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

Acute Hypoxemic Respiratory Failure Clinical Trial

Official title:

Prospective, Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Intravenous L-Citrulline (Turnobi) to Delay and Potentially Prevent the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients With COVID-19 (SARS-CoV-2) Illness

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04570384
• Other study ID #: CIT-COVID19-002-01
• Status: Completed
• Phase: Phase 2
• Start date: October 15, 2020
• Est. completion date: September 30, 2021

Study information

• Verified date: January 2023
• Source: Asklepion Pharmaceuticals, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Prospective, Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Intravenous L-Citrulline (Turnobi) to Delay and Potentially Prevent the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients with COVID-19 (SARS-CoV2) Illness. To evaluate safety and efficacy of a bolus loading dose and continuous intravenous infusion of L-Citrulline compared to placebo in patients hospitalized with COVID-19 infection (SARS-CoV-2).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 65
• Est. completion date: September 30, 2021
• Est. primary completion date: August 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Age 18-65 years.

2. Clinical evidence of COVID-19 (SARS-CoV2) infection, defined as a positive COVID-19 laboratory test plus evidence of an acute hypoxemic respiratory illness requiring oxygen.

3. Admitted and transferred to floor without intubation.

Exclusion Criteria:

1. No consent/inability to obtain consent

2. Patient, surrogate, or physician not committed to full support

3. Malignant or other irreversible condition and estimated 28-day mortality = 50%

4. Moribund patient not expected to survive 48 hours (as defined by primary medical team) from start of study infusion

5. End-stage Liver Disease as defined by Child-Pugh Score > 9

6. Currently enrolled in, or participated in another study of an investigational compound within the last 30 days

7. Pregnant female, or female who is breast feeding

8. Allergy to L-citrulline or arginine or any citrulline- or arginine-containing product

9. Patient not otherwise suitable for the study in the opinion of any of the investigators

10. Requirement for intubation and invasive mechanical ventilation before study enrollment

Related Conditions & MeSH terms

• Acute Hypoxemic Respiratory Failure
• Respiratory Insufficiency

Intervention

Drug:
• 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
Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.

Locations

Country	Name	City	State
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas

Sponsors (1)

Lead Sponsor	Collaborator
Asklepion Pharmaceuticals, LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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).	From the start of infusion to Day 60 Follow-up
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) .	From the start of infusion to Day 60 Follow-up
Primary	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
Primary	Systolic Blood Pressure	Systolic blood pressure measured in mmHg	Day 1
Primary	Diastolic Blood Pressure	Diastolic blood pressure measured in mmHg	Day 1
Primary	Mean Arterial Pressure	Mean arterial pressure measured in mmHg	Day 1
Secondary	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
Secondary	Blood Levels of Citrulline	Plasma levels of citrulline	Plasma levels of citrulline at 0, 2 and 12 hours, and 2, 4, 6, 8, 10 days after initiation of treatment
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	Day 1 through Day 60 Follow Up
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	Day 1 through day 12
Secondary	Percentage of Patients Admitted to Intensive Care		Day 1 through Day 12 (DC)
Secondary	Duration of Intensive Care Unit (ICU) Stay	Length of ICU stay (days)	From admission to ICU until discharge or death
Secondary	Duration of Hospitalisation	Length of hospital stay (days)	From admission to hospital until discharge or death
Secondary	Number of Patients Requiring Intubation	Percentage of patients requiring any mechanical ventilation, invasive mechanical ventilation and non-invasive mechanical ventilation.	From the start of infusion to Day 60 Follow-up
Secondary	Overall Duration of Mechanical Ventilation	Total time on any mechanical ventilation, invasive mechanical ventilation, non-invasive mechanical ventilation and nasal cannula	From the start of infusion to Day 60 Follow-up