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    Clinical Trial Results:
    Randomized clinical trial to evaluate the efficacy of different treatments in patients with COVID-19 who require hospitalization

    Summary
    EudraCT number
    		 2020-001156-18
    Trial protocol
    		 ES  
    Global end of trial date
    17 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Nov 2023
    First version publication date
    01 Nov 2023
    Other versions
    Summary report(s)
    		 Informe Final PANCOVID

    Trial information

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    Trial identification
    Sponsor protocol code
    PanCOVID19
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fundación para la investigación Biomedica Hospital Universitario La Paz
    Sponsor organisation address
    Paseo de la Castellana, 261, Madrid, Spain, 28046
    Public contact
    Alberto Borobia, Servicio de Farmacología Clínica. Unidad de Ensayos Clínicos (UCICEC), +34 912071466, a.borobia@gmail.com
    Scientific contact
    Alberto Borobia, Servicio de Farmacología Clínica. Unidad de Ensayos Clínicos (UCICEC), +34 912071466, a.borobia@gmail.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
    30 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Provide reliable estimates of the effects of these antiviral treatments on hospital mortality.
    Protection of trial subjects
    The cumulative incidence of adverse effects attributed to therapy in the study will be evaluated
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Apr 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 355
    Worldwide total number of subjects
    355
    EEA total number of subjects
    355
    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)
    355
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Principal inclusion criteria • Signing the informed consent. • Men and women aged ≥18 years • Patients admitted with a diagnosis of severe pneumonia due to SARS-CoV-2. • Diagnosis of SARS-CoV-2 infection confirmed by PCR carried out ≤ 4 days prior to randomization. • Onset of symptoms ≤ 4 days. • Using of contraceptive methods

    Pre-assignment
    Screening details
    		 Diagnosis of SARS-CoV-2 infection confirmed by PCR carried out ≤ 4 days prior to randomization.

    Period 1
    Period 1 title
    First Randomization
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not blinded study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Emtricitabine/Tenofovir disoproxil fumarate
    Arm description
    		 Emtricitabine/Tenofovir disoproxil fumarate (200/245 mg): 2 tablets the first day, and 1 tablet per day administered for a total of 14 days, orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Emtricitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200mg: 2 tablets on the first day, and 1 tablet daily for a total of 14 days, orally.

    Investigational medicinal product name
    Tenofovir disoproxil fumarate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250mg: 2 tablets on the first day, and 1 tablet daily for a total of 14 days, orally.

    Arm title
    		 No treatment with Emtricitabine/Tenofovir
    Arm description
    		 No treatment with Emtricitabine/Tenofovir disoproxil fumarate
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Emtricitabine/Tenofovir disoproxil fumarate No treatment with Emtricitabine/Tenofovir
    Started
    177
    178
    Completed
    167
    171
    Not completed
    10
    7
         Death
    7
    4
         Discontinued
    3
    3
    Period 2
    Period 2 title
    Second randomization
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not blinded study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dexamethasone + Baricitinib
    Arm description
    		 Dexamethasone: 6 mg once daily for 7-10 days orally or i.v. + Baricitinib: 4 mg once daily for 10-14 days at the investigator's discretion, orally.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Baricitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg once daily for 10-14 days at the investigator's discretion, orally

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Dexamethasone: 6 mg once daily for 7-10 days oral or i.v. at investigator's discretion.

    Arm title
    		 Dexamethasone
    Arm description
    		 Dexamethasone: 6 mg once daily for 7-10 days oral or i.v. at investigator's discretion.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Injection/infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Dexamethasone: 6 mg once daily for 7-10 days oral or i.v. at investigator's discretion.

    Number of subjects in period 2 [1]
    		Dexamethasone + Baricitinib Dexamethasone
    Started
    145
    142
    Completed
    137
    135
    Not completed
    8
    7
         Death
    3
    7
         Discontinued
    5
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 355 patients were enrolled in the trial and underwent the first randomization. In the first randomization, 177 and 178 patients were respectively assigned to receive or not TDF/FTC. Of these 355 patients, 287 underwent the second randomization to receive baricitinib plus dexamethasone or dexamethasone alone.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    First Randomization
    Reporting group description
    		 -

    Reporting group values
    		 First Randomization Total
    Number of subjects
    		 355 355
    Age categorical
    Adults (18-64)
    Units: Subjects
        Adults (18-64 years)
    		 355 355
    Age continuous
    Adults (18-78)
    Units: years
        median (full range (min-max))
    		 0 (0 to 0) -
    Gender categorical
    Units: Subjects
        Female
    		 126 126
        Male
    		 229 229
    Subject analysis sets

    Subject analysis set title
    Patients treated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients treated

    Subject analysis sets values
    		 Patients treated
    Number of subjects
    177
    Age categorical
    Adults (18-64)
    Units: Subjects
        Adults (18-64 years)
    177
    Age continuous
    Adults (18-78)
    Units: years
        median (full range (min-max))
    0 (0 to 0)
    Gender categorical
    Units: Subjects
        Female
    64
        Male
    113

    End points

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    End points reporting groups
    Reporting group title
    Emtricitabine/Tenofovir disoproxil fumarate
    Reporting group description
    		 Emtricitabine/Tenofovir disoproxil fumarate (200/245 mg): 2 tablets the first day, and 1 tablet per day administered for a total of 14 days, orally.

    Reporting group title
    No treatment with Emtricitabine/Tenofovir
    Reporting group description
    		 No treatment with Emtricitabine/Tenofovir disoproxil fumarate
    Reporting group title
    Dexamethasone + Baricitinib
    Reporting group description
    		 Dexamethasone: 6 mg once daily for 7-10 days orally or i.v. + Baricitinib: 4 mg once daily for 10-14 days at the investigator's discretion, orally.

    Reporting group title
    Dexamethasone
    Reporting group description
    		 Dexamethasone: 6 mg once daily for 7-10 days oral or i.v. at investigator's discretion.

    Subject analysis set title
    Patients treated
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients treated

    Primary: Death

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    End point title
    		 Death [1]
    End point description
    Number of deaths from first randomization to 28 days of treatment.
    End point type
    Primary
    End point timeframe
    During 28 days after the start of treatment
    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: Based on mortality data during the first COVID-19 wave in Spain, sample size calculations assumed a 20% mortality in this mixed population. We also assumed an α error of .025, β error of .2, and a 0.7 risk reduction in mortality. resulting in a predefined sample of 1482 patients for each group (TDF/FTC vs no TDF/FTC). The trial was stopped before reaching the planned sample size due to the decrease in the number of cases during the recruitment period and the much lower global mortality observed
    End point values
    		 Emtricitabine/Tenofovir disoproxil fumarate Dexamethasone + Baricitinib No treatment with Emtricitabine/Tenofovir Dexamethasone Patients treated
    Number of subjects analysed
    177
    145
    178
    142
    177
    Units: Number of deaths
    167
    137
    171
    135
    167
    No statistical analyses for this end point

    Secondary: Disease progression and length of hospital stay

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    End point title
    		 Disease progression and length of hospital stay
    End point description
    Number of patients with disease progression and critical care unit admission (oxygen support, steroid dose, new medication...) Number of days since first randomization until death/discharge
    End point type
    Secondary
    End point timeframe
    During 28 days after the start of treatment
    End point values
    		 Emtricitabine/Tenofovir disoproxil fumarate Dexamethasone + Baricitinib No treatment with Emtricitabine/Tenofovir Dexamethasone Patients treated
    Number of subjects analysed
    177
    145
    178
    142
    177
    Units: Number
        Disease progression
    39
    36
    42
    39
    39
        Critical care unit admission
    39
    36
    42
    39
    39
        28-d mortality
    7
    3
    4
    7
    7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded continuously throughout the entire duration of the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Randomized patients
    Reporting group description
    		 Randomized patients

    Serious adverse events
    		 Randomized patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 355 (3.66%)
         number of deaths (all causes)
    11
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Acute arterial ischemia
         subjects affected / exposed
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Ischiorectal abscess
         subjects affected / exposed
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary thromboembolism
         subjects affected / exposed
    3 / 355 (0.85%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory insufficiency
         subjects affected / exposed
    3 / 355 (0.85%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 355 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bronchial aspiration
         subjects affected / exposed
    1 / 355 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.1%
    Non-serious adverse events
    		 Randomized patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 355 (22.54%)
    Blood and lymphatic system disorders
    Hyperglycaemia
    Additional description: High blood sugar
         subjects affected / exposed
    17 / 355 (4.79%)
         occurrences all number
    17
    Hypertransaminasaemia
    Additional description: Increase in serum transaminase values above normal levels
         subjects affected / exposed
    13 / 355 (3.66%)
         occurrences all number
    13
    Hyperglycemia steroid-induced
    Additional description: Steroids cause high blood sugar levels in people with pre-existing diabetes.
         subjects affected / exposed
    9 / 355 (2.54%)
         occurrences all number
    9
    Arterial hypertension
         subjects affected / exposed
    3 / 355 (0.85%)
         occurrences all number
    3
    General disorders and administration site conditions
    Insomnia
         subjects affected / exposed
    8 / 355 (2.25%)
         occurrences all number
    8
    Asthenia
         subjects affected / exposed
    5 / 355 (1.41%)
         occurrences all number
    5
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    9 / 355 (2.54%)
         occurrences all number
    9
    Constipation
         subjects affected / exposed
    9 / 355 (2.54%)
         occurrences all number
    9
    Nausea and vomiting
         subjects affected / exposed
    4 / 355 (1.13%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Pulmonary thromboembolism
         subjects affected / exposed
    6 / 355 (1.69%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Apr 2020
    Substantial modification: Modified documents: Part I: · Protocol, version 3.1, dated April 2nd 2020 Part II: · Information sheet for the legal representative of the minor patient and an informed consent document, version 3.0, dated March 31st 2020. · Information sheet for the mature minor (12 to 17 years old) and informed consent document, version 3.0, dated March 31st 2020 · Information sheet for the adult patient and an informed consent document, version 3.0, dated March 31st 2020
    08 Oct 2020
    Modified documents: Part I: - Protocol V5.1 of September 13, 2020. Part II: - Mature Minor Patient Information Sheet and Informed Consent Document (addressed to the mature minor 12-17 years), V5.1 of September 13, 2020. Mature Minor 12-17 years old), V5.1 of September 13, 2020 - Minor patient guardian information sheet and informed consent document, V5.1 of September 13, 2020 - Information sheet for patient of legal age and informed consent document, V5.1 dated September 13, 2020 September 13, 2020 - Information sheet for the patient's legal representative/family member, version: 1.0 of July 4, 2020. 2020.
    05 Nov 2020
    Modified documents: Part II: - Expansion of centers (see Annex II)
    03 Dec 2020
    Modified documents: Part II: - A new center is included.
    11 Mar 2021
    Part II: - The principal investigator of the Hospital Universitario de Fuenlabrada is changed, Dr. Callejas will not be able to continue in charge of the study and is replaced by Dr. Lourdes Muñoz.
    11 Mar 2021
    Part II: - Expansion of a center: Hospital de Emergencias Enfermera Isabel: Zendal Dra. Cristina Marcelo Calvo Hospital Universitario de Badajoz: Dr. Francisco Félix Rodríguez Vidigal
    24 Jun 2021
    Part II: - Change of Principal Investigator at the Centro Hospital de Emergencias Enfermera Isabel Zendal: Dr. Sara Castro González replaces Dr. Cristina Marcelo Calvo.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Jun 2020
    In view of new evidence from clinical trials demonstrating the lack of efficacy of two of the treatment arms, the scientific committee has decided to withdraw the treatment arm involving hydroxychloroquine and to redesign the clinical trial.
    13 Oct 2020

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/93846
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