Glutathione, Oxidative Stress and Mitochondrial Function in COVID-19

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Covid19

Intervention / Treatment
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* Dietary Supplement: Glycine
* Dietary Supplement: N-acetylcysteine
* Dietary Supplement: Alanine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial, placebo-controlled, double-blind design
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 |