Intravenous L-Citrulline Influence on the Need for Invasi... | NCT04570384

Status Module

Description Module

Detailed Description

Intravenous L-citrulline (Turnobi) administration will safely restore the homeostasis of nitric oxide synthase by increasing both plasma citrulline and arginine levels. Investigators also reason that restoration of citrulline/arginine balance through citrulline administration will safely re-establish homeostasis of NOS, lower oxidative stress, and reduce inflammation, thereby delaying and potentially preventing the need for invasive mechanical ventilation in participants hospitalized with COVID-19 infection (SARS-CoV-2). The body lives in a delicate balance of homeostasis. The urea/NO cycle plays a critical role in maintaining redox homeostasis and as such, also plays a role in regulating inflammation. The biochemical relationships are complex and depend on inter-organ transfer, membrane transport, and intracellular compartmentation. However, data above demonstrate that citrulline, arginine, and NO are critical in maintaining this homeostasis through their regulation of NOS. Inflammation, especially from infection, results in decreased activity of CPS1 and increased activity of arginase, which decreases levels of both citrulline and arginine. These decreased levels result in dysregulated and uncoupled NOS, which drives both overexuberant NO production and formation of ROS. Both the NO production and ROS further exacerbate the inflammatory cascade, resulting in other organ dysfunctions, including acute lung injury. Both inflammation and oxidative stress have been shown to be driving forces for the development of ALI and regulated NOS function is vital to reducing both. Both plasma citrulline and arginine are deficient in sepsis and levels are inversely associated with development of ALI. Furthermore, citrulline replacement safely increases plasma levels of both citrulline and arginine in healthy volunteers, BMT patients, adults with sepsis, children with sickle cell disease, and children after congenital heart surgery. It seems highly likely that citrulline therapy in the setting of COVID-19 (SARS-CoV2) induced acute hypoxemic respiratory illness will safely increase citrulline and arginine levels and help re-establish NOS homeostasis, resulting in NO production in compartments that are more homeostatically appropriate so as to reduce pulmonary vascular resistance and enhance coupling of NOS to minimize superoxide production thus reducing free radical mediated ALI.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
IV L-Citrulline (Turnobi) Arm	Active Comparator	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.	Drug: L-Citrulline
Placebo Arm	Placebo Comparator	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.	Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
L-Citrulline	Drug	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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Time to Non-invasive/Invasive Mechanical 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).	From the start of infusion to Day 60 Follow-up
Time to 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) .	From the start of infusion to Day 60 Follow-up
Time to Invasive Mechanical Ventilation	Time in hours from the initiation of the treatment until intubation for invasive mechanical ventilation is required.	From the start of infusion to Day 60 Follow-up
Systolic Blood Pressure	Systolic blood pressure measured in mmHg	Day 1
Diastolic Blood Pressure	Diastolic blood pressure measured in mmHg	Day 1
Mean Arterial Pressure	Mean arterial pressure measured in mmHg	Day 1

Secondary Outcomes

Measure	Description	Time Frame
Blood Levels of Arginine	Plasma levels of arginine	Plasma levels of arginine at 0, 2 and 12 hours, and 2, 4, 6, 8, 10 days after initiation of treatment
Blood Levels of Citrulline	Plasma levels of citrulline

Eligibility Module

Name	Affiliation	Role
Gurdyal Kalsi, MD, MFPM	Asklepion Pharmaceuticals, LLC	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
University of Arkansas for Medical Sciences		Little Rock	Arkansas	72205	United States

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jun 15, 2021	Jul 27, 2022

Arm/Group Information

ID	Title	Description
BG000	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.
BG001	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.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00033 BG00132 BG00265

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Time to Non-invasive/Invasive Mechanical 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).

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

Posted

Mean

Standard Deviation

Hours

From the start of infusion to Day 60 Follow-up

ID	Title	Description
OG000	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.
OG001	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.

Units	Counts
Participants	OG00011 OG00110

Title

Denominators

Categories

Title	Measurements
	OG00096.65± 143.73 OG00170.49± 62.44

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Log Rank		0.782		Hazard Ratio (HR)	1.14			2-Sided	95	0.45	2.86					Other
OG000 OG001		Regression, Logistic		0.668

Primary

Time to 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) .

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

Posted

Mean

Standard Deviation

Hours

From the start of infusion to Day 60 Follow-up

ID	Title	Description
OG000	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.
OG001	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.

Primary

Time to Invasive Mechanical Ventilation

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

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

Posted

Mean

Standard Deviation

Hours

From the start of infusion to Day 60 Follow-up

ID	Title	Description
OG000	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.
OG001	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.

Primary

Systolic Blood Pressure

Systolic blood pressure measured in mmHg

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

Posted

Mean

Standard Deviation

Millimeters of mercury

Day 1

ID	Title	Description
OG000	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.
OG001	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.

Primary

Diastolic Blood Pressure

Diastolic blood pressure measured in mmHg

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

Posted

Mean

Standard Deviation

Millimeters of mercury

Day 1

ID	Title	Description
OG000	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.
OG001	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.

Primary

Mean Arterial Pressure

Mean arterial pressure measured in mmHg

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

Posted

Mean

Standard Deviation

Millimeters of mercury

Day 1

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Blood Levels of Arginine

Plasma levels of arginine

Patients with at least 1 measurement of plasma arginine

Posted

Mean

Standard Deviation

µmol/L

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

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Blood Levels of Citrulline

Plasma levels of citrulline

All patients with at least 1 plasma citrulline measurement

Posted

Mean

Standard Deviation

µmol/L

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

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Evaluate the Effect of Intravenous L-Citrulline Compared to Placebo as Measured by the Total Length of All Mechanical Ventilation

Total length of time of any mechanical ventilation

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

Posted

Mean

Standard Deviation

Hours

Day 1 through Day 60 Follow Up

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Evaluate the Effect of IV L-Citrulline to Placebo for Hospital All Cause Mortality

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

Intent-to-treat

Posted

Count of Participants

Participants

Day 1 through day 12

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Percentage of Patients Admitted to Intensive Care

Intent-to-treat

Posted

Count of Participants

Participants

Day 1 through Day 12 (DC)

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Duration of Intensive Care Unit (ICU) Stay

Length of ICU stay (days)

Intent-to-treat

Posted

Mean

Standard Deviation

Days

From admission to ICU until discharge or death

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Duration of Hospitalisation

Length of hospital stay (days)

Intent-to-treat

Posted

Mean

Standard Deviation

Days

From admission to hospital until discharge or death

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Number of Patients Requiring Intubation

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

Intent-to-treat

Posted

Count of Participants

Participants

From the start of infusion to Day 60 Follow-up

ID	Title	Description
OG000	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.
OG001	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.

Secondary

Overall Duration of Mechanical Ventilation

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

Intent-to-treat

Posted

Mean

Standard Deviation

Hours

From the start of infusion to Day 60 Follow-up

ID	Title	Description
OG000	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.
OG001	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.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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.	2	33	6	33	11	33
EG001	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.	5	32	10	32	11	32

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Acute kidney injury	Renal and urinary disorders	MedDRA 24.0	Systematic Assessment	EG0001 affected33 at risk EG0010 affected32 at risk
Cardiac failure; metabolic acidosis	Cardiac disorders	MedDRA 24.0	Systematic Assessment	EG0001 affected33 at risk EG0010 affected32 at risk
Chest pain; Dyspnoea; COVID-19	Respiratory, thoracic and mediastinal disorders	MedDRA 24.0	Systematic Assessment	EG0001 affected33 at risk EG0010 affected32 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 24.0	Systematic Assessment	EG0002 affected33 at risk EG0010 affected32 at risk
Intracranial hemorrhage	Vascular disorders	MedDRA 24.0	Systematic Assessment	EG0001 affected33 at risk EG0011 affected32 at risk
Acute Myocardial Infarction	Cardiac disorders	MedDRA 24.0	Systematic Assessment	EG0001 affected33 at risk EG0010 affected32 at risk
Status epilepticus	Nervous system disorders	MedDRA 24.0	Systematic Assessment	EG0001 affected33 at risk EG0010 affected32 at risk
Syncope	Cardiac disorders	MedDRA 24.0	Systematic Assessment	EG0001 affected33 at risk EG0010 affected32 at risk
Acute Respiratory Distress Syndrome, Pneumonia	Respiratory, thoracic and mediastinal disorders	MedDRA 24.0	Systematic Assessment	EG0000 affected33 at risk EG0011 affected32 at risk
Acute kidney injury; renal tubular necrosis	Renal and urinary disorders	MedDRA 24.0	Systematic Assessment	EG0000 affected33 at risk EG0011 affected32 at risk
Brain Injury	Nervous system disorders	MedDRA 24.0	Systematic Assessment	EG0000 affected33 at risk EG0011 affected32 at risk
Cardiac arrest	Cardiac disorders	MedDRA 24.0	Systematic Assessment	EG0000 affected33 at risk EG0012 affected32 at risk
Cardiac valve vegetation	Cardiac disorders	MedDRA 24.0	Systematic Assessment	EG0000 affected33 at risk EG0011 affected32 at risk
Cardio-respiratory Arrest	Respiratory, thoracic and mediastinal disorders	MedDRA 24.0	Systematic Assessment	EG0000 affected33 at risk EG0011 affected32 at risk
Cardiac Failure Congestive	Cardiac disorders	MedDRA 24.0	Systematic Assessment	EG0000 affected33 at risk EG0011 affected32 at risk
Cytomegalovirus infection	Infections and infestations	MedDRA 24.0	Systematic Assessment	EG0000 affected33 at risk EG0011 affected32 at risk
Oesophagitis	Gastrointestinal disorders	MedDRA 24.0	Systematic Assessment	EG0000 affected33 at risk EG0011 affected32 at risk
Lower Gastrointestinal Haemorrhage	Gastrointestinal disorders	MedDRA 24.0	Systematic Assessment	EG0000 affected33 at risk EG0011 affected32 at risk
Pneumothorax	Respiratory, thoracic and mediastinal disorders	MedDRA 24.0	Systematic Assessment	EG0000 affected33 at risk EG0013 affected32 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 24.0	Systematic Assessment	EG0000 affected33 at risk EG0011 affected32 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Acute kidney injury	Renal and urinary disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0012 events2 affected32 at risk
Chest Pain	General disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Clostridium Difficile Infection	Infections and infestations	MedDRA 24.0	Systematic Assessment	EG0002 events2 affected33 at risk EG0010 events0 affected32 at risk
Constipation	Gastrointestinal disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Deep Vein Thrombosis	Vascular disorders	MedDRA 24.0	Systematic Assessment	EG0002 events2 affected33 at risk EG0011 events1 affected32 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Endocarditis	Cardiac disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Enterococcal Bacteraemia	Infections and infestations	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Enterococcal Infection	Infections and infestations	MedDRA 24.0	Systematic Assessment	EG0001 events1 affected33 at risk EG0011 events1 affected32 at risk
Enterococcus Test Positive	Investigations	MedDRA 24.0	Systematic Assessment	EG0001 events1 affected33 at risk EG0010 events0 affected32 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA 24.0	Systematic Assessment	EG0001 events1 affected33 at risk EG0010 events0 affected32 at risk
Gastrointestinal Haemorrhage	Gastrointestinal disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Hyperlipidaemia	Metabolism and nutrition disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA 24.0	Systematic Assessment	EG0001 events1 affected33 at risk EG0011 events1 affected32 at risk
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA 24.0	Systematic Assessment	EG0001 events1 affected33 at risk EG0010 events0 affected32 at risk
Infusion Site Reaction	General disorders	MedDRA 24.0	Systematic Assessment	EG0003 events3 affected33 at risk EG0012 events2 affected32 at risk
Ischaemic Hepatitis	Hepatobiliary disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Lactic Acidosis	Metabolism and nutrition disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Liver Function Test Increased	Investigations	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Pain In Extremity	Musculoskeletal and connective tissue disorders	MedDRA 24.0	Systematic Assessment	EG0001 events1 affected33 at risk EG0010 events0 affected32 at risk
Skin Wound	Injury, poisoning and procedural complications	MedDRA 24.0	Systematic Assessment	EG0001 events1 affected33 at risk EG0010 events0 affected32 at risk
Staphylococcal Sepsis; Alpha Haemolytic Streptococcal Infection	Infections and infestations	MedDRA 24.0	Systematic Assessment	EG0001 events1 affected33 at risk EG0010 events0 affected32 at risk
Subcutaneous Emphysema	Skin and subcutaneous tissue disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Tachycardia	Cardiac disorders	MedDRA 24.0	Systematic Assessment	EG0001 events1 affected33 at risk EG0011 events1 affected32 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Troponin I Increased	Investigations	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk
Urinary Tract Infection	Infections and infestations	MedDRA 24.0	Systematic Assessment	EG0002 events2 affected33 at risk EG0010 events0 affected32 at risk
Ventricular Extrasystoles	Cardiac disorders	MedDRA 24.0	Systematic Assessment	EG0001 events1 affected33 at risk EG0010 events0 affected32 at risk
Ventricular Tachycardia	Cardiac disorders	MedDRA 24.0	Systematic Assessment	EG0000 events0 affected33 at risk EG0011 events1 affected32 at risk

ID	Term
D012120	Respiration Disorders
D012140	Respiratory Tract Diseases

ID	Term
D000599	Amino Acids, Diamino
D000596	Amino Acids
D000602	Amino Acids, Peptides, and Proteins