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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, parallel group, phase 3, multicenter trial investigating the efficacy and safety of C21 as add-on to standard of care in adult subjects with COVID-19.

    Summary
    EudraCT number
    		 2021-000264-29
    Trial protocol
    		 CZ  
    Global end of trial date
    25 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Nov 2023
    First version publication date
    23 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VP-C21-008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04880642
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vicore Pharma AB
    Sponsor organisation address
    Kornhamnstorg 53, Stockholm, Sweden, SE-111 27
    Public contact
    Anne-Katrine Cohrt Head of Clinical Operations, Vicore Pharma AB, anne-katrine.cohrt@vicorepharma.com
    Scientific contact
    Rohit Batta Chief Medical Officer, Vicore Pharma AB, info@vicorepharma.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
    13 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the efficacy of C21 versus placebo as add-on to standard of care on recovery in subjects with COVID-19.
    Protection of trial subjects
    None specific.
    Background therapy
    		 All enrolled patients received standard of care (SoC) COVID-19 treatment.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Sep 2021
    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
    Czechia: 39
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Colombia: 2
    Country: Number of subjects enrolled
    United States: 8
    Country: Number of subjects enrolled
    Philippines: 8
    Country: Number of subjects enrolled
    Ukraine: 109
    Country: Number of subjects enrolled
    Russian Federation: 16
    Country: Number of subjects enrolled
    India: 76
    Country: Number of subjects enrolled
    South Africa: 5
    Worldwide total number of subjects
    272
    EEA total number of subjects
    39
    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)
    195
    From 65 to 84 years
    74
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 316 subjects signed informed consent and were screened for participation in the trial. Of these, 44 subjects were screening failures and the remaining 272 subjects were randomised to treatment. Of the 272 randomised subjects, 267 subjects actually received treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One oral capsule of placebo administered twice daily

    Arm title
    		 C21 100 mg BID
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    C21
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One oral capsule of 100 mg C21 administered twice daily

    Number of subjects in period 1
    		Placebo C21 100 mg BID
    Started
    136
    136
    Completed
    133
    134
    Not completed
    3
    2
         Consent withdrawn by subject
    3
    2
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One oral capsule of placebo administered twice daily

    Arm title
    		 C21 100 mg BID
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    C21
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One oral capsule of 100 mg C21 administered twice daily

    Number of subjects in period 2
    		Placebo C21 100 mg BID
    Started
    133
    134
    Completed
    118
    117
    Not completed
    18
    19
         Adverse event, serious fatal
    6
    5
         Consent withdrawn by subject
    3
    5
         Adverse event, non-fatal
    3
    5
         Not randomized/not treated
    3
    2
         Subject decision to stop IMP treatment
    1
    -
         Subject was withdrawn due to Sponsor discretion
    1
    -
         Lost to follow-up
    -
    1
         Protocol deviation
    1
    1
    Joined
    3
    2
         Non-randomized subjects, added to fit with ITI
    3
    -
         Non-randomized subject, added to fit ITI
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    C21 100 mg BID
    Reporting group description
    		 -

    Reporting group values
    		 Placebo C21 100 mg BID Total
    Number of subjects
    		 136 136 272
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 93 102 195
        From 65-84 years
    		 40 34 74
        85 years and over
    		 3 0 3
    Age continuous
    Age at baseline for the ITT analysis set.
    Units: years
        arithmetic mean (full range (min-max))
    		 56.5 (21 to 91) 53.5 (18 to 79) -
    Gender categorical
    Gender for the ITT analysis set.
    Units: Subjects
        Female
    		 63 57 120
        Male
    		 73 79 152
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 45 43 88
        Black or African American
    		 2 0 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        White
    		 87 90 177
        Other
    		 1 3 4
        Not reported
    		 1 0 1
        Unknown
    		 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 6 6 12
        Not Hispanic or Latino
    		 127 127 254
        Not Reported
    		 0 0 0
        Unknown
    		 3 3 6
    Region of enrolment
    Units: Subjects
        Columbia
    		 0 2 2
        United States
    		 4 4 8
        Czechia
    		 19 20 39
        Philippines
    		 5 3 8
        Ukraine
    		 55 54 109
        Brazil
    		 5 4 9
        South Africa
    		 3 2 5
        India
    		 38 38 76
        Russia
    		 7 9 16
    Height
    Units: cm
        arithmetic mean (full range (min-max))
    		 167.6 (149 to 187) 168.8 (145 to 195) -
    Weight
    Units: kg
        arithmetic mean (full range (min-max))
    		 79.3 (43.0 to 159.0) 81.9 (50.0 to 200.0) -
    Body mass index (BMI)
    Units: kg/m2
        arithmetic mean (full range (min-max))
    		 28.1 (13.3 to 57.0) 28.7 (19.0 to 69.2) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    C21 100 mg BID
    Reporting group description
    		 -
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    C21 100 mg BID
    Reporting group description
    		 -

    Primary: All-cause mortality up to Day 60 (ITT)

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    End point title
    		 All-cause mortality up to Day 60 (ITT)
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 to Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136 [1]
    136 [2]
    Units: Subjects
        Death
    10
    10
        Censored
    126
    126
    Notes
    [1] - ITT analysis set
    [2] - ITT analysis set
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    C21 100 mg BID v Placebo
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.949
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 2.36

    Primary: All-cause mortality up to Day 60 (PP)

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    End point title
    		 All-cause mortality up to Day 60 (PP)
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 to Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    116
    111
    Units: Subjects
        Death
    9
    8
        Censored
    107
    103
    Statistical analysis title
    		 Sensitivity analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.948
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 2.34

    Secondary: Time to sustained hospital discharge up to Day 60 (ITT)

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    End point title
    		 Time to sustained hospital discharge up to Day 60 (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136
    136
    Units: Days
        median (confidence interval 95%)
    9.0 (8.0 to 11.0)
    9.0 (7.0 to 11.0)
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.301
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.52

    Secondary: Time to sustained hospital discharge up to Day 60 (PP)

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    End point title
    		 Time to sustained hospital discharge up to Day 60 (PP)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    116
    111
    Units: Days
        median (confidence interval 95%)
    10.0 (8.0 to 13.0)
    9.0 (7.0 to 12.0)
    Statistical analysis title
    		 Sensitivity analysis (PP)
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.327
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.55

    Secondary: Supplemental oxygen-free Days up to Day 29 (ITT)

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    End point title
    		 Supplemental oxygen-free Days up to Day 29 (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 29
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    126
    125
    Units: Days
    median (full range (min-max))
        Observed value
    24.0 (-1 to 28)
    24.0 (-1 to 28)
        Imputed dataset
    23.0 (-1 to 28)
    23.0 (-1 to 28)
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.425 [3]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1
    Notes
    [3] - Missing data at a time point were imputed using multiple imputation with a logistic regression model.
    Statistical analysis title
    		 Sensitivity analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.447
    Method
    		 ANOVA
    Parameter type
    		 LS mean
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 2.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.03
    Notes
    [4] - Statistics are based on Imputed Values using multiple imputation with a logistic regression model.

    Secondary: Proportion of subjects free of respiratory failure at Day 15 (ITT)

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    End point title
    		 Proportion of subjects free of respiratory failure at Day 15 (ITT)
    End point description
    The proportion of subjects free of respiratory failure (responders) at Day 15 was calculated
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    130
    128
    Units: Percentage of responders
    number (not applicable)
        Observed values
    92.3
    90.6
        Imputed values
    90.1
    88.4
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    C21 100 mg BID v Placebo
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.671
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.3
         upper limit
    		 6
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.91
    Notes
    [5] - Statistics are based on imputed values.

    Secondary: Proportion of subjects free of respiratory failure at Day 15 (PP)

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    End point title
    		 Proportion of subjects free of respiratory failure at Day 15 (PP)
    End point description
    The proportion of subjects free of oxygen (responders) at Day 15 was calculated
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    116
    111
    Units: Percentage responders
    number (not applicable)
        Observed value
    92.2
    91.9
        Imputed value
    91.6
    92.0
    Statistical analysis title
    		 Sensitivity analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.926
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 7.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.67
    Notes
    [6] - Statistics are based on imputed values using multiple imputation with a logistic regression model.

    Secondary: Proportion of subjects discharged from hospital and free of supplemental oxygen-use at Day 15 (ITT)

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    End point title
    		 Proportion of subjects discharged from hospital and free of supplemental oxygen-use at Day 15 (ITT)
    End point description
    Proportion of Subjects Discharged From the Hospital and Free of Supplemental Oxygen-Use (responders) at Day 15 was calculated
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    130
    128
    Units: Percentage responder
    number (not applicable)
        Observed value
    70.0
    68.8
        Imputed value
    67.9
    67.6
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.948
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.4
         upper limit
    		 10.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.62
    Notes
    [7] - Statistics were based on imputed values using multiple imputation with a logistic regression model.

    Secondary: Proportion of subjects discharged from hospital and free of supplemental oxygen-use at Day 15 (PP)

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    End point title
    		 Proportion of subjects discharged from hospital and free of supplemental oxygen-use at Day 15 (PP)
    End point description
    The proportion of subjects discharged from hospital and free of supplemental oxygen-use (responders) at Day 15 was calculated.
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    115
    111
    Units: Percentage responder
    number (not applicable)
        Observed value
    67.8
    67.6
        Imputed value
    66.7
    68.2
    Statistical analysis title
    		 Sensitivity analysis (PP)
    Comparison groups
    C21 100 mg BID v Placebo
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.801
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.3
         upper limit
    		 13.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.02

    Secondary: Supplemental oxygen-free Days up to Day 29 (PP)

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    End point title
    		 Supplemental oxygen-free Days up to Day 29 (PP)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 29
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    112
    109
    Units: Days
    median (full range (min-max))
        Observed value
    23.0 (-1 to 28)
    23.0 (-1 to 28)
        Imputed value
    23.0 (-1 to 28)
    23.0 (-1 to 28)
    Statistical analysis title
    		 Sensitivity analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.273
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 2.1
    Notes
    [8] - Statistics are based on imputed values using multiple imputation with a logistic regression model.

    Secondary: All-cause mortality up to Days 8, 15, 22, and 29 (ITT)

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    End point title
    		 All-cause mortality up to Days 8, 15, 22, and 29 (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    Days 8, 15, 22, and 29
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136
    136
    Units: Deaths
        Day 8
    7
    3
        Day 15
    7
    7
        Day 22
    7
    9
        Day 29
    8
    9
    No statistical analyses for this end point

    Secondary: Proportion of subjects discharged from hospital and free of supplemental oxygen-use, Day 8, Day 22, and Day 29 (ITT)

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    End point title
    		 Proportion of subjects discharged from hospital and free of supplemental oxygen-use, Day 8, Day 22, and Day 29 (ITT)
    End point description
    Summary of proportion of subjects discharged from hospital and free of supplemental oxygen-use by time point using a multiple imputation method
    End point type
    Secondary
    End point timeframe
    Day 8, Day 22 or Day 29
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136
    136
    Units: Percentage responders
    number (not applicable)
        Day 8
    36.8
    46.8
        Day 22
    82.0
    80.8
        Day 29
    85.1
    84.6
    Statistical analysis title
    		 Statistical analysis, Day 8
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.075
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 21
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.62
    Notes
    [9] - Statistics are based on imputed values using multiple imputation with a logistic regression model.
    Statistical analysis title
    		 Statistical analysis, Day 22
    Comparison groups
    C21 100 mg BID v Placebo
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.806
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.7
         upper limit
    		 8.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.83
    Notes
    [10] - Statistics are based on imputed values using multiple imputation with a logistic regression model.
    Statistical analysis title
    		 Statistical analysis, Day 29
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.9
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.2
         upper limit
    		 8.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.39
    Notes
    [11] - Statistics are based on imputed values using multiple imputation with a logistic regression model.

    Secondary: Proportion of hospitalized subjects on non-invasive mechanical ventilation, invasive mechanical ventilation, ECMO or using supplemental oxygen, Day 8, Day 15, Day 22, Day 29 and Day 60 (ITT)

    		 Close Top of page
    End point title
    		 Proportion of hospitalized subjects on non-invasive mechanical ventilation, invasive mechanical ventilation, ECMO or using supplemental oxygen, Day 8, Day 15, Day 22, Day 29 and Day 60 (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 8, Day 15, Day 22, Day 29 or Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136
    136
    Units: Percentage of responders
    number (not applicable)
        Day 8
    33.1
    27.8
        Day 15
    19.0
    14.7
        Day 22
    15.5
    13.3
        Day 29
    14.1
    13.2
        Day 60
    7.5
    7.3
    Statistical analysis title
    		 Statistical analysis, Day 8
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.332
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -5.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.8
         upper limit
    		 5.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.38
    Notes
    [12] - Statistics are based on imputed values using multiple imputation with a logistic regression model.
    Statistical analysis title
    		 Statistical analysis, Day 15
    Statistical analysis description
    Proportion of Hospitalized Subjects on Non-Invasive Mechanical Ventilation, Invasive Mechanical Ventilation, ECMO or with Supplemental Oxygen Use by Time Point was calculated using imputed values
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.348
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 4.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.64
    Notes
    [13] - Statistics are based on imputed values using multiple imputation with a logistic regression model
    Statistical analysis title
    		 Statistical analysis, Day 22
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.61
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.9
         upper limit
    		 6.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.4
    Notes
    [14] - Statistics are based on imputed values using multiple imputation with a logistic regression model.
    Statistical analysis title
    		 Statistical analysis, Day 29
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.843
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.1
         upper limit
    		 7.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.23
    Notes
    [15] - Statistics are based on imputed values using multiple imputation with a logistic regression model.
    Statistical analysis title
    		 Statistical analysis, Day 60
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.948
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 6
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.16
    Notes
    [16] - Statistics are based on imputed values using multiple imputation with a logistic regression model.

    Secondary: Proportion of Subjects Free of Respiratory Failure at Days 8, 22, 29, and 60 (ITT)

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    End point title
    		 Proportion of Subjects Free of Respiratory Failure at Days 8, 22, 29, and 60 (ITT)
    End point description
    Proportion of Subjects Free of Respiratory Failure by Time Point was calculated using a Multiple Imputation Method
    End point type
    Secondary
    End point timeframe
    Day 8, Day 22, Day 29 and Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136
    136
    Units: Percentage responders
    number (not applicable)
        Day 8
    91.0
    93.2
        Day 22
    93.3
    93.5
        Day 29
    93.3
    93.5
        Day 60
    92.5
    92.7
    Statistical analysis title
    		 Statistical analysis, Day 8
    Comparison groups
    C21 100 mg BID v Placebo
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.52
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 8.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.36
    Notes
    [17] - Statistics are based on imputed values using multiple imputation with a logistic regression model.
    Statistical analysis title
    		 Statistical analysis, Day 22
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.95
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.7
         upper limit
    		 6.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.01
    Notes
    [18] - Statistics are based on imputed values using multiple imputation with a logistic regression model.
    Statistical analysis title
    		 Statistical analysis, Day 29
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.95
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.7
         upper limit
    		 6.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.01
    Notes
    [19] - Statistics are based on imputed values using multiple imputation with a logistic regression model.
    Statistical analysis title
    		 Statistical analysis, Day 60
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.948
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 6.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.16
    Notes
    [20] - Statistics are based on imputed values using multiple imputation with a logistic regression model

    Secondary: Respiratory Failure-Free Days up to Day 60 (ITT)

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    End point title
    		 Respiratory Failure-Free Days up to Day 60 (ITT)
    End point description
    Respiratory Failure-Free Days up to Day 60 are calculated. Missing data at a time point is imputed using multiple imputation with a logistic regression model.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136
    136
    Units: Days
        median (full range (min-max))
    59.0 (0 to 59.0)
    59.0 (0 to 59.0)
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.881
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0

    Secondary: Proportion of subjects in each category of the 8-point ordinal scale, Day 8 (ITT)

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    End point title
    		 Proportion of subjects in each category of the 8-point ordinal scale, Day 8 (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 8
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    131
    129
    Units: Percentage subjects
    number (not applicable)
        Score 1
    27.5
    38.0
        Score 2
    11.5
    9.3
        Score 3
    9.9
    5.4
        Score 4
    19.1
    18.6
        Score 5
    23.7
    21.7
        Score 6
    2.3
    3.9
        Score 7
    1.5
    0.8
        Score 8
    4.6
    2.3
    No statistical analyses for this end point

    Secondary: Proportion of Subjects in Each Category of the 8-Point Ordinal Scale, Day 15 (ITT)

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    End point title
    		 Proportion of Subjects in Each Category of the 8-Point Ordinal Scale, Day 15 (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    130
    128
    Units: Percentage subjects
    number (not applicable)
        Score 1
    56.9
    59.4
        Score 2
    14.6
    10.9
        Score 3
    3.8
    1.6
        Score 4
    7.7
    15.6
        Score 5
    9.2
    3.1
        Score 6
    1.5
    4.7
        Score 7
    0.8
    0
        Score 8
    5.4
    4.7
    No statistical analyses for this end point

    Secondary: Proportion of subjects in each category of the 8-point ordinal scale, Day 22 (ITT)

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    End point title
    		 Proportion of subjects in each category of the 8-point ordinal scale, Day 22 (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 22
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    128
    127
    Units: Percentage subjects
    number (not applicable)
        Score 1
    75.0
    78.0
        Score 2
    11.7
    8.7
        Score 3
    0
    0.8
        Score 4
    2.3
    3.9
        Score 5
    4.7
    1.6
        Score 6
    0.8
    0
        Score 7
    0
    0
        Score 8
    5.5
    7.1
    No statistical analyses for this end point

    Secondary: Proportion of Subjects in Each Category of the 8-Point Ordinal Scale, Day 29 (ITT)

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    End point title
    		 Proportion of Subjects in Each Category of the 8-Point Ordinal Scale, Day 29 (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    128
    127
    Units: Percentage subjects
    number (not applicable)
        Score 1
    84.4
    85.8
        Score 2
    6.3
    5.5
        Score 3
    0
    0
        Score 4
    0
    0.8
        Score 5
    2.3
    0.8
        Score 6
    0.8
    0
        Score 7
    0
    0
        Score 8
    6.3
    7.1
    No statistical analyses for this end point

    Secondary: Proportion of Subjects in Each Category of the 8-Point Ordinal Scale, Day 60 (ITT)

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    End point title
    		 Proportion of Subjects in Each Category of the 8-Point Ordinal Scale, Day 60 (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    128
    127
    Units: Percentage subjects
    number (not applicable)
        Score 1
    87.5
    89.0
        Score 2
    4.7
    3.1
        Score 3
    0
    0
        Score 4
    0
    0
        Score 5
    0
    0
        Score 6
    0
    0
        Score 7
    0
    0
        Score 8
    7.8
    7.9
    No statistical analyses for this end point

    Secondary: Proportion of Subjects Needing ICU Stay at Days 8, 15, 22, 29, and 60 (ITT)

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    End point title
    		 Proportion of Subjects Needing ICU Stay at Days 8, 15, 22, 29, and 60 (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 8, Day 15, Day 22, Day 29 or Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136
    136
    Units: Percentage responders
    number (not applicable)
        Day 8
    12.5
    8.1
        Day 15
    9.6
    8.1
        Day 22
    7.4
    8.1
        Day 29
    8.1
    8.1
        Day 60
    8.8
    8.1
    Statistical analysis title
    		 Statistical analysis, Day 8
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.193
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -4.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.8
         upper limit
    		 2.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.63
    Statistical analysis title
    		 Statistical analysis, Day 15
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.61
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.5
         upper limit
    		 5
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.42
    Statistical analysis title
    		 Statistical analysis, Day 22
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.88
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 6.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.23
    Statistical analysis title
    		 Statistical analysis, Day 29
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.935
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.7
         upper limit
    		 6.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.3
    Statistical analysis title
    		 Statistical analysis, Day 60
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.761
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.6
         upper limit
    		 5.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.37

    Secondary: Proportion of subjects on invasive mechanical ventilation or ECMO at Days 8, 15, 22, 29, and 60

    		 Close Top of page
    End point title
    		 Proportion of subjects on invasive mechanical ventilation or ECMO at Days 8, 15, 22, 29, and 60
    End point description
    Missing data at a time point is imputed using multiple imputation with a logistic regression model
    End point type
    Secondary
    End point timeframe
    Day 8, Day 15, Day 22, Day 29 or Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136
    136
    Units: Percentage responders
    number (not applicable)
        Day 8
    6.5
    3.1
        Day 15
    8.3
    7.3
        Day 22
    6.0
    6.5
        Day 29
    6.0
    6.5
        Day 60
    7.5
    7.3
    Statistical analysis title
    		 Statistical analysis, Day 8
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.213
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 1.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.7
    Statistical analysis title
    		 Statistical analysis, Day 15
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.768
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.8
         upper limit
    		 5.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.44
    Statistical analysis title
    		 Statistical analysis, Day 22
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.848
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.2
         upper limit
    		 6.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.93
    Statistical analysis title
    		 Statistical analysis, Day 29
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.848
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.2
         upper limit
    		 6.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.93
    Statistical analysis title
    		 Statistical analysis, Day 60
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.948
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 6
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.16

    Secondary: Duration of Invasive Mechanical Ventilation/ECMO Use up to Day 60

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    End point title
    		 Duration of Invasive Mechanical Ventilation/ECMO Use up to Day 60
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136
    136
    Units: Days
        median (full range (min-max))
    0.0 (0 to 58)
    0.0 (0 to 57)
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.818
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0

    Secondary: Duration of hospitalization, incl. re-hospitalization, up to Day 60 (ITT)

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    End point title
    		 Duration of hospitalization, incl. re-hospitalization, up to Day 60 (ITT)
    End point description
    Missing data at a time point is imputed using multiple imputation with a logistic regression model.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136
    136
    Units: Days
        median (full range (min-max))
    10.0 (2.0 to 60.0)
    9.3 (1.0 to 60.0)
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.479
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 1

    Secondary: Duration of ICU stay, incl. re-admission, up to Day 60 (ITT)

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    End point title
    		 Duration of ICU stay, incl. re-admission, up to Day 60 (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136
    136
    Units: Days
        median (full range (min-max))
    5.6 (0 to 60)
    4.8 (0 to 60)
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.419
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0

    Secondary: Change from baseline in SpO2/FiO2 at Day 15 (ITT)

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    End point title
    		 Change from baseline in SpO2/FiO2 at Day 15 (ITT)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    136
    136
    Units: Percentage
        arithmetic mean (full range (min-max))
    1.97 (-0.6 to 3.6)
    2.06 (-0.7 to 3.6)
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.293
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.149
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.129
         upper limit
    		 0.427
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.141
    Notes
    [21] - LS mean, standard error, confidence intervals, and two-sided p-value are from an Analysis of Covariance (ANCOVA).

    Secondary: PK parameters - Cmax, C6

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    End point title
    		 PK parameters - Cmax, C6
    End point description
    PK parameters were calculated in the PK population of 7 subjects. Only 6 subjects were included in the calculation of C6.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 C21 100 mg BID
    Number of subjects analysed
    7
    Units: ng/ml
    geometric mean (full range (min-max))
        Cmax
    981.5 (446 to 3560)
        C6
    86.2 (22 to 450)
    No statistical analyses for this end point

    Secondary: PK Parameters, AUC(0-6), AUC(0-inf), AUClast

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    End point title
    		 PK Parameters, AUC(0-6), AUC(0-inf), AUClast
    End point description
    PK Parameters were calculated in the PK population of 7 subjects. Only 6 subjects were included in the analysis of AUC(0-6) and only 3 subjects were included in the analysis of AUC(0-inf).
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 C21 100 mg BID
    Number of subjects analysed
    7
    Units: h*ng/ml
    geometric mean (full range (min-max))
        AUC(0-6)
    2263.8 (1373 to 5625)
        AUC(0-inf)
    3000.1 (1537 to 6052)
        AUClast
    1902.0 (669 to 5625)
    No statistical analyses for this end point

    Secondary: PK parameters - tmax

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    End point title
    		 PK parameters - tmax
    End point description
    PK parameters were calculated in the PK population of 7 subjects.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 C21 100 mg BID
    Number of subjects analysed
    7
    Units: hours
        median (full range (min-max))
    1.0 (1 to 6)
    No statistical analyses for this end point

    Secondary: Changes in safety laboratory assesments

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    End point title
    		 Changes in safety laboratory assesments
    End point description
    Clinically significant changes from baseline in hematology, clinical chemistry, or urinalysis parameters were monitored and no clinically meaningful mean changes from baseline were observed.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    133
    134
    Units: Clinically meaningful changes
    0
    0
    No statistical analyses for this end point

    Secondary: Withdrawals due to adverse events

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    End point title
    		 Withdrawals due to adverse events
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    133
    134
    Units: Subjects/events
        Subjects
    9
    11
        Events
    10
    11
    No statistical analyses for this end point

    Secondary: PK parameters - t1/2

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    End point title
    		 PK parameters - t1/2
    End point description
    PK parameters were calculated in the PK population of 7 subjects. Only 3 subjects were included in the analysis of t1/2.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 C21 100 mg BID
    Number of subjects analysed
    3
    Units: Hours
        arithmetic mean (standard deviation)
    1.2 ± 0.55
    No statistical analyses for this end point

    Other pre-specified: Change from baseline in CRP at Day 15

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    End point title
    		 Change from baseline in CRP at Day 15
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Day 15
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    80
    79
    Units: mg/L
        arithmetic mean (standard deviation)
    -33.22 ± 53.87
    -20.19 ± 59.031
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043
    Method
    		 ANCOVA
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 2.14

    Other pre-specified: Change from baseline in LDH at Day 15

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    End point title
    		 Change from baseline in LDH at Day 15
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Day 15
    End point values
    		 Placebo C21 100 mg BID
    Number of subjects analysed
    79
    77
    Units: U/L
        arithmetic mean (standard deviation)
    -101.72 ± 178.64
    -81.35 ± 185.06
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Placebo v C21 100 mg BID
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.439
    Method
    		 ANCOVA
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.14

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from signing of the ICF until Day 29. SAEs were collected until Day 60
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Placebo group
    Reporting group description
    		 -

    Reporting group title
    C21 group
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo group C21 group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 133 (9.77%)
    15 / 134 (11.19%)
         number of deaths (all causes)
    10
    10
         number of deaths resulting from adverse events
    10
    10
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    3 / 133 (2.26%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frederick's syndrome
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 133 (0.75%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Acute respiratory failure
         subjects affected / exposed
    1 / 133 (0.75%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pulmonary embolism
         subjects affected / exposed
    0 / 133 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 133 (0.00%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 133 (1.50%)
    2 / 134 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Pneumonia
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 134 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Placebo group C21 group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 133 (18.05%)
    22 / 134 (16.42%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 133 (4.51%)
    7 / 134 (5.22%)
         occurrences all number
    6
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 133 (3.76%)
    4 / 134 (2.99%)
         occurrences all number
    6
    4
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    4 / 133 (3.01%)
    1 / 134 (0.75%)
         occurrences all number
    4
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 133 (3.01%)
    4 / 134 (2.99%)
         occurrences all number
    4
    4
    Pyrexia
         subjects affected / exposed
    6 / 133 (4.51%)
    4 / 134 (2.99%)
         occurrences all number
    6
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 133 (3.01%)
    7 / 134 (5.22%)
         occurrences all number
    7
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jul 2021
    Protocol amendment 2, protocol version 3.0, 2-jul-2021: •Change in LDH was added as an exploratory endpoint • Interim analysis and DMC process was clarified. Ad hoc safety review meeting was added • Description of individual change in ordinal scale scores reflected in the original primary endpoint (see Protocol Version 5.0 below) was added • India-specific age limits and SpO2 criteria added to Inclusion Criteria 1 and 7, respectively. • Active TB was added to Exclusion Criterion 2 • SpO2/FiO2 ratio was added to Exclusion Criterion 9 • Oral dispersion and nasoenteral feeding tube were added as alternative administration forms • List with prohibited medication was added • IMP discontinuation criteria were added for acute kidney and hepatic injury • Text updated to specify that there were no specific criteria for temporary discontinuation of IMP in the protocol • Additional 8-point ordinal scale assessment added at time of hospital discharge and in subjects hospitalized between Days 29 and 60 • Section 8.3 was updated to collect data on all types of hospital re-admissions • Albumin and LDH were added to laboratory parameters • Serum albumin was added to Child-Pugh System table • Plots of cumulative distribution functions were added for the oxygen supplemental free days up to Day 29 endpoint • Additional details on the originally planned interim analysis and sample size re-estimation (See Protocol Version 5.0 below) were provided, including a cap of 450 subjects per treatment group • Option for a third DMC meeting was added • Abstinence was removed from contraceptive and barrier guidance • Procedure for discontinuation of HRT to check menopausal status removed • SoC treatment for COVID-19 was specified • Country specific requirements for India were added
    07 Dec 2021
    Protocol amendment 3, Protocol version 4.0, 7-Dec-2021: • Added “hospital-approved diagnostic” PCR test to Inclusion Criterion 2 • Exclusion Criterion 3 rephrased to clarify that the alterations in the Child-Pugh score were to be caused by altered hepatic function, not another underlying disease • Exclusion Criterion 5 changed to a COVID-19 symptom onset >21 days prior to screening (Visit 1) • Oral dispersion was added as an option for subjects with gastric discomfort • Specified that route of administration was captured in the eCRF • Added option of local laboratory analysis of safety samples in special circumstances • Clarification of grading of hepatic impairment (Update of Table 3 in the Protocol [Appendix 16.1.1]) • Subgroup analysis including presence of risk factors for severe COVID-19 was added • Clarified that no adjustment for alpha was required
    13 Apr 2022
    This version was submitted and approved in all the countries, except for Colombia where the trial was completed under Protocol Version 4.0. The key changes in Version 5.0 of the protocol included: • The primary endpoint was changed after the last subject was enrolled. The primary endpoint was changed from “proportion of subjects discharged from hospital and free of supplemental oxygen at Day 15” to “all-cause mortality up to Day 60”. The previous primary endpoint was then considered a key secondary endpoint. Sections 1.1, 3.0, 4.2, 9.1.1, 9.3.2, and 9.3.3 were updated to reflect these changes. • Sample size was reduced from 600 to 300. Protocol Sections 1.1, 1.2, 4.1, 9.3.1, and 9.5 were updated to reflect the reduced sample size. Power calculations were updated to incorporate the new primary endpoint. •The hierarchy was revised for the statistical comparisons for the primary efficacy endpoint and the key secondary endpoint as follows; all-cause mortality up to Day 60, time to sustained hospital discharge up to Day 60, supplemental oxygen free days up to Day 29, proportion of subjects free of respiratory failure at Day 15, and proportion of subjects discharged from hospital and free of supplemental oxygen at Day 15. This means that statistically significant results for the comparison in the higher rank were required to initiate the testing of the next comparison in the lower rank. Since a step-down procedure was used, each comparison was tested at a significance level of 0.05 and an overall alpha level of 0.05 was preserved. • Removal of the planned interim analysis and sample size re-estimation due to decreased sample size. • Subgroup analyses based on race and ethnicity were added. • The number of subjects for the PK sampling was revised due to the decreased overall sample size.

    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
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