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    Clinical Trial Results:
    A Multicenter, Randomized, Open-label, Parallel Group Pilot Study to Evaluate the Safety and Efficacy of Prolastin® plus Standard Medical Treatment (SMT) versus SMT alone in Hospitalized Subjects with COVID-19.

    Summary
    EudraCT number
    		 2020-001953-36
    Trial protocol
    		 ES  
    Global end of trial date
    11 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GC2005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04495101
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Instituto Grifols, S.A.
    Sponsor organisation address
    Can Guasch, 2, Parets del Vallès, , Barcelona, Spain, 08150
    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
    18 Aug 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jun 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine if Prolastin plus SMT can reduce the proportion of subjects dying or requiring intensive care unit (ICU) admission on or before Day 15 or who are dependent on invasive mechanical ventilation on Day 15 versus SMT alone in hospitalized subjects with COVID-19.
    Protection of trial subjects
    Investigators ensured that the study was conducted in full conformance with GCP, appropriate local laws and regulations, and the Declaration of Helsinki. The protocol and protocol amendments for this study were prepared in accordance with ICH Guidelines (and any other relevant regulations). The protocol dated 05 May 2020, two subsequent protocol amendments, and the Informed Consent Form (ICF) were reviewed and approved by the IRB/EC of each participating research study center prior to implementation. Regulatory Authority approvals/authorizations/ notifications, where required, were in place, and fully documented prior to study start. The IRBs/ECs had to supply to the Sponsor, upon request, a list of members involved in the review and approval of the protocol, protocol amendments, consent form and a statement to confirm that the IRB/EC was organized and operating according to GCP Guidelines and applicable laws and regulations. Modifications to the study protocol and protocol amendments were only implemented following agreement by the Sponsor and Investigator. Any deviations from the protocol required full documentation and explanation by the Investigator.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jul 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)
    67
    From 65 to 84 years
    32
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 8 centers in Spain; however, 2 of the 8 centers did not enroll any subjects. The first patient was enrolled 29 Jul 2020, the last patient was enrolled 12 Apr 2021. The last subject completed their last visit 10 Jun 2021.

    Pre-assignment
    Screening details
    		 Subjects were assessed for trial eligibility during the screening period. All of the inclusion criteria and none of the exclusion criteria had to be met for subject to be eligible for study enrollment. A total of 103 subjects were screened, 100 subjects were included in the ITT population and randomized.

    Pre-assignment period milestones
    Number of subjects started
    		 100
    Number of subjects completed
    		 100

    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
    		 Prolastin + Standard Medical Treatment
    Arm description
    		 Subjects in the Prolastin + Standard Medical Treatment (SMT) arm received two IV doses of Prolastin at 120 mg/kg body weight, 1 week apart (at Day 1 and, an optional dose, at Day 8, for those still hospitalized).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Prolastin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Subjects in the Prolastin + SMT arm were given an IV dose of 120 mg/kg (body weight) on Day 1 and Day 8. For those who had been discharged from the hospital, the second infusion was not mandatory and was at the discretion of the Principal Investigator and subject. Once reconstituted, Prolastin had a concentration of Alpha 1-Proteinase Inhibitor of 25 mg/mL. The infusion rate was at the Principal Investigator's discretion depending on the patient's condition and need to avoid fluid overload. Preparation of the solution for infusion from the lyophilized product was performed by a healthcare professional under aseptic conditions. Prolastin was infused using a separate line by itself, without mixing with other intravenous fluids or medications. Prolastin in Type I glass vials. Each original pack contained 1 powder vial (1000 mg alpha1-PI, human), 1 solvent vial (40 mL water for injections), and 1 Mix2Vial transfer device for reconstitution.

    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
    		Prolastin + Standard Medical Treatment Standard Medical Treatment
    Started
    50
    50
    Completed
    41
    44
    Not completed
    9
    6
         Consent withdrawn by subject
    4
    1
         Death
    3
    4
         Subject transferred to another center 15Apr2021
    1
    -
         Patient refused Day 29 to avoid trip to hospital
    -
    1
         No treatment in pharmacy to administer prolastin
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Prolastin + Standard Medical Treatment
    Reporting group description
    		 Subjects in the Prolastin + Standard Medical Treatment (SMT) arm received two IV doses of Prolastin at 120 mg/kg body weight, 1 week apart (at Day 1 and, an optional dose, at Day 8, for those still hospitalized).

    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
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment Total
    Number of subjects
    		 50 50 100
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 31 36 67
        From 65-84 years
    		 19 13 32
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 60.5 (30 to 83) 55.5 (29 to 89) -
    Gender categorical
    Units: Subjects
        Female
    		 21 19 40
        Male
    		 29 31 60
    Race
    Units: Subjects
        White
    		 44 48 92
        Black or African American
    		 1 0 1
        Asian
    		 1 0 1
        American Indian or Alaska Native
    		 1 2 3
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Other
    		 2 0 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 36 43 79
        Not Hispanic or Latino
    		 14 7 21
    Weight
    Units: Kilograms
        median (full range (min-max))
    		 80.0 (53.6 to 120.0) 80.0 (53.3 to 130.0) -
    BMI
    Units: kg/m^2
        median (full range (min-max))
    		 27.35 (19.6 to 47.9) 28.15 (20.4 to 53.4) -
    Height
    Units: centimeter
        median (full range (min-max))
    		 167.5 (148 to 194) 165.0 (152 to 185) -
    Duration of potential COVID-19 exposure
    The SD value "9.9999" for reporting group 1 should read as "Not applicable".
    Units: day
        arithmetic mean (standard deviation)
    		 16.0 ( 9.9999 ) 13.4 ( 4.28 ) -
    Duration of first COVID-19 symptoms
    Units: day
        arithmetic mean (standard deviation)
    		 9.3 ( 4.31 ) 8.9 ( 3.08 ) -
    Duration of first positive PCR (RT-PCR)/NAT or other commercial or public health assay result
    Units: day
        arithmetic mean (standard deviation)
    		 3.5 ( 2.79 ) 4.0 ( 3.10 ) -
    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)
    		 3.9 ( 0.61 ) 3.8 ( 0.49 ) -
    National Early Warning Score (NEWS)
    This metric is used to assess clinical status. Data were only collected in 33 subjects from the Prolastin + SMT arm and 32 subjects in the SMT arm.
    Units: Point
        arithmetic mean (standard deviation)
    		 3.3 ( 1.73 ) 3.3 ( 1.41 ) -

    End points

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    End points reporting groups
    Reporting group title
    Prolastin + Standard Medical Treatment
    Reporting group description
    		 Subjects in the Prolastin + Standard Medical Treatment (SMT) arm received two IV doses of Prolastin at 120 mg/kg body weight, 1 week apart (at Day 1 and, an optional dose, at Day 8, for those still hospitalized).

    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.

    Primary: Primary: Number of subjects dying, requiring ICU admission, or dependent on high flow oxygen devices on or before Day 15

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    End point title
    		 Primary: Number of subjects dying, requiring ICU admission, or dependent on high flow oxygen devices on or before Day 15
    End point description
    This primary efficacy variable was defined as the proportion of subjects dying or requiring ICU admission on or before Day 15 or who were dependent on invasive mechanical ventilation on Day 15.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 15
    End point values
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Subjects
        Dying on or Before Day 15
    3
    4
        Requiring ICU Admission on or Before Day 15
    4
    7
        Dependent on IMV on Day 15
    3
    2
        Meeting Primary Endpoint
    7
    11
    Statistical analysis title
    		 (Prolastin+SMT)-SMT
    Statistical analysis description
    The difference in the proportions of subjects meeting the primary efficacy endpoint between the treatment groups.
    Comparison groups
    Prolastin + Standard Medical Treatment v Standard Medical Treatment
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.4356
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.2
         upper limit
    		 7.6

    Secondary: Secondary: Assessment of Clinical Severity: Change in NEWS from Baseline through Day 29

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    End point title
    		 Secondary: Assessment of Clinical Severity: Change in NEWS from Baseline through Day 29
    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). Average across all post-baseline visits was not estimable for the SMT arm hence added value "9.9999" to avoid a validation error.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 29.
    End point values
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Score
    least squares mean (confidence interval 95%)
        Day 15
    -2.62 (-3.21 to -2.03)
    -2.39 (-2.96 to -1.82)
        Day 29
    -2.80 (-3.40 to -2.20)
    -2.80 (-3.37 to -2.23)
        Average across all post-baseline visits
    -1.24 (-1.78 to -0.71)
    9.9999 (9.9999 to 9.9999)
    No statistical analyses for this end point

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

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    End point title
    		 Secondary: 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
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Days
    arithmetic mean (confidence interval 95%)
        25th Percentile
    3 (2 to 4)
    4 (2 to 5)
        50th Percentile (Median)
    6 (4 to 8)
    7 (5 to 8)
        75th Percentile
    8 (7 to 16)
    12 (8 to 15)
    No statistical analyses for this end point

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

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    End point title
    		 Secondary: 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
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Days
        arithmetic mean (standard deviation)
    11.68 ( 8.43 )
    11.88 ( 8.35 )
    No statistical analyses for this end point

    Secondary: Secondary: If admitted to ICU: Duration of ICU stay

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    End point title
    		 Secondary: 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
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Days
        arithmetic mean (standard deviation)
    1.62 ( 6.18 )
    2.0 ( 5.93 )
    No statistical analyses for this end point

    Secondary: Secondary: Duration of any oxygen use

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    End point title
    		 Secondary: 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
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Days
        arithmetic mean (standard deviation)
    10.02 ( 9.15 )
    10.56 ( 9.97 )
    No statistical analyses for this end point

    Secondary: Secondary: If requiring mechanical ventilation: Duration mechanical ventilation

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    End point title
    		 Secondary: 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
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Days
        arithmetic mean (standard deviation)
    1.44 ( 5.47 )
    0.74 ( 3.77 )
    No statistical analyses for this end point

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

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    End point title
    		 Secondary: Clinical Status: 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 were 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
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Scale
    least squares mean (confidence interval 95%)
        Day 15
    1.74 (1.40 to 2.07)
    1.89 (1.57 to 2.21)
        Day 29
    2.05 (1.71 to 2.39)
    2.18 (1.86 to 2.50)
        Average across all post-baseline visits
    0.37 (0.11 to 0.64)
    0.62 (0.36 to 0.88)
    No statistical analyses for this end point

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

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    End point title
    		 Secondary: 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
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Percentage of subjects
        Day 15: Scale 1
    3
    3
        Day 15: Scale 2
    3
    1
        Day 15: Scale 3
    1
    3
        Day 15: Scale 4
    2
    4
        Day 15: Scale 5
    4
    4
        Day 15: Scale 6
    4
    4
        Day 15: Scale 7
    26
    29
        Day 29: Scale 1
    3
    4
        Day 29: Scale 2
    3
    1
        Day 29: Scale 3
    0
    1
        Day 29: Scale 4
    0
    2
        Day 29: Scale 5
    1
    0
        Day 29: Scale 6
    8
    6
        Day 29: Scale 7
    29
    34
    No statistical analyses for this end point

    Secondary: 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
    		 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
    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. These values represent the time to first occurrence of sustained normalization of temperature (Days).
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 29
    End point values
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Days
    arithmetic mean (confidence interval 95%)
        25th Percentile
    2 (2 to 3)
    2 (2 to 3)
        50th Percentile (Median)
    3 (2 to 5)
    4 (3 to 4)
        75th Percentile
    6 (5 to 8)
    5 (4 to 6)
    No statistical analyses for this end point

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

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    End point title
    		 Secondary: 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
    Baseline (Day 1), Day 5, Day 15, and Day 29.
    End point values
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Number of subjects
        Baseline
    19
    18
        Day 5
    16
    15
        Day 15
    6
    5
        Day 29
    3
    4
    No statistical analyses for this end point

    Secondary: Secondary: Proportion of subjects without clinical progression (defined as death, start of mechanical ventilation, or ICU admission) at Day 15 and Day 29

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    End point title
    		 Secondary: Proportion of subjects without clinical progression (defined as death, start of mechanical ventilation, or ICU admission) at Day 15 and Day 29
    End point description
    Proportion of subjects without clinical progression (defined as death, start of mechanical ventilation, or ICU admission) at Day 15 and Day 29. No statistically significant difference in proportion of subjects without clinical progression was observed between treatment groups (p=0.3328) Overall Kaplan-Meier Analysis: Prolastin+SMT arm (N=50): 43 were censored and 7 experienced clinical progression. SMT arm (N=50): 39 were censored and 11 experienced clinical progression.
    End point type
    Secondary
    End point timeframe
    Day 15 and Day 29
    End point values
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Percentage of subjects
    number (confidence interval 95%)
        Day 15: % of subjects without clinical progression
    84.8 (70.8 to 92.5)
    77.9 (63.6 to 87.1)
        Day 29: % of subjects without clinical progression
    84.8 (70.8 to 92.5)
    77.9 (63.6 to 87.1)
    No statistical analyses for this end point

    Secondary: Secondary: Summary and analysis of all-cause mortality through Day 29.

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    End point title
    		 Secondary: Summary and analysis of all-cause mortality through Day 29.
    End point description
    Summary and analysis of all-cause mortality through Day 29.
    End point type
    Secondary
    End point timeframe
    Day 1 through Day 29
    End point values
    		 Prolastin + Standard Medical Treatment Standard Medical Treatment
    Number of subjects analysed
    50
    50
    Units: Subjects
        Alive at Day 29
    47
    46
        Dead at Day 29
    3
    4
    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 Prolastin 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
    Prolastin+SMT
    Reporting group description
    		 -

    Reporting group title
    SMT1
    Reporting group description
    		 -

    Serious adverse events
    		 Prolastin+SMT SMT1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 46 (15.22%)
    12 / 50 (24.00%)
         number of deaths (all causes)
    23
    18
         number of deaths resulting from adverse events
    4
    6
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 46 (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
    Respiratory failure
         subjects affected / exposed
    0 / 46 (0.00%)
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    4 / 46 (8.70%)
    6 / 50 (12.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 4
    0 / 6
    Superinfection bacterial
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (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
    		 Prolastin+SMT SMT1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 46 (43.48%)
    12 / 50 (24.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Catheter site phlebitis
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Acute respiratory failure
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Nasal congestion
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Pneumothorax
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 46 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    Respiratory failure
         subjects affected / exposed
    0 / 46 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Anxiety
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Initial insomnia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Middle insomnia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Fibrin D dimer increased
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    Serum ferritin increased
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Transaminases increased
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Tongue injury
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Myocardial infarction
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    Bicytopenia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 46 (4.35%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Haemorrhagic necrotic pancreatitis
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Pigmentation disorder
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Rash pruritic
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Subcutaneous emphysema
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Haematuria
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Renal failure
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Synovial cyst
         subjects affected / exposed
    1 / 46 (2.17%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    4 / 46 (8.70%)
    6 / 50 (12.00%)
         occurrences all number
    4
    6
    Pneumonia bacterial
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Pneumonia necrotising
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Superinfection bacterial
         subjects affected / exposed
    1 / 46 (2.17%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    Vascular device infection
         subjects affected / exposed
    0 / 46 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 46 (4.35%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 46 (2.17%)
    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
    19 May 2020
    Protocol Amendment 4: Version 5.0 Sections 5.2.1, 7.2.2, and Appendix 1: Inclusion criterion number 2 was changed to include that laboratory-confirmed novel coronavirus infection was performed during the hospital admission and not less than 72 hours prior to randomization. This change aimed to expand the window for documented positive test results and avoid limitations due to the timing of test procedures.
    08 Oct 2020
    Protocol Amendment 5 :Version 6.0 Sections 4.2, 7.2.3: Clarified that all samples were mandatory at all time points regardless of hospital discharge status and that Day 5 ±1 day assessments were mandatory for all subjects, to emphasize that planned laboratory testing remained mandatory regardless of study subjects’ discharge status. Sections 4.2, 4.4.1, 6.1, 7.2.3. and Appendix 1: Clarified that if the subject was discharged from the hospital before Day 8, the second infusion of Prolastin was not mandatory and was at the discretion of the Principal Investigator and the subject. Sections 4.2., 7.2.3, and Appendix 1: The note “for Day 6 through Day 10, this stipulation is for as long as subjects are hospitalized” was added to indicate that daily assessments through Day 10 were required as long as the subjects remained hospitalized. Section 4.2: Figure 4-1 was replaced to include the new study schema and requirements. Section 7.2.2, Appendix 1: Added specific parameters for collection of demographic data (including age [year of birth], gender, race, and ethnicity), to ensure completeness and consistency. Sections 7.2.3, 7.2.4: Changed study schedule and assessments for subjects who could be discharged from the hospital early into the study. Section 7.2.4.1: New Section added to clarify subject visit schedule, and conditions for Day 8 and second infusion of Prolastin.

    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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