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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Safety and Efficacy of a Single Dose of ASN100 for the Prevention of Staphylococcus aureus Pneumonia in Heavily Colonized, Mechanically Ventilated Subjects

    Summary
    EudraCT number
    		 2016-002146-23
    Trial protocol
    		 HU   CZ   DE   ES   PT   AT   PL   IT   RO  
    Global end of trial date
    28 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Dec 2019
    First version publication date
    03 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ASN100-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02940626
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Arsanis, Inc.
    Sponsor organisation address
    890 Winter Street, Waltham, MA, United States, 02451
    Public contact
    Vice President, Clinical Operations, X4 Pharmacuticals, Inc. (merged with Arsanis, Inc.), 1 857-529-8300, rnd@x4pharma.com
    Scientific contact
    Vice President, Clinical Operations, X4 Pharmacuticals, Inc. (merged with Arsanis, Inc.), 1 857-529-8300, rnd@x4pharma.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
    28 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety, tolerability, and efficacy of a single dose of ASN100 (administered as ASN-1 and ASN-2 components) versus placebo for the prevention of S. aureus pneumonia in mechanically ventilated subjects who are heavily colonized with S. aureus. Primary endpoint: Percentage of subjects in the MITT population who have or have not developed S. aureus (SA) pneumonia after a single intravenous (IV) dose of ASN100, based on sponsor defined outcome (SDO1). For each arm, the empirical proportion is defined by a ratio, which is the number of SA pneumonia events divided by the total number of subjects in the arm. The inference about the difference of two population rates is based on the empirical counterpart; specifically, the point estimate, 95% confidence interval and p-value for the rate difference. Subjects discontinued from the study due to any cause prior to Day 22 were considered as not developing SA pneumonia for the primary efficacy analysis.
    Protection of trial subjects
    No specific measures in place
    Background therapy
    		 No background therapy
    Evidence for comparator
    		 No comparator, placebo-controlled study design
    Actual start date of recruitment
    28 Nov 2016
    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
    Poland: 9
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Georgia: 65
    Country: Number of subjects enrolled
    Russian Federation: 42
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    India: 1
    Country: Number of subjects enrolled
    Serbia: 3
    Country: Number of subjects enrolled
    Israel: 4
    Worldwide total number of subjects
    155
    EEA total number of subjects
    18
    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)
    85
    From 65 to 84 years
    62
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were randomized at 35 centers in the United States, Austria, Czechia, France, India, Israel, Poland, Portugal, Romania, Serbia, Spain, Republic of Georgia, and Russian Federation

    Pre-assignment
    Screening details
    		 Eligible subjects underwent daily screening of endotracheal aspirates to determine if they met randomization criteria. Only randomized are included in the study analysis and summarized in the Participant Flow. A single subject was randomized in a site-specific pneumonia treatment sub-study and not included in the main study reporting (baseline).

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Active and placebo vials had identical appearance No unblinded site personnel, pharmacist also blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ASN100
    Arm description
    		 ASN100 administered as 2 separate intravenous (IV) infusions ASN100 3600 mg: monoclonal antibody combination of ASN-1 (1800 mg) and ASN-2 (1800 mg) [administered once]
    Arm type
    		 Experimental

    Investigational medicinal product name
    ASN100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single-dose administration ASN-1 and ASN-2 monoclonal antibody components provided in separate vials Sequential or simultaneous administration

    Arm title
    		 Placebo
    Arm description
    		 Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo [administered once]
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single-dose administration ASN-1 and ASN-2 placebos provided in separate vials Sequential or simultaneous administration

    Number of subjects in period 1 [1]
    		ASN100 Placebo
    Started
    77
    77
    Completed
    30
    42
    Not completed
    47
    35
         Consent withdrawn by subject
    1
    -
         Death
    40
    32
         Transfer to hospice care
    1
    -
         Received prohibitied concomitant medication
    -
    1
         Lost to follow-up
    5
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A single subject was randomized in a site-specific pneumonia treatment sub-study and not included in the reporting for the main, prevention study (baseline period).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ASN100
    Reporting group description
    		 ASN100 administered as 2 separate intravenous (IV) infusions ASN100 3600 mg: monoclonal antibody combination of ASN-1 (1800 mg) and ASN-2 (1800 mg) [administered once]

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo [administered once]

    Reporting group values
    		 ASN100 Placebo Total
    Number of subjects
    		 77 77 154
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 41 44 85
        From 65-84 years
    		 31 30 61
        85 years and over
    		 5 3 8
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.6 ( 16.97 ) 59.0 ( 17.44 ) -
    Gender categorical
    Units: Subjects
        Female
    		 27 26 53
        Male
    		 50 51 101
    Ethnicity
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 3 5
        Not Hispanic or Latino
    		 71 71 142
        Not reported
    		 2 3 5
        Uknown
    		 2 0 2
    Race
    Race of subject
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 1 0 1
        Black or African American
    		 1 2 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        White
    		 71 75 146
        Other
    		 4 0 4

    End points

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    End points reporting groups
    Reporting group title
    ASN100
    Reporting group description
    		 ASN100 administered as 2 separate intravenous (IV) infusions ASN100 3600 mg: monoclonal antibody combination of ASN-1 (1800 mg) and ASN-2 (1800 mg) [administered once]

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo [administered once]

    Primary: Efficacy of a Single Intravenous (IV) Dose of ASN100

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    End point title
    		 Efficacy of a Single Intravenous (IV) Dose of ASN100
    End point description
    Percentage of subjects in the MITT population who have or have not developed S. aureus (SA) pneumonia after a single intravenous (IV) dose of ASN100, based on sponsor defined outcome (SDO1). For each arm, the empirical proportion is defined by a ratio, which is the number of SA pneumonia events divided by the total number of subjects in the arm. The inference about the difference of two population rates is based on the empirical counterpart; specifically, the point estimate, 95% confidence interval and p-value for the rate difference. Subjects discontinued from the study due to any cause prior to Day 22 were considered as not developing SA pneumonia for the primary efficacy analysis.
    End point type
    Primary
    End point timeframe
    Up to but no including 22 days post-dosing
    End point values
    		 ASN100 Placebo
    Number of subjects analysed
    76
    76
    Units: Number of subjects
        Developed S. aureus Pneumonia
    5
    7
        Did Not Develop S. aureus Pneumonia
    42
    48
        Censored
    20
    17
        Indeterminate
    9
    4
    Statistical analysis title
    		 Group comparison for S. aureus pneumonia
    Statistical analysis description
    Subjects were analyzed for efficacy in the group to which they randomized. Sponsor defined outcomes were based on review of microbiology results from samples tested at the central lab. If sample was not sent to the central lab, determination was based on results from the local microbiology lab. In cases where both local & central lab results were available, concordance was confirmed for S. aureus. Therefore, the analysis used local microbiology data in order to utilize a more complete dataset.
    Comparison groups
    ASN100 v Placebo
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.547
    Method
    		 Wald Test on equality of proportions
    Confidence interval
    Notes
    [1] - Wald Test on equality of proportions

    Secondary: Duration of Mechanical Ventilation

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    End point title
    		 Duration of Mechanical Ventilation
    End point description
    Duration of mechanical ventilation during the first 21 days post-randomization for subjects in the Modified Intent-to-Treat (MITT) Population
    End point type
    Secondary
    End point timeframe
    21 days
    End point values
    		 ASN100 Placebo
    Number of subjects analysed
    73
    71
    Units: days
        arithmetic mean (standard deviation)
    11.6 ( 7.47 )
    10.1 ( 6.93 )
    No statistical analyses for this end point

    Secondary: Length of ICU Stay

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    End point title
    		 Length of ICU Stay
    End point description
    Total length of ICU stay during the first 21 days post-randomization for subjects in the MITT Population
    End point type
    Secondary
    End point timeframe
    Until day 21
    End point values
    		 ASN100 Placebo
    Number of subjects analysed
    74
    75
    Units: days
        arithmetic mean (standard deviation)
    13.7 ( 6.69 )
    13.6 ( 7.21 )
    No statistical analyses for this end point

    Secondary: 28-day All-cause Mortality

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    End point title
    		 28-day All-cause Mortality
    End point description
    28-day all-cause mortality in the MITT Population
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 ASN100 Placebo
    Number of subjects analysed
    76
    76
    Units: Subjects
    30
    25
    No statistical analyses for this end point

    Secondary: ASN-1 Maximum Serum Concentration (Cmax)

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    End point title
    		 ASN-1 Maximum Serum Concentration (Cmax) [2]
    End point description
    The levels of ASN-1 was measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 (final study visit) in subjects who are hospitalized or are able to return to the clinic for blood sampling.
    End point type
    Secondary
    End point timeframe
    Through day 90
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: ASN-1 and ASN-2 PK parameters are only reported for subjects receiving active ASN100 (i.e. ASN-1 + ASN-2 administered simultaneously or sequentially), as subjects receiving placebo do not have measurable ASN-1 and ASN-2 concentrations.
    End point values
    		 ASN100
    Number of subjects analysed
    71
    Units: microgram(s)/millilitre
        arithmetic mean (standard deviation)
    414.43 ( 125.55 )
    No statistical analyses for this end point

    Secondary: ASN-2 Maximum Serum Concentration (Cmax)

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    End point title
    		 ASN-2 Maximum Serum Concentration (Cmax) [3]
    End point description
    The levels of ASN-2 were measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 (final study visit) in subjects who are hospitalized or are able to return to the clinic for blood sampling.
    End point type
    Secondary
    End point timeframe
    Through day 90
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: ASN-1 and ASN-2 PK parameters are only reported for subjects receiving active ASN100 (i.e. ASN-1 + ASN-2 administered simultaneously or sequentially), as subjects receiving placebo do not have measurable ASN-1 and ASN-2 concentrations.
    End point values
    		 ASN100
    Number of subjects analysed
    73
    Units: microgram(s)/millilitre
        arithmetic mean (standard deviation)
    460.88 ( 149.76 )
    No statistical analyses for this end point

    Secondary: ASN-1 Time to Maximum Concentration (Tmax) in Serum

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    End point title
    		 ASN-1 Time to Maximum Concentration (Tmax) in Serum [4]
    End point description
    The levels of ASN-1 were measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion
    End point type
    Secondary
    End point timeframe
    Through day 90
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: ASN-1 and ASN-2 PK parameters are only reported for subjects receiving active ASN100 (i.e. ASN-1 + ASN-2 administered simultaneously or sequentially), as subjects receiving placebo do not have measurable ASN-1 and ASN-2 concentrations.
    End point values
    		 ASN100
    Number of subjects analysed
    71
    Units: hour
        arithmetic mean (standard deviation)
    6.34 ( 10.25 )
    No statistical analyses for this end point

    Secondary: ASN-2 Time to Maximum Concentration (Tmax) in Serum

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    End point title
    		 ASN-2 Time to Maximum Concentration (Tmax) in Serum [5]
    End point description
    The levels of ASN-2 were measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion
    End point type
    Secondary
    End point timeframe
    Through day 90
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: ASN-1 and ASN-2 PK parameters are only reported for subjects receiving active ASN100 (i.e. ASN-1 + ASN-2 administered simultaneously or sequentially), as subjects receiving placebo do not have measurable ASN-1 and ASN-2 concentrations.
    End point values
    		 ASN100
    Number of subjects analysed
    73
    Units: hour
        arithmetic mean (standard deviation)
    4.52 ( 5.77 )
    No statistical analyses for this end point

    Secondary: ASN-1 Area Under the Concentration-time Curve in Serum

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    End point title
    		 ASN-1 Area Under the Concentration-time Curve in Serum [6]
    End point description
    The levels of ASN-1 were measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion
    End point type
    Secondary
    End point timeframe
    Through day 90
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: ASN-1 and ASN-2 PK parameters are only reported for subjects receiving active ASN100 (i.e. ASN-1 + ASN-2 administered simultaneously or sequentially), as subjects receiving placebo do not have measurable ASN-1 and ASN-2 concentrations.
    End point values
    		 ASN100
    Number of subjects analysed
    71
    Units: μg*h/mL
        arithmetic mean (standard deviation)
    44192.3 ( 25080.9 )
    No statistical analyses for this end point

    Secondary: ASN-2 Area Under the Concentration-time Curve in Serum

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    End point title
    		 ASN-2 Area Under the Concentration-time Curve in Serum [7]
    End point description
    The levels of ASN-2 were measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion
    End point type
    Secondary
    End point timeframe
    Through day 90
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: ASN-1 and ASN-2 PK parameters are only reported for subjects receiving active ASN100 (i.e. ASN-1 + ASN-2 administered simultaneously or sequentially), as subjects receiving placebo do not have measurable ASN-1 and ASN-2 concentrations.
    End point values
    		 ASN100
    Number of subjects analysed
    73
    Units: μg*h/mL
        arithmetic mean (standard deviation)
    49366.7 ( 29337.9 )
    No statistical analyses for this end point

    Secondary: ASN-1 Terminal Elimination Half-life (t1/2) in Serum

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    End point title
    		 ASN-1 Terminal Elimination Half-life (t1/2) in Serum [8]
    End point description
    The levels of ASN-1 were measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion
    End point type
    Secondary
    End point timeframe
    Through day 90
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: ASN-1 and ASN-2 PK parameters are only reported for subjects receiving active ASN100 (i.e. ASN-1 + ASN-2 administered simultaneously or sequentially), as subjects receiving placebo do not have measurable ASN-1 and ASN-2 concentrations.
    End point values
    		 ASN100
    Number of subjects analysed
    54 [9]
    Units: hour
        arithmetic mean (standard deviation)
    178.9 ( 101.13 )
    Notes
    [9] - Only subjects with sufficient number of PK sampling time points analyzed
    No statistical analyses for this end point

    Secondary: ASN-2 Terminal Elimination Half-life (t1/2) in Serum

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    End point title
    		 ASN-2 Terminal Elimination Half-life (t1/2) in Serum [10]
    End point description
    The levels of ASN-2 were measured at completion of study medication infusion, and at 6 hr, 24 hr, Day 4, Day 7, Day 14, Day 22, and Day 90 after completion
    End point type
    Secondary
    End point timeframe
    Through day 90
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: ASN-1 and ASN-2 PK parameters are only reported for subjects receiving active ASN100 (i.e. ASN-1 + ASN-2 administered simultaneously or sequentially), as subjects receiving placebo do not have measurable ASN-1 and ASN-2 concentrations.
    End point values
    		 ASN100
    Number of subjects analysed
    58 [11]
    Units: hour
        arithmetic mean (standard deviation)
    185.1 ( 136.09 )
    Notes
    [11] - Only subjects with sufficient number of PK sampling time points analyzed
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    3 months. Adverse events (AEs) analyzed include treatment-emergent AEs, from the time of randomization through the Day 90 study visit (i.e. last study visit).
    Adverse event reporting additional description
    Only study procedure related AEs were to be reported from the time that informed consent was signed up to randomization, if they were considered to be study procedure related, however no such AEs were reported. Therefore, study procedure related AEs prior to randomization were not analyzed or reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    ASN100
    Reporting group description
    		 ASN100 administered as 2 separate intravenous (IV) infusions ASN100 3600 mg: monoclonal antibody combination of ASN-1(1800 mg) and ASN-2(1800 mg) [administered once]

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered as 2 separate intravenous (IV) infusions Placebo: Placebo [administered once]

    Serious adverse events
    		 ASN100 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 77 (63.64%)
    38 / 77 (49.35%)
         number of deaths (all causes)
    41
    32
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 77 (2.60%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Shock
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neurogenic shock
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (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
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 77 (1.30%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Death
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    3 / 77 (3.90%)
    6 / 77 (7.79%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 3
    0 / 5
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tracheal stenosis
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (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
    4 / 77 (5.19%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Craniocerebral injury
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Spinal shock
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    5 / 77 (6.49%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 5
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    2 / 77 (2.60%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Ventricular fibrillation
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiovascular insufficiency
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Ventricular asystole
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Left ventricular failure
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (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
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial haemorrhage
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ventricular rupture
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebral congestion
         subjects affected / exposed
    6 / 77 (7.79%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 6
    0 / 3
    Brain oedema
         subjects affected / exposed
    3 / 77 (3.90%)
    4 / 77 (5.19%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 4
    Coma
         subjects affected / exposed
    3 / 77 (3.90%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    3 / 77 (3.90%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Haemorrhagic transformation stroke
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 77 (2.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrospinal fluid circulation disorder
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Cirrhosis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    3 / 77 (3.90%)
    3 / 77 (3.90%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Pneumonia
    Additional description: Pneumonia, which was an endpoint for the trial, was only entered as an Adverse Event (AE) if it met serious reporting criteria (i.e. SAE)
         subjects affected / exposed
    3 / 77 (3.90%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Splenic abscess
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ASN100 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 77 (96.10%)
    69 / 77 (89.61%)
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 77 (1.30%)
    4 / 77 (5.19%)
         occurrences all number
    1
    4
    Vascular disorders
    Hypotension
         subjects affected / exposed
    18 / 77 (23.38%)
    17 / 77 (22.08%)
         occurrences all number
    18
    19
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    6 / 77 (7.79%)
    4 / 77 (5.19%)
         occurrences all number
    6
    4
    Tachycardia
         subjects affected / exposed
    5 / 77 (6.49%)
    5 / 77 (6.49%)
         occurrences all number
    5
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 77 (19.48%)
    11 / 77 (14.29%)
         occurrences all number
    17
    11
    Thrombocytopenia
         subjects affected / exposed
    5 / 77 (6.49%)
    2 / 77 (2.60%)
         occurrences all number
    5
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    17 / 77 (22.08%)
    8 / 77 (10.39%)
         occurrences all number
    25
    12
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 77 (3.90%)
    4 / 77 (5.19%)
         occurrences all number
    3
    4
    Diarrhoea
         subjects affected / exposed
    8 / 77 (10.39%)
    5 / 77 (6.49%)
         occurrences all number
    8
    7
    Respiratory, thoracic and mediastinal disorders
    Hydrothorax
         subjects affected / exposed
    6 / 77 (7.79%)
    3 / 77 (3.90%)
         occurrences all number
    9
    3
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    3 / 77 (3.90%)
    8 / 77 (10.39%)
         occurrences all number
    4
    9
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    8 / 77 (10.39%)
    5 / 77 (6.49%)
         occurrences all number
    8
    5
    Renal failure
         subjects affected / exposed
    2 / 77 (2.60%)
    4 / 77 (5.19%)
         occurrences all number
    2
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    8 / 77 (10.39%)
    5 / 77 (6.49%)
         occurrences all number
    8
    5
    Bronchitis bacterial
         subjects affected / exposed
    16 / 77 (20.78%)
    7 / 77 (9.09%)
         occurrences all number
    16
    7
    Sinusitis
         subjects affected / exposed
    4 / 77 (5.19%)
    2 / 77 (2.60%)
         occurrences all number
    4
    2
    Tracheobronchitis
         subjects affected / exposed
    5 / 77 (6.49%)
    7 / 77 (9.09%)
         occurrences all number
    7
    8
    Urinary tract infection
         subjects affected / exposed
    16 / 77 (20.78%)
    14 / 77 (18.18%)
         occurrences all number
    16
    14
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    5 / 77 (6.49%)
    4 / 77 (5.19%)
         occurrences all number
    5
    4
    Hyperkalaemia
         subjects affected / exposed
    7 / 77 (9.09%)
    6 / 77 (7.79%)
         occurrences all number
    9
    7
    Hypernatraemia
         subjects affected / exposed
    5 / 77 (6.49%)
    3 / 77 (3.90%)
         occurrences all number
    5
    4
    Hypoalbuminaemia
         subjects affected / exposed
    8 / 77 (10.39%)
    2 / 77 (2.60%)
         occurrences all number
    8
    2
    Hypocalcaemia
         subjects affected / exposed
    4 / 77 (5.19%)
    1 / 77 (1.30%)
         occurrences all number
    4
    1
    Hypokalaemia
         subjects affected / exposed
    9 / 77 (11.69%)
    6 / 77 (7.79%)
         occurrences all number
    10
    13
    Metabolic acidosis
         subjects affected / exposed
    8 / 77 (10.39%)
    3 / 77 (3.90%)
         occurrences all number
    9
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Nov 2016
    Revision of inclusion / exclusion criteria Addition of new exclusion criterion for patients with previous diagnosis of cytokine release syndrome Changes in clinical and microbiological assessments Change in statistical analysis / in adjustment for multiplicity procedures Clarification of sequential or simultaneous administration instructions, specification of time windows for IP administration in both cases Revision of excluded medications / any immunoglobulin preparation for any medical indication is prohibited through follow-up Day 90 of the study
    02 May 2017
    Revision of study definition of heavy S. aureus colonization to allow qualitative cultures ("For the purposes of this study, heavy colonization of S. aureus will be defined as a quantitative threshold of ≥10e5 CFU/mL or 3+ to 4+ by semi-quantitative culture from an endotracheal aspirate.") Revision of inclusion/exclusion criteria and minor adjustment of study endpoints Addition of subject enrollment option based on independent physicians' review, applicable in coutries where local legislation allows this, to harmonize global protocol with local versions Clarification and revision of randomization criteria Addition of nasal swab sampling at randomization Updates to clinical, laboratory and microbiology assessments Changes and clarifications related to the BAL PK sub-study , 25 to 35 subjects will be invited to participate in this sub-study, involving BAL sampling for PK analysis at 48 hrs post dosing (+/-36 hrs) Revision of pneumonia definition as study endpoint Addition of interim analysis after 125 patients completing follow-up Clarifications, Consistency, Update to chest x-ray / CT Scan requirements to allow standard of care imaging as specifiedűú Clarifications regarding imaging requirements during all phases of the study
    23 Apr 2018
    Site-specific amendment to allow randomization of subjects with S. aureus VAP diagnosis into a treatment sub-study Added description of VAP treatment sub-study purpose, rationale and analysis Revised study objectives, inclusion/exclusion and randomization criteria; study procedures updated to reflect the inclusion of subjects into a VAP treatment sub-study Updates in assessments, clinical and microbiological outcome determination and statistical analysis to reflect the inclusion of subjects with VAP diagnosis Related updates to schedule of assessment table

    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.
    An interim analysis of 118 subjects was performed by a DRC to assess S. aureus pneumonia rates and the conditional power to detect a statistically significant treatment effect at study completion (354 subjects). The study was terminated for futility.
    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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