<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04421534</url>
  </required_header>
  <id_info>
    <org_study_id>CUKA-001</org_study_id>
    <nct_id>NCT04421534</nct_id>
  </id_info>
  <brief_title>Utility of Lactoferrin as an Adjunct Therapeutic Agent for COVID-19</brief_title>
  <official_title>Efficacy and Safety of Lactoferrin as an Adjunct Therapeutic Agent for COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cairo University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cairo University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      There is currently no clinically proven specific antiviral agent available for SARS-CoV-2&#xD;
      infection. Supportive treatment, including oxygen therapy, remains the most important&#xD;
      management strategy.&#xD;
&#xD;
      Since its discovery, lactoferrin and its related peptides are mainly considered to be&#xD;
      important non-specific host defense molecules against a broad range of viruses including&#xD;
      SARS-CoV, which is closely related to SARS-CoV-2 that causes COVID-19. Lactoferrin has been&#xD;
      found to experimentally inhibit viral entry in murine coronavirus, and human coronaviruses&#xD;
      hCOV-NL63 and pseudotyped SARS-CoV. Besides reducing viral entry, lactoferrin can also&#xD;
      suppress virus replication after the viral entry.&#xD;
&#xD;
      Another major aspect of lactoferrin bioactivity relates to its immunomodulatory and&#xD;
      anti-inflammatory functions. Current thinking suggests that mortality from COVID-19 is not&#xD;
      simply due to viral infection but is a result of a cytokine storm associated with&#xD;
      hyper-inflammation leading to acute respiratory distress and subsequent mortality. A cytokine&#xD;
      profile in severe COVID-19 cases is characterized by increases in cytokines and acute phase&#xD;
      reactants and ferritin. In this regard, lactoferrin was demonstrated to reduce IL-6, TNF a,&#xD;
      and downregulate ferritin in experimental settings simulating sepsis.&#xD;
&#xD;
      In this study, we aim to study the potential application of lactoferrin against SARS-CoV-2&#xD;
      and propose the possibility of using different doses of supplemental lactoferrin as a&#xD;
      potential adjunct treatment for COVID-19.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      COVID-19 has a wide clinical spectrum ranging between asymptomatic infection, mild upper&#xD;
      respiratory tract symptoms, and severe viral pneumonia that may result in respiratory failure&#xD;
      and finally death. There is currently no clinically proven specific antiviral agent available&#xD;
      for SARS-CoV-2 infection. Supportive treatment, including oxygen therapy, conservation fluid&#xD;
      management, and broad-spectrum antibiotics to cover secondary bacterial infection, remains&#xD;
      the most important management strategy.&#xD;
&#xD;
      Lactoferrin is a highly conserved pleiotropic iron-binding 80-kDa glycoprotein of the&#xD;
      transferrin family that is expressed and secreted by glandular cells and found in most body&#xD;
      fluids with especially high concentrations in mammalian milk. Since its discovery,&#xD;
      lactoferrin and its related peptides are mainly considered to be important non-specific host&#xD;
      defense molecules against a broad range of viruses including SARS-CoV, which is closely&#xD;
      related to SARS-CoV-2 that causes COVID-19. Lactoferrin has been found to experimentally&#xD;
      inhibit viral entry in murine coronavirus, and human coronaviruses hCOV-NL63 and pseudotyped&#xD;
      SARS-CoV. Given the homology of SARS-CoV and SARS-CoV-2 spike protein structures, as well as&#xD;
      both viruses depending on the same ACE2 receptor for cell entry, it is likely that&#xD;
      lactoferrin can inhibit SARS-CoV-2 invasion as in the case of SARS-CoV. Besides reducing&#xD;
      viral entry, lactoferrin can also suppress virus replication after the viral entry as in the&#xD;
      case of HIV.&#xD;
&#xD;
      Another major aspect of lactoferrin bioactivity relates to its immunomodulatory and&#xD;
      anti-inflammatory functions. Current thinking suggests that mortality from COVID-19 is not&#xD;
      simply due to viral infection but is a result of a cytokine storm associated with&#xD;
      hyper-inflammation leading to acute respiratory distress and subsequent mortality. A cytokine&#xD;
      profile in severe COVID-19 cases is characterized by increases in cytokines and acute phase&#xD;
      reactants such as interleukin IL-6, tumor necrosis factor-a (TNFa) and ferritin. In this&#xD;
      regard, lactoferrin was demonstrated to reduce IL-6, TNF a, and downregulate ferritin in&#xD;
      experimental settings simulating sepsis.&#xD;
&#xD;
      The aim of this study is to confirm the antiviral properties and immunomodulatory mechanisms&#xD;
      of lactoferrin within the context of its potential application against SARS-CoV-2 and propose&#xD;
      the possibility of supplemental lactoferrin in different doses as a potential adjunct&#xD;
      treatment for COVID-19.&#xD;
&#xD;
      The clinical data as well as the demographic information will be collected from the&#xD;
      clinicians involved in the project. All samples will be collected according to the approved&#xD;
      research protocols. During this period, the database entry platforms will be formed.&#xD;
&#xD;
      Eligible patients will be randomly distributed in 3 groups:&#xD;
&#xD;
      Group 1 (n=50): standard of care treatment; as per Egyptian Ministry of Health and Population&#xD;
      (MOHP) protocol, in addition to 400 mg oral lactoferrin daily Group 2 (n=50): standard of&#xD;
      care treatment; as per MOHP protocol, in addition to 600 mg oral lactoferrin daily Group 3&#xD;
      (n=50): standard of care treatment; as per MOHP protocol (control group)&#xD;
&#xD;
      The trial will be done according to the principles of the Declaration of Helsinki and the&#xD;
      Good Clinical Practice guidelines.&#xD;
&#xD;
      Patients will be assessed daily on a scale reflecting a range from uninfected to dead, where&#xD;
      0 is &quot;no clinical or virological evidence of infection&quot;, 1 is &quot;no limitation of activities&quot;,&#xD;
      2 is &quot;limitation of activities&quot;, 3 is &quot;hospitalized, no oxygen therapy&quot;, 4 is &quot;oxygen by mask&#xD;
      or nasal prongs&quot;, 5 is &quot;non-invasive ventilation or high-flow oxygen&quot;, 6 is &quot;intubation and&#xD;
      mechanical ventilation&quot;, 7 is &quot;ventilation + additional organ support - pressors, RRT (renal&#xD;
      replacement therapy), ECMO (extracorporeal membrane oxygenation)&quot;, and 8 is &quot;death&quot;.&#xD;
&#xD;
      Serial oropharyngeal swab samples will be obtained after treatment until discharge or death&#xD;
      had occurred.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">June 2020</start_date>
  <completion_date type="Anticipated">November 2020</completion_date>
  <primary_completion_date type="Anticipated">September 2020</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to clinical improvement</measure>
    <time_frame>28 days</time_frame>
    <description>time from randomization to improvement of two points on used scale or live discharge from the hospital, whichever came first.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of virological cure</measure>
    <time_frame>28 days</time_frame>
    <description>time from randomization to cure (2 SARS-COV-2 PCR samples negative with 48 hours apart)</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">150</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Standard of care in addition to 400 mg lactoferrin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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]</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of care in addition to 600 mg lactoferrin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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]</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of care only</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard of care treatment; as per MOHP protocol</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lactoferrin</intervention_name>
    <description>adding lactoferrin to standard of care treatment regimens</description>
    <arm_group_label>Standard of care in addition to 400 mg lactoferrin</arm_group_label>
    <arm_group_label>Standard of care in addition to 600 mg lactoferrin</arm_group_label>
    <arm_group_label>Standard of care only</arm_group_label>
    <other_name>Standard of care treatment regimens</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Positive reverse-transcriptase-polymerase chain- reaction (RT-PCR) assay for SARS-&#xD;
             CoV-2 in a respiratory tract sample.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known allergy or hypersensitivity to the used medications&#xD;
&#xD;
          -  Severe symptoms: respiratory insufficiency that requires admission in intensive care&#xD;
             unit or mechanical ventilation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 5, 2020</study_first_submitted>
  <study_first_submitted_qc>June 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>June 5, 2020</last_update_submitted>
  <last_update_submitted_qc>June 5, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 9, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cairo University</investigator_affiliation>
    <investigator_full_name>Gamal Esmat</investigator_full_name>
    <investigator_title>Professor of Endemic Medicine</investigator_title>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <keyword>lactoferrin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lactoferrin</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04421534
org study id: CUKA-001
nct id: NCT04421534
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Time to clinical improvement
time frame: 28 days
description: time from randomization to improvement of two points on used scale or live discharge from the hospital, whichever came first.
measure: Rate of virological cure
time frame: 28 days
description: time from randomization to cure (2 SARS-COV-2 PCR samples negative with 48 hours apart)
arm group label: Standard of care in addition to 400 mg lactoferrin
arm group type: Experimental
description: 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]
arm group label: Standard of care in addition to 600 mg lactoferrin
arm group type: Experimental
description: 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]
arm group label: Standard of care only
arm group type: Active Comparator
description: Standard of care treatment; as per MOHP protocol
intervention type: Drug
intervention name: Lactoferrin
description: adding lactoferrin to standard of care treatment regimens
arm group label: Standard of care in addition to 400 mg lactoferrin
arm group label: Standard of care in addition to 600 mg lactoferrin
arm group label: Standard of care only
other name: Standard of care treatment regimens
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
responsible party type: Principal Investigator
investigator affiliation: Cairo University
investigator full name: Gamal Esmat
investigator title: Professor of Endemic Medicine
mesh term: COVID-19
mesh term: Lactoferrin