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    Clinical Trial Results:
    Placebo-controlled, double-blind, randomized study of Aerucin® as adjunct therapy to antibiotics in the treatment of P. aeruginosa pneumonia

    Summary
    EudraCT number
    		 2016-004261-10
    Trial protocol
    		 BE   DE   CZ   HU   ES   GR   PL   IT  
    Global end of trial date
    25 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Oct 2021
    First version publication date
    30 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AR-105-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03027609
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aridis Pharmaceuticals, Inc.
    Sponsor organisation address
    983 University Avenue, Building B, Los Gatos, United States, CA 95032-7637
    Public contact
    Lynne Deans, Vice President (Clinical Development), Aridis Pharmaceuticals, Inc., +1 408385 1742, deansl@aridispharma.com
    Scientific contact
    Hasan S. Jafri, Chief Medical Officer, Aridis Pharmaceuticals, Inc., +1 408385 1742, jafrih@aridispharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To assess the efficacy of Aerucin®, administered as a single dose in addition to standard antibiotic regimen, in terms of clinical cure at day 14, i.e., resolution of the P. aeruginosa pneumonia event diagnosed at enrollment, as compared to standard antibiotic therapy alone. 2. To assess the clinical safety and tolerability of Aerucin® in the study population.
    Protection of trial subjects
    All subjects are hospitalized and monitored for vital function and safety.
    Background therapy
    		 Standard of care antibiotics for bacterial pneumonia
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Czech Republic: 10
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Russian Federation: 42
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 2
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Belarus: 12
    Country: Number of subjects enrolled
    Georgia: 1
    Country: Number of subjects enrolled
    Ukraine: 17
    Worldwide total number of subjects
    158
    EEA total number of subjects
    72
    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)
    79
    From 65 to 84 years
    79
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with a documented diagnosis of pneumonia, who are requiring ICU care and who are intubated are eligible for screening. Assuming all other eligibility criteria are met, randomization and treatment will be based on identifying P. Aeruginosa as pathogen causing pneumonia.

    Pre-assignment
    Screening details
    		 Screening is divided in two parts. The first part is the pre-screening phase, all subjects with a pneumonia, who are intubated, treated on the ICU and who have a signed Informed consent can move to the second part of screening. In this phase an airway sample (BAL, mini-BAL or ETA) is obtained and sent to the Microbiology Lab or a rapid test is bein

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Study Drug
    Arm description
    		 AR-105
    Arm type
    		 Experimental

    Investigational medicinal product name
    AR-105
    Investigational medicinal product code
    AR-105
    Other name
    Aerucin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    20 mg/kg via intravenous infusion lasting 2 hours

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Same volume as AR-105 by intravenous infusion lasting 2 hours

    Number of subjects in period 1
    		Study Drug Placebo
    Started
    79
    79
    Completed
    79
    79

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Study Drug
    Reporting group description
    		 AR-105

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 Study Drug Placebo Total
    Number of subjects
    		 79 79 158
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 40 39 79
        Elderly (>65 years)
    		 39 40 79
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.5 ( 13.83 ) 61.2 ( 15.58 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 21 38
        Male
    		 62 58 120
    Race
    People belonging to different races
    Units: Subjects
        Asian
    		 4 4 8
        Black or African American
    		 2 1 3
        White
    		 73 74 147
    Region of Enrollment
    Regions of Countries from Locations in Protocol
    Units: Subjects
        Americas
    		 3 4 7
        Eastern EU
    		 50 50 100
        Western EU
    		 22 22 44
        Asia
    		 4 3 7
    Subject analysis sets

    Subject analysis set title
    AR-105
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized patients who received study drug

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized patients who received study drug (placebo)

    Subject analysis set title
    Subset AR-105 Study1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A subset of 9 patients had the following characteristics and were found to belong to 1. appropriate clinical Severity 2. inadequate antibiotic regimen and 3. lower 3rd quartile of level of CRP

    Subject analysis set title
    Subset Placebo Study1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A subset of 9 patients had the following characteristics and were found to belong to 1. appropriate clinical Severity 2. inadequate antibiotic regimen and 3. lower 3rd quartile of level of CRP

    Subject analysis set title
    Subset AR-105 Study2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A subset of 9 patients had the following characteristics and were found to belong to 1. appropriate clinical Severity 2. inadequate antibiotic regimen and 3. lower 3rd quartile of level of CRP

    Subject analysis set title
    Subset Placebo Study2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A subset of 9 patients had the following characteristics and were found to belong to 1. appropriate clinical Severity 2. inadequate antibiotic regimen and 3. lower 3rd quartile of level of CRP

    Subject analysis sets values
    		 AR-105 Placebo Subset AR-105 Study1 Subset Placebo Study1 Subset AR-105 Study2 Subset Placebo Study2
    Number of subjects
    79
    79
    9
    18
    3
    7
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    40
    39
        Elderly (>65 years)
    39
    40
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.5 ( 13.83 )
    61.2 ( 15.58 )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    17
    21
        Male
    62
    58
    Race
    People belonging to different races
    Units: Subjects
        Asian
    4
    4
        Black or African American
    2
    1
        White
    73
    74
    Region of Enrollment
    Regions of Countries from Locations in Protocol
    Units: Subjects
        Americas
    3
    4
        Eastern EU
    50
    50
        Western EU
    22
    22
        Asia
    4
    3

    End points

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    End points reporting groups
    Reporting group title
    Study Drug
    Reporting group description
    		 AR-105

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Subject analysis set title
    AR-105
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized patients who received study drug

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized patients who received study drug (placebo)

    Subject analysis set title
    Subset AR-105 Study1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A subset of 9 patients had the following characteristics and were found to belong to 1. appropriate clinical Severity 2. inadequate antibiotic regimen and 3. lower 3rd quartile of level of CRP

    Subject analysis set title
    Subset Placebo Study1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A subset of 9 patients had the following characteristics and were found to belong to 1. appropriate clinical Severity 2. inadequate antibiotic regimen and 3. lower 3rd quartile of level of CRP

    Subject analysis set title
    Subset AR-105 Study2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A subset of 9 patients had the following characteristics and were found to belong to 1. appropriate clinical Severity 2. inadequate antibiotic regimen and 3. lower 3rd quartile of level of CRP

    Subject analysis set title
    Subset Placebo Study2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A subset of 9 patients had the following characteristics and were found to belong to 1. appropriate clinical Severity 2. inadequate antibiotic regimen and 3. lower 3rd quartile of level of CRP

    Primary: Clinical Cure on Day 21

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    End point title
    		 Clinical Cure on Day 21
    End point description
    A summary of the number (%) of patients who were cured on or before Day 21 (micro-ITT population) is provided, by treatment group
    End point type
    Primary
    End point timeframe
    Up to Day 21
    End point values
    		 AR-105 Placebo
    Number of subjects analysed
    70
    67
    Units: patients
        Observed Cured
    34
    37
        Imputed Cured
    6
    5
        Not Cured
    25
    20
        Reinfection same pathogen
    5
    2
        New Infection Different Pathogen
    0
    3
        New infection Unknown pathogen
    0
    0
    Statistical analysis title
    		 CMH Test Day 21 Clinical Cure
    Statistical analysis description
    Comparison between the treatment and placebo
    Comparison groups
    AR-105 v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.6154 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -5.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.9
         upper limit
    		 10.8
    Notes
    [1] - comparison between the treatment and placebo
    [2] - P-value was obtained with the stratified CMH test adjusted for baseline randomization strata

    Secondary: Clinical Cure on Day 7

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    End point title
    		 Clinical Cure on Day 7
    End point description
    The proportion of patients who achieved Clinical Cure at Day 7
    End point type
    Secondary
    End point timeframe
    Up to Day 7
    End point values
    		 AR-105 Placebo
    Number of subjects analysed
    70
    67
    Units: patients
        Cured Observed
    16
    18
        Cured Imputed
    0
    0
        Not Cured
    52
    47
        Re-infection Same Pathogen
    1
    0
        New Infection Different Pathogen
    1
    1
        New Infection Unknown Pathogen
    0
    1
    Statistical analysis title
    		 Day 7 Clinical Cure CMH
    Comparison groups
    AR-105 v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.8426 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    4.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.5
         upper limit
    		 10.5
    Notes
    [3] - Comparison between the treatment and placebo
    [4] - P-value was obtained with the stratified CMH test adjusted for baseline randomization strata

    Secondary: Clinical Cure on Day 14

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    End point title
    		 Clinical Cure on Day 14
    End point description
    A summary of the number (%) of patients who were cured on or before Day 21 (micro-ITT population) is provided by treatment group
    End point type
    Secondary
    End point timeframe
    Up to Day 14
    End point values
    		 AR-105 Placebo
    Number of subjects analysed
    70
    67
    Units: Patients
        Observed Cured
    36
    31
        Imputed Cured
    1
    2
        Not Cured
    29
    30
        Reinfection same pathogen
    1
    0
        New Infection Different Pathogen
    2
    4
        New infection Unknown pathogen
    1
    0
    Statistical analysis title
    		 CMH Test Day 14 Clinical Cure
    Statistical analysis description
    Comparison between the treatment and placebo
    Comparison groups
    AR-105 v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.3562 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.1
         upper limit
    		 20.3
    Notes
    [5] - comparison between the treatment and placebo
    [6] - P-value was obtained with the stratified CMH test adjusted for baseline randomization strata

    Secondary: Clinical Cure on Day 28

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    End point title
    		 Clinical Cure on Day 28
    End point description
    A summary of the number (%) of patients who were cured on or before Day 28 (micro-ITT population) is provided by treatment group
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 AR-105 Placebo
    Number of subjects analysed
    70
    67
    Units: patients
        Observed Cured
    35
    38
        Imputed Cured
    9
    6
        Not Cured
    23
    16
        Reinfection same pathogen
    3
    3
        New Infection Different Pathogen
    0
    4
        New infection Unknown pathogen
    0
    0
    Statistical analysis title
    		 CMH Test Day 28 Clinical Cure
    Statistical analysis description
    Comparison between the treatment and placebo
    Comparison groups
    AR-105 v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.8472 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.9
         upper limit
    		 13.2
    Notes
    [7] - comparison between the treatment and placebo
    [8] - P-value was obtained with the stratified CMH test adjusted for baseline randomization strata

    Post-hoc: Post-hoc Analysis of Clinical Cure Rates Day 14 and 21 Study1

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    End point title
    		 Post-hoc Analysis of Clinical Cure Rates Day 14 and 21 Study1
    End point description
    Using the appropriate clinical severity, level of CRP and adequate antibiotic criteria, patients were subdivided into subgroups to identify a pattern in the clinical cure rates in both treatment groups. The results suggest the presence of heterogeneity of factors influencing the clinical cure rates, where only a quite small sample is evaluable. A subset of patients had the following characteristics and were found to belong to 1. appropriate clinical Severity 2. inadequate antibiotic regimen and 3. lower 3rd quartile of level of CRP
    End point type
    Post-hoc
    End point timeframe
    Up to Day 21
    End point values
    		 Subset AR-105 Study1 Subset Placebo Study1
    Number of subjects analysed
    9
    18
    Units: Patients
        Cured Day 14
    6
    8
        Cured Day 21
    7
    10
    Statistical analysis title
    		 Day 14 Absolute Difference Study1
    Statistical analysis description
    Difference in percentage of clinical cure rates between the two treatment groups
    Comparison groups
    Subset AR-105 Study1 v Subset Placebo Study1
    Number of subjects included in analysis
    27
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.4616 [9]
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    22.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.2
         upper limit
    		 60.6
    Notes
    [9] - Marginally statistically significant only if p<0.1 Day 14 p = 0.4616 Day 21 p = 0.4053
    Statistical analysis title
    		 Day 21 Absolute Difference Study1
    Statistical analysis description
    Difference in percentage of clinical cure rates between the two treatment groups
    Comparison groups
    Subset AR-105 Study1 v Subset Placebo Study1
    Number of subjects included in analysis
    27
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.4053 [10]
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    22.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.3
         upper limit
    		 57.8
    Notes
    [10] - Marginally statistically significant only if p<0.1 Day 21 p = 0.4053

    Post-hoc: Post-hoc Analysis of Clinical Cure Rates Day 14 and 21 Study2

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    End point title
    		 Post-hoc Analysis of Clinical Cure Rates Day 14 and 21 Study2
    End point description
    Using the appropriate clinical severity, level of CRP and adequate antibiotic criteria, patients were subdivided into subgroups to identify a pattern in the clinical cure rates in both treatment groups. The results suggest the presence of heterogeneity of factors influencing the clinical cure rates, where only a quite small sample is evaluable. A subset of patients had the following characteristics and were found to belong to 1. appropriate clinical Severity 2. inadequate antibiotic regimen and 3. lower 3rd quartile of level of CRP
    End point type
    Post-hoc
    End point timeframe
    up to Day 14 and Day 21
    End point values
    		 Subset AR-105 Study2 Subset Placebo Study2
    Number of subjects analysed
    3
    7
    Units: patients
        Cured Day 14
    2
    2
        Cured Day 21
    2
    3
    Statistical analysis title
    		 Day14 Absolute Difference Study2
    Statistical analysis description
    Difference in percentage of clinical cure rates between the two treatment groups
    Comparison groups
    Subset AR-105 Study2 v Subset Placebo Study2
    Number of subjects included in analysis
    10
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0833 [11]
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    38.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -14.8
         upper limit
    		 90.9
    Notes
    [11] - Marginally statistically significant only if p<0.1 Day 14 p = 0.0833
    Statistical analysis title
    		 Day21 Absolute Difference Study2
    Statistical analysis description
    Difference in percentage of clinical cure rates between the two treatment groups
    Comparison groups
    Subset AR-105 Study2 v Subset Placebo Study2
    Number of subjects included in analysis
    10
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.5151 [12]
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    23.8
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -30.5
         upper limit
    		 78.1
    Notes
    [12] - Marginally statistically significant only if p<0.1 Day 21 p = 0.5151

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 0 to Day 28
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    AR-105
    Reporting group description
    		 The patients that were given study drug AR-105

    Reporting group title
    Placebo
    Reporting group description
    		 Patients receiving placebo

    Serious adverse events
    		 AR-105 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 79 (45.57%)
    22 / 79 (27.85%)
         number of deaths (all causes)
    25
    13
         number of deaths resulting from adverse events
    25
    13
    Vascular disorders
    Arterial rupture
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cardiac death
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    7 / 79 (8.86%)
    4 / 79 (5.06%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 5
    0 / 3
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (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 / 79 (1.27%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Transaminases increased
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain herniation
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhythm idioventricular
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coma
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ischaemic
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 79 (3.80%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 79 (3.80%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Systemic candida
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 79 (1.27%)
         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
    		 AR-105 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    73 / 79 (92.41%)
    73 / 79 (92.41%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    14 / 79 (17.72%)
    9 / 79 (11.39%)
         occurrences all number
    14
    9
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    10 / 79 (12.66%)
    4 / 79 (5.06%)
         occurrences all number
    10
    4
    Oedema peripheral
         subjects affected / exposed
    1 / 79 (1.27%)
    4 / 79 (5.06%)
         occurrences all number
    1
    4
    Pyrexia
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 79 (3.80%)
         occurrences all number
    5
    3
    Respiratory, thoracic and mediastinal disorders
    Hydrothorax
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 79 (3.80%)
         occurrences all number
    5
    3
    Pneumothorax
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 79 (2.53%)
         occurrences all number
    4
    2
    Respiratory failure
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 79 (0.00%)
         occurrences all number
    5
    0
    Tachypnoea
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 79 (3.80%)
         occurrences all number
    4
    3
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 79 (2.53%)
         occurrences all number
    4
    2
    Delirium
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 79 (2.53%)
         occurrences all number
    4
    2
    Insomnia
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 79 (3.80%)
         occurrences all number
    4
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 79 (0.00%)
    6 / 79 (7.59%)
         occurrences all number
    0
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 79 (0.00%)
    6 / 79 (7.59%)
         occurrences all number
    0
    6
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    6 / 79 (7.59%)
    7 / 79 (8.86%)
         occurrences all number
    6
    7
    Bradycardia
         subjects affected / exposed
    2 / 79 (2.53%)
    4 / 79 (5.06%)
         occurrences all number
    2
    4
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 79 (0.00%)
         occurrences all number
    5
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 79 (20.25%)
    13 / 79 (16.46%)
         occurrences all number
    16
    13
    Thrombocytopenia
         subjects affected / exposed
    6 / 79 (7.59%)
    1 / 79 (1.27%)
         occurrences all number
    6
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 79 (7.59%)
    2 / 79 (2.53%)
         occurrences all number
    6
    2
    Diarrhoea
         subjects affected / exposed
    5 / 79 (6.33%)
    13 / 79 (16.46%)
         occurrences all number
    5
    13
    Nausea
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 79 (5.06%)
         occurrences all number
    3
    4
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    6 / 79 (7.59%)
    9 / 79 (11.39%)
         occurrences all number
    6
    9
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 79 (5.06%)
    4 / 79 (5.06%)
         occurrences all number
    4
    4
    Infections and infestations
    Cystitis
         subjects affected / exposed
    4 / 79 (5.06%)
    4 / 79 (5.06%)
         occurrences all number
    4
    4
    Pneumonia
         subjects affected / exposed
    5 / 79 (6.33%)
    5 / 79 (6.33%)
         occurrences all number
    5
    5
    Sepsis
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 79 (0.00%)
         occurrences all number
    5
    0
    Septic shock
         subjects affected / exposed
    6 / 79 (7.59%)
    5 / 79 (6.33%)
         occurrences all number
    6
    5
    Tracheobronchitis
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 79 (2.53%)
         occurrences all number
    4
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 79 (1.27%)
    6 / 79 (7.59%)
         occurrences all number
    1
    6
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    6 / 79 (7.59%)
    4 / 79 (5.06%)
         occurrences all number
    6
    4
    Hypernatraemia
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 79 (1.27%)
         occurrences all number
    4
    1
    Hypokalaemia
         subjects affected / exposed
    12 / 79 (15.19%)
    6 / 79 (7.59%)
         occurrences all number
    12
    6
    Hypovolaemia
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 79 (3.80%)
         occurrences all number
    4
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2018
    This amendment was made in response to further considerations and clarifications of the study design, data integrity, and patient safety. Major updates included, but not limited to: Clarification of clinical cure rates with standard of cure antibiotic regimen Update of rapid diagnostic testing device GeneXpert® PA Cartridge, with addition of CE mark and IUO/RUO Addition of 19 years minimum age for South Korea Addition of third stratification (Country of Origin) Addition of no impact on treatment disclaimer Addition of severity status and biomarker sample tests Removal of time 0 for vital signs control Minor editorial changes, change of relapse to re-infection/new infection, and of VABP with VAP; addition of the terminology ‘quantitative/semi quantitative’ for culture tests and change of the IMP name to AR-105
    09 Nov 2018
    The changes to the protocol were made as a result of the approval of the revised Clinical Cure criteria to be used in a post hoc efficacy assessment by an adjudication committee. The changes included: Section 2: Clarification of Clinical Cure (CC) rates with standard of cure antibiotic regimen in the primary clinical efficacy objective. Removal of Day 4 and reordering of CC rates and removal of adjudication by independent committee in the secondary clinical efficacy objective Section 3.1: Specification of patients with VAP caused by P. aeruginosa; addition of clarification for ETA sample collection, randomization process (including subpopulations with different baseline oxygen status), procedures (CC criteria) used by an adjudication committee (AC), pneumonia causing pathogen and antibiotic treatment limit of 14 days, addition of reference to best practices for the choice of SOC antibiotics. Removal of comparison of culture results between laboratories and assessment of therapy by AC Section 4.3: Removal of withdrawal criteria: occurrence of any medical condition, SAEs, pregnancy, prohibited medication, protocol compliance; addition of loss to follow-up and clarification of study continuation through Day 28 Section 6.5: Removal of reference to AC, additional confirmation of randomization at earliest possible time and nearest specimen collection for microbiological outcome assessment, correction of computation of SOFA scores at set dates Section 7.3: Addition of central laboratory and clarification of ‘eradicated’ criteria All sections (where applicable): Change of ‘relapse’ to ‘re-infection/new infection’, and of VABP with VAP; addition of the terminology ‘quantitative/semi quantitative’ for culture tests and standardization of the font formatting of the ® trademark on the IMP name AR-105

    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.
    Although the efficacy of AR-105 was not superior to placebo in 159 patients, a post-hoc analysis revealed a numeric difference of over 20% (absolute value) in clinical cure rate in favor of AR-105 in a subgroup of patients.
    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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