Trial Outcomes & Findings for Intravenous L-Citrulline Influence on the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients With COVID-19 (NCT NCT04570384)

NCT ID: NCT04570384

Last Updated: 2023-02-22

Results Overview

Time in hours from the initiation of the treatment until mechanical ventilation is required, whether non-invasive (e.g., high flow nasal cannula, bilevel positive airway pressure, oxygen therapy) or invasive (i.e., requiring intubation).

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 65 participants
• Primary outcome timeframe: From the start of infusion to Day 60 Follow-up
• Results posted on: 2023-02-22

Participant Flow

Participant milestones

Measure	IV L-Citrulline (Turnobi) Arm Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Overall Study STARTED	33	32
Overall Study COMPLETED	22	23
Overall Study NOT COMPLETED	11	9

Reasons for withdrawal

Measure	IV L-Citrulline (Turnobi) Arm Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Overall Study Adverse Event	2	1
Overall Study Death	2	5
Overall Study Lost to Follow-up	1	0
Overall Study Other	1	0
Overall Study Protocol Violation	0	1
Overall Study Sponsor Decision	1	0
Overall Study Withdrawal by Subject	4	2

Baseline Characteristics

Intravenous L-Citrulline Influence on the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients With COVID-19

Baseline characteristics by cohort

Measure	IV L-Citrulline (Turnobi) Arm n=33 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=32 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.	Total n=65 Participants Total of all reporting groups
Age, Continuous	50.30 years STANDARD_DEVIATION 11.04 • n=5 Participants	51.13 years STANDARD_DEVIATION 10.34 • n=7 Participants	50.71 years STANDARD_DEVIATION 10.63 • n=5 Participants
Age, Customized 18-49 years	13 Participants n=5 Participants	12 Participants n=7 Participants	25 Participants n=5 Participants
Age, Customized 50-65 years	20 Participants n=5 Participants	20 Participants n=7 Participants	40 Participants n=5 Participants
Sex: Female, Male Female	16 Participants n=5 Participants	9 Participants n=7 Participants	25 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	23 Participants n=7 Participants	40 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	29 Participants n=5 Participants	26 Participants n=7 Participants	55 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	18 Participants n=5 Participants	17 Participants n=7 Participants	35 Participants n=5 Participants
Race (NIH/OMB) White	12 Participants n=5 Participants	12 Participants n=7 Participants	24 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: From the start of infusion to Day 60 Follow-up

Population: Patients in the Intent-to-treat population that required invasive or non-invasive ventilation.

Time in hours from the initiation of the treatment until mechanical ventilation is required, whether non-invasive (e.g., high flow nasal cannula, bilevel positive airway pressure, oxygen therapy) or invasive (i.e., requiring intubation).

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=11 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=10 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Time to Non-invasive/Invasive Mechanical Ventilation	96.65 Hours Standard Deviation 143.73	70.49 Hours Standard Deviation 62.44

PRIMARY outcome

Timeframe: From the start of infusion to Day 60 Follow-up

Population: Patients in the Intent-to-treat population requiring non-invasive mechanical ventilation.

Time in hours from the initiation of the treatment until non-invasive mechanical ventilation is required (e.g., high flow nasal cannula, bilevel positive airway pressure, oxygen therapy) .

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=9 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=8 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Time to Non-invasive Mechanical Ventilation	66.17 Hours Standard Deviation 105.40	105.70 Hours Standard Deviation 108.90

PRIMARY outcome

Timeframe: From the start of infusion to Day 60 Follow-up

Population: Patients in the Intent-to-treat population requiring intubation for invasive mechanical ventilation.

Time in hours from the initiation of the treatment until intubation for invasive mechanical ventilation is required.

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=4 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=6 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Time to Invasive Mechanical Ventilation	290.01 Hours Standard Deviation 254.31	148.07 Hours Standard Deviation 108.08

PRIMARY outcome

Timeframe: Day 1

Population: Patients in the safety population with measurement(s) of systolic blood pressure

Systolic blood pressure measured in mmHg

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=24 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=27 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Systolic Blood Pressure	118.63 Millimeters of mercury Standard Deviation 14.69	130.19 Millimeters of mercury Standard Deviation 15.71

PRIMARY outcome

Timeframe: Day 1

Population: Patients in the safety population with measurement(s) of diastolic blood pressure

Diastolic blood pressure measured in mmHg

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=24 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=27 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Diastolic Blood Pressure	73.58 Millimeters of mercury Standard Deviation 10.06	79.74 Millimeters of mercury Standard Deviation 13.13

PRIMARY outcome

Timeframe: Day 1

Population: Patients in the safety population with measurement(s) of mean arterial blood pressure

Mean arterial pressure measured in mmHg

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=24 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=27 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Mean Arterial Pressure	87.58 Millimeters of mercury Standard Deviation 10.03	94.30 Millimeters of mercury Standard Deviation 13.49

SECONDARY outcome

Timeframe: Plasma levels of arginine at 0, 2 and 12 hours, and 2, 4, 6, 8, 10 days after initiation of treatment

Population: Patients with at least 1 measurement of plasma arginine

Plasma levels of arginine

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=33 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=32 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Blood Levels of Arginine Day 10	160.02 µmol/L Standard Deviation 83.39	83.9 µmol/L Standard Deviation 37.36
Blood Levels of Arginine Hour 0	67.6 µmol/L Standard Deviation 28.27	67.88 µmol/L Standard Deviation 29.51
Blood Levels of Arginine Hour 2	92.57 µmol/L Standard Deviation 30.84	71.51 µmol/L Standard Deviation 29.15
Blood Levels of Arginine Hour 12	128.11 µmol/L Standard Deviation 41.3	75.7 µmol/L Standard Deviation 24.54
Blood Levels of Arginine Day 2	142.02 µmol/L Standard Deviation 54.51	82.19 µmol/L Standard Deviation 26.33
Blood Levels of Arginine Day 4	152.00 µmol/L Standard Deviation 66.7	79.66 µmol/L Standard Deviation 22.84
Blood Levels of Arginine Day 6	169.33 µmol/L Standard Deviation 113.62	70.78 µmol/L Standard Deviation 19.46
Blood Levels of Arginine Day 8	167.64 µmol/L Standard Deviation 82.5	81.79 µmol/L Standard Deviation 32.28

SECONDARY outcome

Timeframe: Plasma levels of citrulline at 0, 2 and 12 hours, and 2, 4, 6, 8, 10 days after initiation of treatment

Population: All patients with at least 1 plasma citrulline measurement

Plasma levels of citrulline

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=33 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=32 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Blood Levels of Citrulline Hour 0	24.64 µmol/L Standard Deviation 25.91	18.08 µmol/L Standard Deviation 13.7
Blood Levels of Citrulline Hour 2	1094.41 µmol/L Standard Deviation 2463.97	18.39 µmol/L Standard Deviation 14.08
Blood Levels of Citrulline Hour 12	997.61 µmol/L Standard Deviation 2133.07	21.84 µmol/L Standard Deviation 16.14
Blood Levels of Citrulline Day 2	278.2 µmol/L Standard Deviation 353.32	24.68 µmol/L Standard Deviation 27.57
Blood Levels of Citrulline Day 4	626.33 µmol/L Standard Deviation 1562.95	20.53 µmol/L Standard Deviation 15.84
Blood Levels of Citrulline Day 6	185.14 µmol/L Standard Deviation 68.63	20.96 µmol/L Standard Deviation 10.16
Blood Levels of Citrulline Day 8	192.72 µmol/L Standard Deviation 127.72	24.84 µmol/L Standard Deviation 9.64
Blood Levels of Citrulline Day 10	206.26 µmol/L Standard Deviation 135.94	24.56 µmol/L Standard Deviation 11.46

SECONDARY outcome

Timeframe: Day 1 through Day 60 Follow Up

Population: Patients in the Intent-to-treat population requiring mechanical ventilation

Total length of time of any mechanical ventilation

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=14 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=12 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Evaluate the Effect of Intravenous L-Citrulline Compared to Placebo as Measured by the Total Length of All Mechanical Ventilation	270.91 Hours Standard Deviation 304.03	451.87 Hours Standard Deviation 503.68

SECONDARY outcome

Timeframe: Day 1 through day 12

Population: Intent-to-treat

To evaluate the effect of intravenous L-Citrulline compared to placebo on Hospital all-cause mortality

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=33 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=32 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Evaluate the Effect of IV L-Citrulline to Placebo for Hospital All Cause Mortality	2 Participants	5 Participants

SECONDARY outcome

Timeframe: Day 1 through Day 12 (DC)

Population: Intent-to-treat

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=33 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=32 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Percentage of Patients Admitted to Intensive Care	12 Participants	13 Participants

SECONDARY outcome

Timeframe: From admission to ICU until discharge or death

Population: Intent-to-treat

Length of ICU stay (days)

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=12 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=13 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Duration of Intensive Care Unit (ICU) Stay	14.83 Days Standard Deviation 12.29	17.31 Days Standard Deviation 18.87

SECONDARY outcome

Timeframe: From admission to hospital until discharge or death

Population: Intent-to-treat

Length of hospital stay (days)

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=33 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=32 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Duration of Hospitalisation	10.61 Days Standard Deviation 12.74	11.88 Days Standard Deviation 14.29

SECONDARY outcome

Timeframe: From the start of infusion to Day 60 Follow-up

Population: Intent-to-treat

Percentage of patients requiring any mechanical ventilation, invasive mechanical ventilation and non-invasive mechanical ventilation.

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=33 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=32 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Number of Patients Requiring Intubation Non-invasive/invasive mechanical ventilation	14 Participants	12 Participants
Number of Patients Requiring Intubation Non-invasive mechanical ventilation	12 Participants	10 Participants
Number of Patients Requiring Intubation Invasive mechanical ventilation	4 Participants	6 Participants

SECONDARY outcome

Timeframe: From the start of infusion to Day 60 Follow-up

Population: Intent-to-treat

Total time on any mechanical ventilation, invasive mechanical ventilation, non-invasive mechanical ventilation and nasal cannula

Outcome measures

Measure	IV L-Citrulline (Turnobi) Arm n=33 Participants Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=32 Participants Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Overall Duration of Mechanical Ventilation Total time on mechanical ventilation	239.31 Hours Standard Deviation 243.08	222.08 Hours Standard Deviation 370.90
Overall Duration of Mechanical Ventilation Total time of non-invasive mechanical ventilation	224.64 Hours Standard Deviation 254.22	219.27 Hours Standard Deviation 309.40
Overall Duration of Mechanical Ventilation Total time of invasive mechanical ventilation	274.27 Hours Standard Deviation 158.86	538.28 Hours Standard Deviation 469.21
Overall Duration of Mechanical Ventilation Total time on Nasal Cannula	239.31 Hours Standard Deviation 243.08	222.08 Hours Standard Deviation 370.90

Adverse Events

IV L-Citrulline (Turnobi) Arm

Serious events: 6 serious events

Other events: 11 other events

Deaths: 2 deaths

Placebo Arm

Serious events: 10 serious events

Other events: 11 other events

Deaths: 5 deaths

Serious adverse events

Measure	IV L-Citrulline (Turnobi) Arm n=33 participants at risk Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=32 participants at risk Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Renal and urinary disorders Acute kidney injury	3.0% 1/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Cardiac disorders Cardiac failure; metabolic acidosis	3.0% 1/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Respiratory, thoracic and mediastinal disorders Chest pain; Dyspnoea; COVID-19	3.0% 1/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Respiratory, thoracic and mediastinal disorders Dyspnoea	6.1% 2/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Vascular disorders Intracranial hemorrhage	3.0% 1/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Cardiac disorders Acute Myocardial Infarction	3.0% 1/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Nervous system disorders Status epilepticus	3.0% 1/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Cardiac disorders Syncope	3.0% 1/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Respiratory, thoracic and mediastinal disorders Acute Respiratory Distress Syndrome, Pneumonia	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Renal and urinary disorders Acute kidney injury; renal tubular necrosis	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Nervous system disorders Brain Injury	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Cardiac disorders Cardiac arrest	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	6.2% 2/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Cardiac disorders Cardiac valve vegetation	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Respiratory, thoracic and mediastinal disorders Cardio-respiratory Arrest	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Cardiac disorders Cardiac Failure Congestive	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Infections and infestations Cytomegalovirus infection	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Gastrointestinal disorders Oesophagitis	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Gastrointestinal disorders Lower Gastrointestinal Haemorrhage	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	9.4% 3/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.

Other adverse events

Measure	IV L-Citrulline (Turnobi) Arm n=33 participants at risk Patients randomized to citrulline will receive an initial intravenous bolus of 20 mg/kg (to a maximum of 1500 mg) L-citrulline over 10 minutes. The study solution will be prepared as a 5% isotonic solution (50 mg/mL) in 5% dextrose water. Immediately after the initial bolus, a continuous intravenous infusion of L-citrulline at 9 mg/kg (max 700 mg) per hour will be administered through a dedicated intravenous line or port of a multi-lumen catheter. L-Citrulline: L-Citrulline (Turnobi) for Injection. Patients will receive an initial bolus of 20 mg/kg (maximum 1500 mg), followed by study infusion of 9 mg/kg per hour (maximum 700mg) for up to 10 days.	Placebo Arm n=32 participants at risk Patients randomized to placebo arm will receive an infusion of 5% dextrose water matched for volume and color to the citrulline infusion. The placebo infusion will consist of an initial iv bolus (up to 30 mL) over 10 minutes followed by a continuous infusion of 5% dextrose water (about 15 mL/hr). The initial bolus and subsequent infusion will be administered through a dedicated intravenous line or port of a multi-lumen catheter. Placebo: Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Renal and urinary disorders Acute kidney injury	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	6.2% 2/32 • Number of events 2 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
General disorders Chest Pain	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Infections and infestations Clostridium Difficile Infection	6.1% 2/33 • Number of events 2 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Gastrointestinal disorders Constipation	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Vascular disorders Deep Vein Thrombosis	6.1% 2/33 • Number of events 2 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Metabolism and nutrition disorders Dehydration	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Cardiac disorders Endocarditis	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Infections and infestations Enterococcal Bacteraemia	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Infections and infestations Enterococcal Infection	3.0% 1/33 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Investigations Enterococcus Test Positive	3.0% 1/33 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Respiratory, thoracic and mediastinal disorders Epistaxis	3.0% 1/33 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Gastrointestinal disorders Gastrointestinal Haemorrhage	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Metabolism and nutrition disorders Hyperlipidaemia	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Metabolism and nutrition disorders Hypoglycaemia	3.0% 1/33 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Respiratory, thoracic and mediastinal disorders Hypoxia	3.0% 1/33 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
General disorders Infusion Site Reaction	9.1% 3/33 • Number of events 3 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	6.2% 2/32 • Number of events 2 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Hepatobiliary disorders Ischaemic Hepatitis	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Metabolism and nutrition disorders Lactic Acidosis	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Investigations Liver Function Test Increased	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Musculoskeletal and connective tissue disorders Pain In Extremity	3.0% 1/33 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Injury, poisoning and procedural complications Skin Wound	3.0% 1/33 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Infections and infestations Staphylococcal Sepsis; Alpha Haemolytic Streptococcal Infection	3.0% 1/33 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Skin and subcutaneous tissue disorders Subcutaneous Emphysema	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Cardiac disorders Tachycardia	3.0% 1/33 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Investigations Troponin I Increased	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Infections and infestations Urinary Tract Infection	6.1% 2/33 • Number of events 2 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Cardiac disorders Ventricular Extrasystoles	3.0% 1/33 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	0.00% 0/32 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.
Cardiac disorders Ventricular Tachycardia	0.00% 0/33 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.	3.1% 1/32 • Number of events 1 • Adverse events data were collected from the time that the participant was first administered the study infusion (study hour = 0) until Day 10. Adverse events spontaneously reported to the investigator or observed by the investigator after Day 10 until Day 60 Follow Up were also collected and recorded. All available clinical data were monitored for AEs. Clinically important/unexpected adverse experiences were recorded as AEs. Clinical outcomes of acute hypoxemic respiratory illness progressing to critical illness due to COVID-19 were not considered AEs and therefore not collected or reported. A Vasopressor Dependency Index was calculated at baseline, 60 minutes after completion of the bolus, and every 4 hours during infusion. An increase in VDI of \>33% from baseline was considered as an AE.

Additional Information

Gurdyal Kalsi, MD, MFPM (Hon)

Asklepion Pharmaceuticals, LLC

Phone: +1 410.736.3750

Email: gurdyal.kalsi@asklepionpharm.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place