ART-COVID19: Arginine Replacement Therapy in COVID-19
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: L-arginine loading dose + standard dose L-arginine loading dose (200 mg/kg IV) + standard dose (100 mg/kg IV TID). |
Drug: Arginine Hydrochloride
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.
Other Names:
|
| Active Comparator: Standard dose Standard dose (100mg/kg IV TID). |
Drug: Arginine Hydrochloride
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.
Other Names:
|
| Active Comparator: Low dose Low dose (25mg/kg IV TID). |
Drug: Arginine Hydrochloride
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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change in mitochondrial function [Baseline and day 5]
Complex-IV activity changes will be measured to estimate mitochondrial function before and after administration for L-arginine
Secondary Outcome Measures
- Change in amino acids [Baseline and day 5]
arginine (ARG) ornithine (ORN) and citrulline (CIT) will be measured before and after administration for L-arginine
- Change in the arginase-1 activity/concentration [Baseline and day 5]
arginase-1 will be measured before and after administration for L-arginine
- Change in myeloid-derived suppressor cells (MDSC-source of arginase-1) [Baseline and day 5]
Myeloid-derived suppressor cells (MDSC) producing arginase-1 will be measured in the peripheral blood before and after administration of L-arginine
- Change in the level of cytokines (IL-6) [Baseline and day 5]
Cytokines are biomarkers for inflammation. Cell supernatants will be collected and analyzed for different cytokines.
- Change on secretory phospholipase (sPLA2). [Baseline and day 5]
Serum activity of secretory phospholipase (sPLA2) will be measured before and after administration for L-arginine
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Healthcare of Atlanta (CHOA), Egleston | Atlanta | Georgia | United States | 30322 |
Sponsors and Collaborators
- Emory University
Investigators
- Principal Investigator: Claudia R. Morris, MD, Emory University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- STUDY00005572