Intravenous L-Citrulline Influence on the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients With COVID-19
Condition: Acute Hypoxemic Respiratory Failure
MeSH terms: Respiratory Insufficiency
Study type: Interventional
Phase: Phase 2

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).
    

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.
    

Intervention name(s): L-Citrulline; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; Patients randomized to placebo will receive equal volume bolus and study infusion of 5% dextrose water for a maximum of 10 days.
Other intervention name(s): L-CIT, CIT
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Placebo controlled and Active Drug
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment