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    Clinical Trial Results:
    A Multicentre, Open label, Randomised, Controlled, Basket, Pragmatic, Phase II, Clinical and Translational Study to Determine the Efficacy and Safety of Plitidepsin versus Control in Immunocompromised Adult Patients with Symptomatic COVID-19 requiring Hospital Care (NEREIDA)

    Summary
    EudraCT number
    		 2022-002489-34
    Trial protocol
    		 ES   HU   PT   PL   IT   BE   FR  
    Global end of trial date
    19 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Oct 2024
    First version publication date
    31 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AV-APL-B-002-22
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05705167
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharma Mar, S.A.
    Sponsor organisation address
    Avda. de los Reyes, 1, Polígono Industrial “La Mina”, Colmenar Viejo (Madrid), Spain, 28770
    Public contact
    Clinical Development, Department of PharmaMar´s Oncology., Business Unit., Pharma Mar, S.A., +34 918466000, clinicaltrials@pharmamar.com
    Scientific contact
    Clinical Development, Department of PharmaMar´s Oncology., Business Unit., Pharma Mar, S.A., +34 918466000, clinicaltrials@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
    19 Apr 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Apr 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of the study was to evaluate the efficacy of plitidepsin in pre-specified groups of immunocompromised participants with symptomatic COVID-19 requiring hospital care versus control in terms of mortality.
    Protection of trial subjects
    This study was conducted in compliance with Good Clinical Practice, including the archiving of essential documents. An independent data monitoring committee was established to provide study oversight considering that this was a multicentre, randomised study being performed in a population at high risk for morbidity and mortality.
    Background therapy
    		 Best standard care as per applicable local, institutional, national, supranational COVID-19 treatment guidelines.
    Evidence for comparator
    		 Other regulatory-approved antiviral (if clinically indicated) were administered to participants in control groups.
    Actual start date of recruitment
    30 Dec 2022
    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
    Belgium: 3
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Greece: 14
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Portugal: 4
    Worldwide total number of subjects
    37
    EEA total number of subjects
    37
    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)
    11
    From 65 to 84 years
    25
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 37 participants were enrolled at 15 investigative sites between April 2023 and April 2024. Randomised participants who received at least 1 dose of study treatment and completed follow-up for survival until Day 30 (±2) were included in the Full Analysis Set (FAS) population.

    Pre-assignment
    Screening details
    		 Disposition data pertaining to the participants not included in the FAS Population are presented within the pre-assignment period due to EudraCT system limitations.

    Pre-assignment period milestones
    Number of subjects started
    		 37
    Number of subjects completed
    		 25

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Randomised but not Treated: 9
    Reason: Number of subjects
    		 Discontinued Prior to FAS Eligibility: 3
    Period 1
    Period 1 title
    Overall Study - FAS Population (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1: Plitidepsin 2.5 mg
    Arm description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute intravenous (IV) infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 1. Group 1 – Participants who received immune-suppression due to haematopoietic or organ transplantation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Plitidepsin
    Investigational medicinal product code
    SAPL01
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV infusion over 60-minutes.

    Arm title
    		 Group 1: Control
    Arm description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) were administered to participants in Group 1. Group 1 – Participants who received immune-suppression due to haematopoietic or organ transplantation.
    Arm type
    		 Other regulatory-approved antiviral

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Group 2: Plitidepsin 2.5 mg
    Arm description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 2. Group 2 – Participants who received B-cell depleting therapies.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Plitidepsin
    Investigational medicinal product code
    SAPL01
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV infusion over 60-minutes.

    Arm title
    		 Group 2: Control
    Arm description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) were administered to participants in Group 2. Group 2 – Participants who received B-cell depleting therapies.
    Arm type
    		 Other regulatory-approved antiviral

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Group 3: Plitidepsin 2.5 mg
    Arm description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 3. Group 3 – Participants who received other immune-suppressive therapies.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Plitidepsin
    Investigational medicinal product code
    SAPL01
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV infusion over 60-minutes.

    Arm title
    		 Group 3: Control
    Arm description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) were administered to participants in Group 3. Group 3 – Participants who received other immune-suppressive therapies.
    Arm type
    		 Other regulatory-approved antiviral

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Group 4: Plitidepsin 2.5 mg
    Arm description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 4. Group 4 – Other situations with immune deficiencies.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Plitidepsin
    Investigational medicinal product code
    SAPL01
    Other name
    Pharmaceutical forms
    Powder and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV infusion over 60-minutes.

    Number of subjects in period 1 [1]
    		Group 1: Plitidepsin 2.5 mg Group 1: Control Group 2: Plitidepsin 2.5 mg Group 2: Control Group 3: Plitidepsin 2.5 mg Group 3: Control Group 4: Plitidepsin 2.5 mg
    Started
    2
    1
    10
    3
    1
    1
    7
    Completed
    2
    1
    7
    3
    0
    0
    6
    Not completed
    0
    0
    3
    0
    1
    1
    1
         Death
    -
    -
    3
    -
    1
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Disposition data pertaining to the participants not included in the FAS Population are presented within the pre-assignment period due to EudraCT system limitations.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1: Plitidepsin 2.5 mg
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute intravenous (IV) infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 1. Group 1 – Participants who received immune-suppression due to haematopoietic or organ transplantation.

    Reporting group title
    Group 1: Control
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) were administered to participants in Group 1. Group 1 – Participants who received immune-suppression due to haematopoietic or organ transplantation.

    Reporting group title
    Group 2: Plitidepsin 2.5 mg
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 2. Group 2 – Participants who received B-cell depleting therapies.

    Reporting group title
    Group 2: Control
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) were administered to participants in Group 2. Group 2 – Participants who received B-cell depleting therapies.

    Reporting group title
    Group 3: Plitidepsin 2.5 mg
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 3. Group 3 – Participants who received other immune-suppressive therapies.

    Reporting group title
    Group 3: Control
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) were administered to participants in Group 3. Group 3 – Participants who received other immune-suppressive therapies.

    Reporting group title
    Group 4: Plitidepsin 2.5 mg
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 4. Group 4 – Other situations with immune deficiencies.

    Reporting group values
    		 Group 1: Plitidepsin 2.5 mg Group 1: Control Group 2: Plitidepsin 2.5 mg Group 2: Control Group 3: Plitidepsin 2.5 mg Group 3: Control Group 4: Plitidepsin 2.5 mg Total
    Number of subjects
    		 2 1 10 3 1 1 7 25
    Age categorical
    Units: Subjects
        < 65 years
    		 1 0 3 1 0 0 1 6
        ≥ 65 years - < 75 years
    		 1 1 6 2 0 1 1 12
        ≥ 75 years
    		 0 0 1 0 1 0 5 7
    Gender categorical
    Units: Subjects
        Female
    		 1 1 5 2 0 0 5 14
        Male
    		 1 0 5 1 1 1 2 11
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 0 0 0
        Black
    		 0 0 0 0 0 0 0 0
        Native Hawaiian or other Pacific Islander
    		 0 0 0 0 0 0 1 1
        White
    		 2 1 10 3 1 1 5 23
        Other
    		 0 0 0 0 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Group 1: Plitidepsin 2.5 mg
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute intravenous (IV) infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 1. Group 1 – Participants who received immune-suppression due to haematopoietic or organ transplantation.

    Reporting group title
    Group 1: Control
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) were administered to participants in Group 1. Group 1 – Participants who received immune-suppression due to haematopoietic or organ transplantation.

    Reporting group title
    Group 2: Plitidepsin 2.5 mg
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 2. Group 2 – Participants who received B-cell depleting therapies.

    Reporting group title
    Group 2: Control
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) were administered to participants in Group 2. Group 2 – Participants who received B-cell depleting therapies.

    Reporting group title
    Group 3: Plitidepsin 2.5 mg
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 3. Group 3 – Participants who received other immune-suppressive therapies.

    Reporting group title
    Group 3: Control
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) were administered to participants in Group 3. Group 3 – Participants who received other immune-suppressive therapies.

    Reporting group title
    Group 4: Plitidepsin 2.5 mg
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 4. Group 4 – Other situations with immune deficiencies.

    Primary: One-month All-cause Mortality Rate

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    End point title
    		 One-month All-cause Mortality Rate [1]
    End point description
    In the event of the participant initiating another non-protocol therapy, 1-month all-cause mortality rate was evaluated regardless of initiation of new non-protocol therapy. FAS Population: All randomised participants who received at least 1 dose of study treatment (plitidepsin or control) and completed follow-up for survival until Day 30 (±2). Participants who died before the end of the follow-up period were also included in the FAS population.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 30 (±2)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Additional statistical analysis pre-specified for the primary endpoint could not be entered as we are unable to add "N/A" values within the system due to system limitations.
    End point values
    		 Group 1: Plitidepsin 2.5 mg Group 1: Control Group 2: Plitidepsin 2.5 mg Group 2: Control Group 3: Plitidepsin 2.5 mg Group 3: Control Group 4: Plitidepsin 2.5 mg
    Number of subjects analysed
    2
    1
    10
    3
    1
    1
    7
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 84.2)
    0.0 (0.0 to 97.5)
    20.0 (2.5 to 55.6)
    0.0 (0.0 to 70.8)
    0.0 (0.0 to 97.5)
    100.0 (2.5 to 100.0)
    14.3 (0.4 to 57.9)
    No statistical analyses for this end point

    Secondary: Time to Confirmed Negativisation in SARS-CoV-2 Antigen Test or Real Time Polymerase Chain Reaction (RT-PCR) Cycle Threshold (Ct) > 30

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    End point title
    		 Time to Confirmed Negativisation in SARS-CoV-2 Antigen Test or Real Time Polymerase Chain Reaction (RT-PCR) Cycle Threshold (Ct) > 30
    End point description
    Time to confirmed negativisation in SARS-CoV antigen test or RT-PCR Ct>30 was calculated as time from randomisation to the corresponding event using Kaplan-Meier (KM) estimates. Participants with no available data for any time to event efficacy endpoint were censored at time 0, end of study (Day 60 ±3), or date of early study termination. Also, participants who had not achieved the time to event endpoint were censored at the last valid assessment. FAS Population: All randomised participants who received at least 1 dose of study treatment (plitidepsin or control) and completed follow-up for survival until Day 30 (±2). Participants who died before the end of the follow-up period were also included in the FAS population. Values of "-99999" and "99999" indicate median and/or confidence intervals (CI) were not reached due to low number of events.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60 (±3)
    End point values
    		 Group 1: Plitidepsin 2.5 mg Group 1: Control Group 2: Plitidepsin 2.5 mg Group 2: Control Group 3: Plitidepsin 2.5 mg Group 3: Control Group 4: Plitidepsin 2.5 mg
    Number of subjects analysed
    2
    1
    10
    3
    1
    1
    7
    Units: days
        median (confidence interval 95%)
    61.0 (-99999 to 99999)
    2.0 (-99999 to 99999)
    14.0 (2.0 to 99999)
    14.0 (4.0 to 99999)
    13.0 (-99999 to 99999)
    10.0 (-99999 to 99999)
    14.0 (3.0 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Sustained End of COVID-related Hospital Care

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    End point title
    		 Time to Sustained End of COVID-related Hospital Care
    End point description
    Time to sustained end of COVID-related hospital care from the time of randomisation was calculated as time from randomisation to the corresponding event using KM estimates. Participants with no available data for any time to event efficacy endpoint were censored at time 0, end of study (Day 60 ±3), or date of early study termination. Also, participants who had not achieved the time to event endpoint were censored at the last valid assessment. FAS Population: All randomised participants who received at least 1 dose of study treatment (plitidepsin or control) and completed follow-up for survival until Day 30 (±2). Participants who died before the end of the follow-up period were also included in the FAS population. Values of "-99999" and "99999" indicate median and/or CI were not reached due to low number of events.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60 (±3)
    End point values
    		 Group 1: Plitidepsin 2.5 mg Group 1: Control Group 2: Plitidepsin 2.5 mg Group 2: Control Group 3: Plitidepsin 2.5 mg Group 3: Control Group 4: Plitidepsin 2.5 mg
    Number of subjects analysed
    2
    1
    10
    3
    1
    1
    7
    Units: days
        median (confidence interval 95%)
    20.5 (2.0 to 99999)
    4.0 (-99999 to 99999)
    4.5 (2.0 to 99999)
    37.0 (13.0 to 99999)
    24.0 (-99999 to 99999)
    2.0 (-99999 to 99999)
    7.0 (3.0 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Sustained Improvement and Resolution of Selected COVID-19 Signs/Symptoms

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    End point title
    		 Time to Sustained Improvement and Resolution of Selected COVID-19 Signs/Symptoms
    End point description
    Time to sustained improvement and resolution of all targeted COVID-19 signs/symptoms was calculated as time from randomisation to the corresponding event using KM estimates. Corresponding events were defined as the event occurring on the first of 4 consecutive days when all symptoms scored as National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v5.0; category of moderate-severe intensity, or requiring medical intervention, or limiting instrumental activity of daily living are scored as mild or absent AND all symptoms scored mild or 0 (absent) at study entry are scored as 0. Participants with no available data for any time to event efficacy endpoint were censored at time 0, end of study (Day 60 ±3), or date of early study termination. Also, participants who had not achieved the time to event endpoint were censored at the last valid assessment. Values of "-99999" and "99999" indicate median and/or CI were not reached due to low number of events.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60 (±3)
    End point values
    		 Group 1: Plitidepsin 2.5 mg Group 1: Control Group 2: Plitidepsin 2.5 mg Group 2: Control Group 3: Plitidepsin 2.5 mg Group 3: Control Group 4: Plitidepsin 2.5 mg
    Number of subjects analysed
    2 [2]
    1 [3]
    10 [4]
    3 [5]
    1 [6]
    1 [7]
    7 [8]
    Units: days
        median (confidence interval 95%)
    99999 (5.0 to 99999)
    99999 (-99999 to 99999)
    99999 (3.0 to 99999)
    14.0 (4.0 to 99999)
    17.0 (-99999 to 99999)
    2.0 (-99999 to 99999)
    37.0 (2.0 to 99999)
    Notes
    [2] - FAS Population.
    [3] - FAS Population.
    [4] - FAS Population.
    [5] - FAS Population.
    [6] - FAS Population.
    [7] - FAS Population.
    [8] - FAS Population.
    No statistical analyses for this end point

    Secondary: Number of Participants in Each Category of the World Health Organization (WHO) Clinical Progression Scale (CPS)

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    End point title
    		 Number of Participants in Each Category of the World Health Organization (WHO) Clinical Progression Scale (CPS)
    End point description
    Distribution of participants according to their clinical status by the 11-category WHO CPS: - Uninfected; no viral ribonucleic acid (RNA) detected - Asymptomatic; viral RNA detected - Symptomatic; independent - Symptomatic; assistance needed - Hospitalised; no oxygen therapy - Hospitalised; oxygen by mask or nasal prongs (NP) - Hospitalised; oxygen by non-invasive ventilation (NIV) or high flow - Intubation and mechanical ventilation (MV) - MV or vasopressors - MV and vasopressors, dialysis, or extracorporeal membrane oxygenation (ECMO) OR - Death. FAS Population: All randomised participants who received at least 1 dose of study treatment (plitidepsin or control) and completed follow-up for survival until Day 30 (±2). Participants who died before the end of the follow-up period were also included in the FAS population. Values of "9999" indicate no participants were analysed at that timepoint.
    End point type
    Secondary
    End point timeframe
    Days 4 (±1), 8 (±1), 15 (±1), 30 (±2), and 60 (±3)
    End point values
    		 Group 1: Plitidepsin 2.5 mg Group 1: Control Group 2: Plitidepsin 2.5 mg Group 2: Control Group 3: Plitidepsin 2.5 mg Group 3: Control Group 4: Plitidepsin 2.5 mg
    Number of subjects analysed
    2
    1
    10 [9]
    3
    1
    1 [10]
    7 [11]
    Units: participants
        Day 4: Uninfected; no viral RNA detected
    0
    0
    0
    0
    0
    9999
    0
        Day 4: Asymptomatic; viral RNA detected
    0
    0
    2
    0
    0
    9999
    0
        Day 4: Symptomatic; independent
    1
    0
    1
    0
    0
    9999
    0
        Day 4: Symptomatic; assistance needed
    0
    0
    0
    0
    0
    9999
    0
        Day 4: Hospitalised; no oxygen therapy
    0
    1
    4
    2
    0
    9999
    5
        Day 4: Hospitalised; oxygen by mask or NP
    1
    0
    0
    1
    0
    9999
    1
        Day 4: Hospitalised; oxygen by NIV or high flow
    0
    0
    2
    0
    1
    9999
    1
        Day 4: Intubation and MV
    0
    0
    0
    0
    0
    9999
    0
        Day 4: MV or vasopressors
    0
    0
    0
    0
    0
    9999
    0
        Day 4: MV and vasopressors, dialysis, or ECMO
    0
    0
    0
    0
    0
    9999
    0
        Day 4: Dead
    0
    0
    0
    0
    0
    9999
    0
        Day 8: Uninfected; no viral RNA detected
    0
    1
    0
    0
    0
    1
    0
        Day 8: Asymptomatic; viral RNA detected
    0
    0
    3
    0
    0
    0
    2
        Day 8: Symptomatic; independent
    1
    0
    4
    1
    0
    0
    1
        Day 8: Symptomatic; assistance needed
    0
    0
    0
    0
    0
    0
    0
        Day 8: Hospitalised; no oxygen therapy
    0
    0
    0
    2
    0
    0
    1
        Day 8: Hospitalised; oxygen by mask or NP
    1
    0
    1
    0
    0
    0
    1
        Day 8: Hospitalised; oxygen by NIV or high flow
    0
    0
    1
    0
    1
    0
    2
        Day 8: Intubation and MV
    0
    0
    0
    0
    0
    0
    0
        Day 8: MV or vasopressors
    0
    0
    1
    0
    0
    0
    0
        Day 8: MV and vasopressors, dialysis, or ECMO
    0
    0
    0
    0
    0
    0
    0
        Day 8: Dead
    0
    0
    0
    0
    0
    0
    0
        Day 15: Uninfected; no viral RNA detected
    0
    1
    2
    0
    0
    1
    1
        Day 15: Asymptomatic; viral RNA detected
    0
    0
    2
    0
    0
    0
    2
        Day 15: Symptomatic; independent
    1
    0
    1
    1
    0
    0
    1
        Day 15: Symptomatic; assistance needed
    0
    0
    1
    0
    0
    0
    0
        Day 15: Hospitalised; no oxygen therapy
    1
    0
    1
    1
    0
    0
    1
        Day 15: Hospitalised; oxygen by mask or NP
    0
    0
    0
    1
    1
    0
    1
        Day 15: Hospitalised; oxygen by NIV or high flow
    0
    0
    0
    0
    0
    0
    0
        Day 15: Intubation and MV
    0
    0
    0
    0
    0
    0
    0
        Day 15: MV or vasopressors
    0
    0
    2
    0
    0
    0
    0
        Day 15: MV and vasopressors, dialysis, or ECMO
    0
    0
    1
    0
    0
    0
    0
        Day 15: Dead
    0
    0
    0
    0
    0
    0
    0
        Day 30: Uninfected; no viral RNA detected
    0
    1
    3
    1
    0
    9999
    2
        Day 30: Asymptomatic; viral RNA detected
    0
    0
    2
    0
    0
    9999
    2
        Day 30: Symptomatic; independent
    2
    0
    1
    0
    0
    9999
    0
        Day 30: Symptomatic; assistance needed
    0
    0
    0
    0
    1
    9999
    1
        Day 30: Hospitalised; no oxygen therapy
    0
    0
    0
    0
    0
    9999
    0
        Day 30: Hospitalised; oxygen by mask or NP
    0
    0
    0
    2
    0
    9999
    0
        Day 30: Hospitalised; oxygen by NIV or high flow
    0
    0
    0
    0
    0
    9999
    0
        Day 30: Intubation and MV
    0
    0
    0
    0
    0
    9999
    0
        Day 30: MV or vasopressors
    0
    0
    1
    0
    0
    9999
    0
        Day 30: MV and vasopressors, dialysis, or ECMO
    0
    0
    0
    0
    0
    9999
    0
        Day 30: Dead
    0
    0
    0
    0
    0
    9999
    0
        Day 60: Uninfected; no viral RNA detected
    1
    1
    3
    1
    0
    9999
    4
        Day 60: Asymptomatic; viral RNA detected
    1
    0
    2
    1
    0
    9999
    0
        Day 60: Symptomatic; independent
    0
    0
    1
    0
    0
    9999
    1
        Day 60: Symptomatic; assistance needed
    0
    0
    0
    0
    1
    9999
    0
        Day 60: Hospitalised; no oxygen therapy
    0
    0
    0
    0
    0
    9999
    0
        Day 60: Hospitalised; oxygen by mask or NP
    0
    0
    0
    1
    0
    9999
    0
        Day 60: Hospitalised; oxygen by NIV or high flow
    0
    0
    0
    0
    0
    9999
    0
        Day 60: Intubation and MV
    0
    0
    0
    0
    0
    9999
    0
        Day 60: MV or vasopressors
    0
    0
    0
    0
    0
    9999
    0
        Day 60: MV and vasopressors, dialysis, or ECMO
    0
    0
    0
    0
    0
    9999
    0
        Day 60: Dead
    0
    0
    0
    0
    0
    9999
    0
    Notes
    [9] - Day 4 N = 9; Day 30 N = 7; Day 60 N = 6.
    [10] - Days 4, 30, and 60 N = 0.
    [11] - Day 15 N = 6; Days 30 and 60 N = 5.
    No statistical analyses for this end point

    Secondary: Number of Participants Requiring Oxygen Therapy

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    End point title
    		 Number of Participants Requiring Oxygen Therapy
    End point description
    The maximum number of participants requiring oxygen therapy on any day during each visit window is reported. FAS Population: All randomised participants who received at least 1 dose of study treatment (plitidepsin or control) and completed follow-up for survival until Day 30 (±2). Participants who died before the end of the follow-up period were also included in the FAS population.
    End point type
    Secondary
    End point timeframe
    Days 4 (±1), 8 (±1), 15 (±1), 30 (±2), and 60 (±3)
    End point values
    		 Group 1: Plitidepsin 2.5 mg Group 1: Control Group 2: Plitidepsin 2.5 mg Group 2: Control Group 3: Plitidepsin 2.5 mg Group 3: Control Group 4: Plitidepsin 2.5 mg
    Number of subjects analysed
    2
    1
    10
    3
    1
    1
    7
    Units: participants
        Day 4
    0
    0
    2
    1
    1
    0
    3
        Day 8
    1
    0
    3
    1
    1
    0
    3
        Day 15
    0
    0
    3
    1
    1
    1
    1
        Day 30
    0
    0
    1
    1
    1
    0
    1
        Day 60
    0
    0
    1
    1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Time to Sustained Discontinuation of Oxygen Supplementation

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    End point title
    		 Time to Sustained Discontinuation of Oxygen Supplementation
    End point description
    Time to sustained discontinuation is calculated as time from randomisation to the corresponding event using KM estimates. Corresponding events were defined as discontinuation of oxygen supplementation for at least 7 days. Participants with no available data for any time to event efficacy endpoint were censored at time 0, end of study (Day 60 ±3), or date of early study termination. Also, participants who had not achieved the time to event endpoint were censored at the last valid assessment. FAS Population: All randomised participants who received at least 1 dose of study treatment (plitidepsin or control) and completed follow-up for survival until Day 30 (±2). Participants who died before the end of the follow-up period were also included in the FAS population. Values of "-99999" and "99999" indicate median and/or CI were not reached due to low number of events.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60 (±3)
    End point values
    		 Group 1: Plitidepsin 2.5 mg Group 1: Control Group 2: Plitidepsin 2.5 mg Group 2: Control Group 3: Plitidepsin 2.5 mg Group 3: Control Group 4: Plitidepsin 2.5 mg
    Number of subjects analysed
    2
    1
    10
    3
    1
    1
    7
    Units: days
        median (confidence interval 95%)
    13.0 (-99999 to 99999)
    99999 (-99999 to 99999)
    63.0 (1.0 to 99999)
    99999 (34.0 to 99999)
    99999 (-99999 to 99999)
    14.0 (-99999 to 99999)
    14.0 (2.0 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE)

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    End point title
    		 Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE)
    End point description
    Frequency of the following events (all-cause and treatment-related) are included: • TEAEs • TEAEs ≥ grade 3 according to the NCI CTCAE v5.0 • TEAEs of special interest • Serious TEAEs • Serious adverse reactions (SARs) • AEs leading to treatment discontinuation (TD) • Deaths (related to COVID-19/all) Clinically relevant/significant changes from Baseline in laboratory parameters and vital signs were reported as AEs. As Treated Population: All participants who received any exposure to study treatment (plitidepsin or control). As Treated population was analysed according to the treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 60 (±3)
    End point values
    		 Group 1: Plitidepsin 2.5 mg Group 1: Control Group 2: Plitidepsin 2.5 mg Group 2: Control Group 3: Plitidepsin 2.5 mg Group 3: Control Group 4: Plitidepsin 2.5 mg
    Number of subjects analysed
    2
    1
    10 [12]
    3 [13]
    1
    1
    7 [14]
    Units: participants
        Any TEAE
    1
    1
    10
    4
    1
    1
    7
        Any treatment-related TEAE
    1
    0
    4
    1
    0
    0
    2
        Any TEAE ≥ grade 3
    1
    0
    5
    4
    1
    1
    4
        Any treatment-related TEAE ≥ grade 3
    0
    0
    0
    0
    0
    0
    1
        Any TEAE of special interest
    1
    0
    4
    2
    0
    0
    4
        Any treatment-related TEAE of special interest
    1
    0
    1
    1
    0
    0
    0
        Any serious TEAE
    1
    0
    5
    4
    1
    1
    2
        Any treatment-related serious TEAE
    0
    0
    0
    0
    0
    0
    0
        Any TEAE leading to TD
    0
    0
    0
    0
    0
    0
    0
        Any treatment-related TEAE leading to TD
    0
    0
    0
    0
    0
    0
    0
        Any TEAE leading to death
    0
    0
    3
    0
    1
    1
    1
        Any treatment-related TEAE leading to death
    0
    0
    0
    0
    0
    0
    0
    Notes
    [12] - N = 11 per As Treated Population.
    [13] - N = 4 per As Treated Population.
    [14] - N = 8 per As Treated Population.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 60 (±3)
    Adverse event reporting additional description
    As Treated Population: All participants who received any exposure to study treatment (plitidepsin or control). As Treated population was analysed according to the treatment they actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Group 3: Control
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) were administered to participants in Group 3. Group 3 – Participants who received other immune-suppressive therapies.

    Reporting group title
    Group 4: Plitidepsin 2.5 mg
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 4. Group 4 – Other situations with immune deficiencies.

    Reporting group title
    Group 1: Plitidepsin 2.5 mg
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 1. Group 1 – Participants who received immune-suppression due to haematopoietic or organ transplantation.

    Reporting group title
    Group 3: Plitidepsin 2.5 mg
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 3. Group 3 – Participants who received other immune-suppressive therapies.

    Reporting group title
    Group 2: Plitidepsin 2.5 mg
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) and plitidepsin (administered as a 60-minute IV infusion, every 24 hours for 3 consecutive days, at a dose of 2.5 mg) were administered to participants in Group 2. Group 2 – Participants who received B-cell depleting therapies.

    Reporting group title
    Group 2: Control
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) were administered to participants in Group 2. Group 2 – Participants who received B-cell depleting therapies.

    Reporting group title
    Group 1: Control
    Reporting group description
    		 Best standard care (as per applicable local, institutional, national, supranational COVID-19 treatment guidelines) ± other regulatory-approved antiviral (if clinically indicated) were administered to participants in Group 1. Group 1 – Participants who received immune-suppression due to haematopoietic or organ transplantation.

    Serious adverse events
    		 Group 3: Control Group 4: Plitidepsin 2.5 mg Group 1: Plitidepsin 2.5 mg Group 3: Plitidepsin 2.5 mg Group 2: Plitidepsin 2.5 mg Group 2: Control Group 1: Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    2 / 8 (25.00%)
    1 / 2 (50.00%)
    1 / 1 (100.00%)
    5 / 11 (45.45%)
    4 / 4 (100.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    1
    1
    0
    1
    3
    0
    0
         number of deaths resulting from adverse events
    1
    1
    0
    1
    3
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma cell myeloma
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Coma
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pneumoperitoneum
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    2 / 11 (18.18%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    2 / 4 (50.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Candida pneumonia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Stenotrophomonas infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group 3: Control Group 4: Plitidepsin 2.5 mg Group 1: Plitidepsin 2.5 mg Group 3: Plitidepsin 2.5 mg Group 2: Plitidepsin 2.5 mg Group 2: Control Group 1: Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    6 / 8 (75.00%)
    1 / 2 (50.00%)
    1 / 1 (100.00%)
    10 / 11 (90.91%)
    4 / 4 (100.00%)
    1 / 1 (100.00%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    2 / 11 (18.18%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Vein disorder
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    5 / 11 (45.45%)
    2 / 4 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    7
    4
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 8 (37.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    2 / 11 (18.18%)
    1 / 4 (25.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    3
    0
    0
    2
    1
    1
    Chills
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Immune system disorders
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Rales
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    Pharyngeal erythema
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Lung consolidation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Cough
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 8 (25.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    4
    0
    0
    1
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 8 (50.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
    3 / 11 (27.27%)
    3 / 4 (75.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    4
    0
    2
    3
    7
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Hypoxia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Blood urea increased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Urine output decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    2 / 4 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    Procedural nausea
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Cardiac disorders
    Sinus arrhythmia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Cardiac failure
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    0
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dizziness postural
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Slow speech
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Migraine
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    3 / 11 (27.27%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    0
    0
    Gastrointestinal sounds abnormal
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    2 / 11 (18.18%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    0
    Constipation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Renal impairment
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Bone pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Campylobacter infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Bacteraemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Decreased appetite
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    1 / 1 (100.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 8 (12.50%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 8 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    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
    19 Sep 2022
    The main objective and rationale for the substantial amendment was to correct the errors detected after the signature of the study protocol and to implement some changes (amendments) in response to clarifications requested by different drug agencies from the countries where the NEREIDA study was to be carried out and that had led to country-specific protocol versions.
    22 Mar 2023
    The main objective and rationale for the substantial amendment was to include all changes applied in the local and global amendments.

    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.
    The study was early terminated due to significant difficulties in the recruitment of participants.
    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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