Glutathione, Oxidative Stress and Mitochondrial Function in COVID-19

• ClinicalTrials.gov Identifier: NCT04703036
• Recruitment Status: Active, not recruiting
• First Posted: January 11, 2021
• Last Update Posted: May 10, 2023
• Sponsor: Baylor College of Medicine
• Information provided by (Responsible Party): Rajagopal V Sekhar, Baylor College of Medicine

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Covid19	Dietary Supplement: Glycine; Dietary Supplement: N-acetylcysteine; Dietary Supplement: Alanine	Early Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 64 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized controlled trial, placebo-controlled, double-blind design
• Masking: Double (Participant, Investigator)
• Masking Description: Participants and the investigative team are masked. Only the biostatistician will be unmasked to the identity of the active and placebo groups.
• Primary Purpose: Other
• Official Title: Randomized Trial of Supplementing Glycine and N-acetylcysteine vs. Placebo in COVID-19
• Actual Study Start Date: January 11, 2021
• Estimated Primary Completion Date: December 31, 2023
• Estimated Study Completion Date: December 31, 2023

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures :

1. Change in Glutathione concentrations [ Time Frame: Day 0, 3-days, 1-week, 2-weeks, 6-weeks, 10-weeks ]
   Glutathione levels will be measured in red-blood cells
2. Change in Interleukein 6 concentrations [ Time Frame: Day 0, 3-days, 1-week, 2-weeks, 6-weeks, 10-weeks ]
   Plasma IL-6 concentrations
3. Change in Ordinal scale [ Time Frame: Day 0, 1-week, 2-weeks ]
   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

Secondary Outcome Measures :

1. Change in oxidative stress [ Time Frame: Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks ]
   Plasma concentrations of TBARS
2. Change in marker of damage due to oxidative stress [ Time Frame: Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks ]
   Plasma concentrations of F2-isoprostanes
3. Change in inflammatory cytokines [ Time Frame: Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks ]
   Plasma concentrations of TNFa, hsCRP, IL-10, PAI-1, D-dimer
4. Change in mitochondrial energetics [ Time Frame: Day 0 1-week, 2-weeks, 6-weeks, 10-weeks ]
   Energetics measured by high-resolution respirometry in peripheral blood monocytes
5. Change in immune function [ Time Frame: Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks ]
   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.
6. Change in cognition [ Time Frame: Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks ]
   Measured using Montreal cognitive assessment which ranges from 0-30
7. Change in function [ Time Frame: Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks ]
   Measured using the Katz-activities of daily living
8. Change in fatigue [ Time Frame: Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks ]
   Measured using the Facit-F fatigue scale
9. Change in circulating marker of memory [ Time Frame: Day 0, 1-week, 2-weeks, 6-weeks, 10-weeks ]
   Plasma BDNF concentrations

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Texas

Baylor College of Medicine

Houston, Texas, United States, 77030

Sponsors and Collaborators

Baylor College of Medicine

More Information

• Responsible Party: Rajagopal V Sekhar, Principal Investigator, Baylor College of Medicine
• ClinicalTrials.gov Identifier: NCT04703036
• Other Study ID Numbers: H48057
• First Posted: January 11, 2021
• Last Update Posted: May 10, 2023
• Last Verified: May 2023

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

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; Acetylcysteine; N-monoacetylcystine; Glycine; Antiviral Agents; Anti-Infective Agents; Expectorants; Respiratory System Agents; Free Radical Scavengers; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Physiological Effects of Drugs; Antidotes; Glycine Agents; Neurotransmitter Agents