Antioxidant Therapy for COVID-19 Study (GSHSOD-COVID)

A Study to Evaluate Antioxidant Therapy for Moderate to Severe COVID-19 With or Without Comorbidities

Finding effective strategies to treat or prevent the novel coronavirus disease that started in 2019 (COVID-19) is a global public health priority. Potential therapeutics and vaccines are now being investigated in over 1500 clinical trials. Clinical features of the disease include overproduction of reactive oxygen species which induces oxidative stress responses and contribute to acute lung injury. This presents a potential treatment strategy involving antioxidation therapy. In this pilot study, 90 COVID-19 patients aged 18-75 years will be recruited into two groups. The 45 patients in group 1 will receive the standard of care determined by their primary care providers while the 45 patients in group 2 will receive both the standard of care combined with daily antioxidant supplement for 14 days. All patients will be monitored for a total of 28 days with daily monitoring of symptoms and nasopharyngeal swab for SARS-CoV-2 test on days 3, 7, 14 and 28. The study will compare the following between the two groups: (1) the proportion of patients with clinical improvement (defined as live discharge from hospital, decrease of at least 2 points from baseline on a 7-point ordinal scale, or both), and (2) the proportion of patients with negative SARS-CoV-2 test by PCR on days 3, 7, and 14.

Study Overview

• Status: Withdrawn
• Conditions: Covid-19
• Intervention / Treatment: Other: Standard of Care; Dietary supplement: Antioxidation Therapy

Detailed Description

Background: COVID-19 caused by SARS-CoV-2 is an unprecedented global public health challenge which as at 06 May 2020 has spread to over 210 with over 3.6 million cases including 250,000 deaths. More than 1500 clinical trials are currently ongoing in an unprecedented global search for potential therapeutics and vaccines. Certain clinical features of SARS-CoV-2 infection provide potential treatment strategies involving antioxidation therapy, including overproduction of reactive oxygen species which induces oxidative stress responses and contribute to acute lung injury.

Primary Outcome Measure: (1) the proportion of patients with clinical improvement (defined as live discharge from hospital, decrease of at least 2 points from baseline on a 7-point ordinal scale, or both), and (2) the proportion of patients with negative SARS-CoV-2 test by PCR on days 3, 7, and 14.

Study Design: Individuals within 18-75 years of age who receive a PCR positive test for COVID-19 and admitted at participating COVID-19 isolation and treatment centres will be invited to participate. Consenting individuals will be randomised 1:1 to receive either standard of care alone (control group) or standard of care plus daily antioxidant supplementation (intervention group). A total of 90 participants will be recruited in the Pilot Stage (n = 45 per arm). The Pivotal Stage will include 300 participants. Antioxidant therapy will be a formulation composed of reduced GSH, N-acetylcysteine, superoxide dismutase and bovine lactoferrin and immunoglobulin as in whey protein isolate. Clinical improvement will be evaluated daily using a 7-category ordinal scale. SARS-CoV-2 PCR test will be repeated on days 3, 7, 14 and 28.

Analysis: An interim analysis of data from the Pilot Stage will be conducted after the first 45 participants have completed days 1-14 of the study period. These data will provide valuable insights regarding possible revision of the design, conduct and analysis of the Pivotal Stage. Analysis of clinical improvement based on the 7-category ordinal scale will be performed using time-to-event data (patients will censored at 28-days of follow-up). Categorical variables will be analysed using the log-rank test and continuous variables will be assessed using a univariable Cox proportional hazard regression analysis. Proportion of participants with SARS-CoV-2 polymerase chain reaction (PCR) negative result at days 3, 7, 14 and 28 will be compared between the intervention and control groups.

Ethics: This trial will be conducted in compliance with the protocol, the principles of ICH Guideline E6 for Good Clinical Practice, the Declaration of Helsinki, and all applicable regulatory requirements.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Nigeria
  • Abia State
    • Umuahia, Abia State, Nigeria
      • Abia State Isolation Centre, Amachara
  • Benue State
    • Makurdi, Benue State, Nigeria
      • Benue State University Teaching Hospital
  • Borno State
    • Borno, Borno State, Nigeria
      • Brigadier Abba Kyari Memorial Hospital
    • Maiduguri, Borno State, Nigeria
      • University of Maiduguri Teaching Hospital
  • Cross River
    • Calabar, Cross River, Nigeria
      • University of Calabar Teaching Hospital
  • Ogun State
    • Abeokuta, Ogun State, Nigeria
      • Federal Medical Centre Idi-Aba
    • Sagamu, Ogun State, Nigeria
      • Olabisi Onabanjo University Teaching Hospital
  • Sokoto State
    • Amanawa, Sokoto State, Nigeria
      • Infectious Disease Hospital
    • Sokoto, Sokoto State, Nigeria
      • Murtala Muhammad Speciaist Hospital
    • Sokoto, Sokoto State, Nigeria
      • Occupational Therapy Center
    • Sokoto, Sokoto State, Nigeria
      • Usmanu Danfodiyo University Teaching Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Willing and able to provide informed consent prior to any study procedures
• Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by polymerase chain reaction (PCR) test ≤ 2 days before randomization
• Currently hospitalized and requiring medical care for COVID-19
• Peripheral capillary oxygen saturation (SpO2) < 94% on room air at screening

Exclusion Criteria

• Participation in any other clinical trial of an experimental treatment for COVID-19
• Concurrent treatment with other agents outside the standard of care than 24 hours prior to study intervention dosing
• Requiring mechanical ventilation at screening
• Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) above 5 times upper limit of normal (ULN)
• Creatinine clearance < 50 mL/min using the Cockcroft-Gault formula

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care (SOC); Participants in this arm will receive SOC alone, which will be as determined by the clinical team at the treatment centres in line with the current National Interim Guidelines for Clinical Management of COVID-19	Other: Standard of Care; SOC will be as determined by the clinical team at the treatment centres in line with the current National Interim Guidelines for Clinical Management of COVID-19
Experimental: SOC plus Intervention; Participants in this arm will receive SOC plus daily antioxidant supplement composed of two proprietary formulations that include reduced glutathione, N-acetylcysteine, superoxide dismutase, and bovine lactoferrin and immunoglobulins.	Other: Standard of Care; SOC will be as determined by the clinical team at the treatment centres in line with the current National Interim Guidelines for Clinical Management of COVID-19; Dietary supplement: Antioxidation Therapy; Two proprietary formulations composed of reduced glutathione, N-acetylcysteine, superoxide dismutase, and bovine lactoferrin and immunoglobulins.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to clinical improvement	Time to clinical improvement (defined as time from randomization to either an improvement of two points on a 7-category ordinal scale or discharge from the hospital, whichever came first, or both)	28 days
Time to SARS-CoV-2 negativity	Proportion of participants with SARS-CoV-2 polymerase chain reaction (PCR) negative result at Day 14	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of hospitalization in survivors		28 days
Time from treatment initiation to death		28 days
Clinical status on day 14	Clinical status as assessed with the seven-category ordinal scale on day 14	14 days
Proportion of participants with SARS-CoV-2 PCR negative result at Day 7		7 days
Proportion of participants with SARS-CoV-2 PCR negative result at Day 28		28 days
28 Day mortality		28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events during treatment		28 days
Serious adverse events	Respiratory failure or Acute Respiratory Distress Syndrome, Acute Kidney Injury, secondary infection, shock, severe anemia, acute gastritis, unconsciousness, acute heart failure	28 days
Gastrointesntinal adverse events	Nausea, vomiting, and diarrhea	28 days
Discontinuation of trial intervention before the end of protocol specified 14 days		14 days

Collaborators and Investigators

• Sponsor: Obafemi Awolowo University
• Collaborators: University of Calabar Teaching Hospital; Borno State Ministry of Health; Ogun State Ministry of Health; Abia State Ministry of Health; Sokoto State Ministry of Health; Benue State Minsitry of Health
• Investigators: Study Chair: Adeniyi Olagunju, BPharm, MRes, PhD, Obafemi Awolowo University

Publications and helpful links

General Publications

• Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. 2020 Jun;215:108427. doi: 10.1016/j.clim.2020.108427. Epub 2020 Apr 20.
• Cao W, Liu X, Bai T, Fan H, Hong K, Song H, Han Y, Lin L, Ruan L, Li T. High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With Coronavirus Disease 2019. Open Forum Infect Dis. 2020 Mar 21;7(3):ofaa102. doi: 10.1093/ofid/ofaa102. eCollection 2020 Mar.
• Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, Ermolaeva M, Veldhuizen R, Leung YH, Wang H, Liu H, Sun Y, Pasparakis M, Kopf M, Mech C, Bavari S, Peiris JS, Slutsky AS, Akira S, Hultqvist M, Holmdahl R, Nicholls J, Jiang C, Binder CJ, Penninger JM. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008 Apr 18;133(2):235-49. doi: 10.1016/j.cell.2008.02.043.
• Hosakote YM, Jantzi PD, Esham DL, Spratt H, Kurosky A, Casola A, Garofalo RP. Viral-mediated inhibition of antioxidant enzymes contributes to the pathogenesis of severe respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med. 2011 Jun 1;183(11):1550-60. doi: 10.1164/rccm.201010-1755OC. Epub 2011 Mar 4.
• Lin X, Wang R, Zou W, Sun X, Liu X, Zhao L, Wang S, Jin M. The Influenza Virus H5N1 Infection Can Induce ROS Production for Viral Replication and Host Cell Death in A549 Cells Modulated by Human Cu/Zn Superoxide Dismutase (SOD1) Overexpression. Viruses. 2016 Jan 8;8(1):13. doi: 10.3390/v8010013.
• Sinha R, Sinha I, Calcagnotto A, Trushin N, Haley JS, Schell TD, Richie JP Jr. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. Eur J Clin Nutr. 2018 Jan;72(1):105-111. doi: 10.1038/ejcn.2017.132. Epub 2017 Aug 30.

Helpful Links

• Immunocal® Product Information
• PurXcel® Product Information

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2020
• Primary Completion (Anticipated): February 28, 2021
• Study Completion (Anticipated): April 30, 2021

Study Registration Dates

• First Submitted: July 9, 2020
• First Submitted That Met QC Criteria: July 9, 2020
• First Posted (Actual): July 10, 2020

Study Record Updates

• Last Update Posted (Actual): November 8, 2021
• Last Update Submitted That Met QC Criteria: October 29, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19; coronavirus; SARS-CoV infection
• 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
• Other Study ID Numbers: GSHSOD-COVID2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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