Arginine Replacement Therapy in COVID-19

Study Overview
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Brief Summary
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The purpose of this study is to investigate if receiving doses of arginine (a protein in the body) will improve mitochondria function in children with COVID-19. The study will be performed in Children's Healthcare of Atlanta, Egleston campus. Patients will be randomized to receive one of three doses of arginine three times a day for five days or at discharge whichever comes first.

Detailed Description
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In the early stages of COVID-19, it was believed that children were immune or had very mild disease. Given the unfolding pandemic, children's cases are exhibiting an increasing global trend and are associated with some serious complications in addition to more long-term complications such as multisystem inflammatory syndrome in children (MIS-C) and Long Covid. A significant number of hospitalized and critically ill pediatric patients have now been documented, in addition to a high number of emergency department (ED) visits despite previous reports suggesting rare or mild disease in children. The research team and others have shown that severe COVID-19 and MIS-C are associated with acute arginine deficiency in both adults and children. There has been increased evidence of the role of the endothelium associated with severe inflammation in COVID-19. Low plasma arginine bioavailability has been implicated in endothelial dysfunction, immune regulation, and hypercoagulation. The research team also identified high sPLA2 levels in COVID-19 and MIS-C, an observation previously made in children with Kawasaki's Disease. Subsequent studies have shown that sPLA2 is associated with the pathobiology leading to COVID-19 mortality, with enzyme levels 10-fold higher in people who died vs. mild disease, and is also associated with Mito dysfunction. Not only could sPLA2 represent a prognostic indicator of disease severity, but it also represents a mechanism with potential therapeutic targets. Information learned from the Mito activity in COVID-19 can contribute to further understanding of severe acute respiratory syndrome by coronavirus (SARS-CoV-2) infection. This data may help guide future treatment targets and strategies.

Official Title
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Prospective Open-Label Pilot Study of Arginine Replacement Therapy in Children Hospitalized With COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Arginine Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Established diagnosis of COVID-19 requiring admission to the hospital for treatment of COVID-19 infection Age 3 years - 21 years of age Exclusion Criteria: Severe hepatic dysfunction: ALT> 6 x Upper limit of normal Renal dysfunction: Creatinine > 1.5 x upper limit of normal or on dialysis Acute Stroke Pregnancy Allergy to arginine Past history of severe cardiac disease or significant cardiac surgery [minor procedures like ventricular septal defect (VSD) repair are not an exclusion] History of significant pulmonary disease [Cystic Fibrosis, sickle cell disease (SCD)] History of organ transplant History of metabolic or mitochondrial disease (including Diabetes) History of severe neurocognitive delays (severe cerebral palsy, anoxic brain injury) History of ventriculoperitoneal (VP) shunt or hydrocephalus PI discretion that the patient is not an ideal candidate for the study History of HIV of immune compromise

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: L-arginine loading dose + standard dose<br>L-arginine loading dose (200 mg/kg IV) + standard dose (100 mg/kg IV TID). | Drug: Arginine Hydrochloride<br>* Arginine will be infused based on the manufacturer's instructions (R-Gene 10, Pfizer), over 30 minutes. However, rates may be slowed to over 60 minutes for patients experiencing symptoms of flushing, nausea, vomiting, or headache at the research team's discretion. Pediatric doses will be drawn up by the pharmacy.<br>* Other names: L-arginine;|
| Active Comparator: Standard dose<br>Standard dose (100mg/kg IV TID). | Drug: Arginine Hydrochloride<br>* Arginine will be infused based on the manufacturer's instructions (R-Gene 10, Pfizer), over 30 minutes. However, rates may be slowed to over 60 minutes for patients experiencing symptoms of flushing, nausea, vomiting, or headache at the research team's discretion. Pediatric doses will be drawn up by the pharmacy.<br>* Other names: L-arginine;|
| Active Comparator: Low dose<br>Low dose (25mg/kg IV TID). | Drug: Arginine Hydrochloride<br>* Arginine will be infused based on the manufacturer's instructions (R-Gene 10, Pfizer), over 30 minutes. However, rates may be slowed to over 60 minutes for patients experiencing symptoms of flushing, nausea, vomiting, or headache at the research team's discretion. Pediatric doses will be drawn up by the pharmacy.<br>* Other names: L-arginine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mitochondrial function | Complex-IV activity changes will be measured to estimate mitochondrial function before and after administration for L-arginine | Baseline and day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in amino acids | arginine (ARG) ornithine (ORN) and citrulline (CIT) will be measured before and after administration for L-arginine | Baseline and day 5 | 
| Change in the arginase-1 activity/concentration | arginase-1 will be measured before and after administration for L-arginine | Baseline and day 5 | 
| Change in myeloid-derived suppressor cells (MDSC-source of arginase-1) | Myeloid-derived suppressor cells (MDSC) producing arginase-1 will be measured in the peripheral blood before and after administration of L-arginine | Baseline and day 5 | 
| Change in the level of cytokines (IL-6) | Cytokines are biomarkers for inflammation. Cell supernatants will be collected and analyzed for different cytokines. | Baseline and day 5 | 
| Change on secretory phospholipase (sPLA2). | Serum activity of secretory phospholipase (sPLA2) will be measured before and after administration for L-arginine | Baseline and day 5 |