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

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

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).

Study Overview

• Status: Completed
• Conditions: Acute Hypoxemic Respiratory Failure
• Intervention / Treatment: Drug: L-Citrulline; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	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.; Other Names: L-CIT, CIT
Placebo Comparator: 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.	Drug: Placebo; Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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 Outcome Measures

Outcome Measure	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	Plasma levels of citrulline at 0, 2 and 12 hours, and 2, 4, 6, 8, 10 days after initiation of treatment
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
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
Percentage of Patients Admitted to Intensive Care		Day 1 through Day 12 (DC)
Duration of Intensive Care Unit (ICU) Stay	Length of ICU stay (days)	From admission to ICU until discharge or death
Duration of Hospitalisation	Length of hospital stay (days)	From admission to hospital until discharge or death
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
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

Collaborators and Investigators

• Sponsor: Asklepion Pharmaceuticals, LLC

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2020
• Primary Completion (Actual): August 30, 2021
• Study Completion (Actual): September 30, 2021

Study Registration Dates

• First Submitted: September 17, 2020
• First Submitted That Met QC Criteria: September 29, 2020
• First Posted (Actual): September 30, 2020

Study Record Updates

• Last Update Posted (Estimate): February 22, 2023
• Last Update Submitted That Met QC Criteria: January 26, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency
• Other Study ID Numbers: CIT-COVID19-002-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No