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    Clinical Trial Results:
    An Adaptive Phase 2/3, Randomised, Open-Label Study Assessing Efficacy and Safety of Hydroxychloroquine for Hospitalised Patients with Moderate to Severe COVID-19

    Summary
    EudraCT number
    2020-001270-29
    Trial protocol
    DK   CZ   DE   GB   FR  
    Global end of trial date
    25 Jun 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Oct 2020
    First version publication date
    24 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC16858
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    U1111-1249-6096
    Sponsors
    Sponsor organisation name
    Sanofi-aventis Recherche & Développement
    Sponsor organisation address
    1, Avenue Pierre Brossolette, Chilly Mazarin, France, 91385
    Public contact
    Trial Transparency Team, Sanofi-aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi-aventis recherche & développement, Contact-US@sanofi.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
    09 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jun 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the effect of hydroxychloroquine (HCQ) in addition to standard of care as compared to standard of care only on oxygen saturation/fraction of inspired oxygen (SpO2/FiO2) ratio in adult subjects hospitalised with moderate to severe coronavirus disease 2019 (COVID-19).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject was participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 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
    United Kingdom: 1
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 3
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    9
    From 65 to 84 years
    4
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 20 study centers in 5 countries between 15 April 2020 and 25 June 2020.

    Pre-assignment
    Screening details
    A total of 14 subjects were randomised and treated in 4 countries.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Hydroxychloroquine + Standard of care
    Arm description
    Subjects received a loading dose of HCQ orally on Day 1 followed by a maintenance dose for 9 days (Days 2 to 10) plus standard of care.
    Arm type
    Experimental

    Investigational medicinal product name
    Hydroxychloroquine
    Investigational medicinal product code
    SAR321068
    Other name
    Plaquenil®, Quensyl®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received loading dose of HCQ (i.e., 800 milligram (mg) on Day 1, then 400 mg 6 hours later) orally on Day 1 along with meals, followed by maintenance doses of 200 mg three times daily (TID) orally for 9 days (Days 2 to 10).

    Arm title
    Standard of care
    Arm description
    Subjects received standard of care only i.e., the usual care provided to COVID-19 subjects in the country/investigational site.
    Arm type
    Standard of care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Hydroxychloroquine + Standard of care Standard of care
    Started
    8
    6
    Completed
    7
    4
    Not completed
    1
    2
         Adverse Event (AE)
    1
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Hydroxychloroquine + Standard of care
    Reporting group description
    Subjects received a loading dose of HCQ orally on Day 1 followed by a maintenance dose for 9 days (Days 2 to 10) plus standard of care.

    Reporting group title
    Standard of care
    Reporting group description
    Subjects received standard of care only i.e., the usual care provided to COVID-19 subjects in the country/investigational site.

    Reporting group values
    Hydroxychloroquine + Standard of care Standard of care Total
    Number of subjects
    8 6 14
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.4 ± 19.4 57.5 ± 24.4 -
    Gender categorical
    Units: Subjects
        Female
    7 5 12
        Male
    1 1 2
    Body Mass Index (BMI) group
    Units: Subjects
        Less than (<) 30
    3 2 5
        Greater than or equal to (>=) 30
    3 2 5
        Not reported
    2 2 4
    Age group (per Interactive Response Technology [IRT])
    Units: Subjects
        < 55 years old
    3 3 6
        >= 55 years old
    5 3 8
    Severity of Illness (per IRT)
    Units: Subjects
        Moderate
    6 4 10
        Severe
    2 2 4
    BMI
    The BMI was reported for a total of 10 subjects i.e., HCQ + Standard of care: 6 subjects and Standard of care: 4 subjects only.
    Units: kilogram per square meter (kg/m^2)
        arithmetic mean (standard deviation)
    29.443 ± 4.114 29.876 ± 6.406 -
    Number of days since symptoms start
    Data was reported for a total of 13 subjects i.e., HCQ + Standard of care: 7 subjects and Standard of care: 6 subjects only.
    Units: days
        arithmetic mean (standard deviation)
    6.7 ± 4.8 4.8 ± 3.3 -
    Oxygen Saturation/Fraction of Inspired Oxygen (SpO2/FiO2) Ratio
    Units: ratio
        median (full range (min-max))
    4.52 (2.3 to 4.6) 3.32 (2.9 to 4.5) -

    End points

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    End points reporting groups
    Reporting group title
    Hydroxychloroquine + Standard of care
    Reporting group description
    Subjects received a loading dose of HCQ orally on Day 1 followed by a maintenance dose for 9 days (Days 2 to 10) plus standard of care.

    Reporting group title
    Standard of care
    Reporting group description
    Subjects received standard of care only i.e., the usual care provided to COVID-19 subjects in the country/investigational site.

    Primary: Change From Baseline in Oxygen Saturation/Fraction of Inspired Oxygen Ratio at Day 15

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    End point title
    Change From Baseline in Oxygen Saturation/Fraction of Inspired Oxygen Ratio at Day 15 [1]
    End point description
    SpO2/FiO2 ratio determined oxygenation status of the subjects. The higher the SpO2/FiO2 ratio is, the better it is for the subject. Intent-to-treat (ITT) population included all randomised subjects. Here, ‘number of subjects analysed’ = subjects with available data at Day 15 for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Day 15
    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: Due to limited data available following study termination, no statistical analysis was performed. Only descriptive summary.
    End point values
    Hydroxychloroquine + Standard of care Standard of care
    Number of subjects analysed
    3
    0 [2]
    Units: ratio
        median (full range (min-max))
    0.93 (0.0 to 1.3)
    ( to )
    Notes
    [2] - No data available at specified time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Oxygen Saturation/Fraction of Inspired Oxygen Ratio at Day 30

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    End point title
    Change From Baseline in Oxygen Saturation/Fraction of Inspired Oxygen Ratio at Day 30
    End point description
    SpO2/FiO2 ratio determined oxygenation status of the subjects. The higher the SpO2/FiO2 ratio is, the better it is for the subject. ITT population included all randomised subjects. Here, ‘number of subjects analysed’ = subjects with available data at Day 30 for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 30
    End point values
    Hydroxychloroquine + Standard of care Standard of care
    Number of subjects analysed
    3
    0 [3]
    Units: ratio
        median (full range (min-max))
    0.44 (0.0 to 1.5)
    ( to )
    Notes
    [3] - No data available at specified time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mean Body Temperature at Day 15

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    End point title
    Change From Baseline in Mean Body Temperature at Day 15
    End point description
    Baseline body temperature was defined as the highest temperature recorded prior to the 1st HCQ dosing for HCQ + Standard of care group and recorded on randomisation date for Standard of care only group. ITT population included all randomised subjects. Here, ‘number analysed’ = subjects with available data at Day 15 for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15
    End point values
    Hydroxychloroquine + Standard of care Standard of care
    Number of subjects analysed
    8
    2
    Units: degree Celsius
        arithmetic mean (standard deviation)
    -0.66 ± 0.72
    -0.25 ± 0.92
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Each Severity Rating on the 7-Point Ordinal Scale

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    End point title
    Number of Subjects Reporting Each Severity Rating on the 7-Point Ordinal Scale
    End point description
    Clinical status of the subjects as per 7-point ordinal scale was described as: Category 1. Death; Category 2. Hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); Category 3. Hospitalised, on non-invasive ventilation or high flow oxygen devices; Category 4. Hospitalised, requiring supplemental oxygen; Category 5. Hospitalised, not requiring supplemental oxygen-requiring ongoing medical care (COVID-19 related or otherwise); Category 6. Hospitalised, not requiring supplemental oxygen-no longer requires ongoing medical care and Category 7. Not hospitalised; where higher score indicates better outcomes. Only those scale categories in which at least 1 subject had data were reported. ITT population included all randomised subjects. Here, "n" = subjects with 7-point ordinal scale data available at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15
    End point values
    Hydroxychloroquine + Standard of care Standard of care
    Number of subjects analysed
    8
    6
    Units: subjects
    number (not applicable)
        Baseline: Category 4 (n=8,4)
    2
    3
        Baseline: Category 5 (n=8,4)
    5
    0
        Baseline: Category 6 (n=8,4)
    1
    1
        Day 15: Category 2 (n=6,3)
    1
    0
        Day 15: Category 6 (n=6,3)
    1
    0
        Day 15: Category 7 (n=6,3)
    4
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects Reporting Quantitative Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Virus Load in the Nasopharyngeal (NP) Sample at Days 1, 2, 5, 10 and 15

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    End point title
    Number of Subjects Reporting Quantitative Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Virus Load in the Nasopharyngeal (NP) Sample at Days 1, 2, 5, 10 and 15
    End point description
    Quantitative SARS-CoV-2 virus in NP samples were evaluated by reverse transcription polymerase chain reaction (RT-PCR). The results were categorized as positive, negative or missing data. A positive result means SARS-COV2 detected; where as a negative result means SARS-COV2 not detected, with virus load highly probable less than 509 copies per milliliter. ITT population included all randomised subjects. Here, "n"= subjects with SARS-Cov-2 data available at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Days 1, 2, 5, 10 and 15
    End point values
    Hydroxychloroquine + Standard of care Standard of care
    Number of subjects analysed
    8
    6
    Units: subjects
    number (not applicable)
        Day 1: Positive (n=6,5)
    6
    4
        Day 1: Negative (n=6,5)
    0
    1
        Day 1: Missing Data (n=6,5)
    0
    0
        Day 2: Positive (n=6,5)
    4
    4
        Day 2: Negative (n=6,5)
    1
    1
        Day 2: Missing Data (n=6,5)
    1
    0
        Day 5: Positive (n=5,3)
    3
    2
        Day 5: Negative (n=5,3)
    2
    1
        Day 5: Missing Data (n=5,3)
    0
    0
        Day 10: Positive (n=5,1)
    4
    1
        Day 10: Negative (n=5,1)
    1
    0
        Day 10: Missing Data (n=5,1)
    0
    0
        Day 15: Positive (n=3,0)
    1
    0
        Day 15: Negative (n=3,0)
    2
    0
        Day 15: Missing Data (n=3,0)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Severe Adverse Events and Adverse Events Leading to Treatment or Study Discontinuation

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    End point title
    Number of Subjects With Severe Adverse Events and Adverse Events Leading to Treatment or Study Discontinuation
    End point description
    An AEs was any untoward medical occurrence in a patient or clinical study subject, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Severe AEs were defined as an event that prevents normal everyday activities. TEAEs were defined as AEs that developed, worsened or became serious during the treatment-emergent period (defined as the day from randomisation to the end of study i.e., Day 30). Safety population included all subjects who were randomized to standard of care alone group, and all subjects who were randomized to HCQ + standard of care group with at least one dose of HCQ use. Analysed by treatment as actually received.
    End point type
    Secondary
    End point timeframe
    From Baseline to Day 30
    End point values
    Hydroxychloroquine + Standard of care Standard of care
    Number of subjects analysed
    8
    6
    Units: subjects
    number (not applicable)
        Any severe TEAE
    1
    1
        AnyTEAE led to permanent treatment discontinuation
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from time of first dose of study drug up to end of study (Day 30) regardless of seriousness or relationship to investigational product. SAEs, severe AEs and AEs leading to treatment or study discontinuation were collected as AE data.
    Adverse event reporting additional description
    Reported AEs and deaths are TEAEs that developed/worsened during ‘treatment period’ (defined as the day from randomisation to the end of study i.e., Day 30). Analysis was performed on safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Hydroxychloroquine + Standard of care
    Reporting group description
    Subjects received a loading dose of HCQ orally on Day 1 followed by a maintenance dose for 9 days (Days 2 to 10) plus standard of care.

    Reporting group title
    Standard of Care
    Reporting group description
    Subjects received standard of care only i.e., the usual care provided to COVID-19 subjects in the country/investigational site.

    Serious adverse events
    Hydroxychloroquine + Standard of care Standard of Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 6 (33.33%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertensive Crisis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic Carcinoma
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Covid-19
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (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: 5%
    Non-serious adverse events
    Hydroxychloroquine + Standard of care Standard of Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 6 (0.00%)
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Urinary Tract Infection Fungal
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Apr 2020
    Following main changes were made: Electrocardiogram (ECG) assessments were added; following exclusion criteria were added: use of antiarythmic medications, subjects with the following ECG findings at screening: QTcF >470 milliseconds (msec) for women or >450 msec for men or heart rate <50 beats/minute, subjects with known G6PD deficiency; pregnant or breastfeeding women. Requirement for contraceptive methods in women of childbearing potential and contraceptive guidance was added in inclusion criteria; clarifications on standard of care, discharge from hospital, schedule of activities SAE reporting. Details of nasopharyngeal swab analysis were added.
    16 Apr 2020
    Following main changes were made: update on inclusion criteria: onset of symptoms was changed from within <= 5 days to within two weeks of randomisation. List of contraindicated medications and medications with precautions for use was updated. Clarification on discharge and schedule of activities.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    25 May 2020
    The study was prematurely discontinued by the Sponsor due to enrollment and feasibility challenges that made study completion infeasible and as data from other studies did not suggest a benefit of HCQ for both COVID-19 treatment and prevention.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to premature discontinuation, only descriptive analysis were performed.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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