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).
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.
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 Name: L-CIT, CIT
Drug: Placebo
Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
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
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Gurdyal Kalsi, MD, MFPM, Study Director
Asklepion Pharmaceuticals, LLC