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    Clinical Trial Results:
    Phase III, randomized, double-blind, placebo controlled, parallel-group, study of AB103 as compared to placebo in patients with necrotizing soft tissue infections (NSTI)

    Summary
    EudraCT number
    		 2018-001125-15
    Trial protocol
    		 FR  
    Global end of trial date
    18 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ATB-202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02469857
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Atox Bio Ltd.
    Sponsor organisation address
    8 Pinhas Sapir St., Ness Ziona, Israel, 7403631
    Public contact
    Wayne M. Dankner, MD, Atox Bio Ltd., 1 9194393400, wayned@atoxbio.com
    Scientific contact
    Wayne M. Dankner, MD, Atox Bio Ltd., 1 9192196377, wayned@atoxbio.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
    17 Aug 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of AB103 as compared to placebo, in patients diagnosed with NSTI, using a clinical composite success endpoint (NICCE score)
    Protection of trial subjects
    Good clinical practices were utilized in the conduct of this trial, including appropriate informed consent procedures and required documentation and reporting of adverse events. Safety data obtained during study visits associated with Study Days 1, 2, 3, 7, 10, 14, 21, and 28 were systematically assessed throughout the study. In addition, data from spontaneously reported AEs were included in safety assessments. Data associated with deaths and study drug-related serious adverse events (SAEs) were collected from study drug administration though the Day 90 visit.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 273
    Country: Number of subjects enrolled
    France: 17
    Worldwide total number of subjects
    290
    EEA total number of subjects
    17
    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)
    212
    From 65 to 84 years
    72
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 Initiation of clinical investigative sites in the US began in September 2015 and new sites were recruited and initiated through November 2018. The last sites to be initiated were in France. Since NSTI is an acute life-threatening infection patients were only identified at the time of hospital presentation and not recruited pre-hospital admission.

    Pre-assignment
    Screening details
    		 Screening started once a clinical diagnosis of NSTI was entertained and a decision for urgent surgical wound exploration and debridement was made. A total of 319 patients were randomized; however, 29 patients were not dosed (did not have NSTI or failed reassessment of eligibility criteria).

    Pre-assignment period milestones
    Number of subjects started
    		 319 [1]
    Intermediate milestone: Number of subjects
    Randomized and Treated: 290
    Number of subjects completed
    		 290

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did not have NSTI or did not meet entry criteria: 29
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The clinical sites had only 6 hours from time of decision to take a patient with suspected NSTI to the OR and obtain surgical confirmation of NSTI to initiate infusion of study drug. Given this very short timeline and the critical need to get pts to the OR to avoid further progression of disease, sites were allowed to randomize subjects so that study drug could be ready once surgical confirmation of NSTI disease was obtained. If no NSTI then pts were considered screen failures and not dosed.
    Period 1
    Period 1 title
    Treatment and Follow Up (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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Reltecimod 0.5 mg/kg
    Arm description
    		 Reltecimod 0.5 mg/kg total body weight administered once as an intravenous infusion over approximately 10 minutes
    Arm type
    		 Experimental

    Investigational medicinal product name
    Reltecimod
    Investigational medicinal product code
    Other name
    AB-102
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Each vial contains 10.5 mg of Reltecimod. Prior to use, each vial of drug product (10.5 mg Reltecimod) is reconstituted in 10.5 mL of water for injection to generate a peptide concentration of 1 mg/mL. The reconstituted drug product is administered directly and is not diluted prior to administration. To prepare the drug quantity needed for infusion, the contents of several vials are pooled together by the study pharmacist (or unblinded study-nurse/physician if performing study drug preparation at individual institution), under sterile conditions plus adequate priming volume of the IV line. The number of vials would depend on the patient's weight, in order to achieve a dose of 0.5 mg/kg. The Reltecimod drug product will be administered at a dose of 0.5 mg/kg via a syringe pump in a separate catheter as a single intravenous infusion given over 10 minutes.

    Arm title
    		 Placebo
    Arm description
    		 Normal saline (0.9% sodium chloride solution) administered once as an intravenous infusion over approximately 10 minutes
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% Sterile Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    Placebo will be pyrogen-free, preservative-free sterile 0.9% saline, USP administered as a single infusion at a volume calculated and based on patient weight, 0.5 mL/kg (a volume equivalent with Reltecimod dosing schema), plus adequate priming volume of the IV line.

    Number of subjects in period 1
    		Reltecimod 0.5 mg/kg Placebo
    Started
    143
    147
    Completed
    142
    144
    Not completed
    1
    3
         Consent withdrawn by subject
    -
    1
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Reltecimod 0.5 mg/kg
    Reporting group description
    		 Reltecimod 0.5 mg/kg total body weight administered once as an intravenous infusion over approximately 10 minutes

    Reporting group title
    Placebo
    Reporting group description
    		 Normal saline (0.9% sodium chloride solution) administered once as an intravenous infusion over approximately 10 minutes

    Reporting group values
    		 Reltecimod 0.5 mg/kg Placebo Total
    Number of subjects
    		 143 147 290
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.4 ( 15.3 ) 56.3 ( 15.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 58 59 117
        Male
    		 85 88 173
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 10 11 21
        Not Hispanic or Latino
    		 131 133 264
        Missing
    		 2 3 5
    Race
    Units: Subjects
        White
    		 106 110 216
        Black or African American
    		 23 24 47
        American Indian or Alaska Native
    		 3 2 5
        Asian
    		 2 0 2
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Other
    		 4 4 8
        Missing
    		 5 6 11
    Region of Enrollment
    This characteristic represents the two countries from which patients were enrolled into this study and received study drug (i.e., United States and France).
    Units: Subjects
        United States
    		 135 138 273
        France
    		 8 9 17
    NSTI Diagnosis
    Units: Subjects
        Necrotizing Fasciitis
    		 96 95 191
        Fournier's Gangrene
    		 43 40 83
        Gas Gangrene/Myonecrosis
    		 1 4 5
        Other NSTI
    		 3 8 11
    Comorbidities: Diabetes
    Units: Subjects
        Diabetes
    		 64 59 123
        No Diabetes
    		 79 88 167
    Sepsis Presentation: Cardiovascular Organ Failure
    Sepsis presentation focuses on the number of patients with cardiovascular failure and the number of patients with respiratory failure at baseline. Some patients had both cardiovascular and respiratory failure at baseline, some patients had either cardiovascular or respiratory failure at baseline, and some patients had neither at baseline. Categories are NOT mutually exclusive.
    Units: Subjects
        Cardiovascular Organ Failure
    		 81 62 143
        No Cardiovascular Organ Failure
    		 62 85 147
    Acute Kidney Injury (AKI) Presentation
    Sepsis presentation focuses on the number of patients with cardiovascular failure and the number of patients with respiratory failure at baseline. Some patients had both cardiovascular and respiratory failure at baseline, some patients had either cardiovascular or respiratory failure at baseline, and some patients had neither at baseline.
    Units: Subjects
        Any AKI at Screening
    		 87 103 190
        No AKI at Screening
    		 56 44 100
    Sepsis Presentation: Respiratory Organ Failure
    Sepsis presentation focuses on the number of patients with cardiovascular failure and the number of patients with respiratory failure at baseline. Some patients had both cardiovascular and respiratory failure at baseline, some patients had either cardiovascular or respiratory failure at baseline, and some patients had neither at baseline.
    Units: Subjects
        Respiratory Organ Failure
    		 19 11 30
        No Respiratory Organ Failure
    		 124 136 260
    Comorbidities: Cardiovascular Disease
    Units: Subjects
        Cardiovascular Disease
    		 37 28 65
        No Cardiovascular Disease
    		 106 119 225
    Body Mass Index (BMI)
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 31.4 ( 8.3 ) 33.7 ( 8.3 ) -
    Modified Sequential Organ Failure Assessment (mSOFA) Score
    Modified Sequential Organ Failure Assessment (mSOFA) total scores range from 0 to 20, with higher scores reflecting a worse clinical status or outcome. An mSOFA total score of 0 or 1 reflects resolution of organ dysfunction/failure.
    Units: none
        arithmetic mean (standard deviation)
    		 5.6 ( 2.5 ) 5.4 ( 2.2 ) -
    Acute Physiology and Chronic Health Evaluation II (APACHE II) Score
    The Acute Physiology and Chronic Health Evaluation (APACHE) Score is a severity of illness classification system. It is determined within 24 hours of admission of a patient to an intensive care unit (ICU): an integer score from 0 to 71 is computed based on several measurements (physiologic variables, age, chronic health status). Higher scores correspond to more severe disease and a greater risk of death.
    Units: none
        arithmetic mean (standard deviation)
    		 16.4 ( 6.8 ) 16.4 ( 6.6 ) -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (FAS)-Reltecimod
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set: The FAS was used in primary efficacy analyses and included patients in the mITT analysis set assigned according to actual treatment received, and excluding patients with significant pre-randomization violations of inclusion/exclusion criteria that prevent patients from achieving the primary endpoint or that substantially confound estimates of drug effects

    Subject analysis set title
    Full Analysis Set (FAS)-Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set: The FAS was used in primary efficacy analyses and included patients in the mITT analysis set assigned according to actual treatment received, and excluding patients with significant pre-randomization violations of inclusion/exclusion criteria that prevent patients from achieving the primary endpoint or that substantially confound estimates of drug effects

    Subject analysis sets values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects
    133
    144
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.3 ( 15.4 )
    56.5 ( 14.9 )
    Gender categorical
    Units: Subjects
        Female
    55
    59
        Male
    78
    85
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    8
    11
        Not Hispanic or Latino
    123
    130
        Missing
    2
    3
    Race
    Units: Subjects
        White
    97
    108
        Black or African American
    22
    23
        American Indian or Alaska Native
    3
    2
        Asian
    2
    0
        Native Hawaiian or Other Pacific Islander
    0
    1
        Other
    4
    4
        Missing
    5
    6
    Region of Enrollment
    This characteristic represents the two countries from which patients were enrolled into this study and received study drug (i.e., United States and France).
    Units: Subjects
        United States
    126
    135
        France
    7
    9
    NSTI Diagnosis
    Units: Subjects
        Necrotizing Fasciitis
    88
    93
        Fournier's Gangrene
    41
    39
        Gas Gangrene/Myonecrosis
    1
    4
        Other NSTI
    3
    8
    Comorbidities: Diabetes
    Units: Subjects
        Diabetes
    57
    58
        No Diabetes
    76
    86
    Sepsis Presentation: Cardiovascular Organ Failure
    Sepsis presentation focuses on the number of patients with cardiovascular failure and the number of patients with respiratory failure at baseline. Some patients had both cardiovascular and respiratory failure at baseline, some patients had either cardiovascular or respiratory failure at baseline, and some patients had neither at baseline. Categories are NOT mutually exclusive.
    Units: Subjects
        Cardiovascular Organ Failure
    80
    62
        No Cardiovascular Organ Failure
    53
    82
    Acute Kidney Injury (AKI) Presentation
    Sepsis presentation focuses on the number of patients with cardiovascular failure and the number of patients with respiratory failure at baseline. Some patients had both cardiovascular and respiratory failure at baseline, some patients had either cardiovascular or respiratory failure at baseline, and some patients had neither at baseline.
    Units: Subjects
        Any AKI at Screening
    82
    102
        No AKI at Screening
    51
    42
    Sepsis Presentation: Respiratory Organ Failure
    Sepsis presentation focuses on the number of patients with cardiovascular failure and the number of patients with respiratory failure at baseline. Some patients had both cardiovascular and respiratory failure at baseline, some patients had either cardiovascular or respiratory failure at baseline, and some patients had neither at baseline.
    Units: Subjects
        Respiratory Organ Failure
    19
    11
        No Respiratory Organ Failure
    114
    133
    Comorbidities: Cardiovascular Disease
    Units: Subjects
        Cardiovascular Disease
    34
    28
        No Cardiovascular Disease
    99
    116
    Body Mass Index (BMI)
    Units: kg/m2
        arithmetic mean (standard deviation)
    31.3 ( 8.4 )
    33.7 ( 8.4 )
    Modified Sequential Organ Failure Assessment (mSOFA) Score
    Modified Sequential Organ Failure Assessment (mSOFA) total scores range from 0 to 20, with higher scores reflecting a worse clinical status or outcome. An mSOFA total score of 0 or 1 reflects resolution of organ dysfunction/failure.
    Units: none
        arithmetic mean (standard deviation)
    5.6 ( 2.5 )
    5.5 ( 2.2 )
    Acute Physiology and Chronic Health Evaluation II (APACHE II) Score
    The Acute Physiology and Chronic Health Evaluation (APACHE) Score is a severity of illness classification system. It is determined within 24 hours of admission of a patient to an intensive care unit (ICU): an integer score from 0 to 71 is computed based on several measurements (physiologic variables, age, chronic health status). Higher scores correspond to more severe disease and a greater risk of death.
    Units: none
        arithmetic mean (standard deviation)
    16.4 ( 6.8 )
    16.6 ( 6.5 )

    End points

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    End points reporting groups
    Reporting group title
    Reltecimod 0.5 mg/kg
    Reporting group description
    		 Reltecimod 0.5 mg/kg total body weight administered once as an intravenous infusion over approximately 10 minutes

    Reporting group title
    Placebo
    Reporting group description
    		 Normal saline (0.9% sodium chloride solution) administered once as an intravenous infusion over approximately 10 minutes

    Subject analysis set title
    Full Analysis Set (FAS)-Reltecimod
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set: The FAS was used in primary efficacy analyses and included patients in the mITT analysis set assigned according to actual treatment received, and excluding patients with significant pre-randomization violations of inclusion/exclusion criteria that prevent patients from achieving the primary endpoint or that substantially confound estimates of drug effects

    Subject analysis set title
    Full Analysis Set (FAS)-Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set: The FAS was used in primary efficacy analyses and included patients in the mITT analysis set assigned according to actual treatment received, and excluding patients with significant pre-randomization violations of inclusion/exclusion criteria that prevent patients from achieving the primary endpoint or that substantially confound estimates of drug effects

    Primary: Necrotizing Infections Clinical Composite Endpoint (NICCE)

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    End point title
    		 Necrotizing Infections Clinical Composite Endpoint (NICCE)
    End point description
    Necrotizing Infections Clinical Composite Endpoint (NICCE) was made up of the following 5 components, all of which had to be met to successfully achieve the primary outcome measure: (i) Alive at Day 28, (ii) ≤ 3 debridements through Day 14, (iii) No amputation performed after the first debridement, (iv) Day 14 modified Sequential Organ Failure Assessment (mSOFA) score ≤ 1, and (v) Reduction of ≥ 3 mSOFA score points between Baseline and Day 14. This analysis was done in the modified intent-to-treat analysis set (mITT) (i.e., all randomized patients who were exposed to study drug [reltecimod or placebo] and who had a confirmed surgical diagnosis of NSTI, with patients analyzed according to their randomized treatment assignment) and in the Full Analysis Set (FAS) (patients who met the mITT criteria but who did not have a violation of an inclusion or exclusion criterion that prevented achievement of the primary efficacy endpoint and were analyzed according to treatment received.
    End point type
    Primary
    End point timeframe
    28 days
    End point values
    		 Reltecimod 0.5 mg/kg Placebo Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    143
    147
    133
    144
    Units: subjects
    69
    59
    70
    58
    Statistical analysis title
    		 Primary Efficacy Analysis (NICCE-mITT population )
    Statistical analysis description
    Responder analysis with success assigned as patients meeting all the 5 components of the composite endpoint and failure assigned as patients not meeting any one or more of the 5 components of the composite endpoint.
    Comparison groups
    Reltecimod 0.5 mg/kg v Placebo
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.135
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 23.7
    Statistical analysis title
    		 Primary Efficacy Analysis (NICCE-FAS Population)
    Statistical analysis description
    Responder analysis with success assigned as patients meeting all the 5 components of the composite endpoint and failure assigned as patients not meeting any one or more of the 5 components of the composite endpoint.
    Comparison groups
    Full Analysis Set (FAS)-Reltecimod v Full Analysis Set (FAS)-Placebo
    Number of subjects included in analysis
    277
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.039
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    12.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 24

    Secondary: Intensive care unit (ICU)-free Days

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    End point title
    		 Intensive care unit (ICU)-free Days
    End point description
    Days that patents are alive and not in the ICU calculated using a 28 day period from receipt of study medication. More free days is considered a positive outcome
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    133
    144
    Units: Days
        median (full range (min-max))
    20 (0 to 28)
    18 (0 to 28)
    No statistical analyses for this end point

    Secondary: Ventilator-free days

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    End point title
    		 Ventilator-free days
    End point description
    Days that patient are alive and not requiring mechanical ventilation support calculated over a 28 day period from receipt of study medication. More free days is considered a positive outcome.
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    133
    144
    Units: Days
        median (full range (min-max))
    22 (0 to 28)
    21 (0 to 28)
    No statistical analyses for this end point

    Secondary: Hospital Days

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    End point title
    		 Hospital Days
    End point description
    Number of days that the patient is hospitalized with less hospital days considered the desired outcome
    End point type
    Secondary
    End point timeframe
    Duration of hospitalization
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    133
    144
    Units: Days
        median (full range (min-max))
    19 (1 to 103)
    20 (2 to 135)
    No statistical analyses for this end point

    Secondary: Hospital Discharge Location

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    End point title
    		 Hospital Discharge Location
    End point description
    Number of patients with favorable discharge location (home or rehabilitation facility) or less than favorable discharge location (skilled nursing facility, another acute care facility, death, other)
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    133
    144
    Units: Patients
        Favorable Discharge Location
    81
    71
        Less Than Favorable Discharge Location
    52
    73
    Statistical analysis title
    		 Hospital Discharge Location
    Statistical analysis description
    Comparison of reltecimod versus placebo by Favorable Discharge Location
    Comparison groups
    Full Analysis Set (FAS)-Reltecimod v Full Analysis Set (FAS)-Placebo
    Number of subjects included in analysis
    277
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.053
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Day 0 Through Day 90 Mortality

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    End point title
    		 Day 0 Through Day 90 Mortality
    End point description
    Cumulative mortality (number of deaths) occurring from Day 0 through Day 90
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    133
    144
    Units: Patients
    22
    29
    Statistical analysis title
    		 Cumulative Mortality Day 0-90
    Comparison groups
    Full Analysis Set (FAS)-Reltecimod v Full Analysis Set (FAS)-Placebo
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.43
    Notes
    [1] - Study was not powered to assess Day 0-90 mortality rate comparison between reltecimod and placebo. Provide hazard ratio with 95% CIs.

    Secondary: Day 14 mSOFA <=1

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    End point title
    		 Day 14 mSOFA <=1
    End point description
    Patients achieving resolution of organ dysfunction at Day 14, defined as a mSOFA score <=1
    End point type
    Secondary
    End point timeframe
    14 Days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    133 [2]
    144 [3]
    Units: Patients
    89
    79
    Notes
    [2] - Reltecimod patients in FAS analysis set
    [3] - Placebo patients in FAS analysis set
    Statistical analysis title
    		 Day 14 mSOFA <=1
    Comparison groups
    Full Analysis Set (FAS)-Reltecimod v Full Analysis Set (FAS)-Placebo
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.04
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    12.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 23.5

    Other pre-specified: NICCE in Patients with Baseline mSOFA >=5

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    End point title
    		 NICCE in Patients with Baseline mSOFA >=5
    End point description
    Necrotizing Infections Clinical Composite Endpoint (NICCE) was made up of the following 5 components, all of which had to be met to successfully achieve the primary outcome measure: (i) Alive at Day 28, (ii) ≤ 3 debridements through Day 14, (iii) No amputation performed after the first debridement, (iv) Day 14 modified Sequential Organ Failure Assessment (mSOFA) score ≤ 1, and (v) Reduction of ≥ 3 mSOFA score points between Baseline and Day 14.
    End point type
    Other pre-specified
    End point timeframe
    28 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    78 [4]
    87 [5]
    Units: Patients
    40
    32
    Notes
    [4] - Reltecimod patients in FAS with mSOFA >=5 at baseline
    [5] - Placebo patients in FAS with mSOFA >=5 at baseline
    Statistical analysis title
    		 NICCE analysis
    Statistical analysis description
    Responder analysis with success assigned as patients meeting all the 5 components of the composite endpoint and failure assigned as patients not meeting any one or more of the 5 components of the composite endpoint.
    Comparison groups
    Full Analysis Set (FAS)-Reltecimod v Full Analysis Set (FAS)-Placebo
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.061
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    14.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 29.5

    Other pre-specified: NICCE Among Patients with Shock at Baseline

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    End point title
    		 NICCE Among Patients with Shock at Baseline
    End point description
    Necrotizing Infections Clinical Composite Endpoint (NICCE) was made up of the following 5 components, all of which had to be met to successfully achieve the primary outcome measure: (i) Alive at Day 28, (ii) ≤ 3 debridements through Day 14, (iii) No amputation performed after the first debridement, (iv) Day 14 modified Sequential Organ Failure Assessment (mSOFA) score ≤ 1, and (v) Reduction of ≥ 3 mSOFA score points between Baseline and Day 14.
    End point type
    Other pre-specified
    End point timeframe
    28 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    80 [6]
    62 [7]
    Units: Patients
    40
    24
    Notes
    [6] - Reltecimod patients in FAS with shock at basline
    [7] - Placebo patients in FAS with shock at baseline
    Statistical analysis title
    		 NICCE analysis
    Statistical analysis description
    Responder analysis with success assigned as patients meeting all the 5 components of the composite endpoint and failure assigned as patients not meeting any one or more of the 5 components of the composite endpoint.
    Comparison groups
    Full Analysis Set (FAS)-Reltecimod v Full Analysis Set (FAS)-Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.18
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    11.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 27.6
    Notes
    [8] - Study not powered for comparison of reltecimod and placebo groups in patients with shock at baseline

    Post-hoc: Day 14 Through Day 90 Mortality

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    End point title
    		 Day 14 Through Day 90 Mortality
    End point description
    Cumulative mortality (number of deaths) from Day 14 through Day 90
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    118 [9]
    130
    Units: Patients
    7
    15
    Notes
    [9] - Reltecimod patients in FAS alive at Day 14
    Statistical analysis title
    		 Day 14-90 Cumulative Mortality
    Statistical analysis description
    Study not powered to perform comparison of Day 14-90 mortality between reltecimod and placebo. Used hazard ratio for comparison.
    Comparison groups
    Full Analysis Set (FAS)-Reltecimod v Full Analysis Set (FAS)-Placebo
    Number of subjects included in analysis
    248
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 1.21

    Post-hoc: Day 0 Through Day 90 Mortality in Patients with Baseline mSOFA >=5

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    End point title
    		 Day 0 Through Day 90 Mortality in Patients with Baseline mSOFA >=5
    End point description
    Cumulative mortality (number of deaths) from Day 0 through Day 90 in patients with baseline mSOFA >=5
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    78 [10]
    87 [11]
    Units: Patients
    14
    19
    Notes
    [10] - Reltecimod patients in FAS with mSOFA >=5 at baseline
    [11] - Placebo patients in FAS with mSOFA >=5 at baseline
    Statistical analysis title
    		 Cumulative Mortality Day 0-90
    Comparison groups
    Full Analysis Set (FAS)-Reltecimod v Full Analysis Set (FAS)-Placebo
    Number of subjects included in analysis
    165
    Analysis specification
    Post-hoc
    Analysis type
    		 other [12]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.68
    Notes
    [12] - Study was not powered to assess Day 0-90 mortality rate comparison between reltecimod and placebo. Provide hazard ratio with 95% CIs.

    Post-hoc: Day 14 Through Day 90 Mortality in Patients with Baseline mSOFA >=5

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    End point title
    		 Day 14 Through Day 90 Mortality in Patients with Baseline mSOFA >=5
    End point description
    Cumulative mortality (number of deaths) from Day 14 to Day 90 in patients with baseline mSOFA >=5
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    66 [13]
    77 [14]
    Units: Patients
    2
    9
    Notes
    [13] - Reltecimod patients in FAS with mSOFA >=5 at baseline and alive at Day 14
    [14] - Placebo patients in FAS with mSOFA >=5 at baseline and alive at Day 14
    Statistical analysis title
    		 Cumulative Mortality Day 14-90
    Comparison groups
    Full Analysis Set (FAS)-Reltecimod v Full Analysis Set (FAS)-Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Post-hoc
    Analysis type
    		 other [15]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 1.15
    Notes
    [15] - Study was not powered to assess Day 14-90 mortality rate comparison between reltecimod and placebo. Provide hazard ratio with 95% CIs.

    Post-hoc: Day 14 mSOFA <=1 in Patients with Baseline mSOFA >=5

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    End point title
    		 Day 14 mSOFA <=1 in Patients with Baseline mSOFA >=5
    End point description
    Patients achieving resolution of organ dysfunction at Day 14, defined as mSOFA score <=1
    End point type
    Post-hoc
    End point timeframe
    14 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    78 [16]
    87 [17]
    Units: Patients
    47
    36
    Notes
    [16] - Reltecimod patients in FAS with mSOFA >=5 at baseline
    [17] - Placebo patients in FAS with mSOFA >=5 at baseline
    Statistical analysis title
    		 Day 14 mSOFA <=1
    Statistical analysis description
    Responder analysis comparing number of patients achieving Day 14 mSOFA <=1 in reltecimod group vs placebo group
    Comparison groups
    Full Analysis Set (FAS)-Placebo v Full Analysis Set (FAS)-Reltecimod
    Number of subjects included in analysis
    165
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.015
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    18.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.9
         upper limit
    		 33.9

    Post-hoc: Day 14 mSOFA <=1 in Patients with Shock at Baseline

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    End point title
    		 Day 14 mSOFA <=1 in Patients with Shock at Baseline
    End point description
    Patients achieving resolution of organ dysfunction at Day 14, defined as mSOFA <=1.
    End point type
    Post-hoc
    End point timeframe
    14 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    80 [18]
    62 [19]
    Units: Patients
    51
    27
    Notes
    [18] - Reltecimod patients in FAS with shock at baseline
    [19] - Placebo patient in FAS with mSOFA >=5 at baseline
    Statistical analysis title
    		 Day 14 mSOFA <=1
    Statistical analysis description
    Responder analysis comparing number of patients achieving Day 14 mSOFA <=1 in reltecimod group vs placebo group
    Comparison groups
    Full Analysis Set (FAS)-Reltecimod v Full Analysis Set (FAS)-Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.016
    Method
    		 Chi-squared
    Parameter type
    		 Mean difference (final values)
    Point estimate
    20.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4
         upper limit
    		 36.4

    Post-hoc: Day 0 Through Day 90 Mortality Among Patients with Shock at Baseline

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    End point title
    		 Day 0 Through Day 90 Mortality Among Patients with Shock at Baseline
    End point description
    Cumulative mortality (number of deaths) occurring from Day 0 through Day 90
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    80 [20]
    62 [21]
    Units: Patients
    14
    15
    Notes
    [20] - Reltecimod patients in FAS with shock at baseline
    [21] - Placebo patients in FAS with shock at baseline
    Statistical analysis title
    		 Cumulative Mortality Day 0-90
    Comparison groups
    Full Analysis Set (FAS)-Reltecimod v Full Analysis Set (FAS)-Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Post-hoc
    Analysis type
    		 other [22]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1.52
    Notes
    [22] - Study was not powered to assess Day 0-90 mortality rate comparison between reltecimod and placebo. Provide hazard ratio with 95% CIs.

    Post-hoc: Day 14 Through Day 90 Mortality Among Patients with Shock at Baseline

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    End point title
    		 Day 14 Through Day 90 Mortality Among Patients with Shock at Baseline
    End point description
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Full Analysis Set (FAS)-Reltecimod Full Analysis Set (FAS)-Placebo
    Number of subjects analysed
    68 [23]
    54 [24]
    Units: Patients
    2
    7
    Notes
    [23] - Reltecimod patients in FAS with shock at baseline and alive at Day 14
    [24] - Placebo patients in FAS with shock at baseline and alive at Day 14
    Statistical analysis title
    		 Cumulative Mortality Day 14-90
    Comparison groups
    Full Analysis Set (FAS)-Reltecimod v Full Analysis Set (FAS)-Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Post-hoc
    Analysis type
    		 other [25]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 1.04
    Notes
    [25] - Study was not powered to assess Day 0-90 mortality rate comparison between reltecimod and placebo. Provide hazard ratio with 95% CIs.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event (AE) data were collected on Study Days 1, 2, 3, 7, 10, 14, 21, and 28 and via spontaneous reporting. Data associated with deaths and study drug-related serious adverse events (SAEs) were collected though the Day 90 visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Reltecimod 0.5 mg/kg (As Treated)
    Reporting group description
    		 -

    Reporting group title
    Placebo (As Treated)
    Reporting group description
    		 -

    Serious adverse events
    		 Reltecimod 0.5 mg/kg (As Treated) Placebo (As Treated)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 143 (30.77%)
    40 / 147 (27.21%)
         number of deaths (all causes)
    24
    29
         number of deaths resulting from adverse events
    21
    24
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 143 (0.70%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant hypertension
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Leg amputation
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Organ failure
         subjects affected / exposed
    2 / 143 (1.40%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute lung injury
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 143 (1.40%)
    4 / 147 (2.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchopleural fistula
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         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 / 143 (0.70%)
    0 / 147 (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
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 143 (1.40%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 143 (1.40%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 143 (1.40%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    4 / 143 (2.80%)
    4 / 147 (2.72%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery perforation
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary valve incompetence
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulseless electrical activity
         subjects affected / exposed
    3 / 143 (2.10%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Seizure
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal compartment syndrome
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colitis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 143 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intestinal infarction
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 143 (0.00%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Hepatic function abnormal
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Liver disorder
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin discolouration
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 143 (2.80%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Funguria
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Necrotising fasciitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Necrotising soft tissue infection
         subjects affected / exposed
    3 / 143 (2.10%)
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 3
    Pneumonia
         subjects affected / exposed
    3 / 143 (2.10%)
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 143 (0.70%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Septic shock
         subjects affected / exposed
    3 / 143 (2.10%)
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Wound infection
         subjects affected / exposed
    2 / 143 (1.40%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 147 (0.68%)
         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
    		 Reltecimod 0.5 mg/kg (As Treated) Placebo (As Treated)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 143 (18.18%)
    33 / 147 (22.45%)
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    7 / 143 (4.90%)
    8 / 147 (5.44%)
         occurrences all number
    7
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 143 (5.59%)
    6 / 147 (4.08%)
         occurrences all number
    10
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 143 (4.20%)
    8 / 147 (5.44%)
         occurrences all number
    6
    8
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 143 (3.50%)
    11 / 147 (7.48%)
         occurrences all number
    5
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Nov 2016
    Primary revisions include the following: * Change of weight to BMI for exclusion criterion #1. * Addition of Observational Sub-Study of Pre-operative mSOFA = 2 which increases to mSOFA ≥ 3 Postoperatively: The addition of the sub-study for patients with mSOFA = 2 pre-operatively is to assess the percentage of patients who achieve mSOFA ≥ 3 post-operatively but still within 6 hours from the clinical diagnosis (the decision at the study site, to have an urgent surgical exploration and debridement). This sub-study is only for data collection, not intervention. These subjects will still be considered screen failures and will not be randomized to receive blinded study drug. Data will be collected at screening (both pre and postoperatively), day 7 or 10, day 14 and day 29. NICCE outcome will be evaluated to assess comparability to patients with mSOFA ≥ 3 pre-operatively. There have been 55 patients captured on the pre-screening logs with mSOFA = 2 over 8-9 months of study. If the patients are comparable from the sub-study, then there would be consideration for adding this patient group to those eligible to be randomized into the Phase 3 trial, which could increase study accrual by 30-40 patients per year. Since the sub-study is observational, it will not affect the efficacy population nor the endpoints. Inclusion criteria 3 [mSOFA score ≥3 (in any one or combination of the 5 major components of SOFA score with one organ component having a score of at least 2: cardiovascular, respiratory, renal, coagulation, CNS), measured as close as possible to the first debridement, (but before first debridement is performed)] is not changing. As such patients from this observational cohort will still be considered to be screen failures and not be included in the safety or efficacy analysis since the MITT population for this trial only includes patients who are randomized and treated with blinded study drug.
    23 Aug 2018
    Primary revisions include the following: * Addition of serum samples for immunogenicity testing: Meet regulatory guidance for immunogenicity testing for peptide molecules. *Study Drug Administration: Added study drug may be manually pushed if approved by the medical monitor, in addition to study drug being administered using a syringe pump. For previous studies with AB103, medical monitor has provided Notes to File to manually push study drug if syringe pump is unavailable or has a malfunction. * Addition of study sites in France: Added sites in France to enhance study enrollment and include EU patients.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32657946
    http://www.ncbi.nlm.nih.gov/pubmed/33797490
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