Trial Outcomes & Findings for Study to Evaluate the Safety and Efficacy of Liquid Alpha1-Proteinase Inhibitor (Human) in Hospitalized Participants With Coronavirus Disease (COVID-19) (NCT NCT04547140)

NCT ID: NCT04547140

Last Updated: 2023-03-22

Results Overview

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 57 participants
• Primary outcome timeframe: Up to Day 29
• Results posted on: 2023-03-22

Participant Flow

Participants took part in the study at sites in the United States, Brazil, Chile, Colombia, and Mexico, from 29 January 2021 (first participant enrolled to receive the study drug) to 28 January 2022 (last participant completed).

78 participants with Coronavirus Disease 2019 (COVID-19) who were hospitalized were screened of which 57 were randomized in 1:1 ratio to receive either Alpha1-Proteinase Inhibitor (PI) (Human) plus Standard Medical Treatment (SMT) or placebo plus Standard Medical Treatment.

Participant milestones

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment Participants received the first intravenous (IV) infusion of liquid alpha1-proteinase inhibitor (human) 120 milligrams per kilogram (mg/kg), based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the principal investigator's \[PI\] discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Overall Study STARTED	29	28
Overall Study Safety Population	27	27
Overall Study COMPLETED	19	22
Overall Study NOT COMPLETED	10	6

Reasons for withdrawal

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment Participants received the first intravenous (IV) infusion of liquid alpha1-proteinase inhibitor (human) 120 milligrams per kilogram (mg/kg), based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the principal investigator's \[PI\] discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Overall Study Adverse Event	0	1
Overall Study Withdrawal by Subject	0	1
Overall Study Lost to Follow-up	3	1
Overall Study Death	2	1
Overall Study Physician Decision (Does not Include Adverse Events)	0	1
Overall Study Pregnancy	1	0
Overall Study Reason Not Specified	4	1

Baseline Characteristics

Study to Evaluate the Safety and Efficacy of Liquid Alpha1-Proteinase Inhibitor (Human) in Hospitalized Participants With Coronavirus Disease (COVID-19)

Baseline characteristics by cohort

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=29 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=28 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Total n=57 Participants Total of all reporting groups
Age, Continuous	52.1 years STANDARD_DEVIATION 14.46 • n=5 Participants	51.2 years STANDARD_DEVIATION 12.14 • n=7 Participants	51.7 years STANDARD_DEVIATION 13.26 • n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants	11 Participants n=7 Participants	25 Participants n=5 Participants
Sex: Female, Male Male	15 Participants n=5 Participants	17 Participants n=7 Participants	32 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	14 Participants n=5 Participants	10 Participants n=7 Participants	24 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	15 Participants n=5 Participants	18 Participants n=7 Participants	33 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	22 Participants n=5 Participants	21 Participants n=7 Participants	43 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black or African American	1 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants
Race/Ethnicity, Customized Race · Asian	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to Day 29

Population: ITT population included all participants who were randomized.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=29 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=28 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Percentage of Participants Dying or Requiring Intensive Care Unit (ICU) Admission Percentage of Participants Dying	6.9 percentage of participants	3.6 percentage of participants
Percentage of Participants Dying or Requiring Intensive Care Unit (ICU) Admission Percentage of Participants Requiring ICU Admission	20.7 percentage of participants	14.3 percentage of participants

PRIMARY outcome

Timeframe: Day 29

Population: ITT population included all participants who were randomized. Percentage of participants are rounded off to the single decimal point.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=29 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=28 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Percentage of Participants Who Are Dependent on High Flow Oxygen Devices or Invasive Mechanical Ventilation Dependent on High Flow Oxygen Devices	6.9 percentage of participants	0.0 percentage of participants
Percentage of Participants Who Are Dependent on High Flow Oxygen Devices or Invasive Mechanical Ventilation Dependent on Invasive Mechanical Ventilation	3.4 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Days 15 and 29

Population: ITT population included all participants who were randomized. Overall number analyzed are the number of participants with data available for analysis.

NEWS is clinical scoring developed to improve detection of deterioration in ill participant. It is based on 7 clinical parameters: Respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure (BP), pulse rate, level of consciousness, and temperature. A score of 0 and 2 was allocated to supplemental oxygen, 0 and 3 for level of consciousness and score of 0, 1, 2 and 3 for remaining parameters (i.e. respiration rate, oxygen saturation, systolic BP, pulse rate and temperature) where 0 = normal health condition to 3 = worst health condition; Higher scores indicated more severity. All scores were summed to get an aggregate score. Aggregate NEWS score ranged from 0 to 20, with higher scores indicating more severity/higher risk.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=18 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=22 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Change From Baseline in National Early Warning Score (NEWS) Change From Baseline at Day 15	-1.1 score on a scale Standard Deviation 3.71	-2.3 score on a scale Standard Deviation 2.22
Change From Baseline in National Early Warning Score (NEWS) Change From Baseline at Day 29	-2.9 score on a scale Standard Deviation 2.38	-2.5 score on a scale Standard Deviation 1.95

SECONDARY outcome

Timeframe: Up to Day 29

Population: ITT population included all participants who were randomized. Overall number analyzed are the participants who achieved clinical response.

Time to clinical response was reported at 50th percentile in days.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=5 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=10 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Time to Clinical Response as Assessed by NEWS Score ≤ 2 Maintained for 24 Hours	NA days Median, upper and lower limit of 95% Confidence Interval (CI) was not estimable due to the number of participants with events much lower than 50%.	NA days Interval 5.0 to Median and upper limit of 95% CI was not estimable due to the number of participants with events lower than 50%.

SECONDARY outcome

Timeframe: Up to Day 29

Population: ITT population included all participants who were randomized. Overall number of participants analyzed signifies the number of participants with available data for analysis.

Time to hospital discharge is defined as duration of hospitalization from Day 1 through Day 29.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=27 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=27 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Time to Hospital Discharge	5.0 days Interval 1.0 to 29.0	5.0 days Interval 2.0 to 29.0

SECONDARY outcome

Timeframe: Up to Day 29

Population: ITT population included all participants who were randomized. Overall number of participants analyzed signifies the number of participants with available data for analysis.

Duration of ICU stay in days is analyzed for participants admitted to ICU post randomization.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=27 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=27 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Duration of ICU Stay	0.0 days Interval 0.0 to 29.0	0.0 days Interval 0.0 to 29.0

SECONDARY outcome

Timeframe: Up to Day 30

Population: ITT population included all participants who were randomized. Overall number of participants analyzed signifies the number of participants with available data for analysis.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=27 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=27 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Duration of Any Oxygen Use	7.0 days Interval 0.0 to 30.0	6.0 days Interval 0.0 to 30.0

SECONDARY outcome

Timeframe: Up to Day 29

Population: ITT population included all participants who were randomized. Overall number of participants analyzed signifies the number of participants with available data for analysis.

Duration of Mechanical Ventilation is analyzed for participants requiring mechanical ventilation post randomization.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=27 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=27 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Duration of Mechanical Ventilation	0.0 days Interval 0.0 to 29.0	0.0 days Interval 0.0 to 28.0

SECONDARY outcome

Timeframe: Baseline, Days 15 and 29

Population: ITT population included all participants who were randomized. Overall number of participants analyzed signifies the number of participants with available data for analysis.

The ordinal scale is a 7-point scale ranging from 1 to 7 used to measure clinical status based on the following points: 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. Higher score indicated no severe illness. Mean change in Ordinal scale was evaluated by fitting a linear mixed-effects model for repeated measures (MMRM).

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=27 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=27 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Mean Change From Baseline in Ordinal Scale Change From Baseline at Day 15	1.58 score on a scale Interval 1.0 to 2.15	2.21 score on a scale Interval 1.64 to 2.78
Mean Change From Baseline in Ordinal Scale Change From Baseline at Day 29	1.80 score on a scale Interval 1.23 to 2.37	2.66 score on a scale Interval 2.09 to 3.22

SECONDARY outcome

Timeframe: Baseline, Days 15 and 29

Population: ITT population included all participants who were randomized. Overall number of participants analyzed signifies the number of participants with available data for analysis.

The ordinal scale is a 7-point scale ranging from 1 to 7 used to measure clinical status based on the following points: 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. Higher score indicated no severe illness.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=21 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=23 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Absolute Change From Baseline in Ordinal Scale Change From Baseline at Day 15	1.5 score on a scale Standard Deviation 1.96	2.3 score on a scale Standard Deviation 1.67
Absolute Change From Baseline in Ordinal Scale Change From Baseline at Day 29	1.8 score on a scale Standard Deviation 1.87	2.7 score on a scale Standard Deviation 1.48

SECONDARY outcome

Timeframe: Day 15 and Day 29

Population: ITT population included all participants who were randomized. Overall number of participants analyzed are unique number of participants with available data for analysis. Number analyzed are unique number of participants out of all the assessed participants with data available at the specified timepoint. Different participants may have contributed data for each timepoint. Participants who died during the study were assigned a value of 1 for the ordinal scale at every timepoint after the death.

The ordinal scale is a 7-point scale ranging from 1 to 7 used to measure clinical status based on the following points: 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. The percentages are rounded off to the single decimal point.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=21 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=24 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 15: Death	5.0 percentage of participants	4.5 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 15: Hospitalized, on invasive mechanical ventilation or ECMO	10.0 percentage of participants	0.0 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 15: Hospitalized, on non-invasive ventilation or high flow oxygen devices	5.0 percentage of participants	4.5 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 15: Hospitalized, requiring supplemental oxygen	10.0 percentage of participants	4.5 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 15: Hospitalized, not requiring supplemental oxygen	0.0 percentage of participants	4.5 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 15: Not hospitalized, limitation on activities	25.0 percentage of participants	22.7 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 15: Not hospitalized, no limitations on activities	45.0 percentage of participants	59.1 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 29: Hospitalized, on non-invasive ventilation or high flow oxygen devices	4.8 percentage of participants	0.0 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 29: Hospitalized, requiring supplemental oxygen	4.8 percentage of participants	0.0 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 29: Hospitalized, not requiring supplemental oxygen	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 29: Not hospitalized, limitation on activities	38.1 percentage of participants	17.4 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 29: Death	9.5 percentage of participants	4.3 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 29: Hospitalized, on invasive mechanical ventilation or ECMO	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants in Each Severity Category of the 7-point Ordinal Scale Day 29: Not hospitalized, no limitations on activities	42.9 percentage of participants	78.3 percentage of participants

SECONDARY outcome

Timeframe: Up to Day 29

Population: ITT population included all participants who were randomized. Participants who achieved sustained normalization of temperature were analyzed.

Time to sustained normalization of temperature was reported at 50th percentile in days.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=13 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=12 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Time to Sustained Normalization of Temperature	7 days Interval 3.0 to Upper limit of 95% CI was not estimable due to insufficient participants with events.	NA days Interval 4.0 to Median and upper limit of 95% CI was not estimable due to the number of participants with events lower than 50%.

SECONDARY outcome

Timeframe: Up to Day 29

Population: ITT population included all participants who were randomized.

Normalization of fever is defined as temperature < 36.6 °C armpit, < 37.2 °C oral, or < 37.8 °C rectal sustained for at least 24 hours.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=29 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=28 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Percentage of Participants Who Experienced Sustained Normalization of Fever	44.8 percentage of participants Interval 26.4 to 64.3	42.9 percentage of participants Interval 24.5 to 62.8

SECONDARY outcome

Timeframe: Up to Day 29

Population: ITT population included all participants who were randomized. Overall number of participants analyzed are the participants assessed for ARDS by Berlin criteria.

ARDS was defined based on Berlin criteria (chest imaging, origin of edema, oxygenation).

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=17 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=21 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Number of Participants Who Develop Acute Respiratory Distress Syndrome (ARDS)	5 Participants	2 Participants

SECONDARY outcome

Timeframe: Up to Day 29

Population: ITT population included all participants who were randomized. Overall number of participants analyzed are the participants with clinical progression.

Time to clinical progression is defined as the time to death, mechanical ventilation, or ICU admission. Time to clinical progression was reported at 50th percentile in days.

Outcome measures

Measure	Alpha1-Proteinase Inhibitor + Standard Medical Treatment n=6 Participants Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo + Standard Medical Treatment n=4 Participants Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Time to Clinical Progression	NA days Median, Upper and Lower Limit of 95% CI was not estimable due to the number of participants with events much lower than 50%.	NA days Median, Upper and Lower Limit of 95% CI was not estimable due to the number of participants with events much lower than 50%.

Adverse Events

Alpha1-Proteinase Inhibitor+Standard Medical Treatment

Serious events: 5 serious events

Other events: 2 other events

Deaths: 2 deaths

Placebo+Standard Medical Treatment

Serious events: 5 serious events

Other events: 8 other events

Deaths: 1 deaths

Serious adverse events

Measure	Alpha1-Proteinase Inhibitor+Standard Medical Treatment n=27 participants at risk Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo+Standard Medical Treatment n=27 participants at risk Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Injury, poisoning and procedural complications Tracheal injury	3.7% 1/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	0.00% 0/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.
Musculoskeletal and connective tissue disorders Muscular weakness	3.7% 1/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	0.00% 0/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.
Nervous system disorders Seizure	0.00% 0/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	3.7% 1/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.
Renal and urinary disorders Acute kidney injury	3.7% 1/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	0.00% 0/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	3.7% 1/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	0.00% 0/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	3.7% 1/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.
Respiratory, thoracic and mediastinal disorders Hypoxia	7.4% 2/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	3.7% 1/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.
Respiratory, thoracic and mediastinal disorders Respiratory failure	7.4% 2/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	7.4% 2/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.

Other adverse events

Measure	Alpha1-Proteinase Inhibitor+Standard Medical Treatment n=27 participants at risk Participants received the first IV infusion of liquid alpha1-proteinase inhibitor (human) 120 mg/kg, based on body weight on Day 1, followed by second liquid alpha1-proteinase inhibitor (human) dose of 120 mg/kg based on body weight, on Day 8 (second dose was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.	Placebo+Standard Medical Treatment n=27 participants at risk Participants received IV infusions of 0.9% normal saline of commensurate volume to that of liquid alpha1-proteinase inhibitor as placebo on Day 1 and Day 8 (Day 8 was not mandatory and was given at the PI's discretion). Participants also received all standard of care interventions while hospitalized, from Day 1 to Day 29.
Cardiac disorders Bradycardia	0.00% 0/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	11.1% 3/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.
Gastrointestinal disorders Dyspepsia	0.00% 0/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	7.4% 2/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.
Gastrointestinal disorders Nausea	0.00% 0/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	7.4% 2/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.
Infections and infestations Pneumonia bacterial	7.4% 2/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	0.00% 0/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.
Investigations Blood pressure increased	0.00% 0/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.	7.4% 2/27 • Up to 90 days All-cause mortality: ITT population included all participants who were randomized. Adverse events: Safety population included all participants who received at least any amount of liquid Alpha1-PI (Human) plus SMT or placebo plus SMT.

Additional Information

Rhonda Griffin, Clinical Program Leader/Director

Grifols Therapeutics LLC

Phone: +1 919 757 1744

Email: Rhonda.griffin@grifols.com

Results disclosure agreements

• Principal investigator is a sponsor employee Site may publish results from the Study, after providing Sponsor thirty days' notice prior to submitting a manuscript or other materials related to the Study to any outside party. At Sponsors' request, Site will remove any Confidential Information (other than Study results), and Site will upon Sponsors' request, delay publication or presentation for a period of up to one hundred twenty days to allow Sponsor to protect its interests in any Sponsor Inventions.
• Publication restrictions are in place

Restriction type: OTHER