Clinical trial NCT04570384: Intravenous L-Citrulline Influence on the Need for Invasive Mechanical Ventilation for Acute Hypoxemic Respiratory Failure in Patients With COVID-19
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Hypoxemic Respiratory Failure
Lead sponsor: Asklepion Pharmaceuticals, LLC
Sponsor class: INDUSTRY
First posted: 2020-09-30
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Placebo controlled and Active Drug
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to Non-invasive/Invasive Mechanical Ventilation
timeFrame: From the start of infusion to Day 60 Follow-up
measure: Time to Non-invasive Mechanical Ventilation
timeFrame: From the start of infusion to Day 60 Follow-up
measure: Time to Invasive Mechanical Ventilation
timeFrame: From the start of infusion to Day 60 Follow-up
measure: Systolic Blood Pressure
timeFrame: Day 1
measure: Diastolic Blood Pressure
timeFrame: Day 1
measure: Mean Arterial Pressure
timeFrame: Day 1
Secondary outcomes:
measure: Blood Levels of Arginine
timeFrame: Plasma levels of arginine at 0, 2 and 12 hours, and 2, 4, 6, 8, 10 days after initiation of treatment
measure: Blood Levels of Citrulline
timeFrame: Plasma levels of citrulline at 0, 2 and 12 hours, and 2, 4, 6, 8, 10 days after initiation of treatment
measure: Evaluate the Effect of Intravenous L-Citrulline Compared to Placebo as Measured by the Total Length of All Mechanical Ventilation
timeFrame: Day 1 through Day 60 Follow Up
measure: Evaluate the Effect of IV L-Citrulline to Placebo for Hospital All Cause Mortality
timeFrame: Day 1 through day 12
measure: Percentage of Patients Admitted to Intensive Care
timeFrame: Day 1 through Day 12 (DC)
measure: Duration of Intensive Care Unit (ICU) Stay
timeFrame: From admission to ICU until discharge or death
measure: Duration of Hospitalisation
timeFrame: From admission to hospital until discharge or death
measure: Number of Patients Requiring Intubation
timeFrame: From the start of infusion to Day 60 Follow-up
measure: Overall Duration of Mechanical Ventilation
timeFrame: From the start of infusion to Day 60 Follow-up
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
Study officials:
affiliation: Asklepion Pharmaceuticals, LLC
name: Gurdyal Kalsi, MD, MFPM
role: STUDY_DIRECTOR
References: