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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 : May 14, 2021
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 May 14, 2021
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
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". 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.

Investigators 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". 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.

Investigators 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.

Investigators conducted a parallel 3 group clinical trial to investigate the effect and tolerability of a liposomal bLf formulation as a supplementary nutraceutical agent in COVID19 patients. A total of 92 COVID19 patients, 25/92 asymptomatic and 67/92 mild-to-moderate, were recruited and divided into 3 groups according to the administered regimen: 32/92 COVID-19 patients, 14 hospitalised and 18 in home-based isolation, received oral and intranasal liposomal bLF supplement; 32 COVID-19 hospitalised patients were treated with hydroxychloroquine, azitromicin and lopinavir/darunavir as standard of care treatment (SOC); twenty eight COVID-19 patients, in home-based isolation did not take any medication against COVID-19. Furthermore, a group of 32 healthy subjects with negative COVID19 rRT-PCR was added as a control group for ancillary analysis.

Thirty-two patients (14 hospitalised and 18 in home-based isolation) belonging to the first group received oral and intranasal liposomal bLf. BLf capsules for oral use containing 100 mg of bLf encapsulated in liposome while bLf nasal spray had about 8 mg/ml of bLf encapsulated in liposome. BLf, contained in both products, was tested by SDS-PAGE and silver nitrate staining and its purity was about 95%. The bLf iron saturation was about 5% as detected via optical spectroscopy at 468 nm based on an extinction coefficient of 0.54 (100% iron saturation, 1% solution). The scheduled dose treatment of liposomal bLf for oral use was 1gr per day for 30 days (10 capsules per day) in addition to the same formulation intranasally administered 3 times daily (a total of about 16 mg/nostril) Thirty-two hospitalized patients belonging to the second group were only treated with SOC regimen according to the national guidelines at the time of the enrollment: lopinavir/ritonavir cps 200/50 mg, 2x2/day (alternatively darunavir 800 mg 1 cp/day+ritonavir 100 mg 1 cp/day or darunavir/cobicistat 800/150 mg 1 cp/day), chloroquine 500 mg, 1x2/day or hydroxychloroquine cp 200 mg, 1x2/day. SOC regimen lasted from 5 to 20 days, with timing to be established according to clinical course.

Twenty-eight patients, in home-based isolation, belonging to the third group did not receive any therapy.

A control group, comprising 32 healthy volunteers, did not receive any treatment or placebo.

Blood samples and clinical assessments were evaluated at baseline (T0), after 15 days (T1) and after 30 days (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
  • Drug: SOC therapy
    oral administration
Study Arms  ICMJE
  • Experimental: Liposomal Lacroferrin
    Thirty-two patients (14 hospitalised and 18 in home-based isolation) belonging to the first group received oral and intranasal liposomal bLf. BLf capsules for oral use containing 100 mg of bLf encapsulated in liposome while bLf nasal spray had about 8 mg/ml of bLf encapsulated in liposome. BLf, contained in both products, was tested by SDS-PAGE and silver nitrate staining and its purity was about 95%. The bLf iron saturation was about 5% as detected via optical spectroscopy at 468 nm based on an extinction coefficient of 0.54 (100% iron saturation, 1% solution). The scheduled dose treatment of liposomal bLf for oral use was 1gr per day for 30 days (10 capsules per day) in addition to the same formulation intranasally administered 3 times daily (a total of about 16 mg/nostril)
    Intervention: Drug: liposomal lactoferrin
  • Active Comparator: SOC therapy
    Thirty-two hospitalized patients belonging to the second group were only treated with SOC regimen according to the national guidelines at the time of the enrollment: lopinavir/ritonavir cps 200/50 mg, 2x2/day (alternatively darunavir 800 mg 1 cp/day+ritonavir 100 mg 1 cp/day or darunavir/cobicistat 800/150 mg 1 cp/day), chloroquine 500 mg, 1x2/day or hydroxychloroquine cp 200 mg, 1x2/day. SOC regimen lasted from 5 to 20 days, with timing to be established according to clinical course.
    Intervention: Drug: SOC therapy
  • No Intervention: Home-based isolation
    Twenty-eight patients, in home-based isolation, belonging to the third group did not receive any therapy.
  • No Intervention: Healthy volunteers
    A control group, comprising 32 healthy volunteers, did not receive any treatment or placebo.
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: May 9, 2021)
92
Original Actual Enrollment  ICMJE
 (submitted: July 16, 2020)
60
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
Current Responsible Party Elena Campione, University of Rome Tor Vergata
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University of Rome Tor Vergata
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account University of Rome Tor Vergata
Verification Date May 2021

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