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Clinical Assessment of Oral Lactoferrin as a Safe Antiviral and Immunoregulatory in Treating COVID-19 Disease (COVID-19_LF)

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ClinicalTrials.gov Identifier: NCT04412395
Recruitment Status : Not yet recruiting
First Posted : June 2, 2020
Last Update Posted : March 11, 2021
Sponsor:
Collaborator:
Egyptian Military Medical Services
Information provided by (Responsible Party):
Rehab Ragab Hegazy, National Research Centre, Egypt

Brief Summary:
The aim of the study is to clinically use bovine Lf as a safe antiviral adjuvant for treatment and to assess the potential in reducing mortality and morbidity rates in COVID-19 patients. The study was approved by the ethical committee of the Egyptian Center for Research and Regenerative Medicine in 11-5-2020.

Condition or disease Intervention/treatment Phase
Corona Virus Infection Middle East Respiratory Syndrome (MERS) Acute Respiratory Distress Syndrome Coronavirus Infection COVID-19 SARS-CoV 2 Dietary Supplement: Lactoferrin (Apolactoferrin) Drug: Placebo of excipient(s) will be administered Phase 2

Detailed Description:
The World Health Organization (WHO) declared the coronavirus (SARS-CoV-2, COVID-19) outbreak a Public Health Emergency of International Concern with a pandemic spread. The situation is rapidly evolving, which raises the approach of reproposing already approved drugs to meet the emerging challenge and to save time and money. Lactoferrin (Lf) is a natural glycoprotein that broadly distributed within the body fluids and found predominantly in milk. It represents a known component of the innate immune system. The antiviral activity of Lf has been reported against many viruses, including SARS-CoV-1, through blocking the viral receptors on the host cells preventing them from entry and replication. Markedly, data reveals that Lf interacts with Heparan Sulfate Proteoglycans (HSPGs) and Angiotensin Converting Enzyme 2 (ACE2) receptors that are reported as SARS-CoV-2-binding sites to enter the host cell, suggesting a potential significance of Lf as an antiviral against SARS-CoV-2. Moreover, the immunoregulatory effects of Lf can protect against the cytokine-storm and thrombotic complications that result from the COVID-19-induced over-stimulated inflammatory response and exaggerated immune reactions. In addition, Lf can decrease the free iron toxicity caused by the virus as it has a strong iron chelating ability. Lf is a safe approved food supplement that is available in the markets for enhancement of immunity and for treatment of anemia. The aim of this study is to perform a randomized, double-blind, placebo-controlled, two arms, clinical trial to assess oral enteric-coated tablet of bovine apolactoferrin (the low iron-content form of Lf) as a safe antiviral and immunoregulatory therapy in patients diagnosed with COVID-19 disease.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 516 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, double-blind, placebo-controlled, clinical trial.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Clinical Assessment of Oral Lactoferrin as a Safe Antiviral and Immunoregulatory Therapy in Patients Diagnosed With COVID-19 Disease
Estimated Study Start Date : June 1, 2021
Estimated Primary Completion Date : August 31, 2021
Estimated Study Completion Date : September 30, 2021


Arm Intervention/treatment
Active Comparator: Arm 01 (SOC + Lactoferrin 1200 mg QID)
Patients randomized to this group will receive two 600 mg Lactoferrin tablets QID plus the Standard of Care (SOC) treatment(s).
Dietary Supplement: Lactoferrin (Apolactoferrin)
Apolactoferrin is an iron-free Lactoferrin (with very low iron saturation). Lactoferrin (Lf) is a natural glycoprotein that is found predominantly in milk. Lf represents a known component of the innate immune system present in neutrophil-specific granules and broadly distributed within the body fluids and exocrine secretions.

Placebo Comparator: Arm 02 (SOC + Placebo QID)
Patients randomized to this group will receive two placebo tablets QID plus the SOC treatment(s).
Drug: Placebo of excipient(s) will be administered
Placebo of the equivalent excipient will be administered to placebo group
Other Name: excipient(s)




Primary Outcome Measures :
  1. Survival rate. [ Time Frame: up to 8 weeks. ]
    Comparing the influence of the intervention on the Survival rate.

  2. Rate of disease remission. [ Time Frame: up to 4 weeks. ]

    For mild/moderate symptoms patients: fever, cough and other symptoms relieved with improved lung CT

    - For severe symptoms patients: fever, cough and other symptoms relieved with improved lung CT, and oxygen saturation by pulse oximetry (SPO2 )> 93% for nonasthmatic patients, and from 88-92% in asthmatic patients.


  3. The number of patients with PCR negative results. [ Time Frame: up to 4 weeks. ]
    Comparing the influence of the intervention on the PCR negative results.


Secondary Outcome Measures :
  1. Mean change in the disease severity (clinical assessment). [ Time Frame: up to 4 weeks. ]
    Recording the changes from severe to moderate or mild and the time taken.

  2. Mean change in blood pressure. [ Time Frame: up to 4 weeks. ]
    Recording the changes in blood pressure mmHg.

  3. Mean change in heart beats. [ Time Frame: up to 4 weeks. ]
    Recording the changes in heart rate in beat/second.

  4. Mean change in body temperature. [ Time Frame: up to 4 weeks. ]
    Recording the changes in body temperature in Celsius.

  5. Mean change in body respiratory rate. [ Time Frame: up to 4 weeks. ]
    Recording the changes in the respiratory rate in breath/minute.

  6. Mean change in oxygen saturation. [ Time Frame: up to 4 weeks. ]
    Recording the changes in arterial oxygen saturation in mmHg.

  7. Mean change in the ratio in arterial oxygen partial pressure to fractional inspired oxygen (PF ratio). [ Time Frame: up to 4 weeks. ]
    Recording the changes in the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF ratio).

  8. Mean change in complete blood picture (CBC). [ Time Frame: up to 4 weeks. ]
    Recording the changes in complete blood picture (CBC) in cells per liter.

  9. Mean change in C reactive protein (CRP). [ Time Frame: up to 4 weeks. ]
    Recording the changes in C reactive protein (CRP) in mg/L.

  10. Mean change in erythrocyte sedimentation rate (ESR). [ Time Frame: up to 4 weeks. ]
    Recording the changes in erythrocyte sedimentation rate (ESR) in mm/hr.

  11. Mean change in D-dimer. [ Time Frame: up to 4 weeks. ]
    Recording the changes in D-dimer in ng/mL.

  12. Mean change in ferritin. [ Time Frame: up to 4 weeks. ]
    Recording the changes in ferritin in ng/mL.

  13. Mean change in liver Albumin. [ Time Frame: up to 4 weeks. ]
    Recording the changes in liver Albumin in g/L.

  14. Mean change in total and direct Bilirubin. [ Time Frame: up to 4 weeks. ]
    Recording the changes in total and direct Bilirubin in mg/dL.

  15. Mean change in prothrombin time (PT) and partial thromboplastin time (PTT ). [ Time Frame: up to 4 weeks. ]
    Recording the changes in prothrombin time (PT), partial thromboplastin time (PTT ) in seconds and calculating International Normalized Ratio (INR).

  16. Mean change in aspartate aminotransferase (AST). [ Time Frame: up to 4 weeks. ]
    Recording the changes in aspartate aminotransferase (AST) in IU/L.

  17. Mean change in Alanine Aminotransferase (ALT). [ Time Frame: up to 4 weeks. ]
    Recording the changes in Alanine Aminotransferase (ALT) in IU/L.

  18. Mean change in Blood Urea Nitrogen (BUN). [ Time Frame: up to 4 weeks. ]
    Recording the changes in Blood Urea Nitrogen (BUN) in mg/dL.

  19. Mean change in Serum Creatinine. [ Time Frame: up to 4 weeks. ]
    Recording the changes in Serum Creatinine in mg/dL.

  20. Mean change in Serum Creatinine clearance. [ Time Frame: up to 4 weeks. ]
    Recording the changes in Serum Creatinine in ml/min.

  21. Mean change in Glomerular filtration rate (GFR ). [ Time Frame: up to 4 weeks. ]
    Recording the changes in Glomerular filtration rate (GFR ) ml/min/m2.

  22. The mean change in serum interleukin-1 (IL-1). [ Time Frame: up to 4 weeks. ]
    Recording the changes in interleukin-1 (IL-1) in pg/ml.

  23. The mean change in serum interleukin-6 (IL-6). [ Time Frame: up to 4 weeks. ]
    Recording the changes in interleukin-6 (IL-6) in pg/ml.

  24. The mean change in serum interleukin-10 (IL-10). [ Time Frame: up to 4 weeks. ]
    Recording the changes in interleukin-10 (IL-10) in pg/ml.

  25. The mean change in serum tumor necrosis factor-alpha (TNF alpha). [ Time Frame: up to 4 weeks. ]
    Recording the changes in tumor necrosis factor-alpha (TNF alpha) in ng/ml.

  26. Mean changes in immunoglobulin G (IgG). [ Time Frame: up to 4 weeks. ]
    Recording the changes in immunoglobulin G (IgG) in ng/ml.

  27. Mean changes in immunoglobulin M (IgM). [ Time Frame: up to 4 weeks. ]
    Recording the changes in immunoglobulin M (IgM) in ng/ml.

  28. The mean change in PCR viral load. [ Time Frame: up to 4 weeks. ]
    Recording the changes in PCR viral load in copies/mL.

  29. Mean change in lung CT manifestation. [ Time Frame: up to 4 weeks. ]
    Recording the changes in lung CT.

  30. Nature and severity of Adverse Events. [ Time Frame: up to 4 weeks. ]
    Recording any unexpected Adverse Events of the intervention.

  31. Time for lung recovery. [ Time Frame: up to 8 weeks. ]
    Recording the changes (the average time of lung imaging recovery), as assessed by lung CT.

  32. The number of missed drug doses among each treatment group. [ Time Frame: up to 4 weeks. ]
    Recording the changes the event of missed drug doses.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients tested positive (PCR) for SARS-CoV-2 and clinically symptomatic.
  • Adult patients with age >18 years.
  • Patients willing and able to sign the study informed consent form.

Exclusion Criteria:

  • Critically severe disease patients (having Respiratory failure requiring mechanical ventilation, or signs of septic shock or multiple organ failure requiring ICU admission).
  • Patients who are unconscious
  • Patients who have convulsions
  • Patients suffering from central cyanosis with SPO2< 90% (for asthmatic patients with SPO2<88%)
  • Pregnant or lactating women
  • Patients with a known history of pro-inflammatory diseases (patients with autoimmune diseases, patients receiving chemotherapy for cancer, patients with malabsorption, patients with inflammatory bowel disease, Crohn's disease or ulcerative colitis).
  • History or suspected immunosuppressive or immunodeficient state including HIV infection, or chronic immunosuppressant medication (more than 14 days) within the past 3 months (inhaled and topical steroids are allowed).
  • Patients with severe renal impairment (GFR <60 ml/min/1.73m2 as measured by the Cockcroft-Gault formula).
  • Patient with severe hepatic impairment, biliary cirrhosis or cholestasis
  • Patients who received immunoregulatory therapy within one month before the start of the study.
  • Patients with Known or suspected allergy or any contraindications to Lactoferrin.
  • Any condition, according to the judgment of the investigator, would interfere with the patient's ability to comply with all study requirements or that would place the patient at unacceptable risk by his/her participation in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04412395


Contacts
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Contact: Rehab Hegazy, PhD +201001507676 rehab_hegazy@hotmail.com
Contact: Osama Azmy, MD +201223103084 osamaazmy@yahoo.com

Locations
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Egypt
National Research Center, Egypt (Clinical and Molecular Pharmacology)
Cairo, Giza, Egypt, 12622
Contact: Marawan Abdelbaset, PhD    +0201002227202    dr.marawan@gmail.com   
Contact: Bassim Mohamed, PhD       Bassim.mohamed@umontreal.ca   
Principal Investigator: Marawan Abdelbaset, PhD         
Principal Investigator: Bassim Mohamed, PhD         
Clinmax CRO (Clinical Research Organization)
Cairo, Egypt, 11835
Contact: Khaled Prince, B Pharm    +20106725802    Khaled.prince@clinmax.net   
Contact: Christine Gindy, B Pharm       christine.gindy@clinmax.net   
Clinical Trial Unit National Research Center
Cairo, Egypt
Contact: Wafaa Abdel Aal, MD         
Contact: Osama Azmy, MD         
Egyptian Military Medical Services (Hospitals)
Cairo, Egypt
Sponsors and Collaborators
National Research Centre, Egypt
Egyptian Military Medical Services
Investigators
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Study Director: Rehab Hegazy, PhD National Research Center
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Responsible Party: Rehab Ragab Hegazy, Assistant Professor, National Research Centre, Egypt
ClinicalTrials.gov Identifier: NCT04412395    
Other Study ID Numbers: COVID-19_LF
First Posted: June 2, 2020    Key Record Dates
Last Update Posted: March 11, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Not yet decided.
Time Frame: within 6 month
Access Criteria: all valid data

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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
Keywords provided by Rehab Ragab Hegazy, National Research Centre, Egypt:
Lactoferrin
Apolactoferrin
Immuno-modulatory
Cytokine-storm
Antiviral
2019nCoV
2019 new coronavirus (2019nCoV)
Middle East Respiratory Syndrome (MERS)
Acute Respiratory Distress Syndrome (ARDS)
COVID-19
SARS-CoV 2
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Coronavirus Infections
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Syndrome
Disease
Pathologic Processes
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Virus Diseases
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Lung Injury
Lactoferrin
Anti-Infective Agents