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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Acute Hypoxemic Respiratory Failure

Intervention / Treatment
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* Drug: L-Citrulline
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-65 years. 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. Admitted and transferred to floor without intubation. Exclusion Criteria: No consent/inability to obtain consent Patient, surrogate, or physician not committed to full support Malignant or other irreversible condition and estimated 28-day mortality ≥ 50% Moribund patient not expected to survive 48 hours (as defined by primary medical team) from start of study infusion End-stage Liver Disease as defined by Child-Pugh Score > 9 Currently enrolled in, or participated in another study of an investigational compound within the last 30 days Pregnant female, or female who is breast feeding Allergy to L-citrulline or arginine or any citrulline- or arginine-containing product Patient not otherwise suitable for the study in the opinion of any of the investigators Requirement for intubation and invasive mechanical ventilation before study enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Placebo controlled and Active Drug
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IV L-Citrulline (Turnobi) Arm<br>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<br>* 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.<br>* Other names: L-CIT, CIT;|
| Placebo Comparator: Placebo Arm<br>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<br>* Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.<br>|

What is the study measuring?
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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 |