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    Clinical Trial Results:
    Proactive Prophylaxis with Azithromycin and Hydroxychloroquine Patients Hospitalized with COVID

    Summary
    EudraCT number
    		 2020-001198-55
    Trial protocol
    		 DK  
    Global end of trial date
    02 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jul 2021
    First version publication date
    04 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KronLungesyg_COVID_19_protokol_2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04322396
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Videnskabsetisk Komite: H-20023010
    Sponsors
    Sponsor organisation name
    Gentofte Hospital
    Sponsor organisation address
    Gentofte Hospitalsvej 1D, Hellerup, Denmark, 2900
    Public contact
    www.coptrin.dk, COP:TRIN, 45 28938168, jens.ulrik.jensen@regionh.dk
    Scientific contact
    www.coptrin.dk, COP:TRIN, 45 28938168, jens.ulrik.jensen@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
    15 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    In patients who are admitted urgently to hospital with coronavirus infection (COVID-19) and symptoms, treatment with virus-modifying agent Hydroxyhloroquine as well as virus-immunomodulatory and antibacterial drug Azithromycin can lead to a shorter hospitalization.
    Protection of trial subjects
    Subjects were systematically monitored, and medication, including study medication, regulated when clinically indicated. The safety of the study subjects was ensured by following Good Clinical Practice
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 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: 117
    Worldwide total number of subjects
    117
    EEA total number of subjects
    117
    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)
    59
    From 65 to 84 years
    46
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 At each trial centre, screening of patients admitted with a positive SARS-CoV-2 test is performed. Patients are assessed against the inclusion and exclusion criteria of the attending physician who receives the patient's consent to contact the investigator. The Investigator then contacts the patient for recruitment to the study.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control
    Arm description
    		 This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine
    Arm type
    		 Placebo

    Investigational medicinal product name
    Azithromycin PLACEBO
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 1–3 and then 250 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 4–15

    Investigational medicinal product name
    Hydroxychloroquine PLACEBO
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 1–3 and then 250 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 4–15

    Arm title
    		 Intervention
    Arm description
    		 This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azithromycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 1–3 and then 250 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 4–15

    Investigational medicinal product name
    Hydroxychloroquine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 1–3 and then 250 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 4–15

    Number of subjects in period 1
    		Control Intervention
    Started
    56
    61
    Completed
    56
    61
    Period 2
    Period 2 title
    Overall trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control
    Arm description
    		 This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine
    Arm type
    		 Placebo

    Investigational medicinal product name
    Azithromycin PLACEBO
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 1–3 and then 250 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 4–15

    Investigational medicinal product name
    Hydroxychloroquine PLACEBO
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 1–3 and then 250 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 4–15

    Arm title
    		 Intervention
    Arm description
    		 This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azithromycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 1–3 and then 250 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 4–15

    Investigational medicinal product name
    Hydroxychloroquine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 1–3 and then 250 mg azithromycin once daily plus 200 mg hydroxychloroquine twice daily on days 4–15

    Number of subjects in period 2
    		Control Intervention
    Started
    56
    61
    Completed
    56
    61

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control
    Reporting group description
    		 This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine

    Reporting group title
    Intervention
    Reporting group description
    		 This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine

    Reporting group values
    		 Control Intervention Total
    Number of subjects
    		 56 61 117
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 63 (52 to 74) 68 (52 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 27 25 52
        Male
    		 29 36 65
    Race/ethnicity
    Units: Subjects
        Caucasian
    		 45 53 98
        African
    		 1 0 1
        Asian
    		 6 6 12
        Unknown/other
    		 4 2 6

    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    		 This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine

    Reporting group title
    Intervention
    Reporting group description
    		 This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine
    Reporting group title
    Control
    Reporting group description
    		 This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine

    Reporting group title
    Intervention
    Reporting group description
    		 This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine

    Primary: Number of Days Alive and Discharged From Hospital Within 14 Days

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    End point title
    		 Number of Days Alive and Discharged From Hospital Within 14 Days [1]
    End point description
    End point type
    Primary
    End point timeframe
    14 days
    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: Statistical analysis was not found to improve understanding of this outcome.
    End point values
    		 Control Intervention
    Number of subjects analysed
    56
    61
    Units: days
        median (inter-quartile range (Q1-Q3))
    9 (7 to 10)
    9 (3 to 11)
    No statistical analyses for this end point

    Secondary: Categorization of Hospitalization Status

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    End point title
    		 Categorization of Hospitalization Status
    End point description
    The patient will becategorized into one of the following 8 categories depending on status of their hospitalization: (1) Dead (yes/no) (2) Hospitalized and receiving mechanical ventilation or ExtraCorporalMembraneOxygenation (ECMO) (yes/no) (3) Hospitalized and receiving Non-invasive ventilation or "high-flow oxygen device" (yes/no) (4) Hospitalized and given oxygen supplements different from (2) and (3) (yes/no) (5) Hospitalized and without oxygen treatment, but receiving other treatment (both related to COVID-19 or other) (yes/no) (6) Hospitalized for observation (yes/no) (7) Discharged from hospital with restriction of activity level (yes/no) (8) Discharged from hospital without any restrictions of activity level (yes/no) Only one category can be "yes".
    End point type
    Secondary
    End point timeframe
    14
    End point values
    		 Control Intervention
    Number of subjects analysed
    56
    61
    Units: participants
        (1)
    2
    1
        (2)
    2
    1
        (3)
    0
    1
        (4)
    2
    2
        (5)
    2
    1
        (6)
    0
    1
        (7)
    27
    26
        (8)
    22
    26
    No statistical analyses for this end point

    Secondary: Admitted to Intensive Care Unit, if Admitted to ICU Then Length of Stay

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    End point title
    		 Admitted to Intensive Care Unit, if Admitted to ICU Then Length of Stay
    End point description
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Control Intervention
    Number of subjects analysed
    56
    61
    Units: days
        median (inter-quartile range (Q1-Q3))
    11 (4 to 14)
    14 (9.5 to 14)
    No statistical analyses for this end point

    Secondary: Have Used Non-invasive Ventilation (NIV) During Hospitalization

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    End point title
    		 Have Used Non-invasive Ventilation (NIV) During Hospitalization
    End point description
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Control Intervention
    Number of subjects analysed
    56
    61
    Units: participants
    1
    3
    No statistical analyses for this end point

    Secondary: Mortality

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    End point title
    		 Mortality
    End point description
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Control Intervention
    Number of subjects analysed
    56
    61
    Units: participants
    2
    1
    No statistical analyses for this end point

    Secondary: Length of Hospitalization

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    End point title
    		 Length of Hospitalization
    End point description
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Control Intervention
    Number of subjects analysed
    56
    61
    Units: days
        median (inter-quartile range (Q1-Q3))
    4 (3 to 6)
    4 (2 to 8)
    No statistical analyses for this end point

    Secondary: Days Alive and Discharged From Hospital

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    End point title
    		 Days Alive and Discharged From Hospital
    End point description
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Control Intervention
    Number of subjects analysed
    56
    61
    Units: days
        median (inter-quartile range (Q1-Q3))
    26 (23 to 27)
    26 (21 to 28)
    No statistical analyses for this end point

    Secondary: Number of Readmissions (All Causes)

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    End point title
    		 Number of Readmissions (All Causes)
    End point description
    End point type
    Secondary
    End point timeframe
    30 days
    End point values
    		 Control Intervention
    Number of subjects analysed
    56
    61
    Units: participants
    6
    9
    No statistical analyses for this end point

    Secondary: Number of Days Using Non-invasive Ventilation (NIV)

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    End point title
    		 Number of Days Using Non-invasive Ventilation (NIV)
    End point description
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Control Intervention
    Number of subjects analysed
    56
    61
    Units: days
        arithmetic mean (confidence interval 95%)
    9 (9 to 9)
    6.7 (-9.1 to 22.4)
    No statistical analyses for this end point

    Secondary: Change in Patient's Oxygen Partial Pressure

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    End point title
    		 Change in Patient's Oxygen Partial Pressure
    End point description
    Delta PaO2 measured in arterial puncture
    End point type
    Secondary
    End point timeframe
    4 days
    End point values
    		 Control Intervention
    Number of subjects analysed
    56
    61
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    -0.2 (-8.3 to 7.8)
    -3.0 (-9.8 to 3.9)
    No statistical analyses for this end point

    Secondary: Change in Patient's Carbondioxid Partial Pressure

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    End point title
    		 Change in Patient's Carbondioxid Partial Pressure
    End point description
    Delta PaCO2 measured in arterial puncture
    End point type
    Secondary
    End point timeframe
    4 days
    End point values
    		 Control Intervention
    Number of subjects analysed
    56
    61
    Units: mmHg
        arithmetic mean (confidence interval 95%)
    1.4 (-0.4 to 3.3)
    -3.0 (-9.8 to 3.9)
    No statistical analyses for this end point

    Secondary: Change of pH in Blood

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    End point title
    		 Change of pH in Blood
    End point description
    Change in pH measured in arterial puncture
    End point type
    Secondary
    End point timeframe
    4 days
    End point values
    		 Control Intervention
    Number of subjects analysed
    56
    61
    Units: pH
        arithmetic mean (confidence interval 95%)
    0.0 (-0.02 to 0.01)
    0.0 (-0.03 to 0.01)
    No statistical analyses for this end point

    Secondary: Time for no Oxygen Supplement (or Regular Oxygen Supplement "LTOT")

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    End point title
    		 Time for no Oxygen Supplement (or Regular Oxygen Supplement "LTOT")
    End point description
    Unadjusted HR
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Control Intervention
    Number of subjects analysed
    56 [2]
    61
    Units: HR
        number (confidence interval 95%)
    1 (1 to 1)
    0.8 (0.5 to 1.5)
    Notes
    [2] - Reference
    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 during the period beginning when the patient received their first dose of trial medication up to and including day 15.
    Adverse event reporting additional description
    A serious adverse event (SAE) was defined as an event or adverse event that, regardless of dose, was life-threatening, resulted in significant or persistent disability or incapacity, or led to a congenital anomaly or malformation. Because comorbidities and mortality are common in this patient group, prolonged admission, re-admission, non-invasive
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Control
    Reporting group description
    		 This arm will receive standard care and placebo in 15 days. Placebo oral tablet: Placebo Azithromycin Placebo oral tablet: Placebo Hydroxychloroquine

    Reporting group title
    Intervention
    Reporting group description
    		 This arm will receive standard care and azithromycin and hydroxychloroquine in 15 days. Azithromycin: Azithromycin Hydroxychloroquine: Hydroxychloroquine

    Serious adverse events
    		 Control Intervention
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 31 (0.00%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hearing loss
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 31 (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
    		 Control Intervention
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 25 (100.00%)
    31 / 31 (100.00%)
    Vascular disorders
    Bleeding
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    4 / 25 (16.00%)
    3 / 31 (9.68%)
         occurrences all number
    4
    3
    Prolonged QTc
         subjects affected / exposed
    7 / 25 (28.00%)
    4 / 31 (12.90%)
         occurrences all number
    7
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 25 (12.00%)
    10 / 31 (32.26%)
         occurrences all number
    3
    10
    Headache
         subjects affected / exposed
    5 / 25 (20.00%)
    3 / 31 (9.68%)
         occurrences all number
    5
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 25 (28.00%)
    7 / 31 (22.58%)
         occurrences all number
    7
    7
    Diarrhoea
         subjects affected / exposed
    3 / 25 (12.00%)
    12 / 31 (38.71%)
         occurrences all number
    3
    12
    Nausea
         subjects affected / exposed
    6 / 25 (24.00%)
    11 / 31 (35.48%)
         occurrences all number
    6
    11
    Vomiting
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 31 (6.45%)
         occurrences all number
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 31 (9.68%)
         occurrences all number
    2
    3
    Skin and subcutaneous tissue disorders
    Itching/Rash
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Early termination based on recommendations from the DSMB leading to small numbers of subjects analyzed.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34083403
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