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    Clinical Trial Results:
    Clinical Trials targeting macro-, micro-immuno-thrombosis, vascular hyperinflammation, and hypercoagulability and renin-angiotensin-aldosterone system (RAAS) in hospitalized patients with COVID-19 (ACTIV-4 Host Tissue)

    Summary
    EudraCT number
    		 2022-000715-31
    Trial protocol
    		 ES   DE   IT  
    Global end of trial date
    31 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Sep 2024
    First version publication date
    29 Sep 2024
    Other versions
    Summary report(s)
    		 NECTAR Abbreviated Clinical Study Report 05Jun2024

    Trial information

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    Trial identification
    Sponsor protocol code
    ACTIV-4
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05593770
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 sIRB Study Number: 210982
    Sponsors
    Sponsor organisation name
    NEAT ID Foundation
    Sponsor organisation address
    CHU Saint Pierre - PL 709 Rue Haute 322, Brussels, Belgium,
    Public contact
    Project Manager, Research Organisation (KC), +44 7508 439711, nectar@rokcservices.com
    Scientific contact
    Project Manager, Research Organisation (KC), +44 7508 439711, nectar@rokcservices.com
    Sponsor organisation name
    Vanderbilt University Medical Center
    Sponsor organisation address
    2525 West End Ave, Suite 600, Nashville, United States,
    Public contact
    Sean P. Collins, MD, MSc, Vanderbilt University Medical Center, sean.collins@vumc.org
    Scientific contact
    Sean P. Collins, MD, MSc, Vanderbilt University Medical Center, sean.collins@vumc.org
    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
    05 Jun 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The overarching goal of the trial is to find effective strategies for inpatient management of patients with COVID-19. Therapeutic goals for patients hospitalized for COVID-19 include hastening recovery and preventing progression to critical illness, multiorgan failure, or death. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19. The overarching objective of this platform is to iteratively test treatment strategies targeting the host tissue response for improving clinical outcomes among adults hospitalized with COVID-19. Treatment strategies will be added to the current best practice and tested against best practice plus placebo. Best practice may itself be updated as therapies become available or are shown to be effective (or ineffective).
    Protection of trial subjects
    The safety profile of the selected agents being considered for this platform is based on prior clinical trials in patients with acute illness, both COVID-19 and non-COVID-19 related. Intensive patient monitoring in the clinical setting during and immediately following treatment was used planned to ensure protection of trial subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2022
    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
    Spain: 19
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    South Africa: 5
    Country: Number of subjects enrolled
    United States: 871
    Worldwide total number of subjects
    899
    EEA total number of subjects
    22
    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)
    514
    From 65 to 84 years
    385
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited following hospital admission with COVID-19

    Pre-assignment
    Screening details
    		 Participants were over 18 years old with documented SARS-COV-2 infection confirmed by nucleic acid test. Participants were assigned to one of the three therapies (TRV-027, TXA-127, and Fostamatinib) and either the active drug or matching placebo.

    Pre-assignment period milestones
    Number of subjects started
    		 6046 [1]
    Intermediate milestone: Number of subjects
    Randomised: 899
    Number of subjects completed
    		 899 [2]

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Ineligible: 3524
    Reason: Number of subjects
    		 Declined: 856
    Reason: Number of subjects
    		 Not approached: 352
    Reason: Number of subjects
    		 the patient was to be discharged from the hospital: 415
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Placebo participants were pooled across trials. Specifically, for each trial, the placebo comparator group consisted of all placebo participants that were eligible for that trial at the time of randomization. Each participant is identified by the trial (i.e., the study drug) and active/placebo assignment at randomization and, for placebo participants, the trials for which that participant was eligible,
    [2] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1.
    Justification: Placebo participants were pooled across trials. Specifically, for each trial, the placebo comparator group consisted of all placebo participants that were eligible for that trial at the time of randomization. Each participant is identified by the trial (i.e., the study drug) and active/placebo assignment at randomization and, for placebo participants, the trials for which that participant was eligible,
    Period 1
    Period 1 title
    Post randomisation- Study Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 TRV-027 Active
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    TRV-027
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage of 12 mg/h as a continuous 24- hour infusion, will be infused for 5 days or until hospital discharge, whichever comes first.

    Arm title
    		 TXA-127 Active
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    TXA-127
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    0.5 mg/kg/day will be infused for 3 hours daily for 5 days or until hospital discharge, whichever comes first.

    Arm title
    		 Fostamatinib Active
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fostamatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150mg or 100mg tablets will be taken twice daily for a total of 14 days

    Arm title
    		 Fostamatinib Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Fostamatinib placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150mg whole tablets administered orally twice a day for 14 days.

    Arm title
    		 TXA-127 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sterile saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single daily intravenous infusion of 100ml for 3 days

    Arm title
    		 TRV-027 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sterile saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    275ml solution will be administered through continuous 24 hour intravenous infusion for 5 days

    Number of subjects in period 1
    		TRV-027 Active TXA-127 Active Fostamatinib Active Fostamatinib Placebo TXA-127 Placebo TRV-027 Placebo
    Started
    149
    176
    207
    206
    175
    147
    Completed
    99
    124
    152
    154
    130
    114
    Not completed
    50
    52
    55
    52
    45
    33
         Adverse event, serious fatal
    34
    29
    27
    26
    32
    25
         Consent withdrawn by subject
    3
    8
    8
    5
    3
    3
         Lost to follow-up
    13
    15
    20
    21
    10
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TRV-027 Active
    Reporting group description
    		 -

    Reporting group title
    TXA-127 Active
    Reporting group description
    		 -

    Reporting group title
    Fostamatinib Active
    Reporting group description
    		 -

    Reporting group title
    Fostamatinib Placebo
    Reporting group description
    		 -

    Reporting group title
    TXA-127 Placebo
    Reporting group description
    		 -

    Reporting group title
    TRV-027 Placebo
    Reporting group description
    		 -

    Reporting group values
    		 TRV-027 Active TXA-127 Active Fostamatinib Active Fostamatinib Placebo TXA-127 Placebo TRV-027 Placebo Total
    Number of subjects
    		 149 176 207 206 175 147 1060
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 109 121 88 81 128 107 634
        From 65-84 years
    		 40 55 119 125 47 40 426
    Gender categorical
    Units: Subjects
        Female
    		 54 70 103 95 76 69 467
        Male
    		 95 106 104 111 99 78 593
    Subject analysis sets

    Subject analysis set title
    Efficacy TXA-127 trial ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized participants grouped by study arm and active/placebo assignment at randomization

    Subject analysis set title
    Efficacy TRV-027 trial ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized participants grouped by study arm and active/placebo assignment at randomization

    Subject analysis set title
    Efficacy Fostamatinib trial ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized participants grouped by study arm and active/placebo assignment at randomization

    Subject analysis set title
    Efficacy TXA-127 trial mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized participants grouped by study arm and active/placebo assignment at randomization, regardless of subsequent compliance or protocol violations, with the following exceptions: 1. Participants who have not received the study drug assigned at randomization will be excluded. 2. Participants who were randomized and later found to be ineligible based on assessments initiated prior to randomization will be excluded. All statistical analyses will be implemented using mITT dataset.

    Subject analysis set title
    Efficacy TRV-027 mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized participants grouped by study arm and active/placebo assignment at randomization, regardless of subsequent compliance or protocol violations, with the following exceptions: 1. Participants who have not received the study drug assigned at randomization will be excluded. 2. Participants who were randomized and later found to be ineligible based on assessments initiated prior to randomization will be excluded. All statistical analyses will be implemented using mITT dataset.

    Subject analysis set title
    Efficacy Fostamatinib trial mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized participants grouped by study arm and active/placebo assignment at randomization, regardless of subsequent compliance or protocol violations, with the following exceptions: 1. Participants who have not received the study drug assigned at randomization will be excluded. 2. Participants who were randomized and later found to be ineligible based on assessments initiated prior to randomization will be excluded. All statistical analyses will be implemented using mITT dataset.

    Subject analysis sets values
    		 Efficacy TXA-127 trial ITT Efficacy TRV-027 trial ITT Efficacy Fostamatinib trial ITT Efficacy TXA-127 trial mITT Efficacy TRV-027 mITT Efficacy Fostamatinib trial mITT
    Number of subjects
    351
    296
    413
    343
    290
    400
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    249
    216
    169
    226
    199
    166
        From 65-84 years
    102
    80
    244
    117
    91
    234
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    146
    123
    198
    143
    122
    190
        Male
    205
    173
    215
    200
    168
    210

    End points

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    End points reporting groups
    Reporting group title
    TRV-027 Active
    Reporting group description
    		 -

    Reporting group title
    TXA-127 Active
    Reporting group description
    		 -

    Reporting group title
    Fostamatinib Active
    Reporting group description
    		 -

    Reporting group title
    Fostamatinib Placebo
    Reporting group description
    		 -

    Reporting group title
    TXA-127 Placebo
    Reporting group description
    		 -

    Reporting group title
    TRV-027 Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Efficacy TXA-127 trial ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized participants grouped by study arm and active/placebo assignment at randomization

    Subject analysis set title
    Efficacy TRV-027 trial ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized participants grouped by study arm and active/placebo assignment at randomization

    Subject analysis set title
    Efficacy Fostamatinib trial ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized participants grouped by study arm and active/placebo assignment at randomization

    Subject analysis set title
    Efficacy TXA-127 trial mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized participants grouped by study arm and active/placebo assignment at randomization, regardless of subsequent compliance or protocol violations, with the following exceptions: 1. Participants who have not received the study drug assigned at randomization will be excluded. 2. Participants who were randomized and later found to be ineligible based on assessments initiated prior to randomization will be excluded. All statistical analyses will be implemented using mITT dataset.

    Subject analysis set title
    Efficacy TRV-027 mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized participants grouped by study arm and active/placebo assignment at randomization, regardless of subsequent compliance or protocol violations, with the following exceptions: 1. Participants who have not received the study drug assigned at randomization will be excluded. 2. Participants who were randomized and later found to be ineligible based on assessments initiated prior to randomization will be excluded. All statistical analyses will be implemented using mITT dataset.

    Subject analysis set title
    Efficacy Fostamatinib trial mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomized participants grouped by study arm and active/placebo assignment at randomization, regardless of subsequent compliance or protocol violations, with the following exceptions: 1. Participants who have not received the study drug assigned at randomization will be excluded. 2. Participants who were randomized and later found to be ineligible based on assessments initiated prior to randomization will be excluded. All statistical analyses will be implemented using mITT dataset.

    Primary: Mean number of oxygen free days

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    End point title
    		 Mean number of oxygen free days
    End point description
    End point type
    Primary
    End point timeframe
    Day 1-28
    End point values
    		 TRV-027 Active TXA-127 Active Fostamatinib Active Fostamatinib Placebo TXA-127 Placebo TRV-027 Placebo
    Number of subjects analysed
    145
    170
    199
    201
    173
    145
    Units: days
        arithmetic mean (standard deviation)
    8.1 ( 10.8 )
    9.0 ( 10.9 )
    13.4 ( 12.4 )
    14.2 ( 12.1 )
    11.3 ( 11.5 )
    10.5 ( 11.5 )
    Statistical analysis title
    		 Effect of study agent vs placebo Fostamatinib
    Comparison groups
    Fostamatinib Active v Fostamatinib Placebo
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.17
    Variability estimate
    Standard deviation
    Notes
    [1] - The effect of the active drug versus placebo will be quantified using an odds ratio – the primary estimand – which quantifies the treatment effect on the odds of greater oxygen-free days at day 28. Evidence for efficacy will be quantified using the posterior probability that the active drug versus placebo odds ratio is greater than one (i.e., treatment is associated with greater oxygen free days at day 28)
    Statistical analysis title
    		 Effect of study agent vs placebo TXA-127
    Comparison groups
    TXA-127 Placebo v TXA-127 Active
    Number of subjects included in analysis
    343
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.3
    Variability estimate
    Standard deviation
    Notes
    [2] - The effect of the active drug versus placebo will be quantified using an odds ratio – the primary estimand – which quantifies the treatment effect on the odds of greater oxygen-free days at day 28. Evidence for efficacy will be quantified using the posterior probability that the active drug versus placebo odds ratio is greater than one (i.e., treatment is associated with greater oxygen free days at day 28)
    Statistical analysis title
    		 Effect of study agent vs placebo TRV-027
    Comparison groups
    TRV-027 Active v TRV-027 Placebo
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.13
    Variability estimate
    Standard deviation
    Notes
    [3] - The effect of the active drug versus placebo will be quantified using an odds ratio – the primary estimand – which quantifies the treatment effect on the odds of greater oxygen-free days at day 28. Evidence for efficacy will be quantified using the posterior probability that the active drug versus placebo odds ratio is greater than one (i.e., treatment is associated with greater oxygen free days at day 28)

    Secondary: All cause mortality

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    End point title
    		 All cause mortality
    End point description
    End point type
    Secondary
    End point timeframe
    28 Days
    End point values
    		 TRV-027 Active TXA-127 Active Fostamatinib Active Fostamatinib Placebo TXA-127 Placebo TRV-027 Placebo
    Number of subjects analysed
    141
    163
    195
    197
    166
    140
    Units: Count
    29
    22
    22
    16
    22
    18
    Statistical analysis title
    		 Secondary efficacy endpoint Fostamatinib Arm
    Comparison groups
    Fostamatinib Active v Fostamatinib Placebo
    Number of subjects included in analysis
    392
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 2.9
    Notes
    [4] - The effect of active agent versus placebo on the odds of binary and ordinal secondary outcomes will be quantified using logistic and PO regression methods, respectively, adjusting for patient demographic and clinical factors. Time-to-event outcomes will be analyzed using Cox proportional hazards methods. The proportion of participants who died at fixed time points (e.g., day 28) will be estimated using Kaplan-Meier methods
    Statistical analysis title
    		 Secondary efficacy endpoint TRV-027 Arm
    Comparison groups
    TRV-027 Active v TRV-027 Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 3.08
    Notes
    [5] - The effect of active agent versus placebo on the odds of binary and ordinal secondary outcomes will be quantified using logistic and PO regression methods, respectively, adjusting for patient demographic and clinical factors. Time-to-event outcomes will be analyzed using Cox proportional hazards methods. The proportion of participants who died at fixed time points (e.g., day 28) will be estimated using Kaplan-Meier methods
    Statistical analysis title
    		 Secondary efficacy endpoint TXA-127 Arm
    Comparison groups
    TXA-127 Placebo v TXA-127 Active
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.66
    Notes
    [6] - The effect of active agent versus placebo on the odds of binary and ordinal secondary outcomes will be quantified using logistic and PO regression methods, respectively, adjusting for patient demographic and clinical factors. Time-to-event outcomes will be analyzed using Cox proportional hazards methods. The proportion of participants who died at fixed time points (e.g., day 28) will be estimated using Kaplan-Meier methods

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 0-28
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 DAIDS
    Dictionary version
    2.1
    Reporting groups
    Reporting group title
    TRV-027 placebo
    Reporting group description
    		 Participants who were randomised to receive placebo for TRV-027. Some placebo participants in the TRV-027 trial received a placebo mimic of TXA-127 or Fostamatinib.

    Reporting group title
    TXA-127 placebo
    Reporting group description
    		 Participants randomized to receive the placebo mimic of the TXA-127. Some placebo participants in the TXA-127 trial received a placebo mimic of TRV-027 or Fostamatinib.

    Reporting group title
    Fostamatinib placebo
    Reporting group description
    		 Participants who were randomized to receive the placebo mimic of Fostamatinib. Some placebo participants in the Fostamatinib trial received a placebo mimic of TXA-127 or TRV-027.

    Reporting group title
    TRV-027 active
    Reporting group description
    		 -

    Reporting group title
    TXA-127 active
    Reporting group description
    		 Participants randomized to receive active TXA-127

    Reporting group title
    Fostamatinib active
    Reporting group description
    		 Participants who were randomized to receive active Fostamatinib.

    Serious adverse events
    		 TRV-027 placebo TXA-127 placebo Fostamatinib placebo TRV-027 active TXA-127 active Fostamatinib active
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 147 (5.44%)
    10 / 174 (5.75%)
    34 / 205 (16.59%)
    12 / 149 (8.05%)
    7 / 177 (3.95%)
    36 / 208 (17.31%)
         number of deaths (all causes)
    25
    32
    26
    34
    29
    27
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arterial thrombosis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    2 / 149 (1.34%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    2 / 205 (0.98%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    2 / 205 (0.98%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fusion surgery
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toe amputation
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tricuspid valve replacement
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Physical deconditioning
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    2 / 205 (0.98%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    2 / 208 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    3 / 205 (1.46%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    2 / 208 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood electrolytes abnormal
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    2 / 208 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    2 / 208 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    2 / 205 (0.98%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    4 / 208 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    5 / 205 (2.44%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    2 / 208 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 5
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cirrhosis alcoholic
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haematoma muscle
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trismus
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    4 / 205 (1.95%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    2 / 205 (0.98%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 174 (0.57%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 147 (0.68%)
    2 / 174 (1.15%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spontaneous bacterial peritonitis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vulval cellulitis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 TRV-027 placebo TXA-127 placebo Fostamatinib placebo TRV-027 active TXA-127 active Fostamatinib active
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 147 (5.44%)
    8 / 174 (4.60%)
    12 / 205 (5.85%)
    9 / 149 (6.04%)
    15 / 177 (8.47%)
    19 / 208 (9.13%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastasis
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Diastolic hypertension
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    2 / 205 (0.98%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    2
    0
    1
    1
    Hypotension
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    3 / 149 (2.01%)
    0 / 177 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    0
    0
    3
    0
    2
    Systolic hypertension
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Surgical and medical procedures
    Transfusion
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Discomfort
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Extravasation
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infusion site erythema
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infusion site phlebitis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Mass
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pneumomediastinum
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    1
    1
    1
    0
    1
    0
    Pneumothorax
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    1 / 177 (0.56%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    2
    1
    1
    Respiratory failure
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Delirium
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    2 / 208 (0.96%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    Insomnia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Investigations
    creatinine renal clearance decreased
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Troponin I increased
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Tracheal haemorrhage
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Urinary retention postoperative
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Atrial flutter
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Bradycardia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    1
    0
    1
    1
    Cardiac arrest
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Cardiac failure
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Cerebral haematoma
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Coordination abnormal
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    5
    0
    headache
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    2 / 177 (1.13%)
    2 / 208 (0.96%)
         occurrences all number
    1
    1
    0
    0
    2
    2
    Hypoaesthesia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Microcytic anaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    2 / 208 (0.96%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    2 / 177 (1.13%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    2 / 205 (0.98%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    2 / 208 (0.96%)
         occurrences all number
    0
    0
    2
    0
    1
    2
    Epigastric discomfort
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    2 / 149 (1.34%)
    2 / 177 (1.13%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    2
    2
    1
    Oral disorder
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 147 (0.68%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    Hepatobiliary disorders
    Cirrhosis alcoholic
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hepatotoxicity
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    2 / 205 (0.98%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    6 / 208 (2.88%)
         occurrences all number
    0
    0
    2
    0
    0
    6
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    1 / 149 (0.67%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pathological fracture
         subjects affected / exposed
    0 / 147 (0.00%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    0 / 208 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Body tinea
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Haemophilus infection
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 147 (0.68%)
    1 / 174 (0.57%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    2
    2
    0
    0
    1
    0
    Sepsis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tracheitis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 147 (1.36%)
    2 / 174 (1.15%)
    1 / 205 (0.49%)
    0 / 149 (0.00%)
    2 / 177 (1.13%)
    0 / 208 (0.00%)
         occurrences all number
    2
    2
    4
    0
    2
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    0 / 177 (0.00%)
    1 / 208 (0.48%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Metabolic acidosis
         subjects affected / exposed
    0 / 147 (0.00%)
    0 / 174 (0.00%)
    0 / 205 (0.00%)
    0 / 149 (0.00%)
    1 / 177 (0.56%)
    0 / 208 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jun 2022
    Remove TRV-027 and TXA-127 from the platform Update to exclusion criteria #1 and #2 to provide clarification Revised fostamatinib appendix to clarify exclusions of concomitant use with strong CYP3A4 medications
    16 Sep 2022
    Minor changes to respond to international regulatory requests Updated text to clarify emergency unblinding
    18 Oct 2022
    Added definition of Adverse Events of Special Interest (AESIs)

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Sep 2023
    Fostamatinib study arm ceased enrollment and discontinued study medication following the DSMB recommendation released on the 26th September 2023.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Patients assigned to placebo TXA-127 or TRV-027 were included in the fostamatinib placebo group. Shared placebo group reduces the total number of patients who received placebo, accounting for difference in baseline total and reporting group total
    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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