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Glutathione, Oxidative Stress and Mitochondrial Function in COVID-19

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ClinicalTrials.gov Identifier: NCT04703036
Recruitment Status : Recruiting
First Posted : January 11, 2021
Last Update Posted : January 11, 2021
Sponsor:
Information provided by (Responsible Party):
Rajagopal V Sekhar, Baylor College of Medicine

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:

  1. 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.
  2. 5ml of blood will be drawn 3-days after starting supplementation to measure GSH levels.

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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
Estimated Study Start Date : January 11, 2021
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


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)




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



Information from the National Library of Medicine

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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.

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): NCT04703036


Contacts
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Contact: Rajagopal V Sekhar, M.D. 7137983908 rsekhar@bcm.edu

Locations
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United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: R V Sekhar, MD    713-798-3908    rsekhar@bcm.edu   
Principal Investigator: R V Sekhar, MD         
Sponsors and Collaborators
Baylor College of Medicine
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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    Key Record Dates
Last Update Posted: January 11, 2021
Last Verified: January 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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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