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).



Eligible Ages
Between 18 Years and 65 Years
Eligible Genders
Accepts Healthy Volunteers

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 Design

Phase 2
Study Type
Intervention Model
Parallel Assignment
Intervention Model Description
Placebo controlled and Active Drug
Primary Purpose
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
Double Blind Clinical Trial

Arm Groups

ArmDescriptionAssigned Intervention
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.

Recruiting Locations

University of Arkansas for Medical Sciences
Little Rock, Arkansas 72205
Study Site Contact

More Details

Asklepion Pharmaceuticals, LLC

Study Contact

Gurdyal Kalsi, MD, MFPM

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.


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