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    Clinical Trial Results:
    Efficacy and safety of ANAkinra during Adult « COVID-19 » with Aggravating respiratory symptoms: a multicenter open-label controlled randomized trial

    Summary
    EudraCT number
    2020-001734-36
    Trial protocol
    FR  
    Global end of trial date
    03 Nov 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    27 May 2022
    First version publication date
    27 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DR200111
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04364009
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    CHRU Tours
    Sponsor organisation address
    Boulevard Tonnellé, Tours, France, 37044 cedex 9
    Public contact
    Clinical Research Associate, CHRU de TOURS, +33 247474665, e.mousset@chu-tours.fr
    Scientific contact
    Coordinating investigator, CHRU de TOURS, +33 247473715, alexandra.audemardverger@univ-tours.fr
    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
    03 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Nov 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of the ANACONDA-COVID-19 trial is to assess the efficacy of Anakinra + optimized Standard of Care (oSOC) as compared to oSOC alone on the condition of patients with COVID-19 infection and worsening respiratory symptoms. Success defined as patient alive and free of invasive mechanical ventilation (IMV) and free of Extracorporeal Membrane Oxygenation (ECMO) at Day 14.
    Protection of trial subjects
    An interim analysis for efficacy analysis was planned after the primary outcome has been obtained for the first 120 patients and for safety concerns each 60 patients.
    Background therapy
    -
    Evidence for comparator
    Analgesic treatment, transfusion of blood products, electrolyte and glucose infusions, IV, parenteral nutrition, inotropic support, antibiotics, anti-fungal and anti-viral treatments, ultrafiltration or hemodialysis, as well as general supportive care were allowed. Other therapy considered necessary for the patient’s welfare could be given at the discretion of the Investigator. Due to the lack of sufficient scientific evidence hydroxychloroquine chloroquine and antiretrovirals were not recommended but not prohibited because clinical trials were ongoing. Regarding corticosteroid therapy, due to a potential effectiveness, and the absence of a clearly negative study and a potential synergy with Anakinra, the clinician taking the choice of whether or not to initiate corticosteroid therapy support the patient. A standardized corticosteroid regimen was proposed. Randomization was stratified on the presence or absence of corticosteroid therapy and don’t lead to bias in our study
    Actual start date of recruitment
    27 Apr 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
    France: 71
    Worldwide total number of subjects
    71
    EEA total number of subjects
    71
    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)
    20
    From 65 to 84 years
    41
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    The recruitment started on 27th avril 2020.

    Pre-assignment
    Screening details
    Patients were screened by 45 COVID referent centers. All patients with a positive COVID-19 diagnosis were considered for inclusions. Inclusion and exclusion criteria were first checked during a routine/daily medical visit. The duration of screening period should not exceed 24h.

    Period 1
    Period 1 title
    Inclusion
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Anakinra plus optimized standard of care
    Arm description
    The experimental group received Anakinra plus optimized standard of care. The patients received intraveinous injection (IV) of Anakinra 400mg/day (100mg IV every 6 hours) at Day 1, 2 and 3. From Day 4 to Day 10, the patient received IV injection of Anakinra 200mg/day (100mg every 12 hours). The total duration of Anakinra was 10 Days.
    Arm type
    Experimental

    Investigational medicinal product name
    Kineret
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The patients received Intraveinous injection (IV) of Anakinra 400mg/day (100mg IV every 6 hours) during 3 days. Then, the patient received IV injection of Anakinra 200mg/day (100mg every 12 hours) during 7 days. The total duration of Anakinra is 10 Days.

    Arm title
    optimized standard of care
    Arm description
    The control group received optimized standard of care alone, including all treatments authorized for COVID-19 by the French Health Ministry at inclusion and during the follow-up.
    Arm type
    Usual care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Anakinra plus optimized standard of care optimized standard of care
    Started
    37
    34
    Completed
    30
    34
    Not completed
    7
    0
         Adverse event, serious fatal
    6
    -
         Consent withdrawn by subject
    1
    -
    Period 2
    Period 2 title
    Day 14
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Anakinra+SOC
    Arm description
    The experimental group received Anakinra plus optimized Standard of Care. The patients received Intraveinous injection (IV) of Anakinra 400mg/day (100mg IV every 6 hours) at Day 1, 2 and 3. From Day 4 to Day 10, the patient received IV injection of Anakinra 200mg/day (100mg every 12 hours). The total duration of Anakinra was 10 Days
    Arm type
    Experimental

    Investigational medicinal product name
    Kineret
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The patients received Intraveinous injection (IV) of Anakinra 400mg/day (100mg IV every 6 hours) during 3 days. Then, the patient received IV injection of Anakinra 200mg/day (100mg every 12 hours) during 7 days. The total duration of Anakinra is 10 Days.

    Arm title
    Optimized Standard of Care
    Arm description
    The control group received optimized standard of care alone, including all treatments authorized for COVID-19 by the French Health Ministry at inclusion and during the follow-up.
    Arm type
    Usual care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Anakinra+SOC Optimized Standard of Care
    Started
    30
    34
    Completed
    27
    28
    Not completed
    3
    6
         Adverse event, serious fatal
    3
    5
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Anakinra plus optimized standard of care
    Reporting group description
    The experimental group received Anakinra plus optimized standard of care. The patients received intraveinous injection (IV) of Anakinra 400mg/day (100mg IV every 6 hours) at Day 1, 2 and 3. From Day 4 to Day 10, the patient received IV injection of Anakinra 200mg/day (100mg every 12 hours). The total duration of Anakinra was 10 Days.

    Reporting group title
    optimized standard of care
    Reporting group description
    The control group received optimized standard of care alone, including all treatments authorized for COVID-19 by the French Health Ministry at inclusion and during the follow-up.

    Reporting group values
    Anakinra plus optimized standard of care optimized standard of care Total
    Number of subjects
    37 34 71
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    10 10 20
        From 65-84 years
    21 20 41
        85 years and over
    6 4 10
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    71 ± 14 70 ± 14 -
    Gender categorical
    Units: Subjects
        Female
    9 10 19
        Male
    28 24 52

    End points

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    End points reporting groups
    Reporting group title
    Anakinra plus optimized standard of care
    Reporting group description
    The experimental group received Anakinra plus optimized standard of care. The patients received intraveinous injection (IV) of Anakinra 400mg/day (100mg IV every 6 hours) at Day 1, 2 and 3. From Day 4 to Day 10, the patient received IV injection of Anakinra 200mg/day (100mg every 12 hours). The total duration of Anakinra was 10 Days.

    Reporting group title
    optimized standard of care
    Reporting group description
    The control group received optimized standard of care alone, including all treatments authorized for COVID-19 by the French Health Ministry at inclusion and during the follow-up.
    Reporting group title
    Anakinra+SOC
    Reporting group description
    The experimental group received Anakinra plus optimized Standard of Care. The patients received Intraveinous injection (IV) of Anakinra 400mg/day (100mg IV every 6 hours) at Day 1, 2 and 3. From Day 4 to Day 10, the patient received IV injection of Anakinra 200mg/day (100mg every 12 hours). The total duration of Anakinra was 10 Days

    Reporting group title
    Optimized Standard of Care
    Reporting group description
    The control group received optimized standard of care alone, including all treatments authorized for COVID-19 by the French Health Ministry at inclusion and during the follow-up.

    Primary: Treatment success at day 14

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    End point title
    Treatment success at day 14
    End point description
    End point type
    Primary
    End point timeframe
    At day 14
    End point values
    Anakinra plus optimized standard of care optimized standard of care
    Number of subjects analysed
    37
    34
    Units: Percentage
    26
    31
    Attachments
    Untitled (Filename: Flow_chart.jpg)
    Statistical analysis title
    Risk difference
    Comparison groups
    optimized standard of care v Anakinra plus optimized standard of care
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Chi-squared
    Parameter type
    Risk difference (RD)
    Point estimate
    -20.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -39.2
         upper limit
    -1.8

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Real time reporting from the day that written informed consent is provided until 28 days after the inclusion
    Adverse event reporting additional description
    This initial reporting must be provided in writing and should quickly be followed by a detailed written supplementary report
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Anakinra plus optimized standard of care
    Reporting group description
    The experimental group received Anakinra plus optimized Standard of Care. The patients received Intraveinous injection (IV) of Anakinra 400mg/day (100mg IV every 6 hours) at Day 1, 2 and 3. From Day 4 to Day 10, the patient received IV injection of Anakinra 200mg/day (100mg every 12 hours). The total duration of Anakinra was 10 Days.

    Reporting group title
    optimized standard of care
    Reporting group description
    The control group received optimized standard of care alone, including all treatments authorized for COVID-19 by the French Health Ministry at inclusion and during the follow-up.

    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: The list of adverse events is not available.
    Serious adverse events
    Anakinra plus optimized standard of care optimized standard of care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 37 (51.35%)
    18 / 34 (52.94%)
         number of deaths (all causes)
    9
    5
         number of deaths resulting from adverse events
    8
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
    Additional description: Progression of prostate cancer
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Wrong dose
    Additional description: delay in adaptation of anakinra following clearance <30
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vasoplegia syndrome
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
    Additional description: sudden death
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastrointestinal disorders
    Haemorrhage
    Additional description: Haemorrhage of digestive tract
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic enzyme abnormal
    Additional description: Hepatic cytolysis
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Acute respiratory failure
    Additional description: Acute respiratory decompensation
         subjects affected / exposed
    12 / 37 (32.43%)
    12 / 34 (35.29%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 12
         deaths causally related to treatment / all
    0 / 5
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
    Additional description: Renal failure aggravated
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Anakinra plus optimized standard of care optimized standard of care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 34 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 May 2020
    - Addition of 4 centers - Protocole's modification : At V3, for the group SOC alone, this visit will be performed at hospital or by phone if the patient is discharged from the hospital in order to avoid hospital saturation
    25 May 2020
    - Restart of inclusions after the declaration of a new-fact - Modification of DSMB meeting - Addition of 4 centers
    18 Jun 2020
    - Prolongation of period recruitment

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 May 2020
    Following the occurrence of serious adverse events reported for patients included in the ANACONDA-COVID-19 study and the difference of this occurrence between the two group of randomisation, the CHRU of Tours, promoter of the study, in agreement with the coordinating investigator, decided to refer the matter to the Independent Monitoring Committee of the study. As a safety measure, pending their opinion and recommendations, it was decided to suspend the inclusions.
    06 Jul 2020

    Limitations and caveats

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