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    Clinical Trial Results:
    Efficacy and safety of novel treatment options for adults with COVID-19 pneumonia. A double-blinded, randomized, multi-stage, 6-armed placebo-controlled trial in the framework of an adaptive trial platform

    Summary
    EudraCT number
    2020-001367-88
    Trial protocol
    DK  
    Global end of trial date
    17 Jun 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Sep 2020
    First version publication date
    27 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    25032020
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04345289
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Thomas Benfield
    Sponsor organisation address
    Kettegaard Alle 30, Hvidovre, Denmark, 2650
    Public contact
    Charlotte Kastberg Levin, Department of infectious diseases, +45 38622941, charlotte.kastberg.levin.01@regionh.dk
    Scientific contact
    Charlotte Kastberg Levin, Department of infectious diseases, +45 38622941, charlotte.kastberg.levin.01@regionh.dk
    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
    11 Aug 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The aim of this study is to evaluate the efficacy and safety of convalescent anti-SARS-CoV-2 plasma, hydroxychloroquine, sarilumab and baricitinib compared with placebo in combination with standard of care (SOC) for the treatment of moderate-to-severe COVID-19 pneumonia on the basis of the composite endpoint: All-cause mortality or need of invasive mechanical ventilation up to 28 days.
    Protection of trial subjects
    The adaptive study design allowed each treatment group to be evaluated separately. If necessary, each treatment group could be discontinued due to futility, effect, safety or new knowledge on specific treatment of COVID-19. This was the case for hydroxychloroqunie which was withdrawn from the study 2020-06-09 due to new research results (from other studies) indicating severe adverse events, when giving to COVID-19 patients. Due to the introduction of dexamethason (and Remdesevir) as first line treatment, we considered it unnecessary to continue baricitinib and sarilumab as the effect immuno-suppressive. The trial will continue as a non-drug trial with convalescence SARS-CoV-2 plasma.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 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
    Denmark: 6
    Worldwide total number of subjects
    6
    EEA total number of subjects
    6
    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)
    4
    From 65 to 84 years
    1
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Recruiment period went from 01-05-2020 to 11-06-2020. Only one sites was initiated, and all 6 patients were recruited from and hospitalized at Hvidovre Hospital, Denmark. All patients with SARS-Covid-19 positive swap or traceal sputum hospitalized patiens during the period were screened for participation by treating physicians.

    Pre-assignment
    Screening details
    60 patients in total went through screening.

    Period 1
    Period 1 title
    Inclusion (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Eligible patients who signed informed content, were enrolled. Randomization was performed in RedCap by unblinded personel. Patients were randomized to one of the six study arms. Study treatment were prepared and administrated by unblinded personel. All six patients were randomized to oral treatment. All oral treatment were capsulated in identical opaque capsules to maintain blinding for all other personel than the unblinded personel.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Hydroxychloroquin
    Arm description
    Hydroxychloroquine (Plaquenil) (capsulated), administred600 mg once daily for 7 days
    Arm type
    Experimental

    Investigational medicinal product name
    Plaquenil
    Investigational medicinal product code
    P01BA02
    Other name
    Hydroxychloroquine
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    tablets contains 200 mg Patients received 600 mg daily

    Arm title
    Baricitinib
    Arm description
    Baricitinib (Olumiant) (capsulated), administred 4 mg daily for 7 days
    Arm type
    Experimental

    Investigational medicinal product name
    Olumiant
    Investigational medicinal product code
    L04AA37
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets of 2 mg 2 tablets (4 mg) daily for 7 days

    Arm title
    Placebo
    Arm description
    Placebo tablet containing glucosemonohydrat (capsulated) administred once daily for 7 days
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3 capsulated placebo tablets once daily for 7 days

    Number of subjects in period 1
    Hydroxychloroquin Baricitinib Placebo
    Started
    1
    4
    1
    Completed
    0
    4
    1
    Not completed
    1
    0
    0
         Adverse event, non-fatal
    1
    -
    -

    Baseline characteristics

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

    Reporting group values
    Inclusion Total
    Number of subjects
    6 6
    Age categorical
    Participant age
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    3 3
        From 65-84 years
    2 2
        85 years and over
    1 1
    Gender categorical
    3/6 (50%) participants were female and 3/6 (50%) were male.
    Units: Subjects
        Female
    3 3
        Male
    3 3
    Comorbidity
    Number of comorbidities at the time of inclusion
    Units: Subjects
        Cardiac disease
    0 0
        Cerebral disease
    0 0
        Peripheral vascular disease
    0 0
        Nephrological disease
    0 0
        Chronical Obstructive Lung Disease (COLD)
    0 0
        Asthma
    0 0
        Diabetes
    1 1
        Cancer
    0 0
        Connective tissue disease
    0 0
        Ulcus
    0 0
        Liver disease
    0 0
        Other
    0 0
        None
    5 5
    Etnicity
    Etnicity
    Units: Subjects
        Caucasian
    3 3
        Middle East
    3 3
        Asian
    0 0
        Latin American
    0 0
    Smoking
    Smoking at baseline
    Units: Subjects
        Yes
    0 0
        No
    4 4
        Previous
    2 2
    Close contact to COVID-19 case
    Close contact to COVID-19 case prior to admission
    Units: Subjects
        Yes
    4 4
        No
    2 2
    Location of transmission
    Suspected location of transmission
    Units: Subjects
        Home
    2 2
        Travel
    0 0
        Workplace
    1 1
        Unknown
    3 3
        Other
    0 0
    Nursing home resident
    Units: Subjects
        Yes
    0 0
        No
    6 6
    Functional level
    Functional level prior to admission
    Units: Subjects
        Self-reliant
    6 6
        Home Help
    0 0
        Need of home nursing support
    0 0
    Dyspnenia
    Dyspnenia as debut COVID-19 symptom
    Units: Subjects
        Yes
    4 4
        No
    2 2
    Dry Coughing
    Dry Coughing as debut COVID-19 symptom
    Units: Subjects
        Yes
    4 4
        No
    2 2
    Coughing with sputum
    Coughing with sputumas debut COVID-19 symptom?
    Units: Subjects
        Yes
    3 3
        No
    3 3
    Chest tightness
    Chest tightness as debut COVID-19 symptom?
    Units: Subjects
        Yes
    0 0
        No
    6 6
    Fever
    Fever as debut COVID-19 symptom?
    Units: Subjects
        Yes
    6 6
        No
    0 0
    Sore throught
    Sore throught as debut COVID-19 symptom?
    Units: Subjects
        Yes
    1 1
        No
    5 5
    Muscle and/or joint pain
    Muscle and/or joint pain as debut COVID-19 symptom?
    Units: Subjects
        Yes
    2 2
        No
    4 4
    Headache
    Headache as debut COVID-19 symptom?
    Units: Subjects
        Yes
    2 2
        No
    4 4
    Changes in smell and/or taste
    Changes in smell and/or taste as debut COVID-19 symptom?
    Units: Subjects
        Yes
    1 1
        No
    5 5
    Nausea/vomit
    Nausea as debut COVID-19 symptom?
    Units: Subjects
        Yes
    2 2
        No
    4 4
    Diarrhea
    Diarrhea as debut COVID-19 symptom?
    Units: Subjects
        Yes
    2 2
        No
    4 4
    Erythema
    Erythema as debut COVID-19 symptom?
    Units: Subjects
        Yes
    0 0
        No
    6 6
    Other debut symptoms
    Other debut COVID-19 symptom?
    Units: Subjects
        Yes
    1 1
        No
    5 5
    Weight
    Weight at baseline
    Units: kg
        arithmetic mean (full range (min-max))
    86 (66 to 157) -
    Height
    Height at baseline
    Units: cm
        arithmetic mean (full range (min-max))
    172 (157 to 183) -
    Symptom debut
    Days with symptoms prior to admission
    Units: days
        arithmetic mean (full range (min-max))
    7 (3 to 11) -

    End points

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    End points reporting groups
    Reporting group title
    Hydroxychloroquin
    Reporting group description
    Hydroxychloroquine (Plaquenil) (capsulated), administred600 mg once daily for 7 days

    Reporting group title
    Baricitinib
    Reporting group description
    Baricitinib (Olumiant) (capsulated), administred 4 mg daily for 7 days

    Reporting group title
    Placebo
    Reporting group description
    Placebo tablet containing glucosemonohydrat (capsulated) administred once daily for 7 days

    Primary: All-cause mortality or need of invasive mechanical ventilation up to 28 days

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    End point title
    All-cause mortality or need of invasive mechanical ventilation up to 28 days
    End point description
    End point type
    Primary
    End point timeframe
    28 days
    End point values
    Hydroxychloroquin Baricitinib Placebo
    Number of subjects analysed
    1
    4
    1
    Units: Subjects
    0
    0
    1
    Statistical analysis title
    Placebo
    Comparison groups
    Hydroxychloroquin v Baricitinib v Placebo
    Number of subjects included in analysis
    6
    Analysis specification
    Post-hoc
    Analysis type
    other [1]
    P-value
    = 0
    Method
    None
    Parameter type
    none
    Confidence interval
    Notes
    [1] - One patient died during the study. No causality between IMP and mortality was suspected. The patient who died received placebo.

    Secondary: Frequency of adverse events

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    End point title
    Frequency of adverse events
    End point description
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    Hydroxychloroquin Baricitinib Placebo
    Number of subjects analysed
    1
    4
    1
    Units: number of AE
    4
    10
    2
    No statistical analyses for this end point

    Secondary: Frequency of severe adverse events

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    End point title
    Frequency of severe adverse events
    End point description
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    Hydroxychloroquin Baricitinib Placebo
    Number of subjects analysed
    1
    4
    1
    Units: number of SAE
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Ventilator-free days to day 28

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    End point title
    Ventilator-free days to day 28
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    Hydroxychloroquin Baricitinib Placebo
    Number of subjects analysed
    1
    4
    1
    Units: days
    1
    4
    1
    No statistical analyses for this end point

    Secondary: Organ failure-free days to day 28

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    End point title
    Organ failure-free days to day 28
    End point description
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    Hydroxychloroquin Baricitinib Placebo
    Number of subjects analysed
    1
    4
    1
    Units: days
    1
    4
    1
    No statistical analyses for this end point

    Secondary: Duration of ICU stay

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    End point title
    Duration of ICU stay
    End point description
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    Hydroxychloroquin Baricitinib Placebo
    Number of subjects analysed
    1
    4
    1
    Units: days
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Mortality rate

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    End point title
    Mortality rate
    End point description
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    Hydroxychloroquin Baricitinib Placebo
    Number of subjects analysed
    1
    4
    1
    Units: subjects
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Length of hospital stay

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    End point title
    Length of hospital stay
    End point description
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    Hydroxychloroquin Baricitinib Placebo
    Number of subjects analysed
    1
    4
    1
    Units: days
    6
    10
    7
    No statistical analyses for this end point

    Secondary: Duration of supplemental oxygen

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    End point title
    Duration of supplemental oxygen
    End point description
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    Hydroxychloroquin Baricitinib Placebo
    Number of subjects analysed
    1
    4
    1
    Units: days
    5
    6
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    90 days
    Adverse event reporting additional description
    Adverse events were collected by reviewing medical records during hospitalizations and by telephone follow-up at day 7, 14, 28 and 90.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Hydroxychloroquin
    Reporting group description
    Hydroxychloroquine (Plaquenil) (capsulated), administred600 mg once daily for 7 days

    Reporting group title
    Baricitinib
    Reporting group description
    Baricitinib (Olumiant) (capsulated), administred 4 mg daily for 7 days

    Reporting group title
    Placebo
    Reporting group description
    Placebo tablet containing glucosemonohydrat (capsulated) administred once daily for 7 days

    Serious adverse events
    Hydroxychloroquin Baricitinib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    QTc-prolongation
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Death
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Hydroxychloroquin Baricitinib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    3 / 4 (75.00%)
    1 / 1 (100.00%)
    Cardiac disorders
    EKG changes
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    pulmonary edema
    Additional description: High pressure pulmonary edema
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    1
    Thrombocytosis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Headache
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Hyperamylasaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Memory impairment
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    Renal and urinary disorders
    hematuria
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Nephropathy
    Additional description: Worsening of chronic nephropathy
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatobiliary disorders
    Incread transaminases
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Skin rash
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Hair loss
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Fever
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jun 2020
    The hydroxychloroquine arm closed.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Jun 2020
    Pre-mature termination of the study. The trial continues as a non-drug trial with convalescense plasma.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The trial is terminated pre-maturely. Only 6 patients were included (1500 predicted) therefore results are not analysed.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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