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    Clinical Trial Results:
    A prospective, randomized, open-label, interventional study to investigate the efficacy of complement C5 inhibition with Zilucoplan® in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure.

    Summary
    EudraCT number
    2020-002130-33
    Trial protocol
    BE  
    Global end of trial date
    09 Apr 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Jun 2022
    First version publication date
    04 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ZILU-COV
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04382755
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UZ Gent
    Sponsor organisation address
    C. Heymanlaan 10, Ghent, Belgium, 9000
    Public contact
    HIRUZ CTU, University Hospital Ghent, +32 93320500, hiruz.ctu@uzgent.be
    Scientific contact
    HIRUZ CTU, University Hospital Ghent, 093322352 93320500, hiruz.ctu@uzgent.be
    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
    12 Oct 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this intervention is to study if Zilucoplan® affects the the median and/or mean change in oxygenation between enrolment (baseline) and at predose day 6 and day 15 (or discharge, whichever comes first) through assessment of the PaO2/FiO2 ratio and through measurement of the P(A-a)O2 gradient, which can easily be performed in the setting of clinical observation of patients admitted to the COVID-19 ward or ICU COVID-19 unit. For patients on ECMO the PaO2/FiO2 ratio and Aa-gradient cannot be calculated as in this case the FiO2 will be missing. Therefore, the last available value of PaO2/FiO2 ratio and Aa gradient prior to ECMO can be used at that timepoint.
    Protection of trial subjects
    Ethics review and approval, informed consent, supportive care and routine monitoring, data protection in accordance with law on General Data Protection Regulation (GDPR) and institutional rules [Belgian law dated on 30 July 2018 and 22 Aug. 2002], insurance.
    Background therapy
    All patients will receive standard of Care (SoC). Due to the rapidly evolving scientific insights, SoC for Covid-19 was not further defined a priori. Prophylaxis against meningococcal disease will be given in the active group A receiving zilucoplan, in the form of antibiotic prophylaxis with a third generation cephalosporin or alternative covering N. menigitidis and S. pneumoniae in case of allergies or clinical indication. A antibiotic is administered until at least 14 days after the last dose of zilucoplan in group A. Group B patients will receive a daily injection of 2g ceftriaxone IV or appropriate alternative in case of allergies or on clinical indication, during one week or until hospital discharge, whichever comes first.
    Evidence for comparator
    Treatment with the approved C5 inhibitors eculizumab and ravulizumab, as well as rare genetic deficiencies in C5, are associated with a markedly increased risk for infection with encapsulated bacteria, most notably Neisseria meningitidis and H. influenzae, but not for viral infections generally, or for coronavirus infections in particular. To prevent the risk of meningococcal disease and prevent other infections with encapsulated bacteria, patients in the active group A will receive prophylactic antibiotics. To control for the effects of antibiotic prophylaxis against menigococcal disease on clinical course of COVID-19, the control group B will also receive 1 week (or until hospital discharge whichever comes first) of IV 3rd generation cephalosporin. In case of allergies to these antibiotics, or on clinical indication, these antibiotics may be switched to antibiotics that also cover Neisseria meningitidis.
    Actual start date of recruitment
    22 May 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Scientific research
    Long term follow-up duration
    5 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 81
    Worldwide total number of subjects
    81
    EEA total number of subjects
    81
    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)
    42
    From 65 to 84 years
    38
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    84 patients were assessed for eligibility and 81 patients were randomized in the period from 15-aug-2020 till 16-dec-2021. 78 patients were included in the safety and primary analysis. End of trial notification was dated 27-may-2021 (last patient last visit) and submitted to EC and CA 30-jul-2021.

    Pre-assignment
    Screening details
    Confirmed COVID-19 patients between the age of 18 and 80 years were screened for acute hypoxic respiratory failure (saturation <93% on minimal 2 L/min O2 or PaO2/FiO2 <350). Invasive mechanical ventilation >24h, history of severe allergic reactions and unlikely to servive beyond 48h were the most important exclusion criteria.

    Period 1
    Period 1 title
    Randomized Set
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    N.A.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    arm A (Zilucoplan + SoC)
    Arm description
    standard of care + 32.4 mg Zilucoplan SC once daily for 14 days or until discharge, whichever comes first + daily prophylactic 3d generation cephalosporin IV for 14 days or untill discharge whichever comes first. After last Zilucoplan dose : - Patient still hospitalized: continue daily prophylactic 3d generation cephalosporin IV until 14 days after last Zilucoplan dose. - Patient discharged: prophylactic oral ciprofloxacin 500mg daily until 14 days after last Zilucoplan dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Zilucoplan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigational drug product will be provided in prefilled syringes containing 32.4 mg of Zilucoplan® for subcutaneous injection in the abdomen (preferred site), thigh, or upper arm. This dose is equivalent to that administered to the highest weight bracket in prior weight-based dosing regimens and is expected to achieve rapid, profound, and sustained complement inhibition with acceptable safety and tolerability. Subjects who present with very low body weight (<54kg) are excluded from enrolment. Subjects with very high body weight (>150 kg) are also excluded.

    Investigational medicinal product name
    ceftriaxone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for emulsion for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    daily IV infusion of 2g of ceftriaxone until hospital discharge (or until 28 days after randomization when still in hospital, whichever comes first). If patient is discharged before day 28 after randomization, patient will switch to oral ciprofloxacin 1x500 mg per day until at least 14 days after the last Zilucoplan® administration.

    Arm title
    Arm B (SoC)
    Arm description
    Group B patients will receive daily IV infusion of 2g of ceftriaxone daily IV during one week or until hospital discharge, whichever comes first. In case of unavailability, ceftriaxone can be replaced by cefotaxime 1g every 8 hours.
    Arm type
    prophylactic antibiotics

    Investigational medicinal product name
    ceftriaxone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for emulsion for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Daily IV infusion of 2g of ceftriaxone daily IV during one week or until hospital discharge, whichever comes first. In case of allergies or on clinical grounds, prophylaxis with ceftriaxone could be changed to another antibiotic also providing coverage for N. meningitidis and S. pneumoniae.

    Number of subjects in period 1
    arm A (Zilucoplan + SoC) Arm B (SoC)
    Started
    55
    26
    Completed
    54
    24
    Not completed
    1
    2
         Protocol deviation
    -
    2
         Consent withdrawn by subject
    1
    -
    Period 2
    Period 2 title
    Full Analysis Set
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A (Zilucoplan + Soc)
    Arm description
    standard of care + 32.4 mg Zilucoplan SC once daily for 14 days or until discharge, whichever comes first + daily prophylactic 3rd generation cephalosporin IV for 14 days or until discharge whichever comes first. After kast Zilucoplan dose: - Patients still hospitalized: continue daily prophylactic 3rd generation cephalosporin IV until 14 days after last Zilucoplan dose. - Patient discharged: prophylactic oral ciprofloxacin 500 mg daily until 14 days after last Zilucoplan dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Zilucoplan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigational drug product will be provided in prefilled syringes containing 32.4 mg of Zilucoplan® for subcutaneous injection in the abdomen (preferred site), thigh, or upper arm. This dose is equivalent to that administered to the highest weight bracket in prior weight-based dosing regimens and is expected to achieve rapid, profound, and sustained complement inhibition with acceptable safety and tolerability. Subjects who present with very low body weight (<54kg) are excluded from enrolment. Subjects with very high body weight (>150 kg) are also excluded.

    Investigational medicinal product name
    ceftriaxone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for emulsion for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    daily IV infusion of 2g of ceftriaxone until hospital discharge (or until 28 days after randomization when still in hospital, whichever comes first). If patient is discharged before day 28 after randomization, patient will switch to oral ciprofloxacin 1x500 mg per day until at least 14 days after the last Zilucoplan® administration.

    Arm title
    Arm B (SoC)
    Arm description
    Group B patients will receive daily IV infusion of 2g of ceftriaxone daily IV during one week or until hospital discharge, whichever comes first. In case of unavailability, ceftriaxone can be replaced by cefotaxime 1 g every 8 hours.
    Arm type
    prophylactic antibiotics

    Investigational medicinal product name
    ceftriaxone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for emulsion for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Daily IV infusion of 2g of ceftriaxone daily IV during one week or until hospital discharge, whichever comes first. In case of allergies or on clinical grounds, prophylaxis with ceftriaxone could be changed to another antibiotic also providing coverage for N. meningitidis and S. pneumoniae.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 is the Randomized Set. This set includes 3 patients of whom we did not collect any data, but who were randomized. Period 2 is the Full Analysis Set (without the aforementioned 3 patients). Therefore, this set is used as baseline period.
    Number of subjects in period 2 [2]
    Arm A (Zilucoplan + Soc) Arm B (SoC)
    Started
    54
    24
    Completed
    54
    24
    Notes
    [2] - 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: Three patients were randomized, but did not meet inclusion criteria or withdrew consent prior to first drug administration. Hence, no data of these patients are collected.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (Zilucoplan + Soc)
    Reporting group description
    standard of care + 32.4 mg Zilucoplan SC once daily for 14 days or until discharge, whichever comes first + daily prophylactic 3rd generation cephalosporin IV for 14 days or until discharge whichever comes first. After kast Zilucoplan dose: - Patients still hospitalized: continue daily prophylactic 3rd generation cephalosporin IV until 14 days after last Zilucoplan dose. - Patient discharged: prophylactic oral ciprofloxacin 500 mg daily until 14 days after last Zilucoplan dose.

    Reporting group title
    Arm B (SoC)
    Reporting group description
    Group B patients will receive daily IV infusion of 2g of ceftriaxone daily IV during one week or until hospital discharge, whichever comes first. In case of unavailability, ceftriaxone can be replaced by cefotaxime 1 g every 8 hours.

    Reporting group values
    Arm A (Zilucoplan + Soc) Arm B (SoC) Total
    Number of subjects
    54 24 78
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    29 12 41
        From 65-84 years
    25 11 36
        85 years and over
    0 1 1
    Age continuous
    The median age was 63 years (range 35-85) .
    Units: years
        median (full range (min-max))
    62 (35 to 83) 64.8 (50 to 85) -
    Gender categorical
    Units: Subjects
        Female
    5 5 10
        Male
    49 19 68
    Ordinal scale
    6-point ordinal scale: 1 death, 2 on invasive mechanical ventilation or ECMO; 3 on non-invasive ventilation or high flow oxygen devices; 4 hospitalized, requiring supplemental oxygen; 5 hospitalized, not requiring supplemental oxygen, 6 not hospitalized.
    Units: Subjects
        2.
    8 2 10
        3.
    19 8 27
        4.
    26 14 40
        5.
    1 0 1
    Ethnicity
    Units: Subjects
        African
    4 0 4
        Arabian
    3 1 4
        Asian
    1 0 1
        Caucasian
    46 22 68
        Other
    0 1 1
    SOFA score
    SOFA, severity of organ failure assessment
    Units: Subjects
        1-2
    29 14 43
        3-4
    14 7 21
        5-6
    1 2 3
        7-8
    7 0 7
        Not done
    3 1 4
    Arterial hypertension
    Units: Subjects
        Yes
    26 10 36
        No
    28 14 42
    Diabetes mellitus
    Units: Subjects
        Yes
    14 4 18
        No
    40 20 60
    Cardiovascular disease
    Units: Subjects
        Yes
    9 10 19
        No
    45 14 59
    Chronic kidney disease
    Units: Subjects
        Yes
    4 0 4
        No
    50 24 74
    Glucocorticoids at randomisation
    Units: Subjects
        Yes
    49 18 67
        No
    5 6 11
    Glucocorticoid use during first 28 days
    Units: Subjects
        Yes
    52 21 73
        No
    2 3 5
    Anticoagulants at randomisation
    Units: Subjects
        Yes
    49 21 70
        No
    5 3 8
    Antibiotics at randomisation
    Units: Subjects
        Yes
    16 2 18
        No
    38 22 60
    Remdesivir at randomisation
    Units: Subjects
        Yes
    7 2 9
        No
    47 22 69
    PaO2/FiO2 ratio at baseline
    The ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2; PaO2/FiO2)
    Units: mmHg
        arithmetic mean (standard deviation)
    169 ± 94 175 ± 93 -

    End points

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    End points reporting groups
    Reporting group title
    arm A (Zilucoplan + SoC)
    Reporting group description
    standard of care + 32.4 mg Zilucoplan SC once daily for 14 days or until discharge, whichever comes first + daily prophylactic 3d generation cephalosporin IV for 14 days or untill discharge whichever comes first. After last Zilucoplan dose : - Patient still hospitalized: continue daily prophylactic 3d generation cephalosporin IV until 14 days after last Zilucoplan dose. - Patient discharged: prophylactic oral ciprofloxacin 500mg daily until 14 days after last Zilucoplan dose.

    Reporting group title
    Arm B (SoC)
    Reporting group description
    Group B patients will receive daily IV infusion of 2g of ceftriaxone daily IV during one week or until hospital discharge, whichever comes first. In case of unavailability, ceftriaxone can be replaced by cefotaxime 1g every 8 hours.
    Reporting group title
    Arm A (Zilucoplan + Soc)
    Reporting group description
    standard of care + 32.4 mg Zilucoplan SC once daily for 14 days or until discharge, whichever comes first + daily prophylactic 3rd generation cephalosporin IV for 14 days or until discharge whichever comes first. After kast Zilucoplan dose: - Patients still hospitalized: continue daily prophylactic 3rd generation cephalosporin IV until 14 days after last Zilucoplan dose. - Patient discharged: prophylactic oral ciprofloxacin 500 mg daily until 14 days after last Zilucoplan dose.

    Reporting group title
    Arm B (SoC)
    Reporting group description
    Group B patients will receive daily IV infusion of 2g of ceftriaxone daily IV during one week or until hospital discharge, whichever comes first. In case of unavailability, ceftriaxone can be replaced by cefotaxime 1 g every 8 hours.

    Primary: LSMean change from baseline in PaO2/FiO2

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    End point title
    LSMean change from baseline in PaO2/FiO2
    End point description
    End point type
    Primary
    End point timeframe
    Day 6
    End point values
    arm A (Zilucoplan + SoC) Arm B (SoC)
    Number of subjects analysed
    52
    20
    Units: mmHg
        least squares mean (confidence interval 95%)
    56.4 (31.9 to 80.9)
    20.6 (-17.3 to 58.5)
    Statistical analysis title
    P-value
    Comparison groups
    arm A (Zilucoplan + SoC) v Arm B (SoC)
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.12
    Method
    Mixed models analysis
    Confidence interval

    Primary: LSMean change from baseline in PaO2/FiO2

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    End point title
    LSMean change from baseline in PaO2/FiO2
    End point description
    End point type
    Primary
    End point timeframe
    Day 15
    End point values
    arm A (Zilucoplan + SoC) Arm B (SoC)
    Number of subjects analysed
    43
    17
    Units: mmHg
        least squares mean (confidence interval 95%)
    123.5 (94.3 to 152.7)
    83.7 (39.0 to 128.4)
    Statistical analysis title
    P-value
    Comparison groups
    arm A (Zilucoplan + SoC) v Arm B (SoC)
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14
    Method
    Mixed models analysis
    Confidence interval

    Primary: LSMean change from baseline in a/A PO2

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    End point title
    LSMean change from baseline in a/A PO2
    End point description
    End point type
    Primary
    End point timeframe
    Day 6
    End point values
    arm A (Zilucoplan + SoC) Arm B (SoC)
    Number of subjects analysed
    52
    20
    Units: mmHg
        least squares mean (confidence interval 95%)
    0.1 (0.06 to 0.15)
    0.04 (-0.04 to 0.11)
    Statistical analysis title
    P-value
    Comparison groups
    arm A (Zilucoplan + SoC) v Arm B (SoC)
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.15
    Method
    Mixed models analysis
    Confidence interval

    Primary: LSMean change from baseline in a/A PO2

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    End point title
    LSMean change from baseline in a/A PO2
    End point description
    End point type
    Primary
    End point timeframe
    Day 15
    End point values
    arm A (Zilucoplan + SoC) Arm B (SoC)
    Number of subjects analysed
    43
    17
    Units: mmHg
        least squares mean (confidence interval 95%)
    0.25 (0.19 to 0.31)
    0.17 (0.08 to 0.26)
    Statistical analysis title
    P-value
    Comparison groups
    arm A (Zilucoplan + SoC) v Arm B (SoC)
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14
    Method
    Mixed models analysis
    Confidence interval

    Primary: Geometric LSMean (A-a) gradient

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    End point title
    Geometric LSMean (A-a) gradient
    End point description
    Geometric LSMean
    End point type
    Primary
    End point timeframe
    Day 6
    End point values
    arm A (Zilucoplan + SoC) Arm B (SoC)
    Number of subjects analysed
    48
    20
    Units: mmHg
        geometric mean (confidence interval 95%)
    114.6 (92.6 to 141.9)
    146.7 (105.4 to 204.3)
    Statistical analysis title
    P-value
    Comparison groups
    arm A (Zilucoplan + SoC) v Arm B (SoC)
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.22
    Method
    Mixed models analysis
    Confidence interval

    Primary: Geometric LSMean (A-a) gradient

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    End point title
    Geometric LSMean (A-a) gradient
    End point description
    Geometric LSMean
    End point type
    Primary
    End point timeframe
    Day 15
    End point values
    arm A (Zilucoplan + SoC) Arm B (SoC)
    Number of subjects analysed
    39
    17
    Units: mmHg
        geometric mean (confidence interval 95%)
    58.6 (44.9 to 76.5)
    86.9 (57.9 to 130.6)
    Statistical analysis title
    P-value
    Comparison groups
    arm A (Zilucoplan + SoC) v Arm B (SoC)
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.11
    Method
    Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    screening and during 28 day assessment period.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    Arm A (Zilucoplan + SoC)
    Reporting group description
    standard of care + 32.4mg Zilucoplan SC once daily for 14 days or until discharge, whichever comes first + daily prophylactic 3d generation cephalosporin IV for 14 days or until dicharge, wichever comes first. After last Zilucoplan dose: - patient still hospitalized: Continue daily prophylactic 3d generation cephalosporin IV untill 14 days after last Zilucoplan dose. - patient discharged: prophylactic oral ciprofloxacin 500mg daily until 14 days after last Zilucoplan dose.

    Reporting group title
    Arm B (SoC)
    Reporting group description
    standard of care + daily prophylactic 3d generation cephalosporin IV for 7 days or until discharge, whichever comes first.

    Serious adverse events
    Arm A (Zilucoplan + SoC) Arm B (SoC)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 54 (18.52%)
    5 / 24 (20.83%)
         number of deaths (all causes)
    5
    5
         number of deaths resulting from adverse events
    5
    5
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypercapnia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 54 (3.70%)
    3 / 24 (12.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Immune system disorders
    Aspergillus infection
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (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
    Hypoxic-sichaemic encephalopathy
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (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
    1 / 54 (1.85%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Thrombosis in device
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopulmonary aspergillus
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    septic shock
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm A (Zilucoplan + SoC) Arm B (SoC)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 54 (72.22%)
    17 / 24 (70.83%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 54 (14.81%)
    2 / 24 (8.33%)
         occurrences all number
    8
    2
    Investigations
    Alanine animontransferase increased
         subjects affected / exposed
    4 / 54 (7.41%)
    1 / 24 (4.17%)
         occurrences all number
    4
    1
    Aspartate animontransferase increased
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 24 (4.17%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    2 / 54 (3.70%)
    3 / 24 (12.50%)
         occurrences all number
    2
    3
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    4 / 54 (7.41%)
    2 / 24 (8.33%)
         occurrences all number
    4
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 54 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    6
    1
    Delirium
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 24 (4.17%)
         occurrences all number
    3
    1
    Insomnia
         subjects affected / exposed
    5 / 54 (9.26%)
    0 / 24 (0.00%)
         occurrences all number
    5
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    7 / 54 (12.96%)
    5 / 24 (20.83%)
         occurrences all number
    7
    5
    Diarrhoea
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 54 (7.41%)
    3 / 24 (12.50%)
         occurrences all number
    4
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 24 (8.33%)
         occurrences all number
    1
    2
    Hyperglycemia
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 24 (12.50%)
         occurrences all number
    1
    3
    Hypoalbuminia
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 54 (9.26%)
    1 / 24 (4.17%)
         occurrences all number
    5
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2020
    Section 2.1: study design added. Section 7.1.2: wording changed to “An Investigator must discontinue or withdraw a subject from the study for the following reason.” Clarification added on prophylaxis for meningococcal disease Section 9.2, 9.4: Follow up visit week 12-22 after randomization: additional assessments were added: WHO performance scale, 6 minutes walk test (per standard of care), HRCT scan to evaluate HRCT fibrosis score Section 9.4: assessment of vital signs: values to be collected at morning assessment, between 7-10 AM for all parameters. 6-point ordinal scale: scoring updated to "1=Death”. HRCT fibrosis score: instructions on how to score HRCT findings. Section 13.5: text added: A careful assessment will be performed in cases where disease related events appear to be enhanced by the IMP. In accordance with CT-3 guidance, a causality assessment will be performed for each SAE, and if the investigator considers disease related event to be IMP-related and the event is serious,related and unexpected, then it will be reported as a SUSAR. Section 13.6: Additional information on DSMB Charter Section 9.3, 9.4, 10: details on samples to be collected updated, cfr. updated lab manual provided by central lab, Covance Section 12.1.2 information added that no data will be collected directly into the eCRF. Section 11.1: primary endpoint changed to day 6, day 15 (or discharge). Section 6.1: information added on anti-conception requirements for male subjects. Section 4.2: definition of ARDS changed according to the Berlin criteria according to Jason Chertoff. Section 1., 5.1: definition of Hypoxic respiratory failure changed.
    10 Jun 2020
    Section 1., 3.2, 4.2: secondary objectives changed. Section 3.1 and 4.1 Clarification for ECMO patients added. Section 4.2: Definition of ARDS: bullet point 4 changed. Section 6.1: Definition hypoxia changed. Section 9.2, 9.4: - laboratory assessments removed (fibrinogen and triglycerides at Day 6, 15 and FU) - Score assessments removed: Clinical Sign Score, Glasgow Come Scale and NEWS2. HScore only at Day 1. - Information added on timing of evaluation of 6 point ordinal scale and HScore.6 minute walk test: protocol requirement, not following SOC. Section 9.3: - Listing of lab assessments removed. - Day 4 was changed into day 6 Timepoint of analysis of cytokines changed from Day 14 to Day 15. General: typo’s corrected. Section 10: D1: samples of 5ml for PK was changed into 6 ml. One 6 ml EDTA tube was added for complement (according to flowchart). Section 13.4: in flowchart reporting , ‘HIRUZ CTU will inform all participating sites’ was added for SUSARs Section 9.2: clinical exam and ECG added to section “at screening”, to correspond with 9.4.
    10 Jul 2020
    Section 3.1 and 5.1 and 7.1 and 9.4: statement/clarification on use of alternative antibiotics in case of allergy to cephalosporin or ciprofloxacin Section 6.2: Exclusion Criteria added: patient on ECMO at screening Section 8.1.4: clarification added on administration of IMP during 24 hours dialysis. Section 9.4: Physical Examination: to be assessed on clinical grounds, as per standard of care. Clarification for ECMO patients added
    09 Apr 2021
    Section 4.2: Typo “≥60” corrected to “≥ 50”. Section 4.2: Secondary endpoints updated according to SAP Section 4.3 has been added and describes the pharmacodynamics and pharmacokinetic endpoints Section 7.3, 9.4: information added on assessment of arterial blood gas: if an arterial blood gas value is available of less than 24 hours before randomization, there’s no need to have a new ABG done on Day 0/1. Section 9.4: correction in footnote: time window of assessment of vital signs is not applicable for the follow-up visit. Section 13.3: Reporting address for SAEs changed to DS_ICT@ucb.com Section 13.7: clarification added on timelines of submission of DSUR. Section 10.3, 10.4: clarification added on analysis and storage by selected centres of optional samples. Section 10.5: identification of FAGG certified biobank to store remaining samples for future use. Section 9.2: volume of DNA EDTA changed from 5 ml to 4 ml (typo). Section 11.0: Update of statistical analysis team Section 5.1: “Group B” removed from sentence about prophylactic antibiotic treatment for patient randomized to Group A. *Amendment was approved by the regulatory authority on 27-Apr-2021*
    09 Apr 2021
    Section 4.2 : All secondary endpoints not related to secondary objectives have been moved to new section 4.3 “exploratory endpoints” section. Duplicates within secondary endpoint section have been removed. Removal of analytical language e.g. ‘means’ has been updated to reflect the endpoint itself not the analytical approach Section 4.3 Exploratory Endpoints was added. The content of this section concerns endpoints previously listed under section 4.2 which have been moved to the current section 4.3. For some of the endpoints, analytical language e.g. ‘means’ has been updated to reflect the endpoint itself not the analytical approach Section 4.4: clarification was added related to the exploratory nature of pharmacodynamic and pharmacokinetic endpoints Section 4.4: aPTT and PT have been removed from Pharmacodynamic endpoints Section 11.1 : name of individual UCB statistician Trevor Smart replaced by UCB Section 11.2: Clarification was added regarding the endpoints to be summarized. Section 11.2: the sentence “Data from SOC in another study with a very similar protocol will be incorporated into the analysis using a Bayesian frame work. This will be described more fully in the statistical analysis plan (SAP).” Has been replaced by “Data from SOC in another study with a very similar protocol may be incorporated into the analysis using a Bayesian frame work. This will be described more fully in the statistical analysis plan (SAP).” Section 12.4: The sentence “Pseudonymized biological analyses and study results will also be shared with the provider of Zilucoplan® (UCB Pharma)” has been replaced by “Pseudonymized biological analyses, study data and study results will also be shared with the provider of Zilucoplan® (UCB Pharma) “ *Amendment was approved by the regulatory authority on 09-June-2021*

    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.
    1) open label design 2) 14 days of prophylactic antibiotics in Zilucoplan group vs 7 days in SoC 3) population predominantly composed of white men 4) FiO2 based on the method of oxygen delivery and flow 5) differences in baseline characteristics
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