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    Clinical Trial Results:
    A Multicenter, Randomized, Open-label Parallel Group Pilot Study to Evaluate Safety and Efficacy of High Dose Intravenous Immune Globulin (IVIG) plus Standard Medical Treatment (SMT) versus SMT alone in Hospitalized Subjects with COVID-19

    Summary
    EudraCT number
    		 2020-001696-32
    Trial protocol
    		 ES  
    Global end of trial date
    03 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GC2004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04432324
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Instituto Grifols, S.A.
    Sponsor organisation address
    Can Guasch, 2 08150 Parets del Vallès, Barcelona, Spain,
    Public contact
    Department of Clinical Trials, Instituto Grifols, S.A, 34 935712000, IGregulatory.affairs@grifols.com
    Scientific contact
    Department of Clinical Trials, Instituto Grifols, S.A, 34 935712000, IGregulatory.affairs@grifols.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
    23 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine if high dose IVIG plus SMT can reduce the proportion of subjects dying or requiring intensive care unit (ICU) admission on or before Day 29 or who are dependent on high flow oxygen devices or invasive mechanical ventilation on Day 29 versus SMT alone in hospitalized subjects with COVID-19.
    Protection of trial subjects
    Documented approval from appropriate ECs was to be obtained for all participating centers/countries prior to study start, according to ICH GCP guidelines, local laws, regulations and organizations. The protocol dated 14 Apr 2020, all 3 subsequent amendments, and the Informed Consent Form were reviewed an approved by the EC of each participating research study center prior to implementation. Modifications to the study protocol could not be implemented by either the sponsor or the investigator without agreement by both parties. However, the investigator could implement a deviation from, or a change to, the protocol to eliminate an immediate hazard(s) to the study subjects without prior EC/sponsor approval/favorable opinion. As soon as possible, the implemented deviation or change, the reasons for it and if appropriate the proposed protocol amendment was to be submitted to the EC/sponsor. Any deviations from the protocol had to be fully explained and documented by the investigator.
    Background therapy
    		 Concomitant prophylaxis for potential venous thrombosis or thromboembolism in hospitalized subjects with COVID-19 was supported within this study according to institutional standard practices. Subjects could receive drugs such as azithromycin, tocilizumab and other potential COVID-19 disease modifying drugs as indicated based on clinical status and the investigator's discretion.
    Evidence for comparator
    		 At the time of designing the clinical study protocol, there were no approved treatments for COVID-19 and no approved prophylactic, post-exposure, or therapeutic treatment modalities existed for SARS-CoV-2. Standard medical treatment for COVID-19 was guided by disease severity and reflected a dynamic approach for an optimal disease management, considering the clinical experience and the evidence emerging from clinical trials.
    Actual start date of recruitment
    01 Jun 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: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    81
    From 65 to 84 years
    17
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 10 centers in Spain; 2 of the 10 centers did not enroll any subjects. The first subject was enrolled in the study on 01 Jun 2020, and the last subject completed their last visit 03 Mar 2021.

    Pre-assignment
    Screening details
    		 Subjects were assessed for trial eligibility during the screening period. Subjects had to meet all inclusion criteria and none of the exclusion criteria to be eligible for enrollment. A total of 100 subjects were screened and randomized into the study; no subjects screen failed.

    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
    		 Intravenous Immune Globulin + Standard Medical Treatment
    Arm description
    		 Subjects in the Intravenous Immune Globulin + Standard Medical Treatment (IVIG + SMT) arm received high dose intravenous immune globulin (IVIG), Flebogamma DIF plus standard medical treatment (SMT) based on their research study center's standard practices for the management of COVID-19 patients.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Flebogamma 5 and 10% DIF
    Investigational medicinal product code
    J06BA02
    Other name
    human normal immunoglobulin, IGIV3I, IVIG
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A total net dose of 2g/kg (capped to maximum 160g for subjects >80kg) was to be administered in divided doses over consecutive days, either into (a) infusions of 500mg/kg body weight over 4 days, or (b) 400mg/kg body weight over 5 days. To calculate dose for each infusion, the weight of the subject (kg) was to be multiplied by the dose in mg/kg. IVIG was to be infused using a separate line by itself, without mixing with other IV fluids or medications the subject could be receiving. IVIG infusion line could be flushed with 5% dextrose in water or 0.9% sodium chloride for injection. IVIG was to be initially administered at a rate of 0.01mL/kg/min for 30 minutes. If Flebogamma DIF was well tolerated, the rate could be gradually increased to a maximum infusion rate of 0.1 mL/kg/min and 0.08 mL/kg/min, for Flebogamma DIF 5% and 10%, respectively. For subjects aged >65 years, the maximum rate was 0.06mL/kg/min with Flebogamma DIF 5% and 0.04mL/kg/min with Flebogamma DIF 10%.

    Arm title
    		 Standard Medical Treatment
    Arm description
    		 Subjects in the Standard Medical Treatment (SMT) received medical care based on their research study center's standard practices for the management of COVID-19 patients.
    Arm type
    		 Standard Medical Treatment

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Intravenous Immune Globulin + Standard Medical Treatment Standard Medical Treatment
    Started
    50
    50
    Completed
    44
    47
    Not completed
    6
    3
         Adverse event, non-fatal
    2
    -
         Lost to follow-up
    1
    3
         Consent withdrawn by subject
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intravenous Immune Globulin + Standard Medical Treatment
    Reporting group description
    		 Subjects in the Intravenous Immune Globulin + Standard Medical Treatment (IVIG + SMT) arm received high dose intravenous immune globulin (IVIG), Flebogamma DIF plus standard medical treatment (SMT) based on their research study center's standard practices for the management of COVID-19 patients.

    Reporting group title
    Standard Medical Treatment
    Reporting group description
    		 Subjects in the Standard Medical Treatment (SMT) received medical care based on their research study center's standard practices for the management of COVID-19 patients.

    Reporting group values
    		 Intravenous Immune Globulin + Standard Medical Treatment Standard Medical Treatment Total
    Number of subjects
    		 50 50 100
    Age categorical
    Collected for Intention to Treat population
    Units: Subjects
        >=18 and <65 years
    		 41 40 81
        >=65 years
    		 9 10 19
    Age continuous
    Units: years
        median (full range (min-max))
    		 53.0 (23 to 90) 54.5 (27 to 86) -
    Gender categorical
    Units: Subjects
        Female
    		 10 11 21
        Male
    		 40 39 79
    Race
    Units: Subjects
        White
    		 47 46 93
        Black or African American
    		 1 2 3
        Asian
    		 1 0 1
        American Indian or Alaskan Native
    		 1 1 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Other
    		 0 1 1
    Body Mass Index (BMI)
    Units: kg/m2
        median (full range (min-max))
    		 29.45 (17.7 to 42.5) 27.6 (19.3 to 39.1) -
    Weight
    Units: kg
        median (full range (min-max))
    		 84.5 (43.7 to 120.0) 80.10 (58.0 to 121.0) -
    Duration of COVID-19 exposure
    Date of randomization - Date of first potential COVID-19 exposure + 1
    Units: Days
        arithmetic mean (standard deviation)
    		 13.2 ( 4.10 ) 12.7 ( 4.66 ) -
    Duration of first COVID-19 symptoms
    Date of randomization - Date of first COVID-19 symptoms + 1.
    Units: Days
        arithmetic mean (standard deviation)
    		 10.5 ( 5.47 ) 9.8 ( 3.57 ) -
    Duration of first positive RT-PCR/NAT or other commercial or other public health assay result
    Date of randomization - Date of first PCR (RT-PCR)/NAT or other commercial or public health assay positive + 1
    Units: Days
        arithmetic mean (standard deviation)
    		 3.0 ( 2.93 ) 2.6 ( 1.96 ) -
    7-Point Ordinal Scale
    Ordinal scale measure of clinical status: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or ECMO; 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities
    Units: Point
        arithmetic mean (standard deviation)
    		 4.3 ( 0.45 ) 4.2 ( 0.40 ) -
    National Early Warning Score (NEWS)
    Used to assess clinical status. Only collected in 49 subjects in the IVIG+SMT arm and 49 subjects in the SMT only arm.
    Units: Point
        arithmetic mean (standard deviation)
    		 3.2 ( 1.59 ) 2.9 ( 1.56 ) -

    End points

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    End points reporting groups
    Reporting group title
    Intravenous Immune Globulin + Standard Medical Treatment
    Reporting group description
    		 Subjects in the Intravenous Immune Globulin + Standard Medical Treatment (IVIG + SMT) arm received high dose intravenous immune globulin (IVIG), Flebogamma DIF plus standard medical treatment (SMT) based on their research study center's standard practices for the management of COVID-19 patients.

    Reporting group title
    Standard Medical Treatment
    Reporting group description
    		 Subjects in the Standard Medical Treatment (SMT) received medical care based on their research study center's standard practices for the management of COVID-19 patients.

    Subject analysis set title
    Intention to Treat: IVIG + SMT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects

    Subject analysis set title
    Per Protocol: IVIG + SMT
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of subjects included in the ITT population who did not present major protocol violations which might had an impact on the primary efficacy endpoint and completed at least 80% of the investigational product

    Subject analysis set title
    Safety: IVIG + SMT
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Defined for the combination arm as the subset of subjects who received at least any amount of Flebogamma® DIF in addition to SMT. The Safety Population for the SMT alone arm included all subjects randomized to this arm, because by definition SMT was universally provided and hence all randomized subjects would have received SMT

    Subject analysis set title
    Intention to Treat: SMT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects

    Subject analysis set title
    Per Protocol: SMT
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subset of subjects included in the ITT population who did not present major protocol violations which might had an impact on the primary efficacy endpoint and completed at least 80% of the investigational product

    Subject analysis set title
    Safety: SMT
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects randomized

    Primary: Number of subjects dying, requiring ICU admission, or dependent on high flow oxygen devices on or before Day 29

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    End point title
    		 Number of subjects dying, requiring ICU admission, or dependent on high flow oxygen devices on or before Day 29
    End point description
    This efficacy endpoint is the proportion of subjects dying or requiring ICU admission on or before Day 29 or who are dependent on high flow oxygen devices or invasive mechanical ventilation on Day 29. ICU=intensive care unit, IMV=invasive mechanical ventilation, CI=Confidence Interval
    End point type
    Primary
    End point timeframe
    Up to Day 29
    End point values
    		 Intention to Treat: IVIG + SMT Intention to Treat: SMT
    Number of subjects analysed
    50
    50
    Units: Subjects
        Dying on or Before Day 29
    0
    0
        Requiring ICU Admission on or before Day 29
    1
    2
        Dependent on High Flow Oxygen Devices on Day 29
    0
    0
        Depend on IMV on Day 29
    0
    0
        Meeting Primary Endpoint
    1
    2
    Statistical analysis title
    		 (IVIG+SMT)-SMT
    Statistical analysis description
    The difference in the proportions of subjects meeting the primary efficacy endpoint between the treatment groups.
    Comparison groups
    Intention to Treat: IVIG + SMT v Intention to Treat: SMT
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.4
         upper limit
    		 7.1

    Secondary: Assessment of Clinical Severity: Change in NEWS from baseline

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    End point title
    		 Assessment of Clinical Severity: Change in NEWS from baseline
    End point description
    The NEWS was calculated based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness).
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 29
    End point values
    		 Intention to Treat: IVIG + SMT Intention to Treat: SMT
    Number of subjects analysed
    Units: Score
    least squares mean (confidence interval 95%)
        Day 15
    -2.2 (-2.7 to -1.6)
    -1.8 (-2.3 to -1.2)
        Day 29
    -2.0 (-2.6 to -1.5)
    -1.7 (-2.2 to -1.2)
        Average across all post-baseline visits
    -1.5 (-2.0 to -1.0)
    -1.2 (-1.7 to -0.7)
    No statistical analyses for this end point

    Secondary: Time to clinical response: NEWS <= 2 maintained for 24 hours

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    End point title
    		 Time to clinical response: NEWS <= 2 maintained for 24 hours
    End point description
    Clinical response is defined as the NEWS score <=2 maintained for 24 hours from Day 1 through Day 29. The time to the first occurrence of clinical response was estimated using the Kaplan-Meier (KM) method.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 29
    End point values
    		 Intention to Treat: IVIG + SMT Intention to Treat: SMT
    Number of subjects analysed
    50
    50
    Units: Days
    arithmetic mean (confidence interval 95%)
        25th Percentile
    3 (2 to 4)
    2 (2 to 4)
        50th Percentile (Median)
    5 (4 to 8)
    5 (4 to 7)
        75th Percentile
    9 (7 to 16)
    10 (7 to 17)
    No statistical analyses for this end point

    Secondary: Time to hospital discharge: defined as duration of hospitalization

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    End point title
    		 Time to hospital discharge: defined as duration of hospitalization
    End point description
    Time to hospital discharge is defined as duration of hospitalization from Day 1 through Day 29. The proportion of subjects who were discharged from the hospital was estimated using the Cumulative Incidence Function. Deaths that occurred prior to discharge from the hospital was treated as a competing risk.
    End point type
    Secondary
    End point timeframe
    Post-randomization through Day 29
    End point values
    		 Intention to Treat: IVIG + SMT Intention to Treat: SMT
    Number of subjects analysed
    50
    50
    Units: Days
        arithmetic mean (standard deviation)
    8.1 ( 4.73 )
    8.8 ( 4.69 )
    No statistical analyses for this end point

    Secondary: If admitted to ICU: Duration of ICU stay

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    End point title
    		 If admitted to ICU: Duration of ICU stay
    End point description
    The duration of ICU stay from post-randomization through Day 29 was calculated based on ICU admission and discharge dates. Number of days in the ICU was compared between treatment groups using an ANOVA model, including number of days in the ICU as a dependent variable and treatment group as a fixed effect.
    End point type
    Secondary
    End point timeframe
    Post-randomization through Day 29
    End point values
    		 Intention to Treat: IVIG + SMT Intention to Treat: SMT
    Number of subjects analysed
    50
    50
    Units: Days
        arithmetic mean (standard deviation)
    0.0 ( 0.28 )
    0.3 ( 1.52 )
    No statistical analyses for this end point

    Secondary: Duration of any oxygen use

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    End point title
    		 Duration of any oxygen use
    End point description
    The duration of any oxygen use from Day 1 through Day 29 was calculated based on the start/stop date of using oxygen supplementation. Number of days on oxygen was compared between treatment groups using an analysis of variance (ANOVA) model, including number of days on oxygen as a dependent variable and treatment group as a fixed effect.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 29
    End point values
    		 Intention to Treat: IVIG + SMT Intention to Treat: SMT
    Number of subjects analysed
    50
    50
    Units: Days
        arithmetic mean (standard deviation)
    5.6 ( 6.37 )
    6.0 ( 5.87 )
    No statistical analyses for this end point

    Secondary: If requiring mechanical ventilation: Duration mechanical ventilation

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    End point title
    		 If requiring mechanical ventilation: Duration mechanical ventilation
    End point description
    The duration on mechanical ventilation from post randomization through Day 29 was calculated based on the start/stop dates of mechanical ventilation. Number of days on mechanical ventilation was compared between treatment groups using an ANOVA model, including number of days on mechanical ventilation as a dependent variable and treatment group as a fixed effect.
    End point type
    Secondary
    End point timeframe
    Post-randomization through Day 29
    End point values
    		 Intention to Treat: IVIG + SMT Intention to Treat: SMT
    Number of subjects analysed
    50
    50
    Units: Days
        arithmetic mean (standard deviation)
    0.0 ( 0.00 )
    0.0 ( 0.00 )
    No statistical analyses for this end point

    Secondary: Absolute value and mean change from baseline in the Ordinal scale

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    End point title
    		 Absolute value and mean change from baseline in the Ordinal scale
    End point description
    The absolute value and change from baseline in the Ordinal scale from Day 1 through Day 29 was summarized by treatment group and visit using descriptive statistics. The 7-point Ordinal scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 29
    End point values
    		 Intention to Treat: IVIG + SMT Intention to Treat: SMT
    Number of subjects analysed
    50
    50
    Units: Scale
    least squares mean (confidence interval 95%)
        Day 15
    2.44 (2.255 to 2.63)
    2.36 (2.18 to 2.55)
        Day 29
    2.55 (2.36 to 2.75)
    2.58 (2.39 to 2.77)
        Average across all post-baseline visits
    0.62 (0.44 to 0.81)
    0.91 (0.73 to 1.08)
    No statistical analyses for this end point

    Secondary: Proportion (percentage) of subjects in each severity category of the 7-point Ordinal scale

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    End point title
    		 Proportion (percentage) of subjects in each severity category of the 7-point Ordinal scale
    End point description
    The proportion of subjects in each severity category of the 7-point Ordinal scale at Day 15 and Day 29 was tabulated. The difference in severity category distribution between treatment groups at Day 15 and Day 29 was examined using proportional-odds cumulative logit model. The 7- point Ordinal scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities.
    End point type
    Secondary
    End point timeframe
    At Day 15 and Day 29
    End point values
    		 Intention to Treat: IVIG + SMT Intention to Treat: SMT
    Number of subjects analysed
    50
    50
    Units: Percentage of subjects
    number (not applicable)
        Day 15: Scale 1
    0.0
    0.0
        Day 15: Scale 2
    0.0
    0.0
        Day 15: Scale 3
    2.3
    0.0
        Day 15: Scale 4
    2.3
    6.3
        Day 15: Scale 5
    4.5
    8.3
        Day 15: Scale 6
    6.8
    8.3
        Day 15: Scale 7
    84.1
    77.1
        Day 29: Scale 1
    0.0
    0.0
        Day 29: Scale 2
    0.0
    0.0
        Day 29: Scale 3
    0.0
    0.0
        Day 29: Scale 4
    4.3
    2.1
        Day 29: Scale 5
    2.2
    0.0
        Day 29: Scale 6
    6.5
    17.0
        Day 29: Scale 7
    87.0
    80.9
    No statistical analyses for this end point

    Secondary: Time to sustained normalization of temperature and proportion of patients with normalization of fever at all time points, defined as temperature < 36.6 °C armpit, < 37.2 °C oral, or < 37.8 °C rectal sustained for at least 24 hours

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    End point title
    		 Time to sustained normalization of temperature and proportion of patients with normalization of fever at all time points, defined as temperature < 36.6 °C armpit, < 37.2 °C oral, or < 37.8 °C rectal sustained for at least 24 hours
    End point description
    Sustained normalization of temperature is defined as the temperature <36.6 ºC armpit (axillary), <37.2 ºC oral, or <37.8 ºC rectal sustained for at least 24 hours through Day 29. The value '2' for 25th Percentile CI% is not correct and represents "not estimable value". Validation error occurs if I use any other value than "2".
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 29
    End point values
    		 Intention to Treat: IVIG + SMT Intention to Treat: SMT
    Number of subjects analysed
    50
    50
    Units: Days
    arithmetic mean (confidence interval 95%)
        25th Percentile
    2 (2 to 3)
    2 (2 to 2)
        50th Percentile (Median)
    3 (3 to 4)
    2 (2 to 3)
        75th Percentile
    6 (4 to 9)
    4 (3 to 5)
    No statistical analyses for this end point

    Secondary: Number of subjects who develop Acute Respiratory Distress Syndrome (ARDS)

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    End point title
    		 Number of subjects who develop Acute Respiratory Distress Syndrome (ARDS)
    End point description
    Berlin criteria for ARDS was assessed on Day 1, 5, 15, and 29. The presence of ARDS and the degree of ARDS by Berlin criteria (Mild, Moderate, Severe) was tabulated by treatment group at each visit.
    End point type
    Secondary
    End point timeframe
    On Day 1, 5, 15, and 29
    End point values
    		 Intention to Treat: IVIG + SMT Intention to Treat: SMT
    Number of subjects analysed
    50
    50
    Units: Number of subjects
        Baseline
    0
    0
        Day 5
    0
    5
        Day 15
    1
    0
        Day 29
    2
    0
    No statistical analyses for this end point

    Secondary: Length of time to clinical progression (defined as the time to death, mechanical ventilation, or ICU admission)

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    End point title
    		 Length of time to clinical progression (defined as the time to death, mechanical ventilation, or ICU admission)
    End point description
    Clinical progression is defined as death, start of mechanical ventilation, or ICU admission through Day 29, whichever occurred first. The time to clinical progression was estimated using the KM method. '999999' represents Not Estimable.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 29
    End point values
    		 Intention to Treat: IVIG + SMT Intention to Treat: SMT
    Number of subjects analysed
    50
    50
    Units: Days
    arithmetic mean (confidence interval 95%)
        25th Percentile
    999999 (999999 to 999999)
    999999 (999999 to 999999)
        50th Percentile (Median)
    999999 (999999 to 999999)
    999999 (999999 to 999999)
        75th Percentile
    999999 (999999 to 999999)
    999999 (999999 to 999999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 29
    Adverse event reporting additional description
    Safety population included subjects who received any amount of Flebogamma DIF in addition to SMT. For the SMT alone arm, the Safety population included all subjects randomized to this arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Intravenous Immune Globulin + Standard Medical Treatment
    Reporting group description
    		 Subjects in the Intravenous Immune Globulin + Standard Medical Treatment (IVIG + SMT) arm received high dose intravenous immune globulin (IVIG), Flebogamma DIF plus standard medical treatment (SMT) based on their research study center's standard practices for the management of COVID-19 patients.

    Reporting group title
    Standard Medical Treatment
    Reporting group description
    		 Subjects in the standard medical treatment (SMT) arm received medical care based on their research study center's standard practices for the management of COVID-19 patients.

    Serious adverse events
    		 Intravenous Immune Globulin + Standard Medical Treatment Standard Medical Treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Acute interstitial pneumonitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intravenous Immune Globulin + Standard Medical Treatment Standard Medical Treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 47 (61.70%)
    25 / 50 (50.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 47 (4.26%)
    4 / 50 (8.00%)
         occurrences all number
    2
    4
    Phlebitis
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Secondary hypertension
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Face oedema
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Infusion site extravasation
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Acute interstitial pneumonitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Acute respiratory failure
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Lung infiltration
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Organising pneumonia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Sputum discoloured
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Insomnia
         subjects affected / exposed
    3 / 47 (6.38%)
    4 / 50 (8.00%)
         occurrences all number
    3
    4
    Confusional state
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Transaminases increased
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Interleukin level increased
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Sinus tachycardia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Tachycardia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 47 (10.64%)
    2 / 50 (4.00%)
         occurrences all number
    5
    2
    Dizziness
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    Paraesthesia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Sciatica
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Leukocytosis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Lymphopenia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Normochromic normocytic anaemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 50 (2.00%)
         occurrences all number
    4
    1
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    Hepatitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Hepatitis acute
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Non-alcoholic steatohepatitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Pruritus
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Bacterial disease carrier
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Bronchitis haemophilus
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Fungal disease carrier
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Gingivitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Infected skin ulcer
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Nosocomial infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Tooth abscess
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    Hyponatraemia
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Dyslipidaemia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (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
    28 Apr 2020
    The purpose of this amendment was to: - Reduce the frequency of safety due diligence interim analyses to one instance at approximately 50 patients (25/group) for simplicity without adjustments given exploratory, pilot nature of study. - Add analysis of concomitant and potentially COVID-19 disease modifying treatments between arms. - Emphasize importance of recording concomitant, potentially COVID-19 disease modifying treatments during the study. - Provide additional detail to describe nature of specimen to be obtained for quantitative viral load.
    27 May 2020
    The purpose of this amendment was to: - Clarify broader window for documented positive COVID-19 test results and emphasizing allowance for other commercial/public health assays for documentation of COVID-19 diagnosis. - Expand the window or documented positive test results in order to avoid limitations due to the timing of test procedures.
    25 Jun 2020
    The purpose of this amendment was to: - Modify eligibility criteria reflective of COVID-19 patient population recently admitted to hospital. Provision of table to derive PaO2/FiO2 ratio using SpO2 (if patient not on mechanical ventilation in absence of blood gas). - Indicate that Daily Assessments for Day 6 through Day 10 are required for as long as subjects are hospitalized, to clarify in-hospital daily evaluations. The Day 5±1 day assessments including laboratory parameters and Berlin criteria are mandatory to be performed for all subjects, and this is important because it also corresponds potentially to the last day of Flebogamma DIF infusion in the combination arm.

    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.
    None reported
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