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    Clinical Trial Results:
    A randomised, double-blind, placebo-controlled, phase 2 trial investigating the safety and efficacy of C21 in hospitalised subjects with COVID-19 infection not requiring mechanical ventilation

    Summary
    EudraCT number
    2020-001502-38
    Trial protocol
    GB  
    Global end of trial date
    13 Oct 2020

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

    Trial information

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    Trial identification
    Sponsor protocol code
    VP-C21-006
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04452435
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Vicore Pharma AB
    Sponsor organisation address
    Kronhusgatan 11, Göteborg, Sweden, SE-411 05
    Public contact
    Anne Katrine Cohrt, Vicore Pharma AB, +45 2011 1391, anne-katrine.cohrt@vicorepharma.com
    Scientific contact
    Carl-Johan Dalsgaard, Vicore Pharma AB, +46 70 975 98 63, carl-johan.dalsgaard@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
    18 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy of C21 200 mg daily dose (100 mg b.i.d.) on COVID-19 infection not requiring mechanical ventilation
    Protection of trial subjects
    None.
    Background therapy
    All subject received standard of care as background therapy.
    Evidence for comparator
    -
    Actual start date of recruitment
    27 May 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    India: 206
    Worldwide total number of subjects
    206
    EEA total number of subjects
    0
    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)
    186
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial planned to enrol 150 subjects. The 106 subjects randomised were all recruited at sites in India. As the number of subjects randomised was considered sufficient to meet the statistical demands of the trial, enrolment was stopped prematurely. This ensured that trial results could be available in a timely manner.

    Pre-assignment
    Screening details
    206 subjects were enrolled. 96 of the enrolled subjects were screening failures because inclusion criteria 4 (CRP ≥50 and ≤150 mg/L) was not met. 2 enrolled subjects decided to withdraw from the trial before randomisation. 2 subjects died before randomisation (pneumonia). The remaining 106 subjects were randomised to trial treatment

    Pre-assignment period milestones
    Number of subjects started
    206
    Number of subjects completed
    106

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Screening failure: 96
    Reason: Number of subjects
    Adverse event, serious fatal: 2
    Reason: Number of subjects
    Consent withdrawn by subject: 2
    Period 1
    Period 1 title
    Overall period
    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 treatment
    Arm description
    Oral placebo treatment twice daily for 7 days
    Arm type
    Placebo

    Investigational medicinal product name
    Reference treatment (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg twice daily (BID) for 7 days

    Arm title
    C21 treatment
    Arm description
    Oral C21 treatment of 100 mg twice daily for 7 days
    Arm type
    Experimental

    Investigational medicinal product name
    C21
    Investigational medicinal product code
    Other name
    Compound 21, VP01
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg twice daily (BID) for 7 days

    Number of subjects in period 1 [1]
    Placebo treatment C21 treatment
    Started
    55
    51
    Completed
    42
    45
    Not completed
    13
    6
         Required non-invasive ventilation
    1
    1
         Adverse event, serious fatal
    3
    -
         Consent withdrawn by subject
    4
    1
         Discharged from hospital
    4
    4
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 206 subjects were enrolled in the trial but only 106 subjects were randomised and were included in the overall or baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo treatment
    Reporting group description
    Oral placebo treatment twice daily for 7 days

    Reporting group title
    C21 treatment
    Reporting group description
    Oral C21 treatment of 100 mg twice daily for 7 days

    Reporting group values
    Placebo treatment C21 treatment Total
    Number of subjects
    55 51 106
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Age at screening
    Units: years
        arithmetic mean (full range (min-max))
    51.1 (22 to 68) 54.3 (29 to 68) -
    Gender categorical
    Units: Subjects
        Female
    13 13 26
        Male
    42 38 80
    Supplemental oxygen use at baseline
    Units: Subjects
        Yes
    32 29 61
        No
    23 22 45
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    55 51 106
        Not Hispano or Latino
    0 0 0
        Unknown or Not Reported
    0 0 0
    Race
    Units: Subjects
        Asian
    55 51 106
    CRP value (mg/L) at baseline
    Units: Subjects
        ≤ Median
    22 24 46
        > Median
    25 21 46
        Missing
    8 6 14
    Height
    Height at screening
    Units: cm
        arithmetic mean (full range (min-max))
    166.0 (143 to 188) 166.1 (132 to 198) -
    Weight
    Weight at screening
    Units: kg
        arithmetic mean (full range (min-max))
    69.2 (47 to 112) 70.1 (46 to 116) -
    BMI
    BMI at screening
    Units: kg/m2
        arithmetic mean (full range (min-max))
    25.1 (20 to 34) 25.4 (15 to 41) -
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis set (FAS) consisted of all subjects who were randomized and received at least 1 dose of IMP and who had at least 1 post-baseline assessment of efficacy.

    Subject analysis set title
    Per protocol analysis set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per-protocol analysis set (PPAS) was a subset of the FAS and consisted of all subjects without any major protocol deviations that were judged to compromise the analysis of the data.

    Subject analysis sets values
    Full analysis set Per protocol analysis set
    Number of subjects
    106
    98
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Age at screening
    Units: years
        arithmetic mean (full range (min-max))
    52.6 (22 to 68)
    52.8 (24 to 68)
    Gender categorical
    Units: Subjects
        Female
    26
        Male
    80
    Supplemental oxygen use at baseline
    Units: Subjects
        Yes
    61
        No
    45
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0
        Not Hispano or Latino
    106
        Unknown or Not Reported
    0
    Race
    Units: Subjects
        Asian
    106
    CRP value (mg/L) at baseline
    Units: Subjects
        ≤ Median
    46
        > Median
    46
        Missing
    14
    Height
    Height at screening
    Units: cm
        arithmetic mean (full range (min-max))
    166.1 (132 to 198)
    166.7 (132 to 198)
    Weight
    Weight at screening
    Units: kg
        arithmetic mean (full range (min-max))
    69.6 (46 to 116)
    70.3 (46 to 116)
    BMI
    BMI at screening
    Units: kg/m2
        arithmetic mean (full range (min-max))
    25.2 (15 to 41)
    25.3 (15 to 41)

    End points

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    End points reporting groups
    Reporting group title
    Placebo treatment
    Reporting group description
    Oral placebo treatment twice daily for 7 days

    Reporting group title
    C21 treatment
    Reporting group description
    Oral C21 treatment of 100 mg twice daily for 7 days

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis set (FAS) consisted of all subjects who were randomized and received at least 1 dose of IMP and who had at least 1 post-baseline assessment of efficacy.

    Subject analysis set title
    Per protocol analysis set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per-protocol analysis set (PPAS) was a subset of the FAS and consisted of all subjects without any major protocol deviations that were judged to compromise the analysis of the data.

    Primary: Change From Baseline in C-reactive Protein (CRP) After Treatment With C21 200 mg Daily Dose (100 mg b.i.d.)

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    End point title
    Change From Baseline in C-reactive Protein (CRP) After Treatment With C21 200 mg Daily Dose (100 mg b.i.d.)
    End point description
    Change in C-reactive protein (CRP) from baseline to the average of the last two assessments in the treatment period.
    End point type
    Primary
    End point timeframe
    Treatment period of 7 days
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    46
    45
    Units: mg/L
        least squares mean (confidence interval 90%)
    0.22 (0.17 to 0.29)
    0.19 (0.14 to 0.25)
    Statistical analysis title
    Primary endpoint analysis
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [1]
    P-value
    = 0.4891 [2]
    Method
    ANCOVA
    Confidence interval
    Notes
    [1] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
    [2] - The ratio of adjusted treatment means was 0.85 (90% CI: 0.57, 1.26; p=0.4891), indicating that the null hypothesis could not be rejected.
    Statistical analysis title
    Subgroup analysis - use of oxygen at baseline
    Statistical analysis description
    A subgroup analyses was performed in subjects with supplemental oxygen use at baseline. A total of 26 subjects in the C21 group and 27 in the placebo group were included in the analysis of change in CRP from baseline to the mean of the last 2 non-missing scheduled assessments during the treatment period by baseline supplemental oxygen use.
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [3]
    P-value
    = 0.0881 [4]
    Method
    ANCOVA
    Confidence interval
    Notes
    [3] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
    [4] - The ratio of adjusted treatment means was 0.59, the 90% CI did not span 1.0 (0.35, 0.98); and the p-value was less than 0.1 (p=0.0881) indicating a statistically significant difference between the groups.
    Statistical analysis title
    Subgroup analysis - no oxygen use at baseline
    Statistical analysis description
    A total of 19 (86.4%) subjects with no supplemental oxygen use at baseline in the C21 group and 19 (82.6%) subjects in the placebo group were included in the analysis of change in CRP by baseline supplemental oxygen use.
    Comparison groups
    C21 treatment v Placebo treatment
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.6285 [5]
    Method
    ANCOVA
    Confidence interval
    Notes
    [5] - The ratio of adjusted treatment means was 1.20 (90% CI: 0.64, 2.26; p=0.6285), indicating no statistically significant difference between the groups.
    Statistical analysis title
    Subgroup analysis - age ≤ median
    Statistical analysis description
    A total of 20 (87.0%) subjects of median age (54 years) or lower at baseline in the C21 group and 26 (83.9%) in the placebo group were included in the analysis of change in CRP from baseline to the mean of the last 2 non-missing scheduled assessments during the treatment period by baseline age category.
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.5978 [6]
    Method
    ANCOVA
    Confidence interval
    Notes
    [6] - The ratio of adjusted treatment means was 0.85 (90% CI: 0.51, 1.42; p=0.5978), indicating no statistically significant difference between the treatment groups.
    Statistical analysis title
    Subgroup analysis - age > median
    Statistical analysis description
    For subjects above median age (54 years) at baseline, a total of 25 (89.3%) subjects in the C21 group and 20 (83.3%) subjects in the placebo group were included in the analysis of change in CRP by baseline age category.
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.3109 [7]
    Method
    ANCOVA
    Confidence interval
    Notes
    [7] - The ratio of adjusted treatment means was 0.70 (90% CI: 0.39, 1.26; p=0.3109), indicating no statistically significant difference between the treatment groups.
    Statistical analysis title
    Subgroup analysis by sex - women
    Statistical analysis description
    A total of 12 (92.3%) women in the C21 group and 10 (76.9%) women in the placebo group were included in the analysis of change in CRP by sex.
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.0923 [8]
    Method
    ANCOVA
    Confidence interval
    Notes
    [8] - The ratio of adjusted treatment means was 0.38, the 90% CI did not span 1.0 (90% CI: 0.14, 0.98) and the p-value was less than 0.1 (p=0.0923), indicating a statistically significant difference between the groups
    Statistical analysis title
    Subgroup analysis by sex - men
    Statistical analysis description
    A total of 33 (86.8%) men in the C21 group and 36 (85.7%) men in the placebo group were included in the analysis of change in CRP from baseline to the mean of the last 2 non-missing scheduled assessments during the treatment period by sex.
    Comparison groups
    C21 treatment v Placebo treatment
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.7134 [9]
    Method
    ANCOVA
    Confidence interval
    Notes
    [9] - The ratio of adjusted treatment means was 1.10 (90% CI: 0.71, 1.71; p=0.7134), indicating no statistically significant difference between the treatments.
    Statistical analysis title
    Subgroup analysis by baseline CRP value ≥ median
    Statistical analysis description
    A total of 22 (100.0%) subjects in the C21 group and 24 (100.0%) subjects in the placebo group with median CRP values or higher at baseline were included in the analysis.
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.9374 [10]
    Method
    ANCOVA
    Confidence interval
    Notes
    [10] - The ratio of adjusted treatment means was 1.03 (90% CI: 0.58, 1.82; p=0.9374), 0.9374), indicating no statistically significant difference between the treatment groups.
    Statistical analysis title
    Subgroup analysis by baseline CRP value < median
    Statistical analysis description
    A total of 24 (96.0%) subjects with CRP levels lower than median at baseline in the C21 group and 21 (100.0%) in the placebo group were included in the analysis of change in CRP from baseline to the mean of the last 2 non-missing scheduled assessments during the treatment period by baseline CRP category.
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.22444 [11]
    Method
    ANCOVA
    Confidence interval
    Notes
    [11] - The ratio in adjusted treatment means was 0.68 (90% CI: 0.40, 1.15; p=0.2244), indicating no statistically significant difference between the treatment groups.

    Secondary: Change from baseline in body temperature

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    End point title
    Change from baseline in body temperature
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment period of 7 days
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    54
    51
    Units: °C
        least squares mean (confidence interval 90%)
    -0.34 (-0.47 to -0.21)
    -0.11 (-0.25 to 0.02)
    Statistical analysis title
    Secondary endpoint analysis - body temperature
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [12]
    P-value
    = 0.0492 [13]
    Method
    ANCOVA
    Confidence interval
    Notes
    [12] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%
    [13] - The difference of 0.23°C in adjusted treatment means between the groups was statistically significant (90% CI: 0.04, 0.42; p=0.0492).

    Secondary: Change from baseline in IL-6

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    End point title
    Change from baseline in IL-6
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment period of 7 days
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    34
    31
    Units: pg/mL
        least squares mean (confidence interval 90%)
    0.73 (0.51 to 1.03)
    0.73 (0.51 to 1.05)
    Statistical analysis title
    Secondary endpoint analysis- IL-6
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [14]
    P-value
    = 0.9923 [15]
    Method
    ANCOVA
    Confidence interval
    Notes
    [14] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
    [15] - The ratio of adjusted treatment means was 1.00 (90% CI: 0.61, 1.66; p=0.9923), indicating no statistically significant difference between the treatment groups.

    Secondary: Change from baseline in IL-10

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    End point title
    Change from baseline in IL-10
    End point description
    Change in IL-10 from baseline to the average of the last two assessments during the treatment period
    End point type
    Secondary
    End point timeframe
    Treatment period of 7 days
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    39
    37
    Units: pg/mL
        least squares mean (confidence interval 90%)
    0.73 (0.60 to 0.89)
    0.66 (0.54 to 0.80)
    Statistical analysis title
    Secondary endpoint analysis - IL-10
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [16]
    P-value
    = 0.5355 [17]
    Method
    ANCOVA
    Confidence interval
    Notes
    [16] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
    [17] - The ratio of adjusted treatment means was 0.90 (90% CI: 0.68, 1.19; p=0.5355), indicating no statistically significant difference between the treatment groups.

    Secondary: Change from baseline in TNF

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    End point title
    Change from baseline in TNF
    End point description
    Change in TNF from baseline to the average of the last two assessments during the treatment period.
    End point type
    Secondary
    End point timeframe
    Change in TNF from baseline to the average of the last two assessments during the treatment period.
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    46
    46
    Units: pg/mL
        least squares mean (confidence interval 90%)
    1.01 (0.86 to 1.19)
    0.91 (0.77 to 1.07)
    Statistical analysis title
    Secondary endpoint analysis - TNF
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [18]
    P-value
    = 0.4738 [19]
    Method
    ANCOVA
    Confidence interval
    Notes
    [18] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
    [19] - The ratio of adjusted treatment means was 0.90 (90% CI: 0.72, 1.14; p=0.4738), indicating no statistically significant difference between the treatment groups.

    Secondary: Change from baseline in CA125

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    End point title
    Change from baseline in CA125
    End point description
    Change in CA125 from baseline to the average of the last two assessments in the treatment period
    End point type
    Secondary
    End point timeframe
    Treatment period of 7 days
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    48
    46
    Units: u/mL
        least squares mean (confidence interval 90%)
    1.16 (1.04 to 1.31)
    1.17 (1.05 to 1.31)
    Statistical analysis title
    Secondary endpoint analysis - CA125
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [20]
    P-value
    = 0.9418 [21]
    Method
    ANCOVA
    Confidence interval
    Notes
    [20] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
    [21] - The ratio of adjusted treatment means was 0.99 (90% CI: 0.84, 1.17; p=0.9418), indicating no statistically significant difference between the treatment groups.

    Secondary: Change from baseline in ferritin

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    End point title
    Change from baseline in ferritin
    End point description
    Change in ferritin from baseline to the average of the last two assessments during the treatment period.
    End point type
    Secondary
    End point timeframe
    Treatment period of 7 days
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    47
    46
    Units: ng/mL
        least squares mean (confidence interval 90%)
    0.74 (0.66 to 0.84)
    0.75 (0.66 to 0.84)
    Statistical analysis title
    Secondary endpoint analysis - ferritin
    Comparison groups
    C21 treatment v Placebo treatment
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [22]
    P-value
    = 0.9733 [23]
    Method
    ANCOVA
    Confidence interval
    Notes
    [22] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
    [23] - The ratio of adjusted treatment means was 1.00 (90% CI: 0.85, 1.19; p=0.9733), indicating no statistically significant difference between the treatment groups.

    Secondary: Number of subjects not in need of oxygen supply

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    End point title
    Number of subjects not in need of oxygen supply
    End point description
    Number of subjects not in need of oxygen supply at the end of treatment
    End point type
    Secondary
    End point timeframe
    Treatment period of 7 days
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    55
    51
    Units: Subjects
    30
    37
    Statistical analysis title
    Number of subjects not in need of oxygen
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [24]
    P-value
    = 0.0568 [25]
    Method
    Regression, Logistic
    Confidence interval
    Notes
    [24] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%
    [25] - The odds ratio for C21 versus placebo was 2.20, the 90% CI did not span 1.0 (90% CI: 1.11, 4.35) and the p-value was less than 0.1 (p=0.0568), showing a statistically significant difference in favour of C21.

    Secondary: Number of subjects not in need of mechanical invasive or non-invasive ventilation

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    End point title
    Number of subjects not in need of mechanical invasive or non-invasive ventilation
    End point description
    Number of subjects not in need of mechanical invasive or non-invasive ventilation during the treatment period.
    End point type
    Secondary
    End point timeframe
    Treatment period of 7 days
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    55
    51
    Units: Subjects
    53
    50
    Statistical analysis title
    Secondary endpoint analysis - ventilation
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [26]
    P-value
    = 0.6088 [27]
    Method
    Regression, Logistic
    Confidence interval
    Notes
    [26] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
    [27] - The odds ratio for 21 versus placebo was 1.89, indicating no statistically significant difference between the treatment groups (90% CI: 0.25, 14.52; p=0.6088.

    Secondary: Time to need of mechanical invasive or non-invasive ventilation

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    End point title
    Time to need of mechanical invasive or non-invasive ventilation
    End point description
    Time to need of mechanical invasive or non-invasive ventilation during treatment period.
    End point type
    Secondary
    End point timeframe
    Treatment period of 7 days
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    2
    1
    Units: hours
        arithmetic mean (full range (min-max))
    77.925 (59.98 to 95.87)
    60.0 (60.0 to 60.0)
    Statistical analysis title
    Secondary endpoint analysis - time to ventilation
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    3
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [28]
    P-value
    = 0.5757
    Method
    Logrank
    Confidence interval
    Notes
    [28] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.

    Secondary: Time on oxygen supply (for those not needing mechanical invasive or non-invasive ventilation)

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    End point title
    Time on oxygen supply (for those not needing mechanical invasive or non-invasive ventilation)
    End point description
    Time on oxygen supply during the treatment period (for those not needing mechanical invasive or non-invasive ventilation)
    End point type
    Secondary
    End point timeframe
    Treatment period of 7 days
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    55
    51
    Units: Days
        median (inter-quartile range (Q1-Q3))
    5.0 (1.0 to 7.0)
    5.0 (1.0 to 7.0)
    Statistical analysis title
    Secondary endpoint analysis - time on oxygen
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [29]
    P-value
    = 0.8588
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [29] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.

    Secondary: Adverse Events

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    End point title
    Adverse Events
    End point description
    Adverse events were reported from signing of informed consent until end-of-trial visit and are described under adverse events.
    End point type
    Secondary
    End point timeframe
    From signing of informed consent until end-of-trial, 14-17 days
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    55
    51
    Units: Adverse events and subjects
    90
    64
    No statistical analyses for this end point

    Post-hoc: Oxygen Supplementation at Day 14

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    End point title
    Oxygen Supplementation at Day 14
    End point description
    Number of subjects requiring oxygen supplementation at Day 14
    End point type
    Post-hoc
    End point timeframe
    Follow-up Day 14 (7 days after end-of-treatment)
    End point values
    Placebo treatment C21 treatment
    Number of subjects analysed
    55
    51
    Units: Subjects
    11
    1
    Statistical analysis title
    Post-hoc analysis - Day 14
    Comparison groups
    Placebo treatment v C21 treatment
    Number of subjects included in analysis
    106
    Analysis specification
    Post-hoc
    Analysis type
    equivalence [30]
    P-value
    = 0.003 [31]
    Method
    Chi-squared
    Confidence interval
    Notes
    [30] - The null hypothesis was that the treatments were equivalent and was to be rejected in favour of the alternative hypothesis that a treatment difference existed, if the probability of the null hypothesis being true was less than 10%.
    [31] - The post hoc analysis showed that 1 (2.0%) subject in the C21 group and 11 (20.0%) subjects in the placebo group were in need of oxygen supplementation at Day 14, with a statistically significant difference between the treatment groups (p=0.003).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of informed consent until end-of-trial visit, 14-19 days.
    Adverse event reporting additional description
    At each visit, the subject was asked about AEs in an objective manner, e.g., “Have you experienced any problems since the last visit?”
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo treatment
    Reporting group description
    Oral placebo treatment twice daily for 7 days

    Reporting group title
    C21 treatment
    Reporting group description
    Oral C21 treatment of 100 mg twice daily for 7 days

    Serious adverse events
    Placebo treatment C21 treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 51 (1.96%)
         number of deaths (all causes)
    3
    1
         number of deaths resulting from adverse events
    3
    1
    Cardiac disorders
    Cardio-respiratory arrest
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Infections and infestations
    COVID-19 pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Placebo treatment C21 treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 55 (65.45%)
    30 / 51 (58.82%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 55 (7.27%)
    3 / 51 (5.88%)
         occurrences all number
    5
    3
    Alpha tumour necrosis factor increased
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 55 (5.45%)
    6 / 51 (11.76%)
         occurrences all number
    4
    6
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 55 (3.64%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    Blood calcium decreased
         subjects affected / exposed
    2 / 55 (3.64%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    Blood glucose increased
         subjects affected / exposed
    3 / 55 (5.45%)
    5 / 51 (9.80%)
         occurrences all number
    3
    7
    Blood potassium increased
         subjects affected / exposed
    2 / 55 (3.64%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    Blood urea increased
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Carbohydrate antigen 125 increased
         subjects affected / exposed
    4 / 55 (7.27%)
    0 / 51 (0.00%)
         occurrences all number
    4
    0
    Interleukin level increased
         subjects affected / exposed
    4 / 55 (7.27%)
    4 / 51 (7.84%)
         occurrences all number
    4
    6
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 51 (1.96%)
         occurrences all number
    4
    1
    Neutrophil count increased
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 51 (1.96%)
         occurrences all number
    5
    1
    Platelet count decreased
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    Platelet count increased
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Serum ferritin increased
         subjects affected / exposed
    2 / 55 (3.64%)
    5 / 51 (9.80%)
         occurrences all number
    2
    5
    White blood cell count increased
         subjects affected / exposed
    3 / 55 (5.45%)
    0 / 51 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 55 (7.27%)
    0 / 51 (0.00%)
         occurrences all number
    4
    0
    Renal and urinary disorders
    Glycosuria
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    2 / 55 (3.64%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    Hyperglycaemia
         subjects affected / exposed
    4 / 55 (7.27%)
    11 / 51 (21.57%)
         occurrences all number
    5
    14
    Hyponatraemia
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 51 (3.92%)
         occurrences all number
    3
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2020
    The key changes introduced in protocol version 2.0 (14-Aug-2020) were as follows: The planned total number of subjects was increased from 100 to 150 (N=75 in each group) Concomitant medication was allowed to be given according to local SoC (in version 1.0, this had been qualified with ‘If considered unlikely to interfere with IMP or the outcome of the trial’) The trial was to be conducted at sites globally (version 1.0 was only in the United Kingdom) With the original sample size of 50 subjects per group, there was an approximate 80% power to detect a true CRP reduction of 30 mg/L in C21-treated subjects compared with placebo. With the new sample size of 75 subjects per group, there was an approximate 80% power to detect a true CRP reduction of 25 mg/L in C21-treated subjects compared with placebo

    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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