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Efficacy and Safety of Liposomal Lactoferrin in COVID-19 Patients With Mild-to-Moderate Disease and in COVID-19 Asymptomatic Patients

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ClinicalTrials.gov Identifier: NCT04475120
Recruitment Status : Completed
First Posted : July 17, 2020
Last Update Posted : July 17, 2020
Sponsor:
Information provided by (Responsible Party):
Elena Campione, University of Rome Tor Vergata

Tracking Information
First Submitted Date  ICMJE July 16, 2020
First Posted Date  ICMJE July 17, 2020
Last Update Posted Date July 17, 2020
Actual Study Start Date  ICMJE April 15, 2020
Actual Primary Completion Date July 2, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 16, 2020)
Rate of viral clearance Time to viral clearance [ Time Frame: 30 days ]
time to naso-oro-pharingeal swab negativization
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: July 16, 2020)
Time to clinical improvement [ Time Frame: 30 days ]
time to improvement of clinical symptoms and blood parameters
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Liposomal Lactoferrin in COVID-19 Patients With Mild-to-Moderate Disease and in COVID-19 Asymptomatic Patients
Official Title  ICMJE Interventional Pilot Study to Assess the Use of Oral and Intra-nasal Liposomal Lactoferrin in COVID-19 Patients With Mild-to-Moderate Disease and in COVID-19 Asymptomatic Patients
Brief Summary

COVID-19 is considered an ongoing international global health problem which already caused 12 million confirmed cases. No specific effective treatment has been identified so far, and available supportive therapies are intended just to severe patients. Asymptomatic and mildly symptomatic patients remain a transmission reservoir, with possible evolution to the most severe disease form, without a clear treatment indication.

Lactoferrin (Lf) is a multifunctional glycoprotein, belonging to transferrin family, secreted by exocrine glands and neutrophils and present in all human secretion. The pleiotropic activity of Lf is mainly based on its four different functions: chelate two ferric iron per molecule, interact with anionic molecules, enter inside nucleus and modulate iron homeostasis. The ability to chelate two ferric ions per molecule is associated to the inhibition of reactive oxygen species formation as well as this sequestration of iron, pivotal for bacterial and viral replication, is at the basis of its antibacterial and antiviral activity. Moreover, Lf exerts its antiviral activity against the majority of the tested viruses by binding to heparan sulphate, while against few viruses by interacting with surface components of viral particles. The capability of Lf to exert antiviral activity, by binding to host cells or viral particles or both, strengthens the idea that this glycoprotein is "an important brick in the mucosal wall, effective against viral attacks". Lang and colleagues investigated the role of Lf in the entry of SARS pseudovirus into Myc cells. Their results reveal that Lf was able to block the binding of the spike protein to host cells, indicating that Lf exerted its inhibitory function at the viral attachment stage. The current accepted model suggests that Lf could block viral entry by interacting with heparan sulfate proteoglycans (HSPGs), which mediate the transport of extracellular virus particles from the low affinity anchoring sites to the high affinity specific entry as ACE-2.

We performed a prospective, interventional pilot study to assess the efficacy of liposomal lactoferrin in COVID-19 patients with mild-to moderate disease and in COVID-19 asymptomatic patients.

Secondary objectives evaluated the safety and tolerability of liposomal lactoferrin for oral and intra-nasal use.

Detailed Description

COVID-19 is considered an ongoing international global health problem which already caused 12 million confirmed cases. No specific effective treatment has been identified so far, and available supportive therapies are intended just to severe patients. Asymptomatic and mildly symptomatic patients remain a transmission reservoir, with possible evolution to the most severe disease form, without a clear treatment indication.

Lactoferrin (Lf) is a multifunctional glycoprotein, belonging to transferrin family, secreted by exocrine glands and neutrophils and present in all human secretion. The pleiotropic activity of Lf is mainly based on its four different functions: chelate two ferric iron per molecule, interact with anionic molecules, enter inside nucleus and modulate iron homeostasis. The ability to chelate two ferric ions per molecule is associated to the inhibition of reactive oxygen species formation as well as this sequestration of iron, pivotal for bacterial and viral replication, is at the basis of its antibacterial and antiviral activity.

Moreover, Lf exerts its antiviral activity against the majority of the tested viruses by binding to heparan sulphate, while against few viruses by interacting with surface components of viral particles. The capability of Lf to exert antiviral activity, by binding to host cells or viral particles or both, strengthens the idea that this glycoprotein is "an important brick in the mucosal wall, effective against viral attacks". Lang and colleagues investigated the role of Lf in the entry of SARS pseudovirus into Myc cells. Their results reveal that Lf was able to block the binding of the spike protein to host cells, indicating that Lf exerted its inhibitory function at the viral attachment stage. The current accepted model suggests that Lf could block viral entry by interacting with heparan sulfate proteoglycans (HSPGs), which mediate the transport of extracellular virus particles from the low affinity anchoring sites to the high affinity specific entry as ACE-2.

We performed a prospective, interventional, pilot study to assess the efficacy of liposomal lactoferrin in COVID-19 patients with mild-to moderate disease and in COVID-19 asymptomatic patients.

Secondary objectives evaluated the safety and tolerability of liposomal lactoferrin for oral and intra-nasal use.

Patients were divided in two groups: COVID-19 mild-to-moderate patients (group 1a) and COVID-19 asymptomatic patients (group 2a), both of 15 patients. Other two groups (control groups) were included in the study to be paired to the above two case-groups. The "matched-pair-analysis" concerned the structural and clinical characteristics of the corresponding groups.

Group 1a received liposomal lactoferrin in 200 mg cps (equal to 100 mg of lactoferrin), 10 capsules per day for patients weighing less than or equal to 70 kg divided into 5 capsules in the morning and 5 capsules in the evening for 30 days for a total of 1 g of lactoferrin / day; patients with body weight over 70 kg, 15 capsules per day divided into 3 administrations / day for 30 days for a total of 1.5 g of lactoferrin per day; intra-nasal spray: 2 sprays per nostril 3 times a day, inhaling deeply during administration.

Group 2a received liposomal lactoferrin in 200 mg tablets (equal to 100 mg of lactoferrin), 5 capsules per day, 3 of which in the morning and 2 in the evening for 30 days (total dosage 500 mg of apo-lactoferrin per day); intra-nasal spray: 2 sprays per nostril 3 times a day, inhaling deeply during administration. Before administration, it was recommended to carefully clean the nasal cavity.

15 mild-to-moderate symptomatic patients in hospitalization regimen were enrolled in the control group 1b to be paired by age group and gender to the aforementioned experimental group (1a).15 asymptomatic patients were enrolled as a control group (group 2b) to be paired by age group and gender to the aforementioned experimental group (2a) Blood samples were collected at T0, T1 (after 15 days), T2 (after 30days). Body temperature and evaluation of related signs and symptoms were collected at T0. T1 and T2.

Complete blood count and chemistry panel, iron, transferrin, free iron plasma level, PCR, CK, IL-6, IL-10, TNF⍺, miR-1, miR-133, adrenomedullin, fibrinogen, d-dimer, were evaluated at T0, T1 and T2.

Eligible patients were over 20 years old, with a confirmed positivity to COVID-19 at the naso-oro-pharyngeal swab.

Exclusion criteria included pregnant and lactating women, patients taking nitric oxide and nitrates, patients with reported allergy to milk proteins, patients with a previous history of bronchial hyperactivity and patients with pre-existing respiratory diseases.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Covid19
Intervention  ICMJE Drug: liposomal lactoferrin
oral and intra-nasal formulation
Study Arms  ICMJE
  • Experimental: Group 1a (COVID-19 mild to moderate patients)
    Group 1a received liposomal lactoferrin in 200 mg cps (equal to 100 mg of lactoferrin), 10 capsules per day for patients weighing less than or equal to 70 kg divided into 5 capsules in the morning and 5 capsules in the evening for 30 days for a total of 1 g of lactoferrin / day; patients with body weight over 70 kg, 15 capsules per day divided into 3 administrations / day for 30 days for a total of 1.5 g of lactoferrin per day; intra-nasal spray: 2 sprays per nostril 3 times a day, inhaling deeply during administration.
    Intervention: Drug: liposomal lactoferrin
  • Experimental: Group 2a (COVID-19 asymptomatic patients)
    Group 2a received liposomal lactoferrin in 200 mg tablets (equal to 100 mg of lactoferrin), 5 capsules per day, 3 of which in the morning and 2 in the evening for 30 days (total dosage 500 mg of apo-lactoferrin per day); intra-nasal spray: 2 sprays per nostril 3 times a day, inhaling deeply during administration. Before administration, it was recommended to carefully clean the nasal cavity.
    Intervention: Drug: liposomal lactoferrin
  • No Intervention: Group 1b
    15 mild-to-moderate symptomatic patients in hospitalization regimen were enrolled in the control group 1b to be paired by age group and gender to the aforementioned experimental group (1a)
  • No Intervention: Group 2b
    15 asymptomatic patients were enrolled as a control group (group 2b) to be paired by age group and gender to the aforementioned experimental group (2a)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 16, 2020)
60
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 2, 2020
Actual Primary Completion Date July 2, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Eligible patients were over 20years old, with a confirmed positivity to COVID-19 at the oropharyngeal swab

Exclusion Criteria:

pregnant and lactating women, patients taking nitric oxide and nitrates, patients with reported allergy to milk proteins, patients with a previous history of bronchial hyperactivity and patients with pre-existing respiratory diseases. COVID-19 patients requiring intensive care or mechanical ventilation were excluded.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04475120
Other Study ID Numbers  ICMJE 4220
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Responsible Party Elena Campione, University of Rome Tor Vergata
Study Sponsor  ICMJE University of Rome Tor Vergata
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account University of Rome Tor Vergata
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP