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    Clinical Trial Results:
    Use of Defibrotide to reduce progression of acute respiratory failure rate in patients with COVID-19 pneumonia

    Summary
    EudraCT number
    		 2020-001513-20
    Trial protocol
    		 IT  
    Global end of trial date
    25 Jan 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Oct 2022
    First version publication date
    28 Oct 2022
    Other versions
    Summary report(s)
    		 AR-ASH Abstract

    Trial information

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    Trial identification
    Sponsor protocol code
    DEFI-VID19
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04335201
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IRCCS OSPEDALE SAN RAFFAELE
    Sponsor organisation address
    VIA OLGETTINA 60, MILAN, Italy,
    Public contact
    URC-SCP, IRCCS Ospedale San Raffaele, +39 0226434289, urc.scp@hsr.it
    Scientific contact
    URC-SCP, IRCCS Ospedale San Raffaele, +39 0226434289, urc.scp@hsr.it
    Sponsor organisation name
    IRCCS OSPEDALE SAN RAFFAELE
    Sponsor organisation address
    VIA OLGETTINA 60, MILAN, Italy,
    Public contact
    UFFICIO SPERIMENTAZIONI CLINICHE, IRCCS OSPEDALE SAN RAFFAELE , +39 0226434289, urc.ul@hsr.it
    Scientific contact
    UFFICIO SPERIMENTAZIONI CLINICHE, IRCCS OSPEDALE SAN RAFFAELE, +39 0226434289, urc.ul@hsr.it
    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
    25 Jan 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the treatment with Defibrotide administered intravenously in addition to the best available therapy according to institutional guidelines is able to reduce the progression of acute respiratory failure, the need of mechanical ventilation, the transfer to the intensive care unit or death, in patients with severe COVID-19 pneumonia
    Protection of trial subjects
    The patient’s confidentiality will be maintained and will not be made publicly available to the extent permitted by the applicable laws and regulations (Low n. 675/1996 and amendments) and Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation). An identification number will be automatically attributed to each patient enrolled in the trial. This number will identify the patient and must be included on all case report forms. In order to avoid identification errors, date of birth will also be reported on forms.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 52
    Worldwide total number of subjects
    52
    EEA total number of subjects
    52
    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)
    42
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From May 2020 to May 2021 , we enrolled 52 patients consecutive hospitalized with COVID-19 acute pneumonia with and without ARDS/CPAP dependency.

    Pre-assignment
    Screening details
    		 Both male and female were included ( >18 years), each with documented COVID-19 pneumonia defined as upper respiratory tract specimen (nasopharyngeal swab (NPS) or viral throat swab) positive for COVID-19 and/or imaging at computed tomography scan suggestive of COVID-19 pneumonia. Written informed consent.

    Period 1
    Period 1 title
    Overll Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Defibrotide
    Arm description
    		 Patients will be treated according to the standard institutional procedures and will receive the best available treatment as per institutional guidelines in association with the experimental drug: Defibrotide 25 mg/kg body weight total dose in 2 hours duration infusion each, every 6 hours (Defibrotide 6.25 mg/kg body weight each dose).Treatment duration = 14 days Any medication that the participant is receiving at the time of enrollment or receives during the study must be recorded indicating the reason for use, the dates of administration including start and end dates and dosage information including dose and frequency.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Defibrotide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Defibrotide 25 mg/kg body weight total dose in 2 hours duration infusion each, every 6 hours (Defibrotide 6.25 mg/kg body weight each dose) Treatment duration = 14 days

    Number of subjects in period 1
    		Defibrotide
    Started
    52
    Completed
    34
    Not completed
    18
         Adverse event, serious fatal
    8
         Consent withdrawn by subject
    2
         Adverse event, non-fatal
    6
         screening failure
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overll Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overll Trial Total
    Number of subjects
    		 52 52
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 42 42
        From 65-84 years
    		 10 10
    Age continuous
    Units: years
        median (full range (min-max))
    		 60.5 (53 to 71) -
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 35 35
    Subject analysis sets

    Subject analysis set title
    Primary endpoint
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The percentage of subjects with respiratory rate failure at day+14 will be estimated and will be reported along with the corresponding 95% Confidence Intervals (CI).

    Subject analysis set title
    Secondary endpoints
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The time to event endpoints will be described using the Kaplan-Meier approach and estimates at pre-defined time points will be obtained along with 95%Cis. Continuous variables will be summarized with indices of location (i.e. mean or median) and dispersion (i.e. standard deviation or interquartile range), as appropriate. All relevant estimates will be reported with the corresponding 95% Confidence Intervals (CI). As for safety analysis, the number of ADR (expected/unexpected) and SAEs (expected/unexpected and/or related/not related) and the percentage of subjects experiencing ADR and SAEs in the 3 months of observation of the study will be summarized by severity and within body system involved. Narratives will also be presented. The rate of occurrence of these events will also be estimated. The same approach will be used for the analysis of infections.Subgroup analyses and regression models (i.e. logistic model on proportions and Cox model on time to event outcomes) will be perform.

    Subject analysis sets values
    		 Primary endpoint Secondary endpoints
    Number of subjects
    48
    48
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    34
    34
        From 65-84 years
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    60.5 (53 to 71)
    60.5 (53 to 71)
    Gender categorical
    Units: Subjects
        Female
    8
    8
        Male
    26
    26

    End points

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    End points reporting groups
    Reporting group title
    Defibrotide
    Reporting group description
    		 Patients will be treated according to the standard institutional procedures and will receive the best available treatment as per institutional guidelines in association with the experimental drug: Defibrotide 25 mg/kg body weight total dose in 2 hours duration infusion each, every 6 hours (Defibrotide 6.25 mg/kg body weight each dose).Treatment duration = 14 days Any medication that the participant is receiving at the time of enrollment or receives during the study must be recorded indicating the reason for use, the dates of administration including start and end dates and dosage information including dose and frequency.

    Subject analysis set title
    Primary endpoint
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The percentage of subjects with respiratory rate failure at day+14 will be estimated and will be reported along with the corresponding 95% Confidence Intervals (CI).

    Subject analysis set title
    Secondary endpoints
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The time to event endpoints will be described using the Kaplan-Meier approach and estimates at pre-defined time points will be obtained along with 95%Cis. Continuous variables will be summarized with indices of location (i.e. mean or median) and dispersion (i.e. standard deviation or interquartile range), as appropriate. All relevant estimates will be reported with the corresponding 95% Confidence Intervals (CI). As for safety analysis, the number of ADR (expected/unexpected) and SAEs (expected/unexpected and/or related/not related) and the percentage of subjects experiencing ADR and SAEs in the 3 months of observation of the study will be summarized by severity and within body system involved. Narratives will also be presented. The rate of occurrence of these events will also be estimated. The same approach will be used for the analysis of infections.Subgroup analyses and regression models (i.e. logistic model on proportions and Cox model on time to event outcomes) will be perform.

    Primary: The Respiratory-failure rate

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    End point title
    		 The Respiratory-failure rate [1]
    End point description
    End point type
    Primary
    End point timeframe
    The rate will be calculated as the proportion of patients who experienced at least one of the events above by day+14 from treatment start
    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: No statistical analyses complete we have. The incidence of RFR at day 14 was 25 (+/- 6)%, and at day 28, 27 (+/- 6)%.
    End point values
    		 Defibrotide Primary endpoint
    Number of subjects analysed
    48
    48
    Units: percent
        number (confidence interval 95%)
    25 (19 to 31)
    25 (19 to 31)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    from day 0 to day 60
    Adverse event reporting additional description
    -patients' chart -laboratory reports -doctor's letter -nurses documentation
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse events were not recorded.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 May 2020
    With reference to the AIFA press release "Management of clinical trials in Italy in progress COVID-19 emergency (coronavirus disease 19) (Version 2 of 7 April 2020) ", per adding centers to clinical trials already approved exclusively for COVID-19 studies, we proceed by submitting a substantial amendment "Previous". The date indicated as the date of the opinion of the Satellite Ethics Committee interested is the one in which it was decided to include the new center.
    29 Jun 2020
    Change of Principal Investigator Satellite Clinical Center IRCCS Foundation Polyclinic San Matteo of Pavia.
    21 Apr 2021
    The substantive amendment request concerns the new DEFI-VID19 Protocol, Version 4.0 dated March 25, 2021.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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