Glutathione, Oxidative Stress and Mitochondrial Function in COVID-19

Randomized Trial of Supplementing Glycine and N-acetylcysteine vs. Placebo in COVID-19

COVID-19 is associated with increased mortality, and has been linked to a 'cytokine inflammatory storm'. Populations at higher risk of COVID complications and mortality include the elderly, diabetic patients and immunocompromised patients (such as HIV), and the investigators have studied these 3 populations over the past 20 years and have found that they all have deficiency of the endogenous antioxidant protein glutathione (GSH), elevated oxidative stress, inflammation, impaired mitochondrial function, immune dysfunction, and endothelial dysfunction.

It is known and established that GSH adequacy is necessary for neutralizing harmful oxidative stress, and that elevated oxidative stress appears to promote mitochondrial dysfunction. The combination of oxidative stress and mitochondrial dysfunction have also been linked to inflammation, immune dysfunction, and endothelial dysfunction. In prior studies in aging, the investigators have also identified that supplementing glutathione precursor amino-acids glycine and cysteine (provided as N-acetylcysteine) improves GSH deficiency and mitochondrial function, and lowers oxidative stress, inflammation, and endothelial dysfunction. The investigators have coined the term GlyNAC to refer to the combination of glycine and N-acetylcysteine.

This study will evaluate the prevalence and extent of these defects in patients with COVID-19 admitted to the hospital, and the response to supplementing GlyNAC or placebo for 2-weeks. Because patients with COVID-19 are also being reported to have fatigue and cognitive impairment, the investigators will also measure fatigue and cognition at admission, 1-week and 2-weeks after beginning supplementation. The supplementation is stopped after completing 2-weeks, and these outcomes will be measured again after 4-weeks and 8-weeks after stopping supplementation.

Study Overview

• Status: Terminated
• Conditions: Covid19
• Intervention / Treatment: Dietary supplement: Glycine; Dietary supplement: N-acetylcysteine; Dietary supplement: Alanine

Detailed Description

This study will investigate associated defects in the following two populations of patients with COVID-19:

Hospitalized patients admitted for COVID-19 will sign an informed consent form, and be randomized to receive either active (Glycine plus N-acetylcysteine) or a placebo (alanine) supplementation for 2-weeks. On day-0, the participants will have a single blood draw to measure measure oxidative stress, Glutathione levels, inflammatory cytokines, endothelial dysfunction, mitochondrial dysfunction, immune dysfunction, and complete questionnaires to assess fatigue, activity and cognition. Additional clinical and lab information will be obtained from the hospital electronic medical records. These measurements will be repeated 1-week and 2-weeks after starting supplementation, and at 4-weeks and 8-weeks after stopping supplementation.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 55-85y;
• Diagnosis of COVID-19;
• Hospitalized patients.

Exclusion Criteria:

• Active heart disease or active cancer at time of recruitment;
• Patients in Intensive Care Unit at the time of recruitment;
• Patents with alanine transaminase and aspartate transaminase greater than 5 times the upper limit of normal at any time;
• Patients requiring >4L per minute of oxygen support at the time of recruitment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active arm; The active supplements are glycine and N-acetylcysteine	Dietary supplement: Glycine; Glycine is an amino-acid (protein); Dietary supplement: N-acetylcysteine; This is a donor of the amino-acid cysteine (protein)
Placebo Comparator: Placebo arm; The placebo arm is alanine	Dietary supplement: Alanine; Alanine is an amino-acid (protein)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Glutathione concentrations	Glutathione levels will be measured in red-blood cells	Day 0, 3-days, 1-week, 2-weeks, 6-weeks, 10-weeks
Change in Interleukein 6 concentrations	Plasma IL-6 concentrations	Day 0, 3-days, 1-week, 2-weeks, 6-weeks, 10-weeks
Change in Ordinal scale	This is a scale developed by the World-Health Organization for COVID trials. The clinical condition of each participant will be determined using this scale at 3 time points - Day 0, after 1-week and after-2weeks of supplementation	Day 0, 1-week, 2-weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in oxidative stress	Plasma concentrations of TBARS	Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks
Change in marker of damage due to oxidative stress	Plasma concentrations of F2-isoprostanes	Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks
Change in inflammatory cytokines	Plasma concentrations of TNFa, hsCRP, IL-10, PAI-1, D-dimer	Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks
Change in mitochondrial energetics	Energetics measured by high-resolution respirometry in peripheral blood monocytes	Day 0 1-week, 2-weeks, 6-weeks, 10-weeks
Change in immune function	The trial will evaluate if COVID-related disease severity is associated with NK cell deficiency and antigen presenting cell production of IL-6 and TNF.	Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks
Change in cognition	Measured using Montreal cognitive assessment which ranges from 0-30	Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks
Change in function	Measured using the Katz-activities of daily living	Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks
Change in fatigue	Measured using the Facit-F fatigue scale	Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks
Change in circulating marker of memory	Plasma BDNF concentrations	Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks

Collaborators and Investigators

• Sponsor: Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2021
• Primary Completion (Actual): March 31, 2023
• Study Completion (Actual): March 31, 2023

Study Registration Dates

• First Submitted: January 6, 2021
• First Submitted That Met QC Criteria: January 8, 2021
• First Posted (Actual): January 11, 2021

Study Record Updates

• Last Update Posted (Actual): June 26, 2024
• Last Update Submitted That Met QC Criteria: June 24, 2024
• Last Verified: June 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; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Glycine Agents; Acetylcysteine; N-monoacetylcystine; Glycine
• Other Study ID Numbers: H48057

Drug and device information, study documents

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