Clinical trial NCT04466657: Antioxidant Therapy for COVID-19 Study
Official title: A Study to Evaluate Antioxidant Therapy for Moderate to Severe COVID-19 With or Without Comorbidities
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: Covid-19
Keywords: SARS-CoV infection
COVID-19
coronavirus
Lead sponsor: Obafemi Awolowo University
Sponsor class: OTHER
Collaborators: name: Borno State Ministry of Health
name: Ogun State Ministry of Health
name: Abia State Ministry of Health
name: Sokoto State Ministry of Health
name: Benue State Minsitry of Health
name: University of Calabar Teaching Hospital
First posted: 2020-07-10
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to clinical improvement
timeFrame: 28 days
measure: Time to SARS-CoV-2 negativity
timeFrame: 14 days
Secondary outcomes:
measure: Clinical status on day 14
timeFrame: 14 days
measure: Proportion of participants with SARS-CoV-2 PCR negative result at Day 7
timeFrame: 7 days
measure: Proportion of participants with SARS-CoV-2 PCR negative result at Day 28
timeFrame: 28 days
measure: 28 Day mortality
timeFrame: 28 days
measure: Duration of hospitalization in survivors
timeFrame: 28 days
measure: Time from treatment initiation to death
timeFrame: 28 days
Other outcomes:
measure: Adverse events during treatment
timeFrame: 28 days
measure: Serious adverse events
timeFrame: 28 days
measure: Gastrointesntinal adverse events
timeFrame: 28 days
measure: Discontinuation of trial intervention before the end of protocol specified 14 days
timeFrame: 14 days
Locations:
city: Umuahia
country: Nigeria
facility: Abia State Isolation Centre, Amachara
state: Abia State
city: Makurdi
country: Nigeria
facility: Benue State University Teaching Hospital
state: Benue State
city: Borno
country: Nigeria
facility: Brigadier Abba Kyari Memorial Hospital
state: Borno State
city: Maiduguri
country: Nigeria
facility: University of Maiduguri Teaching Hospital
state: Borno State
city: Calabar
country: Nigeria
facility: University of Calabar Teaching Hospital
state: Cross River
city: Abeokuta
country: Nigeria
facility: Federal Medical Centre Idi-Aba
state: Ogun State
city: Sagamu
country: Nigeria
facility: Olabisi Onabanjo University Teaching Hospital
state: Ogun State
city: Amanawa
country: Nigeria
facility: Infectious Disease Hospital
state: Sokoto State
city: Sokoto
country: Nigeria
facility: Murtala Muhammad Speciaist Hospital
state: Sokoto State
city: Sokoto
country: Nigeria
facility: Occupational Therapy Center
state: Sokoto State
city: Sokoto
country: Nigeria
facility: Usmanu Danfodiyo University Teaching Hospital
state: Sokoto State
Study officials:
affiliation: Obafemi Awolowo University
name: Adeniyi Olagunju, BPharm, MRes, PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.