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    Clinical Trial Results:
    Randomized double blind (sponsor unblind) study evaluating the effect of 14 days of treatment with danirixin (GSK1325756) on neutrophil extracellular traps (NETs) formation in participants with stable chronic obstructive pulmonary disease (COPD)

    Summary
    EudraCT number
    		 2017-001069-25
    Trial protocol
    		 GB  
    Global end of trial date
    08 Oct 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 Nov 2019
    First version publication date
    21 Sep 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    207551
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.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
    03 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Oct 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the change from baseline in NETs formation in participants with COPD following 14 days treatment with danirixin hydrobromide (HBr) 35 milligram (mg) twice daily
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Nov 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    8
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at single center in United Kingdom. This study was terminated early due to a change in the benefit risk profile of danirixin observed in another study NCT03034967, leading to cessation of the overall danirixin development program.

    Pre-assignment
    Screening details
    		 A total of 43 participants were screened, of which 23 were screen failures (23 participants did not meet inclusion/exclusion criteria). From the 20 participants who passed screening, 1 was not randomized due to study being terminated early. Hence, 19 participants were enrolled and received treatment in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received one tablet of matching placebo twice daily orally with food for 14 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received one tablet of matching placebo twice daily orally with food for 14 days.

    Arm title
    		 Danirixin hydrobromide 35 mg
    Arm description
    		 Participants received one tablet of danirixin hydrobromide 35 milligram (mg) twice daily orally with food for 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Danirixin hydrobromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received one tablet of danirixin hydrobromide 35 mg twice daily orally with food for 14 days.

    Number of subjects in period 1
    		Placebo Danirixin hydrobromide 35 mg
    Started
    5
    14
    Completed
    5
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received one tablet of matching placebo twice daily orally with food for 14 days.

    Reporting group title
    Danirixin hydrobromide 35 mg
    Reporting group description
    		 Participants received one tablet of danirixin hydrobromide 35 milligram (mg) twice daily orally with food for 14 days.

    Reporting group values
    		 Placebo Danirixin hydrobromide 35 mg Total
    Number of subjects
    		 5 14 19
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 4 4 8
        From 65-84 years
    		 1 10 11
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.6 ( 6.02 ) 65.3 ( 7.03 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 2 6 8
        Male
    		 3 8 11
    Race/Ethnicity, Customized
    Units: Subjects
        White: White/Caucasian/European Heritage
    		 5 14 19

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received one tablet of matching placebo twice daily orally with food for 14 days.

    Reporting group title
    Danirixin hydrobromide 35 mg
    Reporting group description
    		 Participants received one tablet of danirixin hydrobromide 35 milligram (mg) twice daily orally with food for 14 days.

    Primary: Percentage change from Baseline in sputum neutrophil extracellular traps (NETs) quantified by Histone-Elastase Complexes

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    End point title
    		 Percentage change from Baseline in sputum neutrophil extracellular traps (NETs) quantified by Histone-Elastase Complexes [1]
    End point description
    Sputum samples were collected at indicated time points to assess NET formation via histone elastase complexes. Baseline was considered as Day 1. If Day 1 values were missing, screening value was imputed for Baseline. Change from Baseline was calculated as post-Baseline value minus Baseline value. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. Analysis was performed using a mixed effect repeated measures model with covariates of treatment group, log(Baseline NETs) and treatment group by day interaction. The response variable was the log of the ratio of post-Baseline NETs to Baseline NETs. Primary completer population consisted of all participants in the Modified Intent-To-Treat population who had completed the assessments supporting the primary endpoint (sputum NETs). Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Day 7 and Day 14
    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: There are no statistical analysis to report.
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    3 [2]
    8 [3]
    Units: Percent change
    arithmetic mean (confidence interval 95%)
        Day 7, n=3,6
    -3.2 (-77.0 to 306.6)
    -9.4 (-64.4 to 130.6)
        Day 14, n=3,8
    -30.5 (-71.7 to 70.7)
    -13.6 (-49.1 to 46.5)
    Notes
    [2] - Primary Completer Population.
    [3] - Primary Completer Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in sputum NETs quantified by deoxyribonucleic acid (DNA)-elastase complexes

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    End point title
    		 Change from Baseline in sputum NETs quantified by deoxyribonucleic acid (DNA)-elastase complexes
    End point description
    Sputum samples were collected at indicated time points to assess NET formation via DNA elastase complexes. Baseline was considered as Day 1. If Day 1 values were missing, screening value was imputed for Baseline. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7 and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    3 [4]
    8 [5]
    Units: Units per milliliter
    arithmetic mean (standard error)
        Day 7, n=3,6
    1.83 ( 4.610 )
    0.63 ( 1.859 )
        Day 14, n=3,8
    -4.53 ( 2.696 )
    2.08 ( 4.072 )
    Notes
    [4] - Primary Completer Population.
    [5] - Primary Completer Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in percentage of microscope field area occupied by sputum NETs

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    End point title
    		 Change from Baseline in percentage of microscope field area occupied by sputum NETs
    End point description
    Sputum samples were collected at indicated time points and NETs area was quantified by microscopy. Baseline was considered as Day 1. If Day 1 values were missing, screening value was imputed for Baseline. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed. 99999 indicates data was not collected because 7 days treatment was insufficient to observe the changes in the sputum NETs via microscopy.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7 and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    2 [6]
    7 [7]
    Units: Percentage of microscope field area
    arithmetic mean (standard error)
        Day 7
    99999 ( 99999 )
    99999 ( 99999 )
        Day 14
    0.900 ( 0.9200 )
    -0.259 ( 0.5183 )
    Notes
    [6] - Primary Completer Population.
    [7] - Primary Completer Population.
    No statistical analyses for this end point

    Secondary: Number of participants with adverse events (AEs) and serious adverse events (SAEs)

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    End point title
    		 Number of participants with adverse events (AEs) and serious adverse events (SAEs)
    End point description
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes, Modified Intent-to-Treat Population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to Day 21
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [8]
    14 [9]
    Units: Participants
        AEs
    3
    6
        SAEs
    0
    0
    Notes
    [8] - Modified Intent-to-Treat Population.
    [9] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP)

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    End point title
    		 Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP)
    End point description
    SBP and DBP were measured in seated position after 5 minutes rest for the participants at indicated time points. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7 and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [10]
    14 [11]
    Units: Millimeters of mercury
    arithmetic mean (standard deviation)
        SBP, Day 7
    -11.2 ( 17.01 )
    -4.1 ( 17.70 )
        SBP, Day 14
    -1.4 ( 16.10 )
    -5.3 ( 15.77 )
        DBP, Day 7
    -2.2 ( 9.91 )
    -2.1 ( 10.34 )
        DBP, Day 14
    2.6 ( 11.01 )
    -5.3 ( 7.98 )
    Notes
    [10] - Modified Intent-to-Treat Population.
    [11] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in heart rate

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    End point title
    		 Change from Baseline in heart rate
    End point description
    Heart rate was measured in seated position after 5 minutes rest for the participants at indicated time points. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7 and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [12]
    14 [13]
    Units: Beats per minute
    arithmetic mean (standard deviation)
        Day 7
    6.8 ( 6.02 )
    1.6 ( 11.28 )
        Day 14
    4.0 ( 6.89 )
    0.1 ( 6.86 )
    Notes
    [12] - Modified Intent-to-Treat Population.
    [13] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in respiration rate

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    End point title
    		 Change from Baseline in respiration rate
    End point description
    Respiration rate was measured in seated position after 5 minutes rest for the participants at indicated time points. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7 and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [14]
    14 [15]
    Units: Breaths per minute
    arithmetic mean (standard deviation)
        Day 7
    -0.6 ( 1.95 )
    1.8 ( 2.67 )
        Day 14
    0.2 ( 0.84 )
    2.1 ( 3.43 )
    Notes
    [14] - Modified Intent-to-Treat Population.
    [15] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia’s Formula (QTcF)

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    End point title
    		 Change from Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia’s Formula (QTcF)
    End point description
    Triplicate 12-lead electrocardiograms (ECG) were obtained to measure PR Interval, QRS Duration, QT Interval and QTcF Interval. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [16]
    14 [17]
    Units: Milliseconds
    arithmetic mean (standard deviation)
        PR Interval
    7.6 ( 20.44 )
    -4.8 ( 15.69 )
        QRS Duration
    -0.3 ( 1.12 )
    0.5 ( 5.55 )
        QT Interval
    -4.8 ( 10.05 )
    3.7 ( 15.67 )
        QTcF Interval
    -4.6 ( 0.38 )
    -1.6 ( 5.96 )
    Notes
    [16] - Modified Intent-to-Treat Population.
    [17] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Spirometry: Forced expiratory volume in one second (FEV1) at indicated time points

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    End point title
    		 Spirometry: Forced expiratory volume in one second (FEV1) at indicated time points
    End point description
    FEV1 is the amount of air that can be forcefully exhaled from the lungs in the first second of a forced exhalation. It was measured by spirometry test. Mean and standard deviation data of FEV1 measured at Day 1 and Day 14 have been presented.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [18]
    14 [19]
    Units: Liter
    arithmetic mean (standard deviation)
        Day 1
    2.458 ( 0.6331 )
    1.914 ( 0.7267 )
        Day 14
    2.344 ( 0.7174 )
    1.910 ( 0.7428 )
    Notes
    [18] - Modified Intent-to-Treat Population.
    [19] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Spirometry: Forced vital capacity (FVC) at indicated time points

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    End point title
    		 Spirometry: Forced vital capacity (FVC) at indicated time points
    End point description
    FVC is defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. It was measured by spirometry test. Mean and standard deviation data of FVC measured at Day 1 and Day 14 have been presented.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [20]
    14 [21]
    Units: Liter
    arithmetic mean (standard deviation)
        Day 1
    4.026 ( 1.2021 )
    3.416 ( 1.1304 )
        Day 14
    4.036 ( 1.3992 )
    3.369 ( 1.1456 )
    Notes
    [20] - Modified Intent-to-Treat Population.
    [21] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets counts, Total neutrophils, White Blood Cell (WBC) count

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    End point title
    		 Change from Baseline in hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets counts, Total neutrophils, White Blood Cell (WBC) count
    End point description
    Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets counts, Total neutrophils and WBC count. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [22]
    14 [23]
    Units: Giga cells per liter
    arithmetic mean (standard deviation)
        Basophils
    0.00 ( 0.000 )
    -0.02 ( 0.058 )
        Eosinophils
    0.040 ( 0.0686 )
    -0.020 ( 0.0609 )
        Lymphocytes
    -0.20 ( 0.316 )
    -0.08 ( 0.269 )
        Monocytes
    -0.04 ( 0.114 )
    0.02 ( 0.080 )
        Platelets counts
    8.2 ( 18.94 )
    -7.9 ( 41.66 )
        Total neutrophils
    -0.38 ( 0.965 )
    0.29 ( 0.943 )
        WBC count
    -0.56 ( 0.948 )
    0.16 ( 1.075 )
    Notes
    [22] - Modified Intent-to-Treat Population.
    [23] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in hematology parameter: Hematocrit

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    End point title
    		 Change from Baseline in hematology parameter: Hematocrit
    End point description
    Blood samples were collected to analyze the hematology parameter: Hematocrit. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [24]
    14 [25]
    Units: Percentage of red blood cells in blood
        arithmetic mean (standard deviation)
    -0.0058 ( 0.02279 )
    -0.0115 ( 0.02085 )
    Notes
    [24] - Modified Intent-to-Treat Population.
    [25] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in hematology parameter: Hemoglobin

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    End point title
    		 Change from Baseline in hematology parameter: Hemoglobin
    End point description
    Blood samples were collected to analyze the hematology parameter: Hemoglobin. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [26]
    14 [27]
    Units: Grams per liter
        arithmetic mean (standard deviation)
    -2.2 ( 6.72 )
    -5.4 ( 7.99 )
    Notes
    [26] - Modified Intent-to-Treat Population.
    [27] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in hematology parameter: Mean Corpuscular Volume

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    End point title
    		 Change from Baseline in hematology parameter: Mean Corpuscular Volume
    End point description
    Blood samples were collected to analyze the hematology parameter: Mean Corpuscular Volume. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [28]
    14 [29]
    Units: Femtoliter
        arithmetic mean (standard deviation)
    0.06 ( 1.339 )
    0.31 ( 1.263 )
    Notes
    [28] - Modified Intent-to-Treat Population.
    [29] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in hematology parameter: Mean Corpuscular Hemoglobin

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    End point title
    		 Change from Baseline in hematology parameter: Mean Corpuscular Hemoglobin
    End point description
    Blood samples were collected to analyze the hematology parameter: Mean Corpuscular Hemoglobin. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [30]
    14 [31]
    Units: Picograms
        arithmetic mean (standard deviation)
    -0.08 ( 0.920 )
    -0.22 ( 0.749 )
    Notes
    [30] - Modified Intent-to-Treat Population.
    [31] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in hematology parameter: Red Blood Cell count

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    End point title
    		 Change from Baseline in hematology parameter: Red Blood Cell count
    End point description
    Blood samples were collected to analyze the hematology parameter: Red Blood Cell count. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [32]
    14 [33]
    Units: Trillion cells per liter
        arithmetic mean (standard deviation)
    -0.070 ( 0.2081 )
    -0.154 ( 0.2171 )
    Notes
    [32] - Modified Intent-to-Treat Population.
    [33] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in chemistry parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST)

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    End point title
    		 Change from Baseline in chemistry parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST)
    End point description
    Blood samples were collected to analyze the chemistry parameters: ALT, ALP and AST. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [34]
    14 [35]
    Units: International units per liter
    arithmetic mean (standard deviation)
        ALT
    -1.6 ( 4.39 )
    -1.9 ( 8.24 )
        ALP
    2.8 ( 6.26 )
    1.3 ( 13.89 )
        AST
    -0.6 ( 2.61 )
    -3.1 ( 2.11 )
    Notes
    [34] - Modified Intent-to-Treat Population.
    [35] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in chemistry parameters: Calcium, Glucose, Potassium, Sodium, Urea

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    End point title
    		 Change from Baseline in chemistry parameters: Calcium, Glucose, Potassium, Sodium, Urea
    End point description
    Blood samples were collected to analyze the chemistry parameters: Calcium, Glucose, Potassium, Sodium and Urea. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [36]
    14 [37]
    Units: Millimoles per liter
    arithmetic mean (standard deviation)
        Calcium
    -0.032 ( 0.0782 )
    -0.034 ( 0.0947 )
        Glucose
    0.36 ( 0.635 )
    0.12 ( 0.398 )
        Potassium
    -0.12 ( 0.148 )
    0.06 ( 0.287 )
        Sodium
    0.0 ( 1.58 )
    0.2 ( 2.04 )
        Urea
    -0.42 ( 0.867 )
    0.26 ( 0.777 )
    Notes
    [36] - Modified Intent-to-Treat Population.
    [37] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in chemistry parameters: Creatinine, Direct Bilirubin, Total Bilirubin

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    End point title
    		 Change from Baseline in chemistry parameters: Creatinine, Direct Bilirubin, Total Bilirubin
    End point description
    Blood samples were collected to analyze the chemistry parameters: Creatinine, Direct Bilirubin and Total Bilirubin. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [38]
    14 [39]
    Units: Micromoles per liter
    arithmetic mean (standard deviation)
        Creatinine
    2.6 ( 5.86 )
    1.2 ( 6.99 )
        Direct Bilirubin
    -0.4 ( 0.55 )
    0.7 ( 1.65 )
        Total Bilirubin
    0.8 ( 0.84 )
    -1.2 ( 3.26 )
    Notes
    [38] - Modified Intent-to-Treat Population.
    [39] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in urinalysis parameter: Specific Gravity

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    End point title
    		 Change from Baseline in urinalysis parameter: Specific Gravity
    End point description
    Urinary specific gravity measurement is a part of routine urinalysis. Urine specific gravity is a measure of the concentration of solutes in the urine. It measures the ratio of urine density compared with water density and provides information on the kidney’s ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Urine samples were collected from participants at indicated time points for analysis of specific gravity. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [40]
    14 [41]
    Units: Unitless
        arithmetic mean (standard deviation)
    0.0030 ( 0.00908 )
    0.0046 ( 0.00887 )
    Notes
    [40] - Modified Intent-to-Treat Population.
    [41] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in urinalysis parameter: Potential of hydrogen (pH)

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    End point title
    		 Change from Baseline in urinalysis parameter: Potential of hydrogen (pH)
    End point description
    Urine samples were collected from participants at indicated time points for analysis of pH. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [42]
    14 [43]
    Units: pH
        arithmetic mean (standard deviation)
    1.00 ( 1.225 )
    -0.25 ( 0.672 )
    Notes
    [42] - Modified Intent-to-Treat Population.
    [43] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in sputum resistin levels

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    End point title
    		 Change from Baseline in sputum resistin levels
    End point description
    Sputum samples were collected at indicated time points to analyze resistin levels. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7 and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    3 [44]
    8 [45]
    Units: Nanograms per milliliter
    arithmetic mean (standard error)
        Day 7, n=3,6
    8.93 ( 15.513 )
    -2.01 ( 4.629 )
        Day 14, n=3,8
    15.28 ( 27.619 )
    2.61 ( 2.711 )
    Notes
    [44] - Primary Completer Population.
    [45] - Primary Completer Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in the ratio of sputum NETs to sputum neutrophils

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    End point title
    		 Change from Baseline in the ratio of sputum NETs to sputum neutrophils
    End point description
    Sputum samples were collected to calculate ratio of sputum NETs to sputum neutrophils. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. The ratio is calculated as the sputum NETs divided by the number of sputum neutrophils. Only those participants with data available at the specified data points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    2 [46]
    7 [47]
    Units: Ratio
        arithmetic mean (standard error)
    0.5200 ( 0.41000 )
    0.4557 ( 0.53149 )
    Notes
    [46] - Primary Completer Population.
    [47] - Primary Completer Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in sputum elastase activity

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    End point title
    		 Change from Baseline in sputum elastase activity
    End point description
    Sputum samples were collected at indicated time points to analyze sputum elastase activity. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7 and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    3 [48]
    8 [49]
    Units: Nanograms per milliliter
    arithmetic mean (standard error)
        Day 7, n=3,6
    638.0 ( 381.36 )
    238.0 ( 224.50 )
        Day 14, n=3,8
    411.3 ( 439.20 )
    66.1 ( 45.64 )
    Notes
    [48] - Primary Completer Population.
    [49] - Primary Completer Population.
    No statistical analyses for this end point

    Secondary: Change from Baseline in peripheral blood neutrophil NETs formation quantified by DNA release

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    End point title
    		 Change from Baseline in peripheral blood neutrophil NETs formation quantified by DNA release
    End point description
    Blood samples were collected at indicated time points to analyze peripheral blood neutrophil NETs formation by DNA release.DNA-elastase complexes quantified NETs formation.Phorbol12-myristate 13-acetate(PMA)was used to induce inflammation and NETs formation in PMA stimulated samples. Blood from participants were tested at Baseline and Day14 for non-PMA stimulated samples,and at Baseline and Day14 in PMA-stimulated samples to test whether treatment had any effect on NETs formation either naturally(non PMA induced)or where NETs formation was already raised(PMA stimulated).Participants were counted in both the categories-PMA stimulated and not PMA stimulated. NETs formation in peripheral blood was measured with SYTOX green fluorescence quantification of extracellular DNA.Baseline was considered as Day1.Change from Baseline was calculated as post-Baseline value minus Baseline value.Only those participants with data available at the specified data points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    5 [50]
    12 [51]
    Units: Relative fluorescence units
    arithmetic mean (standard error)
        Not PMA stimulated
    3044.8 ( 4251.78 )
    -721.1 ( 731.82 )
        PMA stimulated
    -96.8 ( 9418.43 )
    -1211.0 ( 5102.21 )
    Notes
    [50] - Modified Intent-to-Treat Population.
    [51] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Percentage change from Baseline in peripheral blood neutrophil NETs formation quantified by microscopy

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    End point title
    		 Percentage change from Baseline in peripheral blood neutrophil NETs formation quantified by microscopy
    End point description
    Blood samples were collected at indicated time points to analyze peripheral blood neutrophil NETs formation by microscopy.DNA-elastase complexes quantified NETs formation.PMA was used to induce inflammation and NETs formation in PMA stimulated samples. Blood from participants were tested at Baseline and Day14 for non-PMA stimulated samples,and at Baseline and Day14 in PMA-stimulated samples to test whether treatment had any effect on NETs formation either naturally(non PMA induced)or where NETs formation was already raised(PMA stimulated). NETs formation in peripheral blood was measured with SYTOX green fluorescence quantification of extracellular DNA.Baseline was considered as Day1.Change from Baseline was calculated as post-Baseline value minus Baseline value.Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by100.Only those participants with data available at the specified data points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Day 14
    End point values
    		 Placebo Danirixin hydrobromide 35 mg
    Number of subjects analysed
    4 [52]
    11 [53]
    Units: Percent change
    arithmetic mean (standard error)
        Not PMA stimulated
    927.5 ( 585.03 )
    560.5 ( 395.72 )
        PMA stimulated
    44.7 ( 41.79 )
    90.6 ( 60.33 )
    Notes
    [52] - Modified Intent-to-Treat Population.
    [53] - Modified Intent-to-Treat Population.
    No statistical analyses for this end point

    Secondary: Maximum observed concentration (Cmax) of danirixin

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    End point title
    		 Maximum observed concentration (Cmax) of danirixin [54]
    End point description
    Blood samples were collected to evaluate the pharmacokinetic (PK) of danirixin at the indicated time points for the analysis of Cmax. PK population consisted of all participants in the Modified Intent-To-Treat population who had at least 1 non-missing PK assessment (non-quantifiable values were considered as non-missing values). Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
    Notes
    [54] - 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: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.
    End point values
    		 Danirixin hydrobromide 35 mg
    Number of subjects analysed
    14 [55]
    Units: Nanograms per milliliter
    geometric mean (geometric coefficient of variation)
        Day 1, n=14
    855.2 ( 52.29 )
        Day 14, n=13
    1135.2 ( 65.73 )
    Notes
    [55] - PK Population.
    No statistical analyses for this end point

    Secondary: Time to Cmax (Tmax) of danirixin

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    End point title
    		 Time to Cmax (Tmax) of danirixin [56]
    End point description
    Blood samples were collected to evaluate the PK of danirixin at the indicated time points for the analysis of Tmax. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
    Notes
    [56] - 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: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.
    End point values
    		 Danirixin hydrobromide 35 mg
    Number of subjects analysed
    14 [57]
    Units: Hours
    median (full range (min-max))
        Day 1, n=14
    1.000 (0.50 to 4.00)
        Day 14, n=13
    1.000 (0.50 to 4.00)
    Notes
    [57] - PK Population.
    No statistical analyses for this end point

    Secondary: Area under the blood concentration-time curve [AUC(0-t)] of danirixin

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    End point title
    		 Area under the blood concentration-time curve [AUC(0-t)] of danirixin [58]
    End point description
    Blood samples were collected to evaluate the PK of danirixin at the indicated time points for the analysis of AUC(0-t). Only those participants with data available at the specified data points were analyzed.
    End point type
    Secondary
    End point timeframe
    Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
    Notes
    [58] - 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: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.
    End point values
    		 Danirixin hydrobromide 35 mg
    Number of subjects analysed
    13 [59]
    Units: Hours * nanograms per milliliter
    geometric mean (geometric coefficient of variation)
        Day 1
    2173.4 ( 39.57 )
        Day 14
    2751.1 ( 51.24 )
    Notes
    [59] - PK Population.
    No statistical analyses for this end point

    Secondary: Time of last observed concentration (Tlast) of danirixin

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    End point title
    		 Time of last observed concentration (Tlast) of danirixin [60]
    End point description
    Blood samples were collected to evaluate the PK of danirixin at the indicated time points for the analysis of Tlast. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
    End point type
    Secondary
    End point timeframe
    Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
    Notes
    [60] - 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: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.
    End point values
    		 Danirixin hydrobromide 35 mg
    Number of subjects analysed
    14 [61]
    Units: Hours
    median (full range (min-max))
        Day 1, n=14
    4.000 (4.00 to 4.05)
        Day 14, n=13
    4.000 (4.00 to 4.00)
    Notes
    [61] - PK Population.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs and SAEs were collected from start of the treatment up to Day 21
    Adverse event reporting additional description
    AEs and SAEs were collected for modified Intent-to-Treat Population which consisted of all randomized participants who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Danirixin hydrobromide 35 mg
    Reporting group description
    		 Participants received one tablet of danirixin hydrobromide 35 milligram (mg) twice daily orally with food for 14 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received one tablet of matching placebo twice daily orally with food for 14 days.

    Serious adverse events
    		 Danirixin hydrobromide 35 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Danirixin hydrobromide 35 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 14 (42.86%)
    3 / 5 (60.00%)
    Injury, poisoning and procedural complications
    Procedural complication
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Migraine
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Catheter site haematoma
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Dyspnoea
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    Sputum increased
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Night sweats
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 5 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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