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    Clinical Trial Results:
    A Phase 3, Multicentre, Randomised, Controlled Trial to Determine the Efficacy and Safety of Two Dose Levels of Plitidepsin Versus Control in Adult Patients Requiring Hospitalisation for Management of Moderate COVID-19 Infection

    Summary
    EudraCT number
    		 2020-005951-19
    Trial protocol
    		 FR   BG   GR   PT   ES   RO  
    Global end of trial date
    01 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Feb 2024
    First version publication date
    15 Feb 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APL-D-003-20
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04784559
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharma Mar S.A.
    Sponsor organisation address
    Avda. De los Reyes, 1, Madrid, Spain, 28770
    Public contact
    Clinical Development Virology Business Unit, Pharma Mar S.A., + 34 918466000, virologytrials@pharmamar.com
    Scientific contact
    José Jimeno, MD, PhD, Pharma Mar S.A., + 34 918466000, jjimeno@pharmamar.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
    07 Dec 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Mar 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare efficacy of plitidepsin 1.5 mg or 2.5 mg versus the control assessing the need of supplementary oxygen.
    Protection of trial subjects
    Patients were allowed to withdraw from the study at any time at his/her own request or at the discretion of the investigator for safety, behavioural, or administrative reasons. If the patient withdrew consent for disclosure of future information, the sponsor was to retain and continue to use any data collected before such a withdrawal of consent. Additionally, patients were allowed to request destruction of any samples taken and not tested and the investigator documented this in the site study records. Additional reasons for discontinuation could have included, but were not limited to: • Administration of treatments not allowed in the protocol • Adverse event • Lack of efficacy • Investigator’s decision • Patient refusal as reason for discontinuation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 May 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 61
    Country: Number of subjects enrolled
    Spain: 114
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Greece: 16
    Country: Number of subjects enrolled
    Colombia: 7
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Brazil: 1
    Worldwide total number of subjects
    205
    EEA total number of subjects
    193
    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)
    126
    From 65 to 84 years
    79
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The target population of this study was adult patients requiring hospitalisation and oxygen supplementation for management of moderate COVID-19.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Plitidepsin 2.5 mg
    Arm description
    		 Patients received plitidepsin 2.5 mg/day IV in addition to dexamethasone on Days 1 to 3
    Arm type
    		 Experimental

    Investigational medicinal product name
    Plitidepsin 2.5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received plitidepsin 2.5 mg/day IV in addition to dexamethasone on Days 1 to 3. Best supportive care, consistent with National Institute of Health COVID-19 Treatment Guidelines (www.covid19treatmentguidelines.nig.gov) or local country guidelines was provided (when needed).

    Arm title
    		 Plitidepsin 1.5 mg
    Arm description
    		 Patients received plitidepsin 1.5 mg/day intravenously (IV) in addition to dexamethasone on Days 1 to 3
    Arm type
    		 Experimental

    Investigational medicinal product name
    Plitidepsin 1.5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received plitidepsin 1.5 mg/day IV in addition to dexamethasone on Days 1 to 3. Best supportive care, consistent with National Institute of Health COVID-19 Treatment Guidelines (www.covid19treatmentguidelines.nig.gov) or local country guidelines was provided (when needed).

    Arm title
    		 Control arm
    Arm description
    		 Patients will receive dexamethasone IV on Days 1 to 3. Additionally, in accordance with local treatment guidelines, patients in this group may receive a regulatory-approved antiviral treatment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    All patients were planned to receive dexamethasone phosphate 8 mg/day IV (equivalent to 6.6 mg dexamethasone base) on Days 1 to 3 (administered as a premedication in the plitidepsin arms), followed by dexamethasone phosphate 7.2 mg/day (equivalent to 6 mg/day dexamethasone base) orally (PO)/IV from Day 4 and up to a total cumulative dose of 60 mg dexamethasone base (as per physician judgement according to patient clinical condition and evolution). Additionally, in accordance with local treatment guidelines, patients randomised to the control arm could have received a regulatory-approved antiviral treatment, such as remdesivir (200 mg IV on Day 1 followed by 100 mg/day IV on Days 2 to 5) or favipiravir (1600 mg twice daily [BID] PO on Day 1, followed by 600 mg BID PO for 2 to 5 days). Best supportive care, consistent with National Institute of Health COVID-19 Treatment Guidelines (www.covid19treatmentguidelines.nig.gov) or local country guidelines was provided (when needed).

    Number of subjects in period 1
    		Plitidepsin 2.5 mg Plitidepsin 1.5 mg Control arm
    Started
    68
    70
    67
    Completed
    60
    64
    61
    Not completed
    8
    6
    6
         Patient worsened, PI decision
    1
    -
    -
         Did not meet all inclusion criteria
    -
    1
    -
         The patient was transferred to IRCU
    -
    1
    -
         Discontinued as was found to be ineligible
    -
    -
    1
         Patient admitted in other hospital
    1
    -
    -
         Death
    2
    1
    2
         Patient deterioration
    1
    -
    -
         Serious adverse event
    -
    1
    -
         Lost to follow-up
    -
    -
    2
         Patient refusal (withdrawal of consent)
    3
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Plitidepsin 2.5 mg
    Reporting group description
    		 Patients received plitidepsin 2.5 mg/day IV in addition to dexamethasone on Days 1 to 3

    Reporting group title
    Plitidepsin 1.5 mg
    Reporting group description
    		 Patients received plitidepsin 1.5 mg/day intravenously (IV) in addition to dexamethasone on Days 1 to 3

    Reporting group title
    Control arm
    Reporting group description
    		 Patients will receive dexamethasone IV on Days 1 to 3. Additionally, in accordance with local treatment guidelines, patients in this group may receive a regulatory-approved antiviral treatment.

    Reporting group values
    		 Plitidepsin 2.5 mg Plitidepsin 1.5 mg Control arm Total
    Number of subjects
    		 68 70 67 205
    Age categorical
    Units: Subjects
        ≥18 to 59 years
    		 32 34 32 98
        ≥60 to 64 years
    		 13 9 6 28
        ≥65 to 69 years
    		 8 11 11 30
        ≥70 to 74 years
    		 9 8 4 21
        ≥75 to 79 years
    		 3 6 7 16
        ≥80 years
    		 3 2 7 12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.9 ± 13.33 58.1 ± 14.80 59.3 ± 15.02 -
    Gender categorical
    Units: Subjects
        Female
    		 25 26 25 76
        Male
    		 43 44 42 129
    Race
    Units: Subjects
        Asian
    		 1 3 0 4
        White
    		 63 62 64 189
        Multiple
    		 4 5 3 12
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 33 35 21 89
        Not Hispanic of Latino
    		 35 35 46 116
    Child-bearing potential
    For female participants only
    Units: Subjects
        Yes
    		 4 5 4 13
        No, surgially sterile/post-menopausal
    		 21 18 19 58
        No, other
    		 0 3 2 5
        NA (male participant)
    		 43 44 42 129
    Body mass index group at screening (kg/m2)
    Units: Subjects
        ≥18.5 and <25
    		 10 10 10 30
        ≥25 and <30
    		 31 35 26 92
        ≥30 and <35
    		 15 13 17 45
        ≥35 and <40
    		 9 4 8 21
        ≥40
    		 1 5 4 10
        Missing
    		 2 3 2 7
    Periods of inclusion
    Units: Subjects
        Beginning of accrual – August 2021
    		 2 1 2 5
        September 2021 - March 2022
    		 56 55 51 162
        April 2022 - End of accrual
    		 10 14 14 38
    Vaccination status
    Units: Subjects
        Fully vaccinated
    		 35 36 32 103
        Non-fully vaccinated
    		 6 3 4 13
        Not vaccinated
    		 27 31 31 89
    Height at screening
    Units: Centimeter
        arithmetic mean (standard deviation)
    		 167.79 ± 8.067 169.56 ± 8.534 169.25 ± 10.095 -
    Weight at screening
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 82.72 ± 14.380 86.05 ± 19.778 87.38 ± 19.672 -
    Body mass index at screening
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 29.45 ± 4.555 29.68 ± 5.617 30.26 ± 6.116 -
    Body surface area at screening (m2)
    Units: Participants
        arithmetic mean (standard deviation)
    		 1.922 ± 0.1787 1.961 ± 0.2252 1.968 ± 0.2299 -
    Systolic blood pressure (mmHg) at screening
    Units: mmHg
        arithmetic mean (standard deviation)
    		 123.4 ± 18.44 126.9 ± 16.25 127.9 ± 16.24 -
    Diastolic blood pressure (mmHg) at screening
    Units: mmHg
        arithmetic mean (standard deviation)
    		 74.2 ± 9.53 76.1 ± 9.36 75.0 ± 11.26 -
    Pulse rate (beats/min) at screening
    Units: beats/min
        arithmetic mean (standard deviation)
    		 81.6 ± 13.72 83.9 ± 11.36 84.2 ± 13.50 -
    Temperature (C) at screening
    Units: celsius
        arithmetic mean (standard deviation)
    		 36.91 ± 0.878 36.90 ± 0.899 36.92 ± 0.875 -
    Respiration rate (breaths/min) at screening
    Units: breaths/min
        arithmetic mean (standard deviation)
    		 19.5 ± 3.49 19.0 ± 3.40 19.9 ± 3.32 -
    Oxygen saturation (%) at screening
    Units: Percentage measure
        median (standard deviation)
    		 96.29 ± 1.779 96.26 ± 1.721 96.44 ± 1.749 -
    Fraction of inspired oxygen (%) at screening
    Units: Percentage
        arithmetic mean (standard deviation)
    		 26.92 ± 3.861 26.91 ± 3.370 27.94 ± 9.526 -
    SARS-CoV-2 viral load at Day 1 (log 10 copies/mL)
    Units: Summary was based on full analysis set
        arithmetic mean (standard deviation)
    		 5.02 ± 1.880 4.97 ± 1.985 5.06 ± 2.253 -

    End points

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    End points reporting groups
    Reporting group title
    Plitidepsin 2.5 mg
    Reporting group description
    		 Patients received plitidepsin 2.5 mg/day IV in addition to dexamethasone on Days 1 to 3

    Reporting group title
    Plitidepsin 1.5 mg
    Reporting group description
    		 Patients received plitidepsin 1.5 mg/day intravenously (IV) in addition to dexamethasone on Days 1 to 3

    Reporting group title
    Control arm
    Reporting group description
    		 Patients will receive dexamethasone IV on Days 1 to 3. Additionally, in accordance with local treatment guidelines, patients in this group may receive a regulatory-approved antiviral treatment.

    Primary: Time to sustained withdrawal of supplementary oxygen (11-category WHO Clinical Progression Scale ≤4) with no subsequent reutilisation during remaining study period.

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    End point title
    		 Time to sustained withdrawal of supplementary oxygen (11-category WHO Clinical Progression Scale ≤4) with no subsequent reutilisation during remaining study period.
    End point description
    Time to sustained withdrawal of supplementary oxygen (as defined by the WHO clinical progression scale (Score ≤4). The WHO clinical progression scale provides a measure of illness severity across a range from 0 (uninfected) to 10 (dead).
    End point type
    Primary
    End point timeframe
    From administration date to Day 31(±3)
    End point values
    		 Plitidepsin 2.5 mg Plitidepsin 1.5 mg Control arm
    Number of subjects analysed
    68
    70
    67
    Units: days
        median (confidence interval 95%)
    5 (4 to 7)
    5 (4 to 6)
    7 (6 to 8)
    Statistical analysis title
    		 Plitidepsin 2.5 mg arm versus control arm
    Statistical analysis description
    Stratified Cox proportional-hazards regression model, including the fixed effect of the treatment group and levels of the randomisation stratification factors, ie, geographical region (Europe vs. Rest of the World), Charlson Comorbidity Index (0-1 vs. >1) and pre-baseline Barthel index (≥90 versus <90) as derived using the eCRF data as covariates
    Comparison groups
    Plitidepsin 2.5 mg v Control arm
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.8751 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.727
         upper limit
    		 1.53
    Notes
    [1] - Stratified log-rank test, including the fixed effect of the treatment group and levels of the randomisation stratification factors, ie, geographical region (Europe vs. Rest of the World), Charlson Comorbidity Index (0-1 vs. >1) and pre-baseline Barthel index (≥90 versus <90) as derived using the eCRF data as covariates .
    [2] - 2-sided p-values calculated using a stratified log-rank test, including the fixed effect of the treatment arm and levels of the randomisation stratification factors. Unadjusted pvalue, for multiplicity adjustment uses the Hochberg step-up procedure
    Statistical analysis title
    		 Plitidepsin 1.5 mg arm versus control arm
    Statistical analysis description
    Stratified Cox proportional-hazards regression model, including the fixed effect of the treatment group and levels of the randomisation stratification factors, ie, geographical region (Europe vs. Rest of the World), Charlson Comorbidity Index (0-1 vs. >1) and pre-baseline Barthel index (≥90 versus <90) as derived using the eCRF data as covariates
    Comparison groups
    Control arm v Plitidepsin 1.5 mg
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0625 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.96
    Notes
    [3] - Stratified log-rank test, including the fixed effect of the treatment group and levels of the randomisation stratification factors, ie, geographical region (Europe vs. Rest of the World), Charlson Comorbidity Index (0-1 vs. >1) and pre-baseline Barthel index (≥90 versus <90) as derived using the eCRF data as covariates .
    [4] - 2-sided p-values calculated using a stratified log-rank test, including the fixed effect of the treatment arm and levels of the randomisation stratification factors. Unadjusted pvalue, for multiplicity adjustment uses the Hochberg step-up procedure

    Secondary: Time to sustained (i.e., with no subsequent readmission to Day 31) hospital discharge (since randomisation)

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    End point title
    		 Time to sustained (i.e., with no subsequent readmission to Day 31) hospital discharge (since randomisation)
    End point description
    Time to sustained (i.e., with no subsequent readmission to Day 31) hospital discharge (since randomisation) 000 = not estimated 999 = not estimated
    End point type
    Secondary
    End point timeframe
    From administration date to Day 31(±3)
    End point values
    		 Plitidepsin 2.5 mg Plitidepsin 1.5 mg Control arm
    Number of subjects analysed
    68
    70
    67
    Units: days
        median (confidence interval 95%)
    7 (7 to 9)
    7 (000 to 999)
    7 (7 to 9)
    Statistical analysis title
    		 Plitidepsin 2.5 mg versus control arm
    Comparison groups
    Plitidepsin 2.5 mg v Control arm
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5945 [5]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.948
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.655
         upper limit
    		 1.37
    Notes
    [5] - 2-sided p-values calculated using a stratified log-rank test, including the fixed effect of the treatment arm and levels of the randomisation stratification factors. Unadjusted pvalue, for multiplicity adjustment uses the Hochberg step-up procedure
    Statistical analysis title
    		 Plitidepsin 1.5 mg versus control arm
    Comparison groups
    Control arm v Plitidepsin 1.5 mg
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3358 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.827
         upper limit
    		 1.7
    Notes
    [6] - 2-sided p-values calculated using a stratified log-rank test, including the fixed effect of the treatment arm and levels of the randomisation stratification factors. Unadjusted pvalue, for multiplicity adjustment uses the Hochberg step-up procedure

    Secondary: Clinical Status by the 11-category WHO Clinical Progression Scale

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    End point title
    		 Clinical Status by the 11-category WHO Clinical Progression Scale
    End point description
    The WHO clinical progression scale provides a measure of illness severity across a range from 0 (uninfected) to 10 (dead). *pO2/FiO2 >150 or SpO2/FiO2 >200 **pO2/FiO2 <150 (SpO2/FiO2 <200) or vasopressors ***pO2/FiO2 <150 and vasopressors, dialysis, or ECMO
    End point type
    Secondary
    End point timeframe
    Day 8 (±1)
    End point values
    		 Plitidepsin 2.5 mg Plitidepsin 1.5 mg Control arm
    Number of subjects analysed
    63
    67
    65
    Units: participants
        0 = uninfected, no viral RNA detected
    6
    10
    3
        1 = asymptomatic, viral RNA detected
    12
    15
    12
        2 = symptomatic, independent
    20
    17
    19
        3 = symptomatic, assistance needed
    0
    1
    1
        4 = hospitalised, no oxygen therapy
    4
    8
    7
        5 = hospitalised, oxygen by mask or nasal prongs
    10
    8
    20
        6 = hospitalised, oxygen by NIV or high flow
    5
    7
    1
        7 = intubation and mechanical ventilation*
    4
    1
    2
        8 = mechanical ventilation**
    1
    0
    0
        9 = mechanical ventilation***
    0
    0
    0
        10 = dead
    1
    0
    0
    Statistical analysis title
    		 Plitidepsin 2.5 mg versus control
    Statistical analysis description
    Adjusted Odds Ratio and 95% CI based on a proportional odds model with fixed effects of treatment group and randomisation stratification factors, ie, geographical region (Europe vs. Rest of the World), Charlson Comorbidity Index (0-1 vs. >1) and pre-baseline Barthel index (≥90 versus <90) as derived using the eCRF data as covariates.
    Comparison groups
    Plitidepsin 2.5 mg v Control arm
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.7252 [8]
    Method
    		 proportional odds model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.604
         upper limit
    		 2.06
    Notes
    [7] - Proportional odds model with fixed effects of treatment group and randomisation stratification factors, ie, geographical region (Europe vs. Rest of the World), Charlson Comorbidity Index (0-1 vs. >1) and pre-baseline Barthel index (≥90 versus <90) as derived using the eCRF data as covariates
    [8] - 2-sided p-value. Adjusted odds ratio, 95% CI and 2-sided p-values based on a proportional odds model with fixed effects of treatment arm and randomisation stratification factors
    Statistical analysis title
    		 Plitidepsin 1.5 mg versus control
    Comparison groups
    Control arm v Plitidepsin 1.5 mg
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.091 [9]
    Method
    		 proportional odds model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 3.11
    Notes
    [9] - Adjusted odds ratio, 95% CI and 2-sided p-values based on a proportional odds model with fixed effects of treatment arm and randomisation stratification factors

    Secondary: Total Duration of Advanced Oxygen Support (High-flow Nasal Oxygen, Extracorporeal Membrane Oxygenation - ECMO-, Non-invasive Ventilation or Mechanical Ventilation)

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    End point title
    		 Total Duration of Advanced Oxygen Support (High-flow Nasal Oxygen, Extracorporeal Membrane Oxygenation - ECMO-, Non-invasive Ventilation or Mechanical Ventilation)
    End point description
    Total Duration of Advanced Oxygen Support (High-flow Nasal Oxygen, Extracorporeal Membrane Oxygenation - ECMO-, Non-invasive Ventilation or Mechanical Ventilation)
    End point type
    Secondary
    End point timeframe
    From administration date to Day 31(±3)
    End point values
    		 Plitidepsin 2.5 mg Plitidepsin 1.5 mg Control arm
    Number of subjects analysed
    13
    11
    11
    Units: days
        arithmetic mean (standard deviation)
    12.2 ± 9.71
    10 ± 8.21
    8.3 ± 12.66
    No statistical analyses for this end point

    Secondary: Percentage of Patients in Each Study Group Requiring Admission to ICU

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    End point title
    		 Percentage of Patients in Each Study Group Requiring Admission to ICU
    End point description
    Percentage of Patients in Each Study Group Requiring Admission to ICU
    End point type
    Secondary
    End point timeframe
    Day 4, Day 8(±1) , Day 15(±1) and Day 31(±3)
    End point values
    		 Plitidepsin 2.5 mg Plitidepsin 1.5 mg Control arm
    Number of subjects analysed
    63
    67
    65
    Units: participants
    number (confidence interval 95%)
        From Day 1 to Day 4
    1 (0.0402 to 8.53)
    1 (0.0378 to 8.04)
    3 (0.962 to 12.9)
        From Day 1 to Day 8
    7 (4.59 to 21.6)
    3 (0.933 to 12.5)
    4 (1.70 to 15.0)
        From Day 1 to Day 15
    7 (4.59 to 21.6)
    4 (1.65 to 14.6)
    4 (1.70 to 15.0)
        From Day 1 to Day 31
    7 (4.59 to 21.6)
    5 (2.47 to 16.6)
    4 (1.70 to 15.0)
    No statistical analyses for this end point

    Secondary: Frequency of Adverse Events

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    End point title
    		 Frequency of Adverse Events
    End point description
    Adverse Event Types according to the National Cancer Institute [NCI]-Common Terminology Criteria for AEs (CTCAE v.5.0). The number of participants who experienced treatment-emergent adverse events (TEAEs) are presented.
    End point type
    Secondary
    End point timeframe
    From administration date to Day 31(±3)
    End point values
    		 Plitidepsin 2.5 mg Plitidepsin 1.5 mg Control arm
    Number of subjects analysed
    63
    67
    65
    Units: participants
    45
    44
    40
    No statistical analyses for this end point

    Secondary: Frequency of TEAEs of ≥Grade 3 According to NCI-CTCAE for Adverse Events (Version 5.0), TEAEs of Special Interest, Serious TEAEs, Serious Treatment-related TEAEs, TEAEs Leading to Treatment Discontinuation, and Deaths

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    End point title
    		 Frequency of TEAEs of ≥Grade 3 According to NCI-CTCAE for Adverse Events (Version 5.0), TEAEs of Special Interest, Serious TEAEs, Serious Treatment-related TEAEs, TEAEs Leading to Treatment Discontinuation, and Deaths
    End point description
    Frequency of treatment-emergent adverse events (TEAEs) of ≥grade 3 according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0), TEAEs of special interest, serious TEAEs, serious treatment-related TEAEs, TEAEs leading to treatment discontinuation, and deaths. *Any serious treatment-related TEAE to any study treatment **Any TEAE leading to discontinuation of any study treatment
    End point type
    Secondary
    End point timeframe
    From administration date to Day 31(±3)
    End point values
    		 Plitidepsin 2.5 mg Plitidepsin 1.5 mg Control arm
    Number of subjects analysed
    63
    67
    65
    Units: participants
        Any TEAE Grade ≥3
    22
    17
    11
        Any TEAE of special interest
    22
    25
    18
        Any serious TEAE
    11
    6
    5
        Serious treatment-related TEAE to treatment**
    1
    1
    0
        TEAE leading to discontinuation**
    1
    1
    1
        Any TEAE leading to death
    2
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Screening to Day 31 +/- 3 days
    Adverse event reporting additional description
    Adverse events for the as-treated population are presented. One randomised participant experienced an AE of adult respiratory distress syndrome but never received any study treatment, so is not included here. All AEs and adverse reactions, based on clinical signs and symptoms and laboratory measurements, were measured daily from Day 1 to Day 31.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Plitidepsin 2.5 mg
    Reporting group description
    		 Patients received plitidepsin 2.5 mg/day IV in addition to dexamethasone on Days 1 to 3. Adverse events for the as-treated population are presented.

    Reporting group title
    Plitidepsin 1.5 mg
    Reporting group description
    		 Patients received plitidepsin 1.5 mg/day intravenously (IV) in addition to dexamethasone on Days 1 to 3 Adverse events for the as-treated population are presented.

    Reporting group title
    Control arm
    Reporting group description
    		 Patients will receive dexamethasone IV on Days 1 to 3. Additionally, in accordance with local treatment guidelines, patients in this group may receive a regulatory-approved antiviral treatment. Adverse events for the as-treated population are presented.

    Serious adverse events
    		 Plitidepsin 2.5 mg Plitidepsin 1.5 mg Control arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 63 (17.46%)
    6 / 67 (8.96%)
    5 / 65 (7.69%)
         number of deaths (all causes)
    2
    1
    2
         number of deaths resulting from adverse events
    2
    1
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal ischaemia
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    6 / 63 (9.52%)
    4 / 67 (5.97%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 67 (1.49%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    2 / 65 (3.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Plitidepsin 2.5 mg Plitidepsin 1.5 mg Control arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 63 (68.25%)
    43 / 67 (64.18%)
    38 / 65 (58.46%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acrochordon
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Thymoma
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    11 / 63 (17.46%)
    9 / 67 (13.43%)
    2 / 65 (3.08%)
         occurrences all number
    11
    9
    2
    Hypotension
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 67 (2.99%)
    3 / 65 (4.62%)
         occurrences all number
    1
    2
    3
    Hypertension
         subjects affected / exposed
    0 / 63 (0.00%)
    3 / 67 (4.48%)
    2 / 65 (3.08%)
         occurrences all number
    0
    4
    4
    Deep vein thrombosis
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    0
    Peripheral venous disease
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 63 (4.76%)
    4 / 67 (5.97%)
    4 / 65 (6.15%)
         occurrences all number
    4
    7
    5
    Asthenia
         subjects affected / exposed
    3 / 63 (4.76%)
    3 / 67 (4.48%)
    2 / 65 (3.08%)
         occurrences all number
    3
    3
    2
    Chest discomfort
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 67 (1.49%)
    4 / 65 (6.15%)
         occurrences all number
    1
    1
    4
    Malaise
         subjects affected / exposed
    0 / 63 (0.00%)
    3 / 67 (4.48%)
    3 / 65 (4.62%)
         occurrences all number
    0
    3
    3
    Extravasation
         subjects affected / exposed
    2 / 63 (3.17%)
    2 / 67 (2.99%)
    1 / 65 (1.54%)
         occurrences all number
    2
    2
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 63 (1.59%)
    3 / 67 (4.48%)
    1 / 65 (1.54%)
         occurrences all number
    1
    3
    1
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Catheter site phlebitis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Discomfort
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    2
    Generalised oedema
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Illness
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Perineal erythema
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Prostatitis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Pruritus genital
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    8 / 63 (12.70%)
    7 / 67 (10.45%)
    5 / 65 (7.69%)
         occurrences all number
    10
    7
    6
    Dyspnoea
         subjects affected / exposed
    3 / 63 (4.76%)
    1 / 67 (1.49%)
    4 / 65 (6.15%)
         occurrences all number
    3
    1
    5
    Cough
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 67 (2.99%)
    4 / 65 (6.15%)
         occurrences all number
    1
    2
    5
    Pulmonary embolism
         subjects affected / exposed
    3 / 63 (4.76%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    3
    1
    0
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    1
    0
    1
    Hiccups
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    1
    0
    1
    Bronchial disorder
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Laryngeal oedema
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Lung disorder
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Pleuritic pain
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumomediastinum
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Rales
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Respiratory distress
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Respiratory failure
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    7 / 63 (11.11%)
    6 / 67 (8.96%)
    5 / 65 (7.69%)
         occurrences all number
    8
    6
    6
    Anxiety
         subjects affected / exposed
    5 / 63 (7.94%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    6
    0
    1
    Confusional state
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    2
    1
    0
    Irritability
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    1
    1
    0
    Delirium
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Serum ferritin abnormal
         subjects affected / exposed
    15 / 63 (23.81%)
    13 / 67 (19.40%)
    4 / 65 (6.15%)
         occurrences all number
    18
    16
    5
    C-reactive protein increased
         subjects affected / exposed
    11 / 63 (17.46%)
    7 / 67 (10.45%)
    5 / 65 (7.69%)
         occurrences all number
    11
    11
    5
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    6 / 63 (9.52%)
    6 / 67 (8.96%)
    6 / 65 (9.23%)
         occurrences all number
    6
    7
    7
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 63 (6.35%)
    7 / 67 (10.45%)
    5 / 65 (7.69%)
         occurrences all number
    4
    8
    6
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 63 (7.94%)
    8 / 67 (11.94%)
    3 / 65 (4.62%)
         occurrences all number
    7
    9
    3
    Procalcitonin increased
         subjects affected / exposed
    7 / 63 (11.11%)
    4 / 67 (5.97%)
    2 / 65 (3.08%)
         occurrences all number
    7
    4
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 63 (7.94%)
    3 / 67 (4.48%)
    4 / 65 (6.15%)
         occurrences all number
    5
    3
    4
    Blood glucose increased
         subjects affected / exposed
    4 / 63 (6.35%)
    4 / 67 (5.97%)
    4 / 65 (6.15%)
         occurrences all number
    4
    4
    5
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 67 (2.99%)
    3 / 65 (4.62%)
         occurrences all number
    0
    2
    3
    Fibrin D dimer increased
         subjects affected / exposed
    2 / 63 (3.17%)
    2 / 67 (2.99%)
    1 / 65 (1.54%)
         occurrences all number
    2
    3
    1
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 67 (2.99%)
    2 / 65 (3.08%)
         occurrences all number
    1
    2
    2
    Lipase increased
         subjects affected / exposed
    3 / 63 (4.76%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    4
    1
    0
    Adjusted calcium decreased
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 67 (2.99%)
    0 / 65 (0.00%)
         occurrences all number
    1
    2
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    1
    1
    0
    Oxygen saturation
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    1
    0
    1
    Amylase increased
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    3
    0
    0
    Blood albumin decreased
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Blood sodium decreased
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Chest X-ray abnormal
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Electrocardiogram PR prolongation
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Hepatic enzyme abnormal
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    2
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Interleukin level decreased
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Interleukin level increased
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Troponin T increased
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Epicondylitis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Eschar
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Nerve injury
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Traumatic haematoma
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Wound
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 67 (1.49%)
    1 / 65 (1.54%)
         occurrences all number
    2
    1
    1
    Atrioventricular block
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 67 (2.99%)
    0 / 65 (0.00%)
         occurrences all number
    0
    2
    0
    Tachycardia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Cardiac failure
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 63 (9.52%)
    7 / 67 (10.45%)
    5 / 65 (7.69%)
         occurrences all number
    8
    8
    5
    Dizziness
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 67 (2.99%)
    0 / 65 (0.00%)
         occurrences all number
    1
    2
    0
    Paraesthesia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    1
    Epilepsy
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Neuromyopathy
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Tremor
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    2 / 63 (3.17%)
    1 / 67 (1.49%)
    1 / 65 (1.54%)
         occurrences all number
    2
    2
    1
    Leukocytosis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    2 / 65 (3.08%)
         occurrences all number
    0
    1
    2
    Anaemia
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    2
    1
    0
    Leukopenia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    1
    Neutropenia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Normocytic anaemia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    1
    0
    1
    Tinnitus
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    11 / 63 (17.46%)
    10 / 67 (14.93%)
    4 / 65 (6.15%)
         occurrences all number
    12
    10
    4
    Nausea
         subjects affected / exposed
    9 / 63 (14.29%)
    8 / 67 (11.94%)
    1 / 65 (1.54%)
         occurrences all number
    9
    8
    1
    Diarrhoea
         subjects affected / exposed
    9 / 63 (14.29%)
    3 / 67 (4.48%)
    3 / 65 (4.62%)
         occurrences all number
    9
    3
    3
    Abdominal pain
         subjects affected / exposed
    2 / 63 (3.17%)
    3 / 67 (4.48%)
    2 / 65 (3.08%)
         occurrences all number
    2
    3
    2
    Vomiting
         subjects affected / exposed
    3 / 63 (4.76%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    3
    2
    0
    Dyspepsia
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    3
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    1 / 65 (1.54%)
         occurrences all number
    0
    1
    1
    Frequent bowel movements
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    2
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 67 (2.99%)
    1 / 65 (1.54%)
         occurrences all number
    3
    2
    1
    Erythema
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 67 (2.99%)
    0 / 65 (0.00%)
         occurrences all number
    0
    3
    0
    Dry skin
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Subcutaneous emphysema
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    4 / 63 (6.35%)
    1 / 67 (1.49%)
    1 / 65 (1.54%)
         occurrences all number
    4
    1
    1
    Dysuria
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    1
    1
    0
    Pollakiuria
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Urge incontinence
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    4 / 63 (6.35%)
    2 / 67 (2.99%)
    1 / 65 (1.54%)
         occurrences all number
    5
    2
    1
    Back pain
         subjects affected / exposed
    2 / 63 (3.17%)
    2 / 67 (2.99%)
    1 / 65 (1.54%)
         occurrences all number
    2
    2
    1
    Pain in extremity
         subjects affected / exposed
    2 / 63 (3.17%)
    2 / 67 (2.99%)
    0 / 65 (0.00%)
         occurrences all number
    2
    2
    0
    Myopathy
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    2
    0
    1
    Limb discomfort
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle contracture
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    2
    0
    Neck pain
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    3 / 63 (4.76%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    3
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 63 (0.00%)
    2 / 67 (2.99%)
    0 / 65 (0.00%)
         occurrences all number
    0
    2
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    1
    0
    1
    Bacteraemia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Bacteriuria
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Cellulitis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Herpes simplex
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Herpes zoster
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Hordeolum
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Tracheobronchitis
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    14 / 63 (22.22%)
    12 / 67 (17.91%)
    6 / 65 (9.23%)
         occurrences all number
    14
    12
    6
    Decreased appetite
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 67 (2.99%)
    0 / 65 (0.00%)
         occurrences all number
    1
    2
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 67 (1.49%)
    1 / 65 (1.54%)
         occurrences all number
    1
    1
    1
    Diabetes mellitus
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    1
    1
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    3
    0
    0
    Hyponatraemia
         subjects affected / exposed
    2 / 63 (3.17%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    3
    0
    0
    Acquired mixed hyperlipidaemia
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 67 (1.49%)
    0 / 65 (0.00%)
         occurrences all number
    0
    1
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 63 (0.00%)
    0 / 67 (0.00%)
    1 / 65 (1.54%)
         occurrences all number
    0
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoproteinaemia
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolic alkalosis
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 67 (0.00%)
    0 / 65 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2021
    • Revised study title to specify the adult patients requiring hospitalisation for management of moderate COVID-19. • Indication was revised from “severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (Coronavirus disease-2019 [COVID-19])” to “Treatment of patients hospitalised for management of moderate COVID-19 infection”. • Updated study objectives, respective endpoints, and overall study design and plan description. • Revised end of study definition, diagnosis, and main criteria for inclusion and exclusion. • Updated replacement procedures and follow-up schedule of patients prematurely discontinued from the study treatment regimen or withdrawn from study. • Updated treatments administered, method of treatment assignment, background information, study rationale to align with study design and updated investigator brochure. • Updated section about blinding based on WHO guidance and experience in the APLICOV-PC trial. • List of allowed medications, prohibited medications, and supportive care were updated. • Updated study assessments and procedure section. • Updated section on determination of sample size. • Updated Schedule of Assessments. • Added new appendix (#7) of Barthel index for functional assessment.
    12 Feb 2021
    • Updated inclusion criterion #3: excluded any patient with hyperbilirubinemia, including patients with Gilbert’s syndrome as requested by agency (Medicines and Healthcare products Regulatory Agency). • Updated exclusion criterion #10 to add appropriate risk mitigation for bradycardia. • Updated contraception guidance in line with the Australian Summary of Product Characteristics.
    18 Mar 2021
    • Updated introduction section to add text for APLICOV findings, safety, and efficacy in patients with COVID-19 and benefit-risk considerations • Updated objective and endpoints, as below: o Modified “COVID-19 infection” to “COVID-19 related signs or symptoms” o Include “Proportion of patients with a serologic response anti-SARS-CoV-2” as other secondary objective o Include “Proportion of patients with a serologic response anti-SARS-CoV-2” as other secondary endpoint o Changed patients to be included in QTc substudy (from at least 25 to 50 patients) • Updated section of investigation plan to allow equivalence between doses of dexamethasone phosphate and dexamethasone base, patients to be included in QTc substudy (from at least 25 to 50 patients), and IDMC responsibilities • Updated section for selection of study population • Stopping rules: Added futility analysis for efficacy and safety to be performed when 33% of patients have been randomised and reached a follow-up of 31 days • Deleted interim analysis for efficacy • Updated section of study treatment, concomitant therapies, and other restrictions • Updated section of study assessment and procedures: o Changed the timeframe defined in Schedule of Assessments (from 48 hours to 24 hours) o Clarified time to perform the PCR for COVID-19 (not only at screening but also within the previous 24 hours) o Modified “COVID-19 infection” to “COVID-19 related signs or symptoms” o Clinical laboratory evaluations: Included sodium, potassium, calcium (adjusted), magnesium and troponin, BNP/NT-pro BNP o Prestudy screening assessments o Evaluations during the study treatment updated for serum chemistry, vital signs, and SpO2 o Updated section of sample size and analyses for number of patients o Included Appendix 11 to explain the Charlson comorbidity index o Added futility analysis for efficacy & safety o Included users of antiviral therapies or immunomodulatory drugs in subgroup analyses for primary endpoint
    13 Apr 2021
    • Revised randomisation stratification factor as Geographical Region (Europe versus Rest of the World). • Updated IDMC charter. • A multiplicity adjustment was added in key secondary efficacy outcome measures and Hochberg procedure. • Futility analysis text was updated. • AEs of special interest were added under other secondary objectives/endpoints. • Corrected usage of “in person visit or remotely” and added troponin assessment, at applicable instances. • Revised the text that the troponin tests were to be performed at local laboratory. • Administration of remdesivir if the patient was randomised to the control arm (yes versus no), a subgroup was added for the primary efficacy endpoint analysis.
    27 Jul 2021
    • Two (non-key) secondary objectives were added. • Protocol was adapted to include patients that have received dexamethasone prior to randomisation. • Inclusion criteria updated to allow inclusion of patients with documented diagnosis of SARS-CoV-2 infection by either qualitative PCR or antigen test, to allow patients with maximum of 10 days from onset of COVID-19 symptoms to initiation of study treatment on Day 1, and criteria related to CPK levels, urine samples for pregnancy, and effective contraception methods. • Below exclusion criteria were updated to exclude patients having received treatment for COVID-19 in another trial 4 weeks prior to study enrolment, with severe disease, including mild to severe acute respiratory distress syndrome, history of live vaccination, and with uncontrolled known primary or secondary immunodeficiency. • Disease diagnostic criteria clarified for investigators in the case that the patient had experienced more than one COVID-19 episode. • Clarified for investigators that dose reduction was not allowed. • Concomitant medication text revised to indicate that all COVID-19 vaccinations were to be recorded. • Allowed medication section was amended to allow SARS-CoV-2 vaccination except vaccines with live attenuated virus. • Prohibited medications section updated for usage of approved therapies. • Prebaseline Barthel index score was to be recorded for the previous month before screening. Additionally, SARS-CoV-2 variant was to be recorded, if available.
    13 Oct 2021
    • Peru-specific country amendment was released.
    29 Mar 2022
    • Study rationale updated with new treatments for COVID-19 and updated results for APLICOV-PC study. • Primary and secondary efficacy objectives and respective endpoints were revised to reflect the significant changes in patient population hospitalised for moderate COVID-19. • Other secondary efficacy objective endpoints were updated for clarity. • Inclusion and exclusion criteria were revised to align with evolving clinical practice for COVID-19. • A new stratification factor of Barthel index was added for randomisation. • Futility analysis was revised to align with revised study design, study objectives, and endpoints. • Standard of care was revised based on the additional treatments and locally approved agents per local guidance. • In the study design, description of treatments in the study arms and follow-up period was clarified. Clarified that dexamethasone is administered as part of premedication on Days 1 to 3. • The AEs to be monitored during the follow-up period were clarified. End of study definition was revised. • Randomisation time was extended to 20 months to support recruitment. • Safety and efficacy assessments were updated to align with revised endpoints. End of study assessments were updated. Accordingly, the Schedule of Assessment table was updated. • Statistical analysis was revised to align with revised endpoints.

    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.
    Sponsor prematurely ended study on 31Jan23 due to decreased incidence of study population. Due to system restriction, EoT is entered as 01Mar23, primary completion date, despite Sponsor considering EoT the date of reporting early termination, 31Jan23
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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