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    Clinical Trial Results:
    A randomized double-blind placebo-controlled, pilot trial of intravenous plasma-purified alpha-1 antitrypsin for severe COVID-19 illness.

    Summary
    EudraCT number
    2020-001391-15
    Trial protocol
    IE  
    Global end of trial date
    12 Apr 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Jun 2022
    First version publication date
    26 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V323Oct2020
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Royal College of Surgeons Ireland
    Sponsor organisation address
    111 St Stephens Green, Dublin, Ireland, Dublin 2
    Public contact
    Mandy Jackson, Royal College of Surgeons Ireland, +353 852147569, mandyjackson@Rcsi.ie
    Scientific contact
    Mandy Jackson, Royal College of Surgeons Ireland, +353 852147569, mandyjackson@Rcsi.ie
    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 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the study is to conduct a clinical trial of IV AAT as a prospective anti-inflammatory therapy for severely ill COVID-19 patients with ARDS requiring ICU admission. The primary objective is to demonstrate a biological effect of IV Prolastin administered weekly at 120mg per kilogram of body weight in patients with severe COVID-19 illness requiring intubation and mechanical ventilation for ARDS by reducing circulating levels of IL-6 as measured by plasma ELISA. The study sample size is sufficient to demonstrate a significant difference in patients receiving Prolastin versus patients receiving placebo.
    Protection of trial subjects
    Assent was provided by next of kin for those subjects unable to consent. Adequate time was always given to allow patients/patients next of kin to fully understand the study and ask any questions. In addition, attempts were always made to have subjects sign the consent form themselves if they regained capacity. Where any participant was enrolled and did not regain capacity (due to their death or neurological impairment) the default position was that the enrolled person continued to be a participant in the trial. This was approved by the consent declaration granted by the Health Research Consent Declaration Committee. After the 10th patient was enrolled in the trial, an interim analysis was carried out by the RCSI Statistician and data was presented to two independent physicians, following which a decision regarding whether or not to proceed was undertaken based on (1) safety and tolerability, and (2) the status of the primary endpoint. Regular adverse event checks at each patient visit ensured continuous safety monitoring of participants.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Apr 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ireland: 36
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    24
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients (n=36) were enrolled between April 20, 2020, and March 18, 2021. Hospitalized patients with a working diagnosis of Acute Respiratory Distress Syndrome (ARDS) secondary to COVID-19 were screened on arrival to the ICU.

    Pre-assignment
    Screening details
    Eligible patients were aged ≥18 years, had a laboratory confirmed diagnosis of COVID-19, and were receiving ventilator support for moderate-to-severe ARDS with PaO2:FIO2 <200mmHg. In all patients diagnosed with COVID-19, SARS-CoV-2 infection was confirmed by RT-PCR of a nasopharyngeal swab specimen.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    Designated unblinded trial personnel were used to randomise subjects and prepare the study drug. The study drug was placed into opaque infusion masking bags so that the active could not be differentiated from placebo. In addition, the giving sets used were red which masked the colour of the study drug and the infusion lines were pre-primed by unblinded personnel. These measures then allowed the infusion to be transported and administered by a blinded member of the team.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo Arm (Baseline)
    Arm description
    0.9% sodium chloride
    Arm type
    Placebo

    Investigational medicinal product name
    0.9% sodium chloride
    Investigational medicinal product code
    ATC code: B05XX
    Other name
    NaCL
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The placebo to be used in the study is 0.9% sodium chloride solution for infusion (“normal saline”). Composition: 9.0 g/l sodium chloride (NaCl) in sterile water for injection. Each ml contains 9 mg sodium chloride. mmol/l: Na+ : 154 Cl- : 154. pH: 4.5-7. If randomised to Group 1, the dosing was as follows: - Week 1: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 2: Placebo (same volume, same rate of infusion as for Prolastin) -- Week 3: Placebo (same volume, same rate of infusion as for Prolastin) - Week 4: Placebo (same volume, same rate of infusion as for Prolastin) If randomised to Group 3, the dosing was as follows: - Week 1: Placebo (same volume, same rate of infusion as for Prolastin) - Week 2: Placebo (same volume, same rate of infusion as for Prolastin) - Week 3: Placebo (same volume, same rate of infusion as for Prolastin) - Week 4: Placebo (same volume, same rate of infusion as for Prolastin) Group 2 did not contain any placebo administration.

    Arm title
    Plasma Purified Alpha-1 antitrypsin (Baseline)
    Arm description
    The intervention used was human plasma-purified alpha-1 antitrypsin (Prolastin)
    Arm type
    Experimental

    Investigational medicinal product name
    Human plasma-purified alpha-1 antitrypsin
    Investigational medicinal product code
    ATCcode: B02AB02
    Other name
    Prolastin
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    Group 1: - Week 1: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 2: Placebo (same volume, same rate of infusion as for Prolastin) - Week 3: Placebo (same volume, same rate of infusion as for Prolastin) - Week 4: Placebo (same volume, same rate of infusion as for Prolastin) Group 2: - Week 1: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 2: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 3: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 4: Prolastin 120mg/kg body weight IV over 60 minutes* Group 3 was placebo only and no Prolastin

    Number of subjects in period 1
    Placebo Arm (Baseline) Plasma Purified Alpha-1 antitrypsin (Baseline)
    Started
    11
    25
    Completed
    11
    25
    Period 2
    Period 2 title
    Day 2
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    Designated unblinded trial personnel were used to randomise subjects and prepare the study drug. The study drug was placed into opaque infusion masking bags so that the active could not be differentiated from placebo. In addition, the giving sets used were red which masked the colour of the study drug and the infusion lines were pre-primed by unblinded personnel. These measures then allowed the infusion to be transported and administered by a blinded member of the team.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo Arm (Day 2)
    Arm description
    0.9% sodium chloride
    Arm type
    Placebo

    Investigational medicinal product name
    0.9% sodium chloride
    Investigational medicinal product code
    ATC code: B05XX
    Other name
    NaCL
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The placebo to be used in the study is 0.9% sodium chloride solution for infusion (“normal saline”). Composition: 9.0 g/l sodium chloride (NaCl) in sterile water for injection. Each ml contains 9 mg sodium chloride. mmol/l: Na+ : 154 Cl- : 154. pH: 4.5-7. If randomised to Group 1, the dosing was as follows: - Week 1: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 2: Placebo (same volume, same rate of infusion as for Prolastin) -- Week 3: Placebo (same volume, same rate of infusion as for Prolastin) - Week 4: Placebo (same volume, same rate of infusion as for Prolastin) If randomised to Group 3, the dosing was as follows: - Week 1: Placebo (same volume, same rate of infusion as for Prolastin) - Week 2: Placebo (same volume, same rate of infusion as for Prolastin) - Week 3: Placebo (same volume, same rate of infusion as for Prolastin) - Week 4: Placebo (same volume, same rate of infusion as for Prolastin) Group 2 did not contain any placebo administration.

    Arm title
    Plasma Purified Alpha-1 antitrypsin (Day 2)
    Arm description
    The intervention used was human plasma-purified alpha-1 antitrypsin (Prolastin)
    Arm type
    Experimental

    Investigational medicinal product name
    Human plasma-purified alpha-1 antitrypsin
    Investigational medicinal product code
    ATCcode: B02AB02
    Other name
    Prolastin
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    Group 1: - Week 1: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 2: Placebo (same volume, same rate of infusion as for Prolastin) - Week 3: Placebo (same volume, same rate of infusion as for Prolastin) - Week 4: Placebo (same volume, same rate of infusion as for Prolastin) Group 2: - Week 1: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 2: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 3: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 4: Prolastin 120mg/kg body weight IV over 60 minutes* Group 3 was placebo only and no Prolastin

    Number of subjects in period 2
    Placebo Arm (Day 2) Plasma Purified Alpha-1 antitrypsin (Day 2)
    Started
    11
    25
    Completed
    11
    25
    Period 3
    Period 3 title
    Day 7 (post-infusion)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo Arm (Day 7)
    Arm description
    0.9% sodium chloride
    Arm type
    Placebo

    Investigational medicinal product name
    0.9% sodium chloride
    Investigational medicinal product code
    ATC code: B05XX
    Other name
    NaCL
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The placebo to be used in the study is 0.9% sodium chloride solution for infusion (“normal saline”). Composition: 9.0 g/l sodium chloride (NaCl) in sterile water for injection. Each ml contains 9 mg sodium chloride. mmol/l: Na+ : 154 Cl- : 154. pH: 4.5-7. If randomised to Group 1, the dosing was as follows: - Week 1: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 2: Placebo (same volume, same rate of infusion as for Prolastin) -- Week 3: Placebo (same volume, same rate of infusion as for Prolastin) - Week 4: Placebo (same volume, same rate of infusion as for Prolastin) If randomised to Group 3, the dosing was as follows: - Week 1: Placebo (same volume, same rate of infusion as for Prolastin) - Week 2: Placebo (same volume, same rate of infusion as for Prolastin) - Week 3: Placebo (same volume, same rate of infusion as for Prolastin) - Week 4: Placebo (same volume, same rate of infusion as for Prolastin) Group 2 did not contain any placebo administration.

    Arm title
    Plasma Purified Alpha-1 antitrypsin (Day 7)
    Arm description
    The intervention used was human plasma-purified alpha-1 antitrypsin (Prolastin)
    Arm type
    Experimental

    Investigational medicinal product name
    Human plasma-purified alpha-1 antitrypsin
    Investigational medicinal product code
    ATCcode: B02AB02
    Other name
    Prolastin
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    Group 1: - Week 1: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 2: Placebo (same volume, same rate of infusion as for Prolastin) - Week 3: Placebo (same volume, same rate of infusion as for Prolastin) - Week 4: Placebo (same volume, same rate of infusion as for Prolastin) Group 2: - Week 1: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 2: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 3: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 4: Prolastin 120mg/kg body weight IV over 60 minutes* Group 3 was placebo only and no Prolastin

    Number of subjects in period 3
    Placebo Arm (Day 7) Plasma Purified Alpha-1 antitrypsin (Day 7)
    Started
    11
    25
    Completed
    11
    25
    Period 4
    Period 4 title
    Day 28
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo Arm (Day 28)
    Arm description
    0.9% sodium chloride
    Arm type
    Placebo

    Investigational medicinal product name
    0.9% sodium chloride
    Investigational medicinal product code
    ATC code: B05XX
    Other name
    NaCL
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The placebo to be used in the study is 0.9% sodium chloride solution for infusion (“normal saline”). Composition: 9.0 g/l sodium chloride (NaCl) in sterile water for injection. Each ml contains 9 mg sodium chloride. mmol/l: Na+ : 154 Cl- : 154. pH: 4.5-7. If randomised to Group 1, the dosing was as follows: - Week 1: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 2: Placebo (same volume, same rate of infusion as for Prolastin) -- Week 3: Placebo (same volume, same rate of infusion as for Prolastin) - Week 4: Placebo (same volume, same rate of infusion as for Prolastin) If randomised to Group 3, the dosing was as follows: - Week 1: Placebo (same volume, same rate of infusion as for Prolastin) - Week 2: Placebo (same volume, same rate of infusion as for Prolastin) - Week 3: Placebo (same volume, same rate of infusion as for Prolastin) - Week 4: Placebo (same volume, same rate of infusion as for Prolastin) Group 2 did not contain any placebo administration.

    Arm title
    Plasma Purified Alpha-1 antitrypsin (Day 28)
    Arm description
    The intervention used was human plasma-purified alpha-1 antitrypsin (Prolastin)
    Arm type
    Experimental

    Investigational medicinal product name
    Human plasma-purified alpha-1 antitrypsin
    Investigational medicinal product code
    ATCcode: B02AB02
    Other name
    Prolastin
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    Group 1: - Week 1: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 2: Placebo (same volume, same rate of infusion as for Prolastin) - Week 3: Placebo (same volume, same rate of infusion as for Prolastin) - Week 4: Placebo (same volume, same rate of infusion as for Prolastin) Group 2: - Week 1: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 2: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 3: Prolastin 120mg/kg body weight IV over 60 minutes* - Week 4: Prolastin 120mg/kg body weight IV over 60 minutes* Group 3 was placebo only and no Prolastin

    Number of subjects in period 4
    Placebo Arm (Day 28) Plasma Purified Alpha-1 antitrypsin (Day 28)
    Started
    11
    25
    Completed
    11
    22
    Not completed
    0
    3
         Lost to follow-up
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo Arm (Baseline)
    Reporting group description
    0.9% sodium chloride

    Reporting group title
    Plasma Purified Alpha-1 antitrypsin (Baseline)
    Reporting group description
    The intervention used was human plasma-purified alpha-1 antitrypsin (Prolastin)

    Reporting group values
    Placebo Arm (Baseline) Plasma Purified Alpha-1 antitrypsin (Baseline) Total
    Number of subjects
    11 25 36
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Age was collected from the medical record for each patient at their screening visit.
    Units: years
        arithmetic mean (standard deviation)
    57 ± 13 59 ± 11 -
    Gender categorical
    Units: Subjects
        Female
    2 12 14
        Male
    9 13 22
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    33.4 ± 8.1 35.2 ± 11 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo Arm (Baseline)
    Reporting group description
    0.9% sodium chloride

    Reporting group title
    Plasma Purified Alpha-1 antitrypsin (Baseline)
    Reporting group description
    The intervention used was human plasma-purified alpha-1 antitrypsin (Prolastin)
    Reporting group title
    Placebo Arm (Day 2)
    Reporting group description
    0.9% sodium chloride

    Reporting group title
    Plasma Purified Alpha-1 antitrypsin (Day 2)
    Reporting group description
    The intervention used was human plasma-purified alpha-1 antitrypsin (Prolastin)
    Reporting group title
    Placebo Arm (Day 7)
    Reporting group description
    0.9% sodium chloride

    Reporting group title
    Plasma Purified Alpha-1 antitrypsin (Day 7)
    Reporting group description
    The intervention used was human plasma-purified alpha-1 antitrypsin (Prolastin)
    Reporting group title
    Placebo Arm (Day 28)
    Reporting group description
    0.9% sodium chloride

    Reporting group title
    Plasma Purified Alpha-1 antitrypsin (Day 28)
    Reporting group description
    The intervention used was human plasma-purified alpha-1 antitrypsin (Prolastin)

    Primary: Change in level of circulating IL-6 in plasma at 7 days as measured by ELISA.

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    End point title
    Change in level of circulating IL-6 in plasma at 7 days as measured by ELISA.
    End point description
    Plasma was obtained at day 0 and day 7 from patients receiving placebo (n=11) and patients receiving AAT (n=22). IL-6 levels were increased at day 7 compared to day 0 in the placebo group (day 0: 259.9 +/- 206.5 pg/ml, day 7: 348.2 +/- 264.0 pg/ml; P=0.04) and decreased at day 7 in the AAT group (day 0: 296.0 +/- 219.7 pg/ml, day 7: 217.7 +/- 168.7 pg/ml; P=0.003). The 7-day change in plasma levels of IL-6 from baseline was +88.3 +/- 125.8 pg/ml in the placebo group compared to -78.3 +/- 112.1 pg/ml in the treatment group (P=0.002). Patients assigned to placebo demonstrated a 37.8+/-56.6% increase in plasma IL-6 at day 7 compared to a mean reduction of 17.4+/-42.3% in those receiving IV AAT (P=0.01). IL = interleukin; AAT = alpha-1 antitrypsin.
    End point type
    Primary
    End point timeframe
    Change from Day 0 to Day 7
    End point values
    Placebo Arm (Baseline) Plasma Purified Alpha-1 antitrypsin (Baseline) Placebo Arm (Day 7) Plasma Purified Alpha-1 antitrypsin (Day 7)
    Number of subjects analysed
    11
    22
    11
    22
    Units: pg/mL
        arithmetic mean (standard deviation)
    259.9 ± 206.5
    296 ± 219.7
    348.2 ± 264
    217.7 ± 168.7
    Statistical analysis title
    Statistical analysis of primary endpoint
    Statistical analysis description
    Changes in the levels of inflammatory biomarkers within each patient group were analyzed using paired t-tests for normally distributed data and a nonparametric paired Wilcoxon signed-rank test in the event of data failing the test for normality.
    Comparison groups
    Plasma Purified Alpha-1 antitrypsin (Baseline) v Placebo Arm (Baseline)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    < 0.05 [2]
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation
    Notes
    [1] - Results are reported as absolute numbers or means and standard deviations, as appropriate. Categorical variables are summarized as counts and percentages. No imputation was made for missing data. The primary efficacy analysis was on an intention to treat basis.
    [2] - Changes in the levels of inflammatory biomarkers within each patient group were analyzed using paired t-tests for normally distributed data and a nonparametric paired Wilcoxon signed-rank test in the event of data failing the test for normality.

    Secondary: Sequential Organ Failure Assessment (SOFA) score at day 7

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    End point title
    Sequential Organ Failure Assessment (SOFA) score at day 7
    End point description
    Sequential organ failure assessment (SOFA) score, an assessment of clinical severity incritically unwell patients
    End point type
    Secondary
    End point timeframe
    Baseline to Day 7
    End point values
    Placebo Arm (Baseline) Plasma Purified Alpha-1 antitrypsin (Baseline) Placebo Arm (Day 7) Plasma Purified Alpha-1 antitrypsin (Day 7)
    Number of subjects analysed
    11
    25
    11
    22
    Units: Points
        arithmetic mean (standard deviation)
    7.8 ± 3.3
    7.2 ± 3.4
    8.1 ± 3.5
    5.8 ± 4.1
    No statistical analyses for this end point

    Secondary: Circulating AAT levels

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    End point title
    Circulating AAT levels
    End point description
    Circulating alpha-1 antitrypsin (AAT) levels as measured by nephelometry
    End point type
    Secondary
    End point timeframe
    Baseline to Day 7
    End point values
    Placebo Arm (Baseline) Plasma Purified Alpha-1 antitrypsin (Baseline) Placebo Arm (Day 2) Plasma Purified Alpha-1 antitrypsin (Day 2) Placebo Arm (Day 7) Plasma Purified Alpha-1 antitrypsin (Day 7)
    Number of subjects analysed
    11
    22
    11
    22
    11
    22
    Units: g/L
        arithmetic mean (standard deviation)
    2.3 ± 0.6
    2.3 ± 0.5
    2.3 ± 0.7
    4.2 ± 0.7
    2.2 ± 0.5
    2.8 ± 0.8
    No statistical analyses for this end point

    Secondary: Mortality

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    End point title
    Mortality
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at Day 28
    End point values
    Placebo Arm (Day 28) Plasma Purified Alpha-1 antitrypsin (Day 28)
    Number of subjects analysed
    11
    25
    Units: percent
        number (not applicable)
    36
    32
    No statistical analyses for this end point

    Secondary: ICU Length of Stay

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    End point title
    ICU Length of Stay
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at Day 28
    End point values
    Placebo Arm (Day 28) Plasma Purified Alpha-1 antitrypsin (Day 28)
    Number of subjects analysed
    11
    25
    Units: day
        arithmetic mean (standard deviation)
    21.4 ± 5.9
    16 ± 9.9
    No statistical analyses for this end point

    Secondary: Secondary bacterial pneumonia

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    End point title
    Secondary bacterial pneumonia
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at Day 28
    End point values
    Placebo Arm (Day 28) Plasma Purified Alpha-1 antitrypsin (Day 28)
    Number of subjects analysed
    11
    25
    Units: percent
        number (not applicable)
    63
    44
    No statistical analyses for this end point

    Secondary: Hospital Length of Stay

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    End point title
    Hospital Length of Stay
    End point description
    End point type
    Secondary
    End point timeframe
    measured at day 28
    End point values
    Placebo Arm (Day 28) Plasma Purified Alpha-1 antitrypsin (Day 28)
    Number of subjects analysed
    11
    25
    Units: day
        arithmetic mean (standard deviation)
    24.6 ± 6.2
    19.3 ± 8.7
    No statistical analyses for this end point

    Secondary: Ventilator Free Days

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    End point title
    Ventilator Free Days
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at Day 28
    End point values
    Placebo Arm (Day 28) Plasma Purified Alpha-1 antitrypsin (Day 28)
    Number of subjects analysed
    11
    25
    Units: day
        arithmetic mean (standard deviation)
    3.6 ± 5.7
    8.2 ± 11.3
    No statistical analyses for this end point

    Secondary: Acute Kidney Injury

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    End point title
    Acute Kidney Injury
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at Day 28
    End point values
    Placebo Arm (Day 28) Plasma Purified Alpha-1 antitrypsin (Day 28)
    Number of subjects analysed
    11
    25
    Units: percent
        number (not applicable)
    72
    68
    No statistical analyses for this end point

    Secondary: PaO2:FIO2

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    End point title
    PaO2:FIO2
    End point description
    PaO2:FIO2 – ratio of partial pressure of oxygen in arterial blood to the fraction of inspired oxygen
    End point type
    Secondary
    End point timeframe
    Baseline to Day 7
    End point values
    Placebo Arm (Baseline) Plasma Purified Alpha-1 antitrypsin (Baseline) Placebo Arm (Day 7) Plasma Purified Alpha-1 antitrypsin (Day 7)
    Number of subjects analysed
    11
    25
    11
    22
    Units: mmHg
        arithmetic mean (standard deviation)
    122.5 ± 40.5
    129.7 ± 38.2
    127.7 ± 53.7
    186.7 ± 135.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were checked from the screening period until the Day 28 visit (follow up)
    Adverse event reporting additional description
    Adverse events were collected by the investigator team through medical chart reviews and discussion with patients at visits where possible.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Human alpha-1 antitrypsin (Prolastin)
    Reporting group description
    A total of 4 SAEs were recorded in the treatment group, involving 2 patients. Of these, 3 SAEs were deemed not related to the study IMP by the Chief Investigator (CI). One SAE was considered to be possibly related to study IMP by the CI (hypertension persistent for >30 min post-infusion), and resolved without sequelae. None of the SAEs resulted in discontinuation of treatment.

    Serious adverse events
    Placebo Human alpha-1 antitrypsin (Prolastin)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 25 (8.00%)
         number of deaths (all causes)
    4
    8
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertension
    Additional description: Determined to be possibly related to the study drug.
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 8
    Investigations
    Supraventricular tachycardia
    Additional description: Not related to the study drug
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 8
    Cardiac disorders
    Atrial fibrillation
    Additional description: not related to the study drug
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 8
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Occurred in reporting arm 2 (Prolastin). Not determined to be related to the study drug.
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 8
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo Human alpha-1 antitrypsin (Prolastin)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    5 / 25 (20.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2020
    -Estimated trial duration increased to 12 months -Planned trial sites added -Addition of new Principal Investigators for this trial -Removal of wording “patients who are receiving vasopressors (0.05- 0.1μg/kg/min)” when referring to the study population -Removal of wording “sex & BMI” in randomisation schedule -Medication administration time changed from 30-45 minutes to approximately 60 minutes -Inclusion criteria #2 removal of“requirement for vasopressors (0.05- 0.1μg/kg/min) -Exclusion criteria #5 addition of wording “other than antibiotics or anti- virals” -Exclusion criteria #19 removed -Removal of mandatory Isoelectric focusing of plasma to confirm Pi*MM status at screening -Echocardiogram will be performed at screening only where possible -Additional notes added: • The screening visit and baseline visit can occur on the same day • The follow up visit after Early Discontinuation will be performed as soon as is possible. • A note added that the most recent results should be documented for assessments performed within 5 days of the screening visit -Footnote added to clarify regained capacity consent must be attempted at each visit. X indicated at Visit 1 & 2 to indicate that family member assent must be attempted before subjects are screened. -Sections deleted and wording amended to reflect that the Investigators report only serious adverse events that are possibly related to the study drug -Planned recruitment rate amended from 2 weeks to 12 months -Wording amended to interim analysis of cytokine levels taken at 7 days may be conducted.
    01 Dec 2020
    -Addition of Inclusion #4 “Patients receiving invasive mechanical ventilation or non-invasive ventilation” -Exclusion criteria #1 wording changed from “Not receiving invasive mechanical ventilation” to “Not receiving invasive mechanical ventilation or non-invasive ventilation” (i.e. patients receiving invasive mechanical ventilation or non-invasive ventilation are eligible for the trial) -Exclusion criteria #5 wording changed from “Participation in a clinical trial of an investigational medicinal product (other than antibiotics or anti-virals)” to “Participation in a clinical trial of interferon therapies, immune plasma therapies or immunoglobulin within 30 days” -Exclusion criteria #17 wording changed from “Enrolled in a concomitant clinical trial of a medicinal product (other than antibiotics or anti-virals” to “Enrolled in a concomitant clinical trial of interferon therapies, immune plasma therapies or immunoglobulin”

    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.
    The population studied was small which prevented meaningful conclusions regarding clinical outcomes from being drawn. A larger trial is needed to determine the effect of this therapy on clinical outcomes.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/35291694
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