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    Clinical Trial Results:
    Phase 3 randomized, double-blind, placebo-controlled, multi-center study to assess the efficacy and safety of ruxolitinib in patients with COVID-19 associated cytokine storm (RUXCOVID)

    Summary
    EudraCT number
    2020-001662-11
    Trial protocol
    DE   GB   FR   ES   IT  
    Global end of trial date
    17 Oct 2020

    Results information
    Results version number
    v2(current)
    This version publication date
    20 Jun 2021
    First version publication date
    01 May 2021
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CINC424J12301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04362137
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Oct 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the efficacy and safety of ruxolitinib in the treatment of patients with COVID-19 with severe respiratory disease. The primary objective was to evaluate the efficacy (as measured by a composite endpoint of proportion of patients who die, develop respiratory failure [require mechanical ventilation], or require ICU care) of ruxolitinib + standard of care (SoC) therapy compared with placebo + SoC therapy, for the treatment of COVID-19 by Day 29.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 May 2020
    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
    Brazil: 41
    Country: Number of subjects enrolled
    Colombia: 10
    Country: Number of subjects enrolled
    Argentina: 27
    Country: Number of subjects enrolled
    Mexico: 18
    Country: Number of subjects enrolled
    Peru: 25
    Country: Number of subjects enrolled
    Russian Federation: 171
    Country: Number of subjects enrolled
    Turkey: 20
    Country: Number of subjects enrolled
    United States: 48
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    United Kingdom: 14
    Worldwide total number of subjects
    432
    EEA total number of subjects
    58
    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)
    310
    From 65 to 84 years
    118
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in 61 investigative sites in 12 countries.

    Pre-assignment
    Screening details
    Patients were to be randomized on the same day as screening or up to 2 days after completing the screening procedures.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ruxolitinib 5 mg
    Arm description
    Ruxolitinib 5 mg tablets twice daily (b.i.d.) for 14 days with possible extension of treatment to 28 days
    Arm type
    Experimental

    Investigational medicinal product name
    Ruxolitinib
    Investigational medicinal product code
    INC424
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ruxolitinib 5 mg tablets twice daily (b.i.d.) for 14 days with possible extension of treatment to 28 days

    Arm title
    Placebo
    Arm description
    Matching-image placebo for 14 days with possible extension of treatment to 28 days
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching-image placebo for 14 days with possible extension of treatment to 28 days

    Number of subjects in period 1
    Ruxolitinib 5 mg Placebo
    Started
    287
    145
    Safety Set
    281
    143
    Completed
    269
    139
    Not completed
    18
    6
         Adverse event, serious fatal
    9
    3
         Adverse event, non-fatal
    1
    -
         Protocol deviation
    1
    -
         Patient decision
    6
    3
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ruxolitinib 5 mg
    Reporting group description
    Ruxolitinib 5 mg tablets twice daily (b.i.d.) for 14 days with possible extension of treatment to 28 days

    Reporting group title
    Placebo
    Reporting group description
    Matching-image placebo for 14 days with possible extension of treatment to 28 days

    Reporting group values
    Ruxolitinib 5 mg Placebo Total
    Number of subjects
    287 145 432
    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)
    204 106 310
        From 65-84 years
    79 39 118
        85 years and over
    4 0 4
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    56.4 ± 13.7 56.9 ± 12.5 -
    Sex: Female, Male
    Units: participants
        Female
    125 72 197
        Male
    162 73 235
    Race/Ethnicity, Customized
    Units: Subjects
        White
    242 109 351
        American Indian Or Alaska Native
    26 13 39
        Black Or African American
    6 9 15
        Asian
    5 5 10
        Multiple
    3 2 5
        Unknown
    5 7 12

    End points

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    End points reporting groups
    Reporting group title
    Ruxolitinib 5 mg
    Reporting group description
    Ruxolitinib 5 mg tablets twice daily (b.i.d.) for 14 days with possible extension of treatment to 28 days

    Reporting group title
    Placebo
    Reporting group description
    Matching-image placebo for 14 days with possible extension of treatment to 28 days

    Primary: Proportion of patients who die, develop respiratory failure [require mechanical ventilation] or require intensive care unit (ICU) care

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    End point title
    Proportion of patients who die, develop respiratory failure [require mechanical ventilation] or require intensive care unit (ICU) care
    End point description
    Efficacy is measured by a composite endpoint of proportion of patients who die, develop respiratory failure [require mechanical ventilation], or require intensive care unit [ICU] care for the treatment of COVID-19. Analyses are cumulative, thus analysis on Day 29 includes all events till that day. Patients who developed respiratory failure and/or required ICU at randomization are excluded from the analysis.
    End point type
    Primary
    End point timeframe
    Day 1 - Day 29
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    284
    144
    Units: participants
    34
    17
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Comparison groups
    Placebo v Ruxolitinib 5 mg
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.769
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.73

    Secondary: Clinical status

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    End point title
    Clinical status
    End point description
    Clinical status is measured with the 9-point ordinal scale. The scoring is: - Uninfected patients have a score 0 (no clinical or virological evidence of infection). - Ambulatory patients (not in hospital or in hospital and ready for discharge) can have a score 1 (no limitation of activities) or 2 (limitation of activities). - Hospitalized patients with mild disease can have score 3 (no oxygen therapy defined as peripheral oxygen saturation (SpO2) ≥ 94% on room air) or 4 (oxygen by mask or nasal prongs). - Hospitalized patients with severe disease can have score 5 (non-invasive ventilation or high-flow oxygen), 6 (intubation and mechanical ventilation) or 7 (ventilation + additional organ support - pressors, RRT (renal replacement therapy), ECMO (extracorporeal membrane oxygenation)). - Patients who die have a score 8.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Day 29
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    287
    145
    Units: score on scale
    arithmetic mean (standard deviation)
        Baseline (n=286, 145)
    3.7 ± 0.56
    3.7 ± 0.53
        Day 15 (n=280, 142)
    1.8 ± 1.54
    1.8 ± 1.41
        Day 29 (n=278, 142)
    1.1 ± 1.61
    1.0 ± 1.41
    No statistical analyses for this end point

    Secondary: Percentage of patients with at least two-point improvement from baseline in clinical status

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    End point title
    Percentage of patients with at least two-point improvement from baseline in clinical status
    End point description
    Percentage of patients with at least two points improvement in clinical status on the 9-point ordinal scale. The baseline value of clinical status is defined as the last assessment prior to first dose of double-blind treatment. Patients with missing data at Day 15 and/or Day 29 are treated as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Day 29
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    286
    145
    Units: percentage
    number (not applicable)
        Day 15 (n=286, 145)
    72.0
    74.5
        Day 29 (n=286, 145)
    88.1
    89.0
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Statistical analysis description
    Day 15
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.647
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    1.46
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Statistical analysis description
    Day 29
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.997
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    1.92

    Secondary: Percentage of patients with at least one-point improvement from baseline in clinical status

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    End point title
    Percentage of patients with at least one-point improvement from baseline in clinical status
    End point description
    Percentage of patients with at least one point improvement in clinical status on the 9-point ordinal scale. The baseline value of clinical status is defined as the last assessment prior to first dose of double-blind treatment. Patients with missing data at Day 15 and/or Day 29 are treated as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Day 29
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    286
    145
    Units: percentage
    number (not applicable)
        Day 15 (n=286, 145)
    87.4
    88.3
        Day 29 (n=286, 145)
    91.3
    93.8
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Statistical analysis description
    Day 15
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.946
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.87
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Statistical analysis description
    Day 29
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.573
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.35
         upper limit
    1.79

    Secondary: Percentage of patients with at least one-point deterioration from baseline in clinical status

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    End point title
    Percentage of patients with at least one-point deterioration from baseline in clinical status
    End point description
    Percentage of patients with at least one point deterioration in clinical status on the 9-point ordinal scale. The baseline value of clinical status is defined as the last assessment prior to first dose of double-blind treatment. Patients with missing data at Day 15 and/or Day 29 are treated as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Day 29
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    286
    145
    Units: percentage
    number (not applicable)
        Day 15 (n=286, 145)
    5.6
    6.2
        Day 29 (n=286, 145)
    4.9
    3.4
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Statistical analysis description
    Day 15
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.532
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.31
         upper limit
    1.83
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Statistical analysis description
    Day 29
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.764
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    3.49

    Secondary: Time to improvement in clinical status

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    End point title
    Time to improvement in clinical status
    End point description
    Time to improvement in clinical status from baseline category to one less severe category of the 9-point ordinal scale. The baseline value of clinical status is defined as the last assessment prior to first dose of double-blind treatment. Median time to improvement is estimated by Kaplan-Meier method, with dead patients being censored at the maximum follow-up time in the study. Patients who did not achieve improvement and did not die are censored at their last clinical status assessment date.
    End point type
    Secondary
    End point timeframe
    29 days
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    286
    145
    Units: days
        median (confidence interval 95%)
    9.0 (8.0 to 10.0)
    9.0 (8.0 to 12.0)
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.33
    Method
    Proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    1.37

    Secondary: Mean change from baseline in the clinical status

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    End point title
    Mean change from baseline in the clinical status
    End point description
    Mean change from baseline in the 9-point ordinal scale. The baseline value of clinical status is defined as the last assessment prior to first dose of double-blind treatment. Patients with missing data at Day 15 and/or Day 29 are excluded from the analysis. A negative change from baseline in the clinical status is a favorable outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Day 29
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    287
    145
    Units: score on scale
    least squares mean (standard error)
        Day 15 (n=280, 142)
    -1.96 ± 0.084
    -1.93 ± 0.118
        Day 29 (n=278, 142)
    -2.61 ± 0.090
    -2.69 ± 0.126
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Statistical analysis description
    Day 15
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.831
    Method
    ANCOVA
    Parameter type
    Least squares (LS) mean
    Point estimate
    -0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.31
         upper limit
    0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.144
    Notes
    [1] - Due to EudraCT system limitations the number of subjects included in this analysis is not accurately presented in this record. The number of subjects included in this analysis is 422 instead of 432 as indicated in this record.
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Statistical analysis description
    Day 29
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.624
    Method
    ANCOVA
    Parameter type
    LS Mean
    Point estimate
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.23
         upper limit
    0.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.155
    Notes
    [2] - Due to EudraCT system limitations the number of subjects included in this analysis is not accurately presented in this record. The number of subjects included in this analysis is 420 instead of 432 as indicated in this record.

    Secondary: Mortality rate

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    End point title
    Mortality rate
    End point description
    Mortality rate is determined as the proportion of participants who died by study Day 15 and Day 29
    End point type
    Secondary
    End point timeframe
    Day 15, Day 29
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    286
    145
    Units: participants
        Day 15 (n=286, 145)
    6
    2
        Day 29 (n=286, 145)
    9
    3
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Statistical analysis description
    Day 15
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.944
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    5.57
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Statistical analysis description
    Day 29
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.775
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.35
         upper limit
    5.11

    Secondary: Proportion of patients requiring mechanical ventilation

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    End point title
    Proportion of patients requiring mechanical ventilation
    End point description
    Proportion of patients requiring mechanical ventilation. Analyses are cumulative, thus analysis on Day 29 includes all events till that day. Patients who required mechanical ventilation at randomization are excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    Day 1 - Day 29
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    286
    145
    Units: participants
    22
    10
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.987
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    2.21

    Secondary: Duration of hospitalization

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    End point title
    Duration of hospitalization
    End point description
    Duration of hospitalization is defined as time to hospital discharge. Median time to hospital discharge is estimated by Kaplan-Meier method, with dead patients being censored at the maximum follow-up time in the study. Patients who were not discharged and did not die are censored at their last assessment date.
    End point type
    Secondary
    End point timeframe
    29 days
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    286
    145
    Units: days
        median (confidence interval 95%)
    9.0 (8.0 to 10.0)
    9.0 (8.0 to 12.0)
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.738
    Method
    Proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    1.28

    Secondary: Time to hospital discharge or to a NEWS2 score of ≤2

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    End point title
    Time to hospital discharge or to a NEWS2 score of ≤2
    End point description
    The time to hospital discharge or to a National Early Warning Score 2 (NEWS2) of ≤2 and maintained for 24 hours whichever comes first. The NEWS2 is based on a simple aggregate scoring system in which a score is allocated to physiological measurements, already recorded in routine practice presentation or when a patient is being monitored in hospital. The score ranges from 0 (best) to 23 (worst). Median time is estimated by Kaplan-Meier method, with dead patients being censored at the maximum follow-up time in the study.
    End point type
    Secondary
    End point timeframe
    29 days
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    286
    145
    Units: days
        median (confidence interval 95%)
    4.0 (3.0 to 4.0)
    4.0 (3.0 to 5.0)
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.869
    Method
    Proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    1.23

    Secondary: Change from baseline in NEWS2 score

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    End point title
    Change from baseline in NEWS2 score
    End point description
    The National Early Warning Score 2 (NEWS2) is based on a simple aggregate scoring system in which a score is allocated to physiological measurements, already recorded in routine practice presentation or when a patient is being monitored in hospital. The score ranges from 0 (best) to 23 (worst). At each visit, only patients with a value at both baseline and the respective visit are included. A negative change from baseline in NEWS2 score is a favorable outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Days 3, 5, 8, 11, 15, and 29
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    287
    145
    Units: score on scale
    arithmetic mean (standard deviation)
        Day 3 (n=264, 135)
    -0.7 ± 1.91
    -0.6 ± 2.13
        Day 5 (n=230, 120)
    -1.0 ± 2.02
    -0.8 ± 2.19
        Day 8 (n=175, 91)
    -1.3 ± 2.25
    -1.3 ± 2.60
        Day 11 (n=113, 66)
    -1.1 ± 2.70
    -1.3 ± 2.74
        Day 15 (n=257, 132)
    -1.9 ± 2.34
    -2.2 ± 2.35
        Day 29 (n=234, 122)
    -2.3 ± 2.37
    -2.5 ± 2.17
    No statistical analyses for this end point

    Secondary: Change from baseline in SpO2/FiO2 ratio

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    End point title
    Change from baseline in SpO2/FiO2 ratio
    End point description
    Change from baseline in peripheral oxygen saturation / fraction of inspired oxygen ratio (SpO2/FiO2 ratio). At each visit, only patients with a value at both baseline and the respective visit are included. A positive change from baseline in SpO2/FiO2 ratio is a favorable outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Day 29
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    287
    145
    Units: no units
    arithmetic mean (standard deviation)
        Day 15 (n=260, 132)
    90.110 ± 104.4783
    106.766 ± 100.9778
        Day 29 (n=232, 124)
    105.553 ± 98.2452
    109.710 ± 95.4279
    No statistical analyses for this end point

    Secondary: Proportion of patients with no oxygen therapy

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    End point title
    Proportion of patients with no oxygen therapy
    End point description
    Proportion of patients with no oxygen therapy (defined as oxygen saturation ≥ 94% on room air) at Days 15 and 29. Analyses are cumulative, thus analysis on each day includes all events till that day. Patients with missing data at Day 15 and/or Day 29 are excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    Day 15, Day 29
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    287
    145
    Units: participants
        Day 15 (n= 274, 140)
    255
    133
        Day 29 (n= 269, 139)
    262
    136
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Statistical analysis description
    Day 15
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.325
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    1.63
    Statistical analysis title
    Ruxolitinib 5 mg/Placebo
    Statistical analysis description
    Day 29
    Comparison groups
    Ruxolitinib 5 mg v Placebo
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.25
         upper limit
    5.4

    Post-hoc: All Collected Deaths

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    End point title
    All Collected Deaths
    End point description
    Deaths in the safety population were evaluated in all participants who received at least one dose of double-blind treatment. Total deaths were evaluated in all participants randomized.
    End point type
    Post-hoc
    End point timeframe
    29 days
    End point values
    Ruxolitinib 5 mg Placebo
    Number of subjects analysed
    287
    145
    Units: participants
        Deaths in the safety population (n=281, 143)
    9
    3
        Total deaths (n=287, 145)
    9
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of double-blind treatment and up to the last study visit (Day 29).
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Ruxolitinib 5 mg
    Reporting group description
    Ruxolitinib 5 mg tablets twice daily (b.i.d.) for 14 days with possible extension of treatment to 28 days

    Reporting group title
    Placebo
    Reporting group description
    Matching-image placebo for 14 days with possible extension of treatment to 28 days

    Serious adverse events
    Ruxolitinib 5 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 281 (11.03%)
    15 / 143 (10.49%)
         number of deaths (all causes)
    9
    3
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Endotracheal intubation complication
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 281 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 281 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 281 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Adams-Stokes syndrome
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 281 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 281 (0.36%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    4 / 281 (1.42%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    4 / 281 (1.42%)
    4 / 143 (2.80%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 281 (0.71%)
    2 / 143 (1.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (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
    Adverse event
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 281 (0.36%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Performance status decreased
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 281 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Antibiotic associated colitis
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    8 / 281 (2.85%)
    3 / 143 (2.10%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 281 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 281 (1.07%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 281 (0.36%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 281 (0.00%)
    1 / 143 (0.70%)
         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: 2%
    Non-serious adverse events
    Ruxolitinib 5 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    113 / 281 (40.21%)
    62 / 143 (43.36%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 281 (1.42%)
    3 / 143 (2.10%)
         occurrences all number
    4
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    17 / 281 (6.05%)
    6 / 143 (4.20%)
         occurrences all number
    17
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 281 (1.78%)
    3 / 143 (2.10%)
         occurrences all number
    5
    3
    Transaminases increased
         subjects affected / exposed
    7 / 281 (2.49%)
    2 / 143 (1.40%)
         occurrences all number
    7
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 281 (4.27%)
    3 / 143 (2.10%)
         occurrences all number
    12
    4
    Dyspnoea
         subjects affected / exposed
    3 / 281 (1.07%)
    3 / 143 (2.10%)
         occurrences all number
    3
    3
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    4 / 281 (1.42%)
    4 / 143 (2.80%)
         occurrences all number
    4
    5
    Neutropenia
         subjects affected / exposed
    6 / 281 (2.14%)
    4 / 143 (2.80%)
         occurrences all number
    6
    4
    Thrombocytosis
         subjects affected / exposed
    6 / 281 (2.14%)
    3 / 143 (2.10%)
         occurrences all number
    6
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 281 (0.71%)
    4 / 143 (2.80%)
         occurrences all number
    4
    4
    Headache
         subjects affected / exposed
    23 / 281 (8.19%)
    11 / 143 (7.69%)
         occurrences all number
    28
    12
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 281 (2.14%)
    0 / 143 (0.00%)
         occurrences all number
    6
    0
    Fatigue
         subjects affected / exposed
    10 / 281 (3.56%)
    2 / 143 (1.40%)
         occurrences all number
    10
    4
    Pyrexia
         subjects affected / exposed
    6 / 281 (2.14%)
    2 / 143 (1.40%)
         occurrences all number
    6
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 281 (2.14%)
    1 / 143 (0.70%)
         occurrences all number
    6
    1
    Insomnia
         subjects affected / exposed
    3 / 281 (1.07%)
    4 / 143 (2.80%)
         occurrences all number
    3
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 281 (1.42%)
    4 / 143 (2.80%)
         occurrences all number
    4
    5
    Constipation
         subjects affected / exposed
    9 / 281 (3.20%)
    7 / 143 (4.90%)
         occurrences all number
    9
    7
    Diarrhoea
         subjects affected / exposed
    21 / 281 (7.47%)
    12 / 143 (8.39%)
         occurrences all number
    21
    14
    Nausea
         subjects affected / exposed
    6 / 281 (2.14%)
    11 / 143 (7.69%)
         occurrences all number
    6
    11
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    4 / 281 (1.42%)
    5 / 143 (3.50%)
         occurrences all number
    4
    5
    Hyperkalaemia
         subjects affected / exposed
    6 / 281 (2.14%)
    6 / 143 (4.20%)
         occurrences all number
    7
    6
    Hypokalaemia
         subjects affected / exposed
    8 / 281 (2.85%)
    7 / 143 (4.90%)
         occurrences all number
    9
    8
    Hyponatraemia
         subjects affected / exposed
    1 / 281 (0.36%)
    3 / 143 (2.10%)
         occurrences all number
    1
    4
    Hypoproteinaemia
         subjects affected / exposed
    4 / 281 (1.42%)
    3 / 143 (2.10%)
         occurrences all number
    4
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 281 (1.07%)
    4 / 143 (2.80%)
         occurrences all number
    3
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 May 2020
    The main change of this amendment was the update of inclusion and exclusion criteria based on the evolving understanding of COVID-19 disease.

    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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    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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