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    Clinical Trial Results:
    COUNTER-COVID - Oral imatinib to prevent pulmonary vascular leak in Covid19 – a randomized, double --blind, placebo controlled, clinical trial in patients with severe Covid19 disease’

    Summary
    EudraCT number
    		 2020-001236-10
    Trial protocol
    		 NL   BE  
    Global end of trial date
    01 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Apr 2022
    First version publication date
    22 Apr 2022
    Other versions
    Summary report(s)
    		 Publication 2 of EudraCT 2020–001236–10 in Lancet Respir Med 2021
    Publication of EudraCT 2020–001236–10 in Lancet Respir Med 2021

    Trial information

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    Trial identification
    Sponsor protocol code
    CounterCOVID study
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 EU Clinical Trials Register : EudraCT 2020–001236–10, Netherlands Trial Register: NL8491
    Sponsors
    Sponsor organisation name
    Amsterdam UMC, location VUmc
    Sponsor organisation address
    De Boelelaan 1117, Amsterdam, Netherlands, 1081HV
    Public contact
    Jurjan Aman, Amsterdam UMC, +31 610738910, j.aman@amsterdamumc.nl
    Scientific contact
    Jurjan Aman, Amsterdam UMC, +31 610738910, j.aman@amsterdamumc.nl
    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
    05 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test whether treatment with oral imatinib reduces disease burden and consumption of medical resources.
    Protection of trial subjects
    All trial subjects underwent monitoring of clinical, biochemistry and ECG parameters.
    Background therapy
    		 Dexamethasone, remdesivir (temporarily), oxygen suppletion
    Evidence for comparator
    		 The comparator was the placebo group
    Actual start date of recruitment
    23 Mar 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 385
    Worldwide total number of subjects
    385
    EEA total number of subjects
    385
    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)
    203
    From 65 to 84 years
    170
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between March 31st 2020 and Jan 04th 2021, 805 patients were screened at 13 hospitals in the Netherlands (appendix p 2). Four hundred patients were randomised. Eleven patients withdrew consent before receiving the first gift of study medication. 2 patients left the study before receiving their first study dose, after being reallocated.

    Pre-assignment
    Screening details
    		 Patients eligible for inclusion were 18 years of age or older, were admitted to the hospital with proven SARS-CoV-2 infection (based on a reverse transcriptase PCR test), and required supplemental oxygen to maintain a peripheral oxygen saturation greater than 94%.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    Patients received oral imatinib (tablets of 400mg) or non-matching placebo distributed in sealed containers. Medical staff and investigators were not involved in dispensing of the study drug. Patients, medical staff and investigators were blinded for the intervention.

    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
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two placebo tablets one the first day, follow by one tablet each day for 9 days

    Arm title
    		 Imatinib
    Arm description
    		 Imatinib mesylate, 400mg tablets, starting with loading dose of 800mg (Day 0), followed by 400mg once daily (Day 1-9).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Imatinib mesylate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800mg loading dose once (2 tablets of 400mg) followed by 400mg once daily for 9 days

    Number of subjects in period 1
    		Placebo Imatinib
    Started
    188
    197
    Completed
    188
    197

    Baseline characteristics

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

    Reporting group title
    Imatinib
    Reporting group description
    		 Imatinib mesylate, 400mg tablets, starting with loading dose of 800mg (Day 0), followed by 400mg once daily (Day 1-9).

    Reporting group values
    		 Placebo Imatinib Total
    Number of subjects
    		 188 197 385
    Age categorical
    In the placebo group 100 patiens were <= 65 years, 88 were >65 years In the imatinib group 103 patients were <= 65 years, 94 were >65 years
    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)
    		 100 103 203
        From 65-84 years
    		 86 84 170
        85 years and over
    		 2 10 12
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 64 (55 to 74) 64 (57 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 70 51 121
        Male
    		 118 146 264
    Current/former smoker
    Units: Subjects
        (former)smoker
    		 76 77 153
        non-smoker
    		 112 120 232
    Obesity (BMI>30)
    Units: Subjects
        BMI>30
    		 83 53 136
        BMI<30
    		 105 144 249
    Diabetes
    Units: Subjects
        Diabetes_yes
    		 54 41 95
        Diabetes_No
    		 134 156 290
    Cardiovascular disease
    Units: Subjects
        CVD_Yes
    		 48 35 83
        CVD_No
    		 140 162 302
    LMWH_initiated at admission
    Units: Subjects
        LMWH_yes
    		 150 167 317
        LMWH_no
    		 38 30 68
    oral anticoagulants initiated at baseline
    Units: Subjects
        OAC_yes
    		 8 6 14
        OAC_no
    		 180 191 371
    Antibiotics_initiated at admission
    Units: Subjects
        AB_yes
    		 77 85 162
        AB_no
    		 111 112 223
    Dexamethasone initiated at admission
    Units: Subjects
        Dexa_yes
    		 133 143 276
        Dexa_no
    		 55 54 109
    Remdesivir initiated at admission
    Units: Subjects
        Remdes_yes
    		 40 40 80
        Remdes_no
    		 148 157 305
    Hydroxychloroquine initiated at admission
    Units: Subjects
        HCQ_yes
    		 17 15 32
        HCQ_no
    		 171 182 353
    BMI
    Units: kg/m2
        median (inter-quartile range (Q1-Q3))
    		 29.7 (25.6 to 32.9) 27.5 (25.3 to 31.1) -
    Days from symptom onset
    Units: Days
        median (inter-quartile range (Q1-Q3))
    		 10 (8 to 12) 10 (8 to 12) -
    SpO2/FiO2 ratio_baseline
    Units: ratio
        median (inter-quartile range (Q1-Q3))
    		 323 (238 to 377) 321 (265 to 380) -
    Haemoglobin_baseline
    Units: g/dl
        median (inter-quartile range (Q1-Q3))
    		 13.7 (12.6 to 14.7) 13.5 (12.6 to 14.7) -
    CRP_baseline
    Units: mg/L
        median (inter-quartile range (Q1-Q3))
    		 95 (45 to 149) 102 (47.8 to 157.5) -
    NT-proBNP_baseline
    Units: ng/L
        median (inter-quartile range (Q1-Q3))
    		 132 (50 to 352) 147 (49 to 411) -
    LDH_baseline
    Units: U/L
        median (inter-quartile range (Q1-Q3))
    		 366 (293 to 496) 365 (279 to 445) -

    End points

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

    Reporting group title
    Imatinib
    Reporting group description
    		 Imatinib mesylate, 400mg tablets, starting with loading dose of 800mg (Day 0), followed by 400mg once daily (Day 1-9).

    Primary: Liberation from oxygen and ventilation

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    End point title
    		 Liberation from oxygen and ventilation
    End point description
    The primary outcome was the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period after randomisation
    End point type
    Primary
    End point timeframe
    28 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    188
    197
    Units: Subjects
    143
    160
    Attachments
    		 All figures of first manuscript
    Statistical analysis title
    		 Time to event analysis primary outcome
    Statistical analysis description
    The primary outcome was analysed using Kaplan-Meier curves to plot event rate over time; between group differences were expressed as a hazard ratio with 95% confidence intervals (CI) based on Cox regression analyses.
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.69
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.2

    Secondary: Time to intubation

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    End point title
    		 Time to intubation
    End point description
    Time-to-event analysis for time-to-intubation
    End point type
    Secondary
    End point timeframe
    28 days (Side note: the outcome is the same for the 90 day follow up period, since no patients were intubated after the 28 day follow up period)
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    188
    197
    Units: Subjects
        Intubation_yes
    26
    30
        intubation_no
    162
    167
    Statistical analysis title
    		 Kaplan Meier for intubation
    Statistical analysis description
    The secondary outcomes mechanical ventilation was analysed using Kaplan-Meier curves to plot event rate over time; between group differences were expressed as a hazard ratio with 95% confidence intervals (CI) based on Cox regression analyses.
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.81
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.8

    Secondary: Mortality

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    End point title
    		 Mortality
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    188
    197
    Units: subjects
        Mortality_yes
    27
    15
        mortality_no
    161
    182
    Statistical analysis title
    		 Kaplan Meier analysis for mortality
    Statistical analysis description
    The secondary outcomes mortality was analysed using Kaplan-Meier curves to plot event rate over time; between group differences were expressed as a hazard ratio with 95% confidence intervals (CI) based on Cox regression analyses.
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 0.95
    Notes
    [1] - Uncorrected for baseline variable
    Statistical analysis title
    		 Copy of Kaplan Meier analysis for mortality
    Statistical analysis description
    The secondary outcomes mortality was analysed using Kaplan-Meier curves to plot event rate over time; between group differences were expressed as a hazard ratio with 95% confidence intervals (CI) based on Cox regression analyses.
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.068 [3]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 1.05
    Notes
    [2] - Corrected for baseline imbalances (sex, obesity, diabetes, cardiovascular disease)
    [3] - Corrected for baseline variables mentioned above

    Secondary: Duration of oxygen supplementation

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    End point title
    		 Duration of oxygen supplementation
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    188
    197
    Units: Days
        median (inter-quartile range (Q1-Q3))
    5 (3 to 11)
    7 (3 to 12)
    Statistical analysis title
    		 Duration of oxygen supplementation
    Comparison groups
    Imatinib v Placebo
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.23
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [4] - Mann Whitney U test

    Secondary: Duration of mechanical ventilation

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    End point title
    		 Duration of mechanical ventilation
    End point description
    Continuous variables were analysed using a Wilcoxon rank sum test.
    End point type
    Secondary
    End point timeframe
    28-days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    188
    197
    Units: Days
        median (inter-quartile range (Q1-Q3))
    12 (6 to 20)
    7 (3 to 13)
    Statistical analysis title
    		 Duration of mechanical ventilation
    Statistical analysis description
    Continuous variables were analysed using a Wilcoxon rank sum test.
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.008
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [5] - Continuous variables were analysed using a Wilcoxon rank sum test, analysis was performed in the whole population.

    Secondary: Duration of hospital admission

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    End point title
    		 Duration of hospital admission
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    188
    197
    Units: day
        median (inter-quartile range (Q1-Q3))
    6 (3 to 11)
    7 (4 to 11)
    Statistical analysis title
    		 Median comparison - Mann Whitney U
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%

    Secondary: Duration of intensive care admission

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    End point title
    		 Duration of intensive care admission
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    33
    39
    Units: day
        median (inter-quartile range (Q1-Q3))
    15 (7 to 21)
    8 (5 to 13)
    Statistical analysis title
    		 Median comparison - Mann Whitney U
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.025
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Post-hoc: Number of Ventilator Free Days

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    End point title
    		 Number of Ventilator Free Days
    End point description
    End point type
    Post-hoc
    End point timeframe
    28 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    33
    39
    Units: Days
        median (inter-quartile range (Q1-Q3))
    9 (0 to 23)
    22 (14 to 26)
    Statistical analysis title
    		 Median comparison - Mann Whitney U
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    72
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.018
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval

    Post-hoc: Mortality - Long term Follow up

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    End point title
    		 Mortality - Long term Follow up
    End point description
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    188
    197
    Units: subjects
    18
    31
    Statistical analysis title
    		 Cox regression - Hazard Ratio
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    385
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.03 [6]
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 0.94
    Notes
    [6] - Adjusted for sex HR 0·50 (0·28, 0·90) p=0·021 Adjusted for obesity HR 0·47 (0·25, 0·89) p=0·020 Adjusted for diabetes HR 0·55 (0·31, 0·97) p=0·045 Adjusted for CVD HR 0·56 (0·31, 1·00) p=0·048 Adjusted for all the above HR 0·52 (0·28,0.99)p=0.045

    Post-hoc: Liberation from oxygen and ventilation - Long term follow up

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    End point title
    		 Liberation from oxygen and ventilation - Long term follow up
    End point description
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    188
    197
    Units: subjects
    152
    167
    Statistical analysis title
    		 Cox regression - Hazard Ratio
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    385
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.96
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.17

    Post-hoc: Combined outcome: time to need for mechanical ventilation or death - Long term follow up

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    End point title
    		 Combined outcome: time to need for mechanical ventilation or death - Long term follow up
    End point description
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    188
    197
    Units: subjects
    46
    40
    Statistical analysis title
    		 Cox regression - Hazard Ratio
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    385
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.19

    Post-hoc: Duration of hospital admission - Long term follow up

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    End point title
    		 Duration of hospital admission - Long term follow up
    End point description
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    188
    197
    Units: day
        median (inter-quartile range (Q1-Q3))
    6.5 (3 to 11)
    7 (4 to 11)
    Statistical analysis title
    		 Median comparison - Mann Whitney U
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    385
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Post-hoc: Duration of intensive care admission - Long term follow up

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    End point title
    		 Duration of intensive care admission - Long term follow up
    End point description
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    33
    39
    Units: day
        median (inter-quartile range (Q1-Q3))
    15 (7 to 21)
    9 (5 to 15)
    Statistical analysis title
    		 Median comparison - Mann Whitney U
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    72
    Analysis specification
    Post-hoc
    Analysis type
    P-value
    		 = 0.098
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Post-hoc: Duration of mechanical ventilation - Long term follow up

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    End point title
    		 Duration of mechanical ventilation - Long term follow up
    End point description
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    26
    30
    Units: day
        median (inter-quartile range (Q1-Q3))
    12 (7 to 22)
    7 (3 to 15)
    Statistical analysis title
    		 Median comparison - Mann Whitney U
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    56
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Post-hoc: Number of Ventilator Free Days - Long term follow up

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    End point title
    		 Number of Ventilator Free Days - Long term follow up
    End point description
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    33
    39
    Units: day
        median (inter-quartile range (Q1-Q3))
    64 (0 to 84)
    84 (54 to 88)
    Statistical analysis title
    		 Median comparison - Mann Whitney U
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    72
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.036
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Post-hoc: Additional organ support free days - Long term follow up

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    End point title
    		 Additional organ support free days - Long term follow up
    End point description
    The number of additional organ support free days was defined as the total number of days free from cardiovascular support, renal replacement therapy (RRT), and extracorporeal mechanical oxygenation (ECMO). Patients that died before day 90 were assigned -1 additional organ support free days.
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    33
    39
    Units: day
        median (inter-quartile range (Q1-Q3))
    20 (-1 to 26)
    24 (17 to 27)
    Statistical analysis title
    		 Cox regression - Hazard Ratio
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    72
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.11
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Post-hoc: WHO ordinal scale - Long term follow up

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    End point title
    		 WHO ordinal scale - Long term follow up
    End point description
    Category 1 indicates that the patient was not hospitalised, and received no oxygen supplementation; 2. was not hospitalised, but received supplemental oxygen; 3. was hospitalised, without the use of supplemental oxygen; 4. was hospitalised and received supplemental oxygen using a nasal cannula or mask ; 5. was hospitalised and received oxygen through non-invasive ventilation or high-flow devices; 6. was hospitalised and received invasive ventilation with no extra organ support ; 7. was hospitalised and received invasive ventilation plus additional organ support: vasopressors, renal replacement therapy (RRT), or extra corporal membrane oxygenation (ECMO); and 8. died.
    End point type
    Post-hoc
    End point timeframe
    90 days
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    188
    197
    Units: subjects
        the patient was not hospitalised, and received no
    153
    174
        was not hospitalised, but received supplemental ox
    3
    2
        was hospitalised, without the use of supplemental
    0
    0
        was hospitalised and received supplemental oxygen
    0
    1
        was hospitalised and received invasive ventilation
    0
    0
        invasive ventilation and additional organ support
    0
    0
        died
    31
    18
    Statistical analysis title
    		 Linear mixed model
    Statistical analysis description
    Adjusted for sex, diabetes, obesity (BMI > 30kg/m2), and cardiovascular disease.
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    385
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.012 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimate
    Point estimate
    -0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.94
         upper limit
    		 -0.11
    Notes
    [7] - Through day 90 unadjusted HR -0·53 (-0·94, -0·11) p =0·014 Category at day 9 HR -0·54 (-0·99, -0·09) p= 0·018 Category at day 28 HR-0·52 (-0·97, -0·07) p = 0·023 Category at day 90 HR -0·51 (-0·96, -0·06) p = 0·025

    Post-hoc: PaO2/FiO2

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    End point title
    		 PaO2/FiO2
    End point description
    End point type
    Post-hoc
    End point timeframe
    First 14 days after intubation
    End point values
    		 Placebo Imatinib
    Number of subjects analysed
    26
    30
    Units: mmHg
        number (not applicable)
    26
    30
    Statistical analysis title
    		 Linear mixed model
    Statistical analysis description
    Treatment with imatinib, time, and time*treatment were entered as fixed effects Subject IDs were entered as random effect
    Comparison groups
    Placebo v Imatinib
    Number of subjects included in analysis
    56
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.011
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 3.71
    Notes
    [8] - Time*treatment estimate

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    28 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Imatinib
    Reporting group description
    		 Imatinib mesylate, 400mg tablets, starting with loading dose of 800mg (Day 0), followed by 400mg once daily (Day 1-9).

    Serious adverse events
    		 Placebo Imatinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    62 / 188 (32.98%)
    56 / 197 (28.43%)
         number of deaths (all causes)
    31
    18
         number of deaths resulting from adverse events
    31
    18
    Vascular disorders
    Septic shock
    Additional description: septic shock resulting in admission to the intensive care unit
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 188 (1.60%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Death
    Additional description: Death from respiratory insufficiency
         subjects affected / exposed
    31 / 188 (16.49%)
    18 / 197 (9.14%)
         occurrences causally related to treatment / all
    0 / 31
    0 / 18
         deaths causally related to treatment / all
    0 / 31
    0 / 18
    Mechanical ventilation
    Additional description: Transfer to the ICU because of mechanical ventilation due to respiratory insufficiency, no mortality (grade 4)
         subjects affected / exposed
    20 / 188 (10.64%)
    20 / 197 (10.15%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intensive care
    Additional description: transfer to the intensive care unit because of respiratory insufficiency. No intubation, no mortality
         subjects affected / exposed
    4 / 188 (2.13%)
    10 / 197 (5.08%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extracorporeal circulation
    Additional description: ECMO because of respiratory insufficiency, no mortality
         subjects affected / exposed
    0 / 188 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 188 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 188 (0.53%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Placebo Imatinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    90 / 188 (47.87%)
    82 / 197 (41.62%)
    Investigations
    Liver function test abnormal
    Additional description: increased blood ALT or AST grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    5 / 188 (2.66%)
    6 / 197 (3.05%)
         occurrences all number
    5
    6
    Lymphocyte count decreased
    Additional description: grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    15 / 188 (7.98%)
    20 / 197 (10.15%)
         occurrences all number
    15
    20
    Vascular disorders
    thromboembolic event
    Additional description: grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    14 / 188 (7.45%)
    18 / 197 (9.14%)
         occurrences all number
    14
    18
    Cardiac disorders
    prolonged QT corrected interval
    Additional description: grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    14 / 188 (7.45%)
    8 / 197 (4.06%)
         occurrences all number
    14
    8
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    7 / 188 (3.72%)
    3 / 197 (1.52%)
         occurrences all number
    7
    3
    Respiratory, thoracic and mediastinal disorders
    Lung infection (other than COVID-19)
    Additional description: Grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    10 / 188 (5.32%)
    7 / 197 (3.55%)
         occurrences all number
    10
    7
    Acute respiratory distress syndrome grade 3
    Additional description: grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    6 / 188 (3.19%)
    9 / 197 (4.57%)
         occurrences all number
    6
    9
    Acute respiratory distress syndrome grade 4
    Additional description: grade 4 according to the CTCAE v5.0
         subjects affected / exposed
    20 / 188 (10.64%)
    26 / 197 (13.20%)
         occurrences all number
    20
    26
    Psychiatric disorders
    Delirium
    Additional description: grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    12 / 188 (6.38%)
    2 / 197 (1.02%)
         occurrences all number
    12
    2
    Infections and infestations
    Culture
    Additional description: a positive throat swab culture that resulted in starting intravenous antibiotic, antifungal, or antiviral treatment grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    4 / 188 (2.13%)
    5 / 197 (2.54%)
         occurrences all number
    4
    5
    Metabolism and nutrition disorders
    Acidosis grade 3
    Additional description: grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    8 / 188 (4.26%)
    10 / 197 (5.08%)
         occurrences all number
    8
    10
    Alkalosis
    Additional description: grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    20 / 188 (10.64%)
    21 / 197 (10.66%)
         occurrences all number
    20
    21
    Hyperglycaemia
    Additional description: grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    37 / 188 (19.68%)
    22 / 197 (11.17%)
         occurrences all number
    37
    22
    Acidosis grade 4
    Additional description: grade 4 according to the CTCAE v5.0
         subjects affected / exposed
    5 / 188 (2.66%)
    1 / 197 (0.51%)
         occurrences all number
    5
    1
    Hyperkalaemia
         subjects affected / exposed
    6 / 188 (3.19%)
    1 / 197 (0.51%)
         occurrences all number
    6
    1
    Hypoalbuminaemia
    Additional description: grade 3 according to the CTCAE v5.0
         subjects affected / exposed
    5 / 188 (2.66%)
    2 / 197 (1.02%)
         occurrences all number
    5
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Apr 2020
    Change in: - Protocol: double blind, extra blood drawings, removal of viral swabs, pregnancy test, change in inclusion criteria oxygen saturation - informed consent form version update - added participating centers
    12 May 2020
    Change in protocol: hydroxychloroquine use is now exclusion criterium, prolonged QTc as exclusion criterium, changed the stop criterium for elevated liver enzymes, update of the informed consent form, english version of the informed consent form, New participating center
    16 Oct 2020
    Change in primary in endpoint definition, addition of new centers, addition of new safety point, change in principal investigator from one hospital, update of informed consent form

    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.
    A more detailed overview of the post hoc endpoints are provided only in the supplementary appendix of the long term outcome publication. Rare adverse events (prevalence <3%) are only provided in the first publication.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35172891
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