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    Clinical Trial Results:
    A randomised double-blind placebo-controlled trial of Brensocatib (INS1007) in patients with severe COVID-19

    Summary
    EudraCT number
    		 2020-001643-13
    Trial protocol
    		 GB  
    Global end of trial date
    28 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Mar 2023
    First version publication date
    28 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    01.01.20
    Additional study identifiers
    ISRCTN number
    		 ISRCTN30564012
    US NCT number
    		 NCT04817332
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Dundee
    Sponsor organisation address
    Ninewells Hospital and Medical School, Dundee, United Kingdom, DD1 9SY
    Public contact
    James Chalmers, University of Dundee, +44 01382 383642, j.chalmers@dundee.ac.uk
    Scientific contact
    James Chalmers, University of Dundee, +44 01382 383642, j.chalmers@dundee.ac.uk
    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
    02 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall objective of the study is to evaluate the clinical efficacy of Brensocatib compared to placebo on top of standard care in adult patients hospitalized with COVID-19
    Protection of trial subjects
    Participants (or legally authorized representative) were required to provide written informed consent. Participants were excluded if alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 5 times the upper limit of normal, history of sevefre liver disease, absolute neutrophil count <1.0 x10^9 cells/L, were currently treated with Itraconazole, Ketoconazole, diltiazem or verapamil, were pregnant or breast feeding.
    Background therapy
    		 Patients in both arms received all other therapies required to manage their condition (standard of care) with the exception of other investigational products. Where participants had been enrolled into the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial and had been randomised to the standard care arm, co-enrolment to the STOP-COVID19 trial was allowed. Co-enrolment into RECOVERY RS (Respiratory support) a non-CTIMP intervention trial was allowed. Co-enrolment to other CTIMPs or non-CTIMP intervention trials was not be allowed.
    Evidence for comparator
    		 Neutrophil serine proteases (NSPs) are involved in the pathogenesis of severe COVID-19 infection and are increased in severe and fatal infection (Seren, 2021). Neutrophil elastase, proteinase-3 and cathepsin-G are activated during neutrophil maturation in the bone marrow through dipeptidyl peptidase 1 (DPP1; also known as cathepsin C), which removes the N-terminal dipeptide sequence of neutrophil serine proteases allowing active enzymes to be packaged into granules prior to release of neutrophils into the circulation.(Palmer et al., 2018) Brensocatib (INS1007, formerly AZD7986) is an orally delivered selective, competitive, and reversible inhibitor of DPP1. Brensocatib has been shown to inhibit neutrophil serine protease activity in blood in both animal models and healthy volunteers.(Palmer et al., 2018) We recently conducted a large phase 2 study of Brensocatib in patients with bronchiectasis designed to test if treatment with Brensocatib could reduce infective exacerbations and reduce neutrophil elastase activity in the lung in bronchiectasis patients. The study met its primary endpoint of time to first exacerbation and key secondary endpoint of the frequency of exacerbations as well as showing marked reductions in neutrophil elastase concentrations in sputum (Chalmers, 2020).
    Actual start date of recruitment
    11 May 2020
    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
    United Kingdom: 404
    Worldwide total number of subjects
    404
    EEA total number of subjects
    0
    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)
    226
    From 65 to 84 years
    158
    85 years and over
    20

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 406 participants were randomised into the study across the 14 participating UK centres. Participants were recruited between 05th June 2020 and 25th January 2021.

    Pre-assignment
    Screening details
    		 Patients were screened for eligibility up to 24 hours prior to randomization and patients meeting the eligibility criteria were randomized within 96 hours of admission to hospital for COVID-19. 406 participants were randomised. There were two post-randomisation exclusions due to ineligibility in the Brensocatib arm.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Double-blind, placebo-controlled. Participants were allocated via the randomisation system to receive either active treatment or matching placebo. The active treatment/placebo were packaged and labelled so as to not identify the contents. Trial staff and participants were blind to the allocation received. The final unblinding of the treatment allocation occurred after the creation of a final locked database.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brensocatib
    Arm description
    		 Brensocatib 25mg once daily for 28 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    INS1007
    Investigational medicinal product code
    Other name
    Brensocatib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Brensocatib is an oral tablet with a strength dose of 25mg, administered once a day.

    Arm title
    		 Placebo
    Arm description
    		 Oral placebo tablet
    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
    Placebo tablet contains microcrystalline cellulose and sodium fumarate and is coated. Dosage is 25mg once daily

    Number of subjects in period 1
    		Brensocatib Placebo
    Started
    190
    214
    Completed
    187
    211
    Not completed
    3
    3
         Lost to follow-up
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brensocatib
    Reporting group description
    		 Brensocatib 25mg once daily for 28 days

    Reporting group title
    Placebo
    Reporting group description
    		 Oral placebo tablet

    Reporting group values
    		 Brensocatib Placebo Total
    Number of subjects
    		 190 214 404
    Age categorical
    Age (years)
    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)
    		 104 122 226
        From 65-84 years
    		 80 78 158
        85 years and over
    		 6 14 20
    Age continuous
    Age, years (standard deviation)
    Units: years
        arithmetic mean (standard deviation)
    		 62.3 ( 12.5 ) 62.0 ( 14.9 ) -
    Gender categorical
    Sex: male, female
    Units: Subjects
        Female
    		 65 87 152
        Male
    		 125 127 252
    Ethnicity
    Ethnicity
    Units: Subjects
        White British
    		 167 189 356
        Irish
    		 2 1 3
        Any other White background
    		 6 5 11
        White and Black Caribbean
    		 0 1 1
        White and Black African
    		 0 1 1
        Any other Mixed/Multiple ethnic background
    		 0 1 1
        Indian
    		 1 5 6
        Pakistan
    		 4 3 7
        Bangladeshi
    		 0 1 1
        Any other Asian background
    		 4 2 6
        African
    		 1 0 1
        Any other Black/African/Caribbean background
    		 0 1 1
        Arab
    		 1 1 2
        Any other ethnic group
    		 2 3 5
        Unknown
    		 2 0 2
    Smoking Status
    Smoking Status at enrolment
    Units: Subjects
        Current smoker
    		 9 12 21
        Never smoked
    		 93 98 191
        Former smoker
    		 67 72 139
        Unknown
    		 21 32 53
    Clinical status
    Clinical status at randomisation
    Units: Subjects
        Hospitalized, not requiring supplemental oxygen
    		 42 50 92
        Hospitalized, requiring supplemental oxygen
    		 128 140 268
        Hospitalized, on non-invasive ventilation or high
    		 20 24 44
    SARS-CoV-2 PCR status
    SARS-CoV-2 PCR status
    Units: Subjects
        Confirmed positive SARS CoV-2 PCR test
    		 186 204 390
        Clinically suspected without confirmed SARS-CoV-2
    		 4 10 14
    Duration of symptoms
    Median duration of symptoms (25th, 75th centile)
    Units: days
        median (inter-quartile range (Q1-Q3))
    		 9 (6 to 12) 8 (6 to 11) -

    End points

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    End points reporting groups
    Reporting group title
    Brensocatib
    Reporting group description
    		 Brensocatib 25mg once daily for 28 days

    Reporting group title
    Placebo
    Reporting group description
    		 Oral placebo tablet

    Primary: 1. Comparison of participant clinical status between treatment arms

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    End point title
    		 1. Comparison of participant clinical status between treatment arms
    End point description
    To determine the participant clinical status on a 7-point ordinal scale: 1. Not hospitalised, no limitations on activities 2. Not hospitalised, limitation on activities; 3. Hospitalised, not requiring supplemental oxygen; 4. Hospitalised, requiring supplemental oxygen; 5. Hospitalised, on non-invasive ventilation or high flow oxygen devices; 6. Hospitalised, on invasive mechanical ventilation or Extracorporeal membrane oxygenation (ECMO) 7. Death.
    End point type
    Primary
    End point timeframe
    Up to 29 days
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: Participants
        Not hospitalised, no limitations on activities
    28
    40
        Not hospitalised, limitation on activities
    112
    129
        Hospitalised, not requiring supplemental oxygen
    7
    11
        Hospitalised, requiring supplemental oxygen
    6
    1
        Hospitalised, on non-invasive ventilation or high
    0
    1
        Hospitalised, on invasive mechanical ventilation o
    5
    6
        Death
    29
    23
    Statistical analysis title
    		 Ordinal logistic regression- primary outcome
    Statistical analysis description
    Ordinal logistic regression- primary outcome
    Comparison groups
    Brensocatib v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.92

    Secondary: 2. Time to an Improvement of One Category From Admission Using 7-point Ordinal Scale

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    End point title
    		 2. Time to an Improvement of One Category From Admission Using 7-point Ordinal Scale
    End point description
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: 7-point ordinal scale.
    End point type
    Secondary
    End point timeframe
    Up to 29 days
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: Participants
    159
    186
    Statistical analysis title
    		 Regression, cox - secondary outcome
    Statistical analysis description
    Baseline CSTAT compared to follow-up CSTAT. Days to improvement derived as 1.days from randomization to first follow-up day where CSTAT improved 2.those who died before improvement were censored at date of death 3.those who withdrew or were loss to follow-up before improvement, if their day 29 status was unknown, they were censored at the date of loss to follow-up/withdrawal 4.other participants were censored at day 29 from randomisation in study time if there were no improvement
    Comparison groups
    Placebo v Brensocatib
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.058 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1
    Notes
    [1] - Adjusted hazard ratio

    Secondary: 3. Participant Clinical Status on 7-point Ordinal Scale

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    End point title
    		 3. Participant Clinical Status on 7-point Ordinal Scale
    End point description
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: 7-point ordinal scale
    End point type
    Secondary
    End point timeframe
    Up to 29 days
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: Participants
        Not hospitalised, no limitations on activities
    22
    26
        Not hospitalised, limitations on activities
    103
    124
        Hospitalised, not requiring supplemental oxygen
    12
    19
        Hospitalised, requiring supplemental oxygen
    16
    13
        Hospitalised, on non-invasive ventilation or high
    3
    5
        Hospitalised, on invasive mechanical ventilation o
    9
    6
        Death
    20
    18
        Missing
    5
    3
    No statistical analyses for this end point

    Secondary: 4. Mean Change in the 7-point Ordinal Scale

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    End point title
    		 4. Mean Change in the 7-point Ordinal Scale
    End point description
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: 7-point ordinal scale.
    End point type
    Secondary
    End point timeframe
    Baseline to days 3, 5, 8, 11, 15 and 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    187
    211
    Units: Units on WHO Scale
        arithmetic mean (standard deviation)
    1.0 ( 2.0 )
    1.3 ( 2.0 )
    No statistical analyses for this end point

    Secondary: 5. Time to Discharge or to a National Early Warning Score (NEWS) of ≤ 2 and Maintained for 24 Hours, Whichever Occurs First

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    End point title
    		 5. Time to Discharge or to a National Early Warning Score (NEWS) of ≤ 2 and Maintained for 24 Hours, Whichever Occurs First
    End point description
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: National Early Warning Score
    End point type
    Secondary
    End point timeframe
    Up to 29 days
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    195
    Units: Participants
    172
    195
    Statistical analysis title
    		 Hazard ratio -secondary outcome
    Statistical analysis description
    Time to discharge or NEWS of ≤ 2 was calculated as days from randomization to date of discharged or NEWS of ≤ 2, whichever occurs first. Some patients had multiple admission during the study period and the first date of discharged was used for this analysis.
    Comparison groups
    Brensocatib v Placebo
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.75
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.13
    Notes
    [2] - Adjusted hazard ratio

    Secondary: 6. Change From Baseline of National Early Warning Score (NEWS)

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    End point title
    		 6. Change From Baseline of National Early Warning Score (NEWS)
    End point description
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: National Early Warning Score.Minimum value 0, maximum value 20. Higher scores mean worse outcome.
    End point type
    Secondary
    End point timeframe
    Days 8, 15 and 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: Participants
        -11
    1
    0
        -9
    2
    0
        -8
    0
    1
        -7
    1
    0
        -6
    0
    2
        -5
    1
    0
        -4
    1
    3
        -3
    4
    1
        -2
    1
    1
        -1
    3
    3
        0.0
    15
    24
        1.0
    22
    24
        2.0
    36
    34
        3.0
    28
    36
        4.0
    21
    28
        5.0
    10
    14
        6.0
    11
    6
        7.0
    3
    4
        8.0
    1
    4
        9.0
    0
    2
        10.0
    0
    1
        Missing
    29
    26
    No statistical analyses for this end point

    Secondary: 7. Number of Oxygen Therapy Free Days

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    End point title
    		 7. Number of Oxygen Therapy Free Days
    End point description
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: oxygenation
    End point type
    Secondary
    End point timeframe
    Up to day 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: days
        median (inter-quartile range (Q1-Q3))
    24 (11 to 27)
    24.5 (17 to 27)
    Statistical analysis title
    		 Negative binomial regression
    Statistical analysis description
    Number of days free from oxygen support (CSTAT = 1, 2, 3) were compared between the treatment arms using negative binomial regression, results are expressed as incidence rate ratios (with 95% confidence intervals).
    Comparison groups
    Brensocatib v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.027
    Method
    		 Rate ratio
    Parameter type
    		 Rate ratio
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 0.99

    Secondary: 8. Incidence and Duration of New Oxygen Therapy Use During the Trial

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    End point title
    		 8. Incidence and Duration of New Oxygen Therapy Use During the Trial
    End point description
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: oxygenation
    End point type
    Secondary
    End point timeframe
    Up to day 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: Days
        median (inter-quartile range (Q1-Q3))
    0 (0 to 2)
    0 (0 to 1)
    Statistical analysis title
    		 Incidence and Duration of New Oxygen Therapy Use
    Statistical analysis description
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: oxygenation
    Comparison groups
    Brensocatib v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.058
    Method
    		 Rate ratio
    Parameter type
    		 Rate ratio
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.74

    Secondary: 9. Number of Mechanical Ventilator Free Days

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    End point title
    		 9. Number of Mechanical Ventilator Free Days
    End point description
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: Mechanical ventilation
    End point type
    Secondary
    End point timeframe
    Up to day 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: Days
        median (inter-quartile range (Q1-Q3))
    28 (22 to 28)
    28 (26 to 28)
    Statistical analysis title
    		 Negative binomial regression
    Statistical analysis description
    Number of days free from ventilator (CSTAT = 1, 2, 3, 4) were compared between the treatment arms using negative binomial regression results are expressed as incidence rate ratios (with 95% confidence intervals).
    Comparison groups
    Brensocatib v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.021
    Method
    		 Rate ratio
    Parameter type
    		 Rate ratio
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 0.99

    Secondary: 10. Incidence and Duration of New Mechanical Ventilation Use During the Trial

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    End point title
    		 10. Incidence and Duration of New Mechanical Ventilation Use During the Trial
    End point description
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: Mechanical ventilation
    End point type
    Secondary
    End point timeframe
    Up to day 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: Days
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 Negative binomial regression
    Comparison groups
    Brensocatib v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.018
    Method
    		 Rate ratio
    Parameter type
    		 Rate ratio
    Point estimate
    1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 2.58

    Secondary: 11. Duration of Hospitalisation

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    End point title
    		 11. Duration of Hospitalisation
    End point description
    n: Evaluation of the clinical efficacy of Brensocatib relative to standard care: hospitalisation
    End point type
    Secondary
    End point timeframe
    Duration between date of admission and discharge assessed up to 29 days.
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: Days
        arithmetic mean (standard deviation)
    8.4 ( 8.3 )
    8.2 ( 8.3 )
    Statistical analysis title
    		 Negative binomial regression
    Statistical analysis description
    Duration of hospitalisation was calculated from date of randomisation to date of discharged. If a participant had more than one admission during the study period, the total duration of hospitalisation was calculated. Participants who died in the hospital and participants who withdrew and date of discharged were not recorded were excluded in the analysis.
    Comparison groups
    Brensocatib v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.602
    Method
    		 Rate ratio
    Parameter type
    		 Rate ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.15

    Secondary: 12. 28-day Mortality

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    End point title
    		 12. 28-day Mortality
    End point description
    Evaluation of the clinical efficacy of Brensocatib relative to standard care: mortality
    End point type
    Secondary
    End point timeframe
    Date of death up to 20 days
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: Participants
    29
    23
    Statistical analysis title
    		 Regression, cox
    Statistical analysis description
    Survival analysis was used to compare 28-day mortality between the treatment arms. Participants who did not die will be censored on the last study day. Those who withdrew or were loss to follow-up and their day 29 status was unknown were censored at the date of loss to follow-up/withdrawal. Other participants were censored 28 days from randomisation in study time.
    Comparison groups
    Brensocatib v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 1.88

    Secondary: 13. Cumulative Incidence of Serious Adverse Events (SAEs)

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    End point title
    		 13. Cumulative Incidence of Serious Adverse Events (SAEs)
    End point description
    Evaluation of the safety of the intervention through 29 days of follow-up as compared to the control arm
    End point type
    Secondary
    End point timeframe
    1-29 days
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: Participants
    40
    35
    No statistical analyses for this end point

    Secondary: 14. Discontinuation or Temporary Suspension of Treatment

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    End point title
    		 14. Discontinuation or Temporary Suspension of Treatment
    End point description
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm
    End point type
    Secondary
    End point timeframe
    1-29 days
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: Participants
    13
    12
    No statistical analyses for this end point

    Secondary: 15. Changes in White 15. Cell Count (x10^9/L) Over Time (Hospitalised Participants Only)

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    End point title
    		 15. Changes in White 15. Cell Count (x10^9/L) Over Time (Hospitalised Participants Only)
    End point description
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm
    End point type
    Secondary
    End point timeframe
    Days 0/1, 3, 5, 8, 11, 15, 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    14
    18
    Units: cells/millilitre
        arithmetic mean (standard deviation)
    8.9 ( 4.7 )
    8.5 ( 3.1 )
    No statistical analyses for this end point

    Secondary: 16. Changes in Haemoglobin (g/L) Over Time (Hospitalised Participants Only)

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    End point title
    		 16. Changes in Haemoglobin (g/L) Over Time (Hospitalised Participants Only)
    End point description
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm
    End point type
    Secondary
    End point timeframe
    Days 0/1, 3, 5, 8, 11, 15, 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    14
    18
    Units: g/L
        arithmetic mean (standard deviation)
    195.4 ( 264 )
    105.5 ( 21.7 )
    No statistical analyses for this end point

    Secondary: 17. Changes in Platelets (x10^9/L) Over Time (Hospitalised Participants Only)

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    End point title
    		 17. Changes in Platelets (x10^9/L) Over Time (Hospitalised Participants Only)
    End point description
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm
    End point type
    Secondary
    End point timeframe
    Days 0/1, 3, 5, 8, 11, 15, 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    14
    18
    Units: x10(7) cell/L
        arithmetic mean (standard deviation)
    270 ( 94.3 )
    269 ( 117 )
    No statistical analyses for this end point

    Secondary: 18. Changes in Creatinine (Umol/L) Over Time (Hospitalised Participants Only)

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    End point title
    		 18. Changes in Creatinine (Umol/L) Over Time (Hospitalised Participants Only)
    End point description
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm
    End point type
    Secondary
    End point timeframe
    Days 0/1, 3, 5, 8, 11, 15, 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    14
    19
    Units: umol/L
        arithmetic mean (standard deviation)
    84.9 ( 39 )
    84.1 ( 52 )
    No statistical analyses for this end point

    Secondary: 19. Changes in Total Bilirubin (Umol/L) Over Time (Hospitalised Participants Only)

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    End point title
    		 19. Changes in Total Bilirubin (Umol/L) Over Time (Hospitalised Participants Only)
    End point description
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm
    End point type
    Secondary
    End point timeframe
    Days 0/1, 3, 5, 8, 11, 15, 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    14
    16
    Units: umol/L
        arithmetic mean (standard deviation)
    8.4 ( 3.9 )
    9.3 ( 9.8 )
    No statistical analyses for this end point

    Secondary: 20. Changes in Alanine Aminotransferase (U/L) Over Time (Hospitalised Participants Only)

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    End point title
    		 20. Changes in Alanine Aminotransferase (U/L) Over Time (Hospitalised Participants Only)
    End point description
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm
    End point type
    Secondary
    End point timeframe
    Days 0/1, 3, 5, 8, 11, 15, 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    14
    15
    Units: U/L
        arithmetic mean (standard deviation)
    62.8 ( 43.2 )
    52.3 ( 92.8 )
    No statistical analyses for this end point

    Secondary: 21. Changes in Aspartate Aminotransferase U/L Over Time (Hospitalised Participants Only)

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    End point title
    		 21. Changes in Aspartate Aminotransferase U/L Over Time (Hospitalised Participants Only)
    End point description
    Evaluation of the safety of the intervention through 28 days of follow-up as compared to the control arm
    End point type
    Secondary
    End point timeframe
    Days 0/1, 3, 5, 8, 11, 15, 29
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    3
    4
    Units: U/L
        arithmetic mean (standard deviation)
    22 ( 11.4 )
    28.8 ( 14.9 )
    No statistical analyses for this end point

    Secondary: 22. Adverse Events of Special Interest- Hyperkeratosis, Infections and Dental Complications

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    End point title
    		 22. Adverse Events of Special Interest- Hyperkeratosis, Infections and Dental Complications
    End point description
    Evaluation of the safety of the intervention through 29 days of follow-up as compared to the control arm
    End point type
    Secondary
    End point timeframe
    1-29 days
    End point values
    		 Brensocatib Placebo
    Number of subjects analysed
    190
    214
    Units: Participants
        Hyperkeratosis
    0
    0
        Dental complications
    0
    1
        Secondary infections
    6
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    29 days
    Adverse event reporting additional description
    Adverse events were reported by the participant, site principal investigators or delegated staff responsible for detecting documenting and recording events that met the definition of an adverse event. Participants discharged from hospital before the end of the trial were given a diary to record adverse events up to day 28. Site principal investigat
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Brensocatib
    Reporting group description
    		 Brensocatib 25mg once daily for 28 days

    Reporting group title
    Placebo
    Reporting group description
    		 Oral placebo tablet

    Serious adverse events
    		 Brensocatib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 190 (21.05%)
    35 / 214 (16.36%)
         number of deaths (all causes)
    29
    23
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to liver
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Cerebellar infarction
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 190 (1.58%)
    2 / 214 (0.93%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 190 (0.00%)
    2 / 214 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 190 (0.53%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 190 (0.00%)
    2 / 214 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    14 / 190 (7.37%)
    17 / 214 (7.94%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 17
         deaths causally related to treatment / all
    0 / 13
    0 / 17
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Diverticulitis intestinal haemorrhagic
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Arthritis bacterial
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 190 (0.53%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    COVID-19 pneumonia
         subjects affected / exposed
    9 / 190 (4.74%)
    3 / 214 (1.40%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 9
    0 / 2
    Urosepsis
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Brensocatib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    86 / 190 (45.26%)
    99 / 214 (46.26%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 190 (0.00%)
    3 / 214 (1.40%)
         occurrences all number
    0
    3
    Cold sweat
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Chest discomfort
         subjects affected / exposed
    2 / 190 (1.05%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Swelling face
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 190 (0.53%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Extravasation
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Feeling hot
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Peripheral swelling
         subjects affected / exposed
    2 / 190 (1.05%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 190 (0.53%)
    4 / 214 (1.87%)
         occurrences all number
    1
    4
    Hiccups
         subjects affected / exposed
    2 / 190 (1.05%)
    1 / 214 (0.47%)
         occurrences all number
    2
    1
    Pneumothorax
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    3 / 190 (1.58%)
    0 / 214 (0.00%)
         occurrences all number
    3
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 190 (0.53%)
    3 / 214 (1.40%)
         occurrences all number
    1
    3
    Psychiatric disorders
    Hallucination, visual
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 190 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Delirium
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Nightmare
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Suicidal ideation
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Investigations
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 190 (1.05%)
    2 / 214 (0.93%)
         occurrences all number
    2
    4
    Liver function test abnormal
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Blood glucose abnormal
         subjects affected / exposed
    1 / 190 (0.53%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Transaminases increased
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 190 (0.53%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Palpitations
         subjects affected / exposed
    2 / 190 (1.05%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 190 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Tachyarrhythmia
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 190 (1.58%)
    5 / 214 (2.34%)
         occurrences all number
    3
    5
    Headache
         subjects affected / exposed
    2 / 190 (1.05%)
    2 / 214 (0.93%)
         occurrences all number
    2
    2
    Memory impairment
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Dysarthria
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 190 (1.05%)
    1 / 214 (0.47%)
         occurrences all number
    2
    1
    Eye pruritus
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 190 (0.00%)
    4 / 214 (1.87%)
         occurrences all number
    0
    4
    Dyspepsia
         subjects affected / exposed
    3 / 190 (1.58%)
    4 / 214 (1.87%)
         occurrences all number
    3
    4
    Diarrhoea
         subjects affected / exposed
    0 / 190 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Dry mouth
         subjects affected / exposed
    1 / 190 (0.53%)
    2 / 214 (0.93%)
         occurrences all number
    1
    2
    Nausea
         subjects affected / exposed
    3 / 190 (1.58%)
    3 / 214 (1.40%)
         occurrences all number
    3
    3
    Vomiting
         subjects affected / exposed
    1 / 190 (0.53%)
    4 / 214 (1.87%)
         occurrences all number
    1
    4
    Constipation
         subjects affected / exposed
    1 / 190 (0.53%)
    4 / 214 (1.87%)
         occurrences all number
    1
    4
    Flatulence
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Gastritis erosive
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 190 (0.53%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Oral mucosal eruption
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Gingival bleeding
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Glossodynia
         subjects affected / exposed
    1 / 190 (0.53%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Tongue blistering
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Oral mucosal blistering
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Swollen tongue
         subjects affected / exposed
    1 / 190 (0.53%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Oral pain
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Gingival pain
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Lip pain
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Lip swelling
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Paraesthesia oral
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Tongue erythema
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Tongue discolouration
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash macular
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Pruritus
    Additional description: Pruritis soles of feet
         subjects affected / exposed
    1 / 190 (0.53%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Rash pustular
    Additional description: Pustules on palms of hands
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    5 / 190 (2.63%)
    7 / 214 (3.27%)
         occurrences all number
    5
    7
    Eczema
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Mouth ulceration
         subjects affected / exposed
    2 / 190 (1.05%)
    1 / 214 (0.47%)
         occurrences all number
    2
    1
    Night sweats
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Subcutaneous emphysema
    Additional description: Widespread surgical emphysema in arms and neck, shown in CXR.
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    2 / 190 (1.05%)
    1 / 214 (0.47%)
         occurrences all number
    2
    1
    Rash pruritic
         subjects affected / exposed
    1 / 190 (0.53%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Acne
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 190 (1.05%)
    0 / 214 (0.00%)
         occurrences all number
    2
    0
    Cholelithiasis
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 190 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Dysuria
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 190 (1.05%)
    4 / 214 (1.87%)
         occurrences all number
    2
    4
    Plantar fasciitis
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Pain in jaw
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Infections and infestations
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    2 / 190 (1.05%)
    2 / 214 (0.93%)
         occurrences all number
    2
    2
    Oral candidiasis
         subjects affected / exposed
    0 / 190 (0.00%)
    3 / 214 (1.40%)
         occurrences all number
    0
    3
    Candida infection
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 190 (0.00%)
    2 / 214 (0.93%)
         occurrences all number
    0
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 190 (0.53%)
    1 / 214 (0.47%)
         occurrences all number
    1
    1
    Pharyngitis
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Serratia infection
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    4 / 190 (2.11%)
    2 / 214 (0.93%)
         occurrences all number
    4
    2
    Gout
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Steroid diabetes
    Additional description: Undiagnosed Diabetes (new presentation) - steroid induced
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 190 (0.00%)
    1 / 214 (0.47%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    1 / 190 (0.53%)
    0 / 214 (0.00%)
         occurrences all number
    1
    0

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

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