects received brensocatib 25 mg once daily before breakfast, for 24 weeks. Safety population: All subjects who received at least one dose of study treatment. 1 subject who was randomized to receive brensocatib 10 mg and 1 subject who was randomized to received placebo, also received brensocatib 25 mg. Both subjects are included in brensocatib 25 mg safety population and are excluded from brensocatib 10 mg and placebo safety populations.

    Serious adverse events
    		 Brensocatib 10 mg (Safety population) Placebo (Safety population) Brensocatib 25 mg (Safety population)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 81 (13.58%)
    19 / 85 (22.35%)
    10 / 89 (11.24%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 85 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 85 (2.35%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 85 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 85 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 85 (1.18%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Lung infiltration
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 85 (1.18%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 85 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 85 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 85 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 85 (1.18%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 85 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 85 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphocytosis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 85 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haemorrhoids
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 85 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 85 (0.00%)
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 85 (1.18%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 85 (1.18%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 85 (1.18%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 85 (1.18%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot deformity
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 85 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 85 (3.53%)
    4 / 89 (4.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    5 / 81 (6.17%)
    9 / 85 (10.59%)
    4 / 89 (4.49%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 10
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 85 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspergilloma
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 85 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 85 (0.00%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 85 (1.18%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 85 (1.18%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 85 (1.18%)
    0 / 89 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Brensocatib 10 mg (Safety population) Placebo (Safety population) Brensocatib 25 mg (Safety population)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 81 (58.02%)
    33 / 85 (38.82%)
    43 / 89 (48.31%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 81 (2.47%)
    5 / 85 (5.88%)
    1 / 89 (1.12%)
         occurrences all number
    2
    5
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 81 (9.88%)
    3 / 85 (3.53%)
    12 / 89 (13.48%)
         occurrences all number
    11
    4
    16
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 81 (3.70%)
    6 / 85 (7.06%)
    7 / 89 (7.87%)
         occurrences all number
    3
    6
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 81 (6.17%)
    9 / 85 (10.59%)
    3 / 89 (3.37%)
         occurrences all number
    5
    12
    3
    Periodontal disease
         subjects affected / exposed
    2 / 81 (2.47%)
    0 / 85 (0.00%)
    5 / 89 (5.62%)
         occurrences all number
    2
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 81 (3.70%)
    2 / 85 (2.35%)
    8 / 89 (8.99%)
         occurrences all number
    3
    2
    9
    Cough
         subjects affected / exposed
    15 / 81 (18.52%)
    10 / 85 (11.76%)
    12 / 89 (13.48%)
         occurrences all number
    16
    11
    14
    Sputum increased
         subjects affected / exposed
    9 / 81 (11.11%)
    6 / 85 (7.06%)
    9 / 89 (10.11%)
         occurrences all number
    11
    7
    10
    Haemoptysis
         subjects affected / exposed
    6 / 81 (7.41%)
    1 / 85 (1.18%)
    2 / 89 (2.25%)
         occurrences all number
    8
    1
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 81 (7.41%)
    1 / 85 (1.18%)
    1 / 89 (1.12%)
         occurrences all number
    6
    1
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 81 (7.41%)
    4 / 85 (4.71%)
    4 / 89 (4.49%)
         occurrences all number
    6
    4
    4
    Sinusitis
         subjects affected / exposed
    5 / 81 (6.17%)
    6 / 85 (7.06%)
    4 / 89 (4.49%)
         occurrences all number
    5
    7
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2018
    The amendment included the following changes: * Added description of healthy volunteer studies to Introduction * Added text to align Study Objectives with Study Endpoints * Added 2 weeks to the Screening Period (from 4 to 6 weeks) in order to accommodate additional dental screening and clearning procedures * Added urine samples for biomarker assessment and pregnancy test * Clarified acceptable contraception procedures * Added exclusion for Papillon-Lefѐvre syndrome * Added that subjects who discontinued for adverse event (AE) were followed to resolution or stabilization * Added physical examination, CRP and prothrombin time tests, collection of pharmacokinetic (PK) sample timing to Schedule of Assessments * Added details to the sample size determination
    27 Apr 2018
    The amendment included the following changes: * Clarified the duration of AE collection * Provided ±3 day window for data collection after discontinuation for AE and a ±3 day window allowance for study visits
    24 Sep 2018
    The amendment included the following changes: * Updated contact for Regulatory Affairs personnel * Specified that Data Monitoring Committee (DMC) members would review data in semi-blinded or unblinded manner at predetermined intervals * Added chest computed tomography (CT) scan for subjects whose past radiographic image records were not available * Aligned study days in Study Schematic with Schedule of Assessments * Revised to state that subjects could not undergo sputum induction procedure during Screening; subjects unable to produce sputum at Screening was considered a screen failure * Revised to state that any subject with pulmonary exacerbation requiring antibiotics after Screening and before randomization was a screen failure * Clarified that subjects with hypothyroidism currently treated with thyroid-stimulating hormone (TSH), and whose T3/T4 levels were within normal range were eligible for enrollment in the trial * Clarified enrollment eligibility for subjects who required repeat electrocardiogram (ECG) and or pulmonary function tests that were not deemed clinically significant * Clarified that subjects who were edentulous still received a dental examination to check for sores caused by dentures * Added requirement that subjects complete PRO questionnaires prior to first dose of study drug * Added meal time for subjects in the Intense PK Population * Added Child-Pugh Score for subjects with abnormal liver function tests * Added sparse PK sampling for subjects at all sites with processing ability * Added calculation of neutrophil elastase method * Added literature references

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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