Arginine Replacement Therapy in COVID-19 (ART-COVID19)

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

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.

Study Overview

• Status: Recruiting
• Conditions: COVID-19
• Intervention / Treatment: Drug: Arginine Hydrochloride

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 Type: Interventional
• Enrollment (Estimated): 21
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Claudia R. Morris, MD; Phone Number: 404 727-5500; Email: claudia.r.morris@emory.edu
• Study Contact Backup: Name: Dunia Hatabah, MD; Phone Number: 470-6626706; Email: dunia.hatabah@emory.edu

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Children's Healthcare of Atlanta (CHOA), Egleston
      • Contact: Claudia R Morris, MD; Phone Number: 404-727-5500; Email: claudia.morris@choa.org
      • Principal Investigator: Caludia R Morris, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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: L-arginine
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: L-arginine
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: L-arginine

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Emory University
• Investigators: Principal Investigator: Claudia R. Morris, MD, Emory University

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2024
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: May 9, 2023
• First Submitted That Met QC Criteria: May 9, 2023
• First Posted (Actual): May 11, 2023

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: STUDY00005572

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The research team will share de-identified data upon request with researches who provide a methodologically sound proposal.
• IPD Sharing Time Frame: Data are available for at least 5 years after publication of primary results.
• IPD Sharing Access Criteria: Data are available for at least 5 years, available upon request from PI, directed to claudia.r.morris@emory.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No