Utility of Lactoferrin as an Adjunct Therapeutic Agent for COVID-19

Efficacy and Safety of Lactoferrin as an Adjunct Therapeutic Agent for COVID-19

There is currently no clinically proven specific antiviral agent available for SARS-CoV-2 infection. Supportive treatment, including oxygen therapy, remains the most important management strategy.

Since its discovery, lactoferrin and its related peptides are mainly considered to be important non-specific host defense molecules against a broad range of viruses including SARS-CoV, which is closely related to SARS-CoV-2 that causes COVID-19. Lactoferrin has been found to experimentally inhibit viral entry in murine coronavirus, and human coronaviruses hCOV-NL63 and pseudotyped SARS-CoV. Besides reducing viral entry, lactoferrin can also suppress virus replication after the viral entry.

Another major aspect of lactoferrin bioactivity relates to its immunomodulatory and anti-inflammatory functions. Current thinking suggests that mortality from COVID-19 is not simply due to viral infection but is a result of a cytokine storm associated with hyper-inflammation leading to acute respiratory distress and subsequent mortality. A cytokine profile in severe COVID-19 cases is characterized by increases in cytokines and acute phase reactants and ferritin. In this regard, lactoferrin was demonstrated to reduce IL-6, TNF a, and downregulate ferritin in experimental settings simulating sepsis.

In this study, we aim to study the potential application of lactoferrin against SARS-CoV-2 and propose the possibility of using different doses of supplemental lactoferrin as a potential adjunct treatment for COVID-19.

Study Overview

• Status: Unknown
• Conditions: COVID-19
• Intervention / Treatment: Drug: Lactoferrin

Detailed Description

COVID-19 has a wide clinical spectrum ranging between asymptomatic infection, mild upper respiratory tract symptoms, and severe viral pneumonia that may result in respiratory failure and finally death. There is currently no clinically proven specific antiviral agent available for SARS-CoV-2 infection. Supportive treatment, including oxygen therapy, conservation fluid management, and broad-spectrum antibiotics to cover secondary bacterial infection, remains the most important management strategy.

Lactoferrin is a highly conserved pleiotropic iron-binding 80-kDa glycoprotein of the transferrin family that is expressed and secreted by glandular cells and found in most body fluids with especially high concentrations in mammalian milk. Since its discovery, lactoferrin and its related peptides are mainly considered to be important non-specific host defense molecules against a broad range of viruses including SARS-CoV, which is closely related to SARS-CoV-2 that causes COVID-19. Lactoferrin has been found to experimentally inhibit viral entry in murine coronavirus, and human coronaviruses hCOV-NL63 and pseudotyped SARS-CoV. Given the homology of SARS-CoV and SARS-CoV-2 spike protein structures, as well as both viruses depending on the same ACE2 receptor for cell entry, it is likely that lactoferrin can inhibit SARS-CoV-2 invasion as in the case of SARS-CoV. Besides reducing viral entry, lactoferrin can also suppress virus replication after the viral entry as in the case of HIV.

Another major aspect of lactoferrin bioactivity relates to its immunomodulatory and anti-inflammatory functions. Current thinking suggests that mortality from COVID-19 is not simply due to viral infection but is a result of a cytokine storm associated with hyper-inflammation leading to acute respiratory distress and subsequent mortality. A cytokine profile in severe COVID-19 cases is characterized by increases in cytokines and acute phase reactants such as interleukin IL-6, tumor necrosis factor-a (TNFa) and ferritin. In this regard, lactoferrin was demonstrated to reduce IL-6, TNF a, and downregulate ferritin in experimental settings simulating sepsis.

The aim of this study is to confirm the antiviral properties and immunomodulatory mechanisms of lactoferrin within the context of its potential application against SARS-CoV-2 and propose the possibility of supplemental lactoferrin in different doses as a potential adjunct treatment for COVID-19.

The clinical data as well as the demographic information will be collected from the clinicians involved in the project. All samples will be collected according to the approved research protocols. During this period, the database entry platforms will be formed.

Eligible patients will be randomly distributed in 3 groups:

Group 1 (n=50): standard of care treatment; as per Egyptian Ministry of Health and Population (MOHP) protocol, in addition to 400 mg oral lactoferrin daily Group 2 (n=50): standard of care treatment; as per MOHP protocol, in addition to 600 mg oral lactoferrin daily Group 3 (n=50): standard of care treatment; as per MOHP protocol (control group)

The trial will be done according to the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines.

Patients will be assessed daily on a scale reflecting a range from uninfected to dead, where 0 is "no clinical or virological evidence of infection", 1 is "no limitation of activities", 2 is "limitation of activities", 3 is "hospitalized, no oxygen therapy", 4 is "oxygen by mask or nasal prongs", 5 is "non-invasive ventilation or high-flow oxygen", 6 is "intubation and mechanical ventilation", 7 is "ventilation + additional organ support - pressors, RRT (renal replacement therapy), ECMO (extracorporeal membrane oxygenation)", and 8 is "death".

Serial oropharyngeal swab samples will be obtained after treatment until discharge or death had occurred.

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Positive reverse-transcriptase-polymerase chain- reaction (RT-PCR) assay for SARS- CoV-2 in a respiratory tract sample.

Exclusion Criteria:

• Known allergy or hypersensitivity to the used medications
• Severe symptoms: respiratory insufficiency that requires admission in intensive care unit or mechanical ventilation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard of care in addition to 400 mg lactoferrin; Standard of care treatment; as per MOHP protocol, in addition to 400 mg oral lactoferrin daily [two sachets 100 mg granules (Pravotin sachets, Hygint, Egypt) in 1/4 glass of water twice a day before meals]	Drug: Lactoferrin; adding lactoferrin to standard of care treatment regimens; Other Names: Standard of care treatment regimens
Experimental: Standard of care in addition to 600 mg lactoferrin; Standard of care treatment; as per MOHP protocol, in addition to 600 mg oral lactoferrin daily [three sachets 100 mg granules (Pravotin sachets, Hygint, Egypt) in 1/4 glass of water twice a day before meals]	Drug: Lactoferrin; adding lactoferrin to standard of care treatment regimens; Other Names: Standard of care treatment regimens
Active Comparator: Standard of care only; Standard of care treatment; as per MOHP protocol	Drug: Lactoferrin; adding lactoferrin to standard of care treatment regimens; Other Names: Standard of care treatment regimens

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to clinical improvement	time from randomization to improvement of two points on used scale or live discharge from the hospital, whichever came first.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of virological cure	time from randomization to cure (2 SARS-COV-2 PCR samples negative with 48 hours apart)	28 days

Collaborators and Investigators

• Sponsor: Cairo University

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2020
• Primary Completion (Anticipated): September 1, 2020
• Study Completion (Anticipated): November 1, 2020

Study Registration Dates

• First Submitted: June 5, 2020
• First Submitted That Met QC Criteria: June 5, 2020
• First Posted (Actual): June 9, 2020

Study Record Updates

• Last Update Posted (Actual): June 9, 2020
• Last Update Submitted That Met QC Criteria: June 5, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: COVID-19; lactoferrin
• 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; Anti-Infective Agents; Lactoferrin
• Other Study ID Numbers: CUKA-001

Drug and device information, study documents

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