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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05855330
Recruitment Status : Recruiting
First Posted : May 11, 2023
Last Update Posted : February 28, 2024
Sponsor:
Information provided by (Responsible Party):
Claudia R. Morris, Emory University

Study Description
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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
COVID-19 Drug: Arginine Hydrochloride 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
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 21 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective Open-Label Pilot Study of Arginine Replacement Therapy in Children Hospitalized With COVID-19
Actual Study Start Date : January 8, 2024
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : June 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: 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 Name: 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 Name: L-arginine


Outcome Measures
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Primary Outcome Measures :
  1. Change in mitochondrial function [ Time Frame: 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 :
  1. Change in amino acids [ Time Frame: Baseline and day 5 ]
    arginine (ARG) ornithine (ORN) and citrulline (CIT) will be measured before and after administration for L-arginine

  2. Change in the arginase-1 activity/concentration [ Time Frame: Baseline and day 5 ]
    arginase-1 will be measured before and after administration for L-arginine

  3. Change in myeloid-derived suppressor cells (MDSC-source of arginase-1) [ Time Frame: 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

  4. Change in the level of cytokines (IL-6) [ Time Frame: Baseline and day 5 ]
    Cytokines are biomarkers for inflammation. Cell supernatants will be collected and analyzed for different cytokines.

  5. Change on secretory phospholipase (sPLA2). [ Time Frame: Baseline and day 5 ]
    Serum activity of secretory phospholipase (sPLA2) will be measured before and after administration for L-arginine


Eligibility Criteria
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Ages Eligible for Study:   3 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05855330


Contacts
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Contact: Claudia R. Morris, MD 404 727-5500 claudia.r.morris@emory.edu
Contact: Dunia Hatabah, MD 470-6626706 dunia.hatabah@emory.edu

Locations
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United States, Georgia
Children's Healthcare of Atlanta (CHOA), Egleston Recruiting
Atlanta, Georgia, United States, 30322
Contact: Claudia R Morris, MD    404-727-5500    claudia.morris@choa.org   
Principal Investigator: Caludia R Morris, MD         
Sponsors and Collaborators
Emory University
Investigators
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Principal Investigator: Claudia R. Morris, MD Emory University
More Information
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Responsible Party: Claudia R. Morris, Professor of Medicine, Emory University
ClinicalTrials.gov Identifier: NCT05855330    
Other Study ID Numbers: STUDY00005572
First Posted: May 11, 2023    Key Record Dates
Last Update Posted: February 28, 2024
Last Verified: February 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The research team will share de-identified data upon request with researches who provide a methodologically sound proposal.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Data are available for at least 5 years after publication of primary results.
Access Criteria: Data are available for at least 5 years, available upon request from PI, directed to claudia.r.morris@emory.edu

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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COVID-19
Pneumonia, Viral
Pneumonia
Respiratory Tract Infections
Infections
Virus Diseases
 Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases