Efficacy and Safety of Ovotransferrin in COVID-19 Patients

Covid19 Clinical Trial

Official title:

Efficacy and Safety of Ovotransferrin in COVID-19 Patients With Mild-to-Moderate Disease

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04643054
• Other study ID #: 20201116
• Status: Not yet recruiting
• Phase: N/A
• Start date: December 1, 2020
• Est. completion date: March 30, 2021

Study information

• Verified date: November 2020
• Source: Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone Palermo
• Contact: Antonio Cascio, MD, PhD
• Phone: +393389912198
• Email: antonio.cascio03[@]unipa.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Chicken egg consists of three main components, egg white (56%), yolk (33%) and shell (11%). The key component of egg white is 88 percent water and 12 percent solids, of which over 90 percent are protein. Ovalbumin, ovotransferrin, and ovomucoid are considered the main proteins, while ovomucin, lysozyme, ovoglobulin, ovomacroglobulin, ovoglycoprotein, ovoflavoprotein, thiamin-binding proteins, ficin/papain inhibitors, avidin, and cystatin are the minor white proteins of the embryo. These proteins and their peptides have been recognized as antioxidants, antimicrobials, metal-chelators, anti-viral, anti-tumor, and angiotensin-converting enzyme (ACE)-inhibitors for their functional significance SARS-CoV-2 virus activates the human cell ACE2 receptor, triggering a series of deleterious events. In COVID19, renin-angiotensin is upregulated and the pathway is overexpressed and a progressive cytokine storm is always observed. In all these pathogenic processes, ovotransferrin could play a modifier function to enhance the condition. Ovotransferrin can be beneficial to the antioxidant effects of Angiotensin II by inhibiting NF-kB. Ovotransferrin is an immunomodulator that downregulates pro-inflammatory cytokines including TNF-α, IL-6, and IL-1 that could extinguish the cytokine storm. Ovotransferrin can also serve as a protective agent against COVID19 cardiotoxicity due to disruption in the ACE2-mediated signaling pathway, cytokine storm, pulmonary dysfunction, and side effects of medications.

In patients with coronavirus infection, provided ovotransferrin's possible protective effects, it is suggested as a supportive and therapeutic alternative.

Given this background, in the light of the current COVID-19 emergency, it is the intention of the investigators to conduct a prospective, randomized, open-label, controlled study in the cohort of hospitalized patients with covid-19 pneumonia, administering 200 mg of ovotransferrin orally in addition to the standard of care therapy (SOC).

The investigators hypothesize that the use of ovotransferrin will be associated with an earlier improvement of clinical and humoral parameters after 10 days of ovotransferrin treatment when compared to the group of patients provided with standard care.

Description:

Chicken egg consists of three main components, egg white (56%), yolk (33%), and shell (11%). The key component of egg white is 88 percent water and 12 percent solids, of which over 90 percent are protein. Ovalbumin, ovotransferrin, and ovomucoid are considered the main proteins, while ovomucin, lysozyme, ovoglobulin, ovomacroglobulin, ovoglycoprotein, ovoflavoprotein, thiamin-binding proteins, ficin/papain inhibitors, avidin, and cystatin are the minor white proteins of the embryo. These proteins and their peptides have been recognized as antioxidants, antimicrobials, metal-chelators, anti-viral, anti-tumor, and angiotensin-converting enzyme (ACE)-inhibitors for their functional significance. Among these functional properties, the antioxidant ability is essential to food processing. Generation of reactive oxygen species (ROS) and free radicals is an integral part of biological processes affecting all living organisms in energy production. Ovotransferrin (OTf), which constitutes 12% of the total white egg protein, is known as an iron binder and transporter in animals and can thus be used as an iron replacement, antimicrobial or antioxidant. Japanese researchers find ovotransferrin in a redox-dependent method generates observable self-cleaning.

OTf is composed of 686 amino acids and has a molecular mass of 77.90 kDa. It is a superoxide dismutase (SOD)-mimicking protein with a potent superoxide anion (O2 _-)-scavenging activity and showed dramatically higher scavenging activity than some known antioxidants, such as serum albumin or ascorbate. Interestingly, metal-bound OTfs such as Fe2+-OTf, Mn2+-OTf, Cu2+-OTf exhibited greater O2 _- dismutation capacity than the apoprotein. Conjugation of OTf with small molecules such as catechin shows improved antioxidant activity. During in vitro experiments, OTf displayed some antioxidant effects and its hydrolysates showed approximately 3,2 to 13,5 times higher superoxide anion scavenging activity and better copper/calcium scavenging activity than OTf. Furthermore, autocleaved OTf showed higher antioxidant activity than the natural OTf, and the hydrolysates of autocleaved OTf showed stronger antioxidant activity than those of the autocleaved one.

The peptide IRW, resulting from hydrolysis, exhibited a high-oxygen radical-scavenging that could be related to tryptophan. In addition, two high antioxidant activity tetrapeptides (WNIP and GWNI) were found in OTf thermolysin digests. WNI's motif seemed to be responsible for the high antioxidant potential as amino acid residues coupled with both peptides' N or C terminus decreased their antioxidant capacity. Moreover, when tested in endothelial cells, the peptide GWNI showed the ability to reduce reactive oxygen species generation. Other antioxidant peptides previously reported from OTf using the oxygen radical absorbance ability, on the other hand showed no antioxidant activity in cells, showed deficiencies in cell-free in vitro methods for antioxidant studies, and highlighted the need to use more biological systems such as culture cells to test antioxidant peptides. OTf-derived hydrolyzates obtained with HCl at pH 2.5 or other enzymes such as protamex, alkalase, trypsin, neutrase, flavorzyme, maxazyme, collupulin, protex, promod 278 and alpha-chymotrypsin showing higher superoxide anion scavenging activity and radical oxygen absorption ability than intact protein and showing protective effects against oxidative stress-induced DNA.

Due to their anti-inflammatory and antioxidant properties, otrf-derived peptides, including IRW, IQW, and KVREGT, are viable treatment agents for endothelial dysfunction and CVD prevention. They de-regulate the expression of the cytokine-induced inflammatory protein in the vascular endothelium by modulating the pathway NF-μB. Recent research also revealed that KVREGT has a significant role to inhibit ACE and promote vasodilation. IQW impedes ACE, promoting antioxidation.

Ovotransferrin and lactoferrin are iron-binding proteins with natural immunity-related antiviral and antibacterial activities, displaying marked sequence and structural homologies. Two hen ovotransferrin fragments DQKDEYELL (hOtrf219-227) and KDLLFK (hOtrf269-301 and hOtrf633-638) have registered antiviral activity against Marek virus infection of chicken embryo fibroblasts. These fragments have sequence homology with two bovine lactoferrin fragments with antiviral activity towards herpes simplex virus, indicating that these fragments may play a role in exploiting intact protein antiviral activity towards herpes viruses. NMR analysis showed that these chemically synthesized peptides had no favorite solution conformation, suggesting that both the amino acid sequence and the conformation in the intact protein are necessary for antiviral action.

SARS-CoV-2 virus activates the human cell ACE2 receptor, triggering a series of deleterious events. In COVID19, renin-angiotensin is upregulated and the pathway is overexpressed and a progressive cytokine storm is always observed. In all these pathogenic processes, ovotransferrin could play a modifier function to enhance the condition. Ovotransferrin can be beneficial to the antioxidant effects of Angiotensin II by inhibiting NF-kB. Ovotransferrin is an immunomodulator that downregulates pro-inflammatory cytokines including TNF-α, IL-6, and IL-1 that could extinguish the cytokine storm. Ovotransferrin can also serve as a protective agent against COVID19 cardiotoxicity due to disruption in the ACE2-mediated signaling pathway, cytokine storm, pulmonary dysfunction, and side effects of medications.

In patients with coronavirus infection, provided ovotransferrin's possible protective effects, it is suggested as a supportive and therapeutic alternative.

Given this background, in the light of the current COVID-19 emergency, it is the intention of the investigators to conduct a prospective, randomized, open-label, controlled study in the cohort of hospitalized patients with covid-19 pneumonia, administering 200 mg of ovotransferrin orally in addition to the standard of care therapy (SOC).

The investigators hypothesize that the use of ovotransferrin will be associated with an earlier improvement of clinical and humoral parameters after 10 days of ovotransferrin treatment when compared to the group of patients provided with standard care.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100
• Est. completion date: March 30, 2021
• Est. primary completion date: February 28, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Positive swab test of SARS-CoV-2

• Pneumonia related to SARS-CoV-2

• Signature of informed consent

• Absence of allergies to egg proteins

Exclusion Criteria:

• Unsigned informed consent

• Negative swab test of SARS-CoV-2

• Allergy to egg proteins

• Pregnancy and breastfeeding

• Mechanical ventilation

Related Conditions & MeSH terms

• Covid19

Intervention

Dietary Supplement:
• Ovotransferrin
Administering 200 mg of ovotransferrin orally in addition to the standard of care therapy for 10 days

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone	Palermo

Sponsors (1)

Lead Sponsor	Collaborator
Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone Palermo

Country where clinical trial is conducted

Italy, 

References & Publications (4)

Abeyrathne EDNS, Huang X, Ahn DU. Antioxidant, angiotensin-converting enzyme inhibitory activity and other functional properties of egg white proteins and their derived peptides - A review. Poult Sci. 2018 Apr 1;97(4):1462-1468. doi: 10.3382/ps/pex399. Review. — View Citation

Benedé S, Molina E. Chicken Egg Proteins and Derived Peptides with Antioxidant Properties. Foods. 2020 Jun 3;9(6). pii: E735. doi: 10.3390/foods9060735. Review. — View Citation

Chen S, Jiang H, Peng H, Wu X, Fang J. The Utility of Ovotransferrin and Ovotransferrin-Derived Peptides as Possible Candidates in the Clinical Treatment of Cardiovascular Diseases. Oxid Med Cell Longev. 2017;2017:6504518. doi: 10.1155/2017/6504518. Epub 2017 Mar 13. Review. Erratum in: Oxid Med Cell Longev. 2018 Dec 13;2018:1897257. — View Citation

Giansanti F, Massucci MT, Giardi MF, Nozza F, Pulsinelli E, Nicolini C, Botti D, Antonini G. Antiviral activity of ovotransferrin derived peptides. Biochem Biophys Res Commun. 2005 May 27;331(1):69-73. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	In-hospital mortality	Change of hospital mortality	48hours
Secondary	C reactive protein (CRP) levels	Reduction of CRP levels > 50% in comparison with CRP levels at the admission, within 48 hours after the administration	48 hours
Secondary	IL-6 levels	Reduction of IL-6 levels > 50% in comparison with IL-6 at the admission, within 48 hours after the administration	48 hours
Secondary	D-dimer levels	Reduction of D-dimer levels > 50% in comparison with D-dimer at the admission, within 48 hours after the administration	48 hours
Secondary	Hospital stay	Length of hospital stay	up to 24 weeks
Secondary	Duration of positive PCR swab	Time length of negativization of PCR molecular swab	5 days