<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/NCT04480593</url>
  </required_header>
  <id_info>
    <org_study_id>31099320.6.0000.0048</org_study_id>
    <nct_id>NCT04480593</nct_id>
  </id_info>
  <brief_title>The Use of Brazilian Green Propolis Extract (EPP-AF) in Patients Affected by COVID-19.</brief_title>
  <acronym>Bee-Covid</acronym>
  <official_title>The Use of Brazilian Green Propolis Extract (EPP-AF) in Patients Affected by COVID-19: a Randomized, Open and Pilot Clinical Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>D'Or Institute for Research and Education</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hospital Sao Rafael</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>D'Or Institute for Research and Education</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>
      The COVID-19 pandemic is of grave concern due its impact on human health and on the economy.&#xD;
      Propolis, a natural resin produced by bees from plant materials, has anti-inflammatory,&#xD;
      immunomodulatory, anti-oxidant properties, and various aspects of the SARS-CoV-2 infection&#xD;
      mechanism are potential targets for propolis compounds. Propolis components have inhibitory&#xD;
      effects on the ACE2, TMPRSS2 and PAK1 signaling pathways; in addition, antiviral activity has&#xD;
      been proven in vitro and in vivo. This is a pilot randomized study that aims to assess the&#xD;
      impact of using Brazilian green propolis extract against the deleterious effects of the new&#xD;
      coronavirus.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 2, 2020</start_date>
  <completion_date type="Actual">August 30, 2020</completion_date>
  <primary_completion_date type="Actual">August 30, 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>
    <intervention_model_description>three parallel groups randomly assigned</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>The individual who evaluates the results of interest to the study will not have access to the study steps before the analysis.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Composite clinical outcome with oxygen therapy dependency time or hospitalization time</measure>
    <time_frame>1-28 days</time_frame>
    <description>Composite clinical outcome with oxygen therapy dependency time (in days) or hospitalization time (in days) after randomization.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percentage of participants with adverse events during the use of propolis</measure>
    <time_frame>1-28 days</time_frame>
    <description>We will evaluate the presence or absence of symptoms related to the use of propolis through a questionnaire.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate and severity of acute kidney injury during the study</measure>
    <time_frame>1-28 days</time_frame>
    <description>Assess the degree of acute kidney injury according to KDIGO (through serum creatinine or urine output).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Renal replacement therapy.</measure>
    <time_frame>1-28 days</time_frame>
    <description>Assess need or not for renal replacement therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of need for vasopressor use</measure>
    <time_frame>1-28 days</time_frame>
    <description>Describe the time needed for vasopressors in days after randomization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need for intensive care unit (ICU)</measure>
    <time_frame>1-28 days</time_frame>
    <description>Assess length of stay in the ICU after randomization in days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intensive care unit (ICU) readmission</measure>
    <time_frame>1-28 days</time_frame>
    <description>Rate of readmission to the ICU after randomization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Invasive oxygenation time</measure>
    <time_frame>1-28 days</time_frame>
    <description>Assess the need for mechanical ventilation in days after randomization.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Variation of plasma c-reactive protein</measure>
    <time_frame>1-7 days</time_frame>
    <description>Evaluate the variation in serum levels of c-reactive protein over the 7 days after randomization</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">120</enrollment>
  <condition>Covid19</condition>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>standard care.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>EPP-AF 400mg/day</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Green propolis extract (EPP-AF) at a dose of 400mg / day in addition to the standard treatment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>EPP-AF 800mg/day</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Green propolis extract (EPP-AF) at a dose of 800mg / day in addition to the standard treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Brazilian Green Propolis Extract (EPP-AF)</intervention_name>
    <description>Green propolis extract (EPP-AF) administered orally or via nasoenteral tube.</description>
    <arm_group_label>EPP-AF 400mg/day</arm_group_label>
    <arm_group_label>EPP-AF 800mg/day</arm_group_label>
    <other_name>Standard care</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard care</intervention_name>
    <description>Standard treatment includes, as needed, supplemental oxygen (non-invasive and invasive), antibiotics or antivirals, corticosteroids, vasopressor support, renal replacement therapy and extracorporeal membrane oxygenation (ECMO).</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Hospitalized patients;&#xD;
&#xD;
          -  Positive RT-PCR for SARS-CoV-2;&#xD;
&#xD;
          -  18 Years and older.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant women;&#xD;
&#xD;
          -  People with active cancer;&#xD;
&#xD;
          -  Patients undergoing transplantation of solid organs or bone marrow or who use&#xD;
             immunosuppressive medications;&#xD;
&#xD;
          -  HIV carriers;&#xD;
&#xD;
          -  Allergy to propolis or any of its components;&#xD;
&#xD;
          -  Bacterial infection at randomization;&#xD;
&#xD;
          -  Sepsis or septic shock before randomization;&#xD;
&#xD;
          -  Patients unable to use medication orally or via nasoenteral tube;&#xD;
&#xD;
          -  Patients with severe chronic liver disease (Child B or C);&#xD;
&#xD;
          -  Patients with advanced heart failure;&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marcelo Silveira, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>D'Or Institute for Research and Education (IDOR)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Sao Rafael</name>
      <address>
        <city>Salvador</city>
        <state>BA</state>
        <zip>41820340</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <reference>
    <citation>Hori JI, Zamboni DS, Carrao DB, Goldman GH, Berretta AA. The Inhibition of Inflammasome by Brazilian Propolis (EPP-AF). Evid Based Complement Alternat Med. 2013;2013:418508. doi: 10.1155/2013/418508. Epub 2013 Apr 16.</citation>
    <PMID>23690844</PMID>
  </reference>
  <results_reference>
    <citation>Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020 May 12;323(18):1824-1836. doi: 10.1001/jama.2020.6019.</citation>
    <PMID>32282022</PMID>
  </results_reference>
  <results_reference>
    <citation>Maruta H, He H. PAK1-blockers: Potential Therapeutics against COVID-19. Med Drug Discov. 2020 Jun;6:100039. doi: 10.1016/j.medidd.2020.100039. Epub 2020 Apr 19.</citation>
    <PMID>32313880</PMID>
  </results_reference>
  <results_reference>
    <citation>Serkedjieva J, Manolova N, Bankova V. Anti-influenza virus effect of some propolis constituents and their analogues (esters of substituted cinnamic acids). J Nat Prod. 1992 Mar;55(3):294-302. doi: 10.1021/np50081a003.</citation>
    <PMID>1593279</PMID>
  </results_reference>
  <results_reference>
    <citation>Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.</citation>
    <PMID>32142651</PMID>
  </results_reference>
  <results_reference>
    <citation>Machado JL, Assuncao AK, da Silva MC, Dos Reis AS, Costa GC, Arruda Dde S, Rocha BA, Vaz MM, Paes AM, Guerra RN, Berretta AA, do Nascimento FR. Brazilian green propolis: anti-inflammatory property by an immunomodulatory activity. Evid Based Complement Alternat Med. 2012;2012:157652. doi: 10.1155/2012/157652. Epub 2012 Dec 19.</citation>
    <PMID>23320022</PMID>
  </results_reference>
  <results_reference>
    <citation>Mani JS, Johnson JB, Steel JC, Broszczak DA, Neilsen PM, Walsh KB, Naiker M. Natural product-derived phytochemicals as potential agents against coronaviruses: A review. Virus Res. 2020 Jul 15;284:197989. doi: 10.1016/j.virusres.2020.197989. Epub 2020 Apr 30.</citation>
    <PMID>32360300</PMID>
  </results_reference>
  <results_reference>
    <citation>Silveira MAD, Teles F, Berretta AA, Sanches TR, Rodrigues CE, Seguro AC, Andrade L. Effects of Brazilian green propolis on proteinuria and renal function in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled trial. BMC Nephrol. 2019 Apr 25;20(1):140. doi: 10.1186/s12882-019-1337-7.</citation>
    <PMID>31023272</PMID>
  </results_reference>
  <results_reference>
    <citation>Cusinato DAC, Martinez EZ, Cintra MTC, Filgueira GCO, Berretta AA, Lanchote VL, Coelho EB. Evaluation of potential herbal-drug interactions of a standardized propolis extract (EPP-AF(R)) using an in vivo cocktail approach. J Ethnopharmacol. 2019 Dec 5;245:112174. doi: 10.1016/j.jep.2019.112174. Epub 2019 Aug 20.</citation>
    <PMID>31442620</PMID>
  </results_reference>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>July 12, 2020</study_first_submitted>
  <study_first_submitted_qc>July 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 21, 2020</study_first_posted>
  <last_update_submitted>September 28, 2020</last_update_submitted>
  <last_update_submitted_qc>September 28, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 30, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>D'Or Institute for Research and Education</investigator_affiliation>
    <investigator_full_name>Marcelo Silveira</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Propolis</keyword>
  <keyword>Covid19</keyword>
  <keyword>SARS-CoV-2</keyword>
  <keyword>Anti-inflammatory</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>Propolis</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04480593
org study id: 31099320.6.0000.0048
nct id: NCT04480593
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The COVID-19 pandemic is of grave concern due its impact on human health and on the economy.
      Propolis, a natural resin produced by bees from plant materials, has anti-inflammatory,
      immunomodulatory, anti-oxidant properties, and various aspects of the SARS-CoV-2 infection
      mechanism are potential targets for propolis compounds. Propolis components have inhibitory
      effects on the ACE2, TMPRSS2 and PAK1 signaling pathways; in addition, antiviral activity has
      been proven in vitro and in vivo. This is a pilot randomized study that aims to assess the
      impact of using Brazilian green propolis extract against the deleterious effects of the new
      coronavirus.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: three parallel groups randomly assigned
primary purpose: Treatment
masking: Single (Outcomes Assessor)
masking description: The individual who evaluates the results of interest to the study will not have access to the study steps before the analysis.
measure: Composite clinical outcome with oxygen therapy dependency time or hospitalization time
time frame: 1-28 days
description: Composite clinical outcome with oxygen therapy dependency time (in days) or hospitalization time (in days) after randomization.
measure: Percentage of participants with adverse events during the use of propolis
time frame: 1-28 days
description: We will evaluate the presence or absence of symptoms related to the use of propolis through a questionnaire.
measure: Rate and severity of acute kidney injury during the study
time frame: 1-28 days
description: Assess the degree of acute kidney injury according to KDIGO (through serum creatinine or urine output).
measure: Renal replacement therapy.
time frame: 1-28 days
description: Assess need or not for renal replacement therapy.
measure: Rate of need for vasopressor use
time frame: 1-28 days
description: Describe the time needed for vasopressors in days after randomization
measure: Need for intensive care unit (ICU)
time frame: 1-28 days
description: Assess length of stay in the ICU after randomization in days
measure: Intensive care unit (ICU) readmission
time frame: 1-28 days
description: Rate of readmission to the ICU after randomization
measure: Invasive oxygenation time
time frame: 1-28 days
description: Assess the need for mechanical ventilation in days after randomization.
measure: Variation of plasma c-reactive protein
time frame: 1-7 days
description: Evaluate the variation in serum levels of c-reactive protein over the 7 days after randomization
arm group label: Control
arm group type: Active Comparator
description: standard care.
arm group label: EPP-AF 400mg/day
arm group type: Experimental
description: Green propolis extract (EPP-AF) at a dose of 400mg / day in addition to the standard treatment.
arm group label: EPP-AF 800mg/day
arm group type: Experimental
description: Green propolis extract (EPP-AF) at a dose of 800mg / day in addition to the standard treatment.
intervention type: Drug
intervention name: Brazilian Green Propolis Extract (EPP-AF)
description: Green propolis extract (EPP-AF) administered orally or via nasoenteral tube.
arm group label: EPP-AF 400mg/day
arm group label: EPP-AF 800mg/day
other name: Standard care
intervention type: Other
intervention name: Standard care
description: Standard treatment includes, as needed, supplemental oxygen (non-invasive and invasive), antibiotics or antivirals, corticosteroids, vasopressor support, renal replacement therapy and extracorporeal membrane oxygenation (ECMO).
arm group label: Control
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Marcelo Silveira, MD, PhD
role: Principal Investigator
affiliation: D'Or Institute for Research and Education (IDOR)
facility: 
country: Brazil
citation: Hori JI, Zamboni DS, Carrao DB, Goldman GH, Berretta AA. The Inhibition of Inflammasome by Brazilian Propolis (EPP-AF). Evid Based Complement Alternat Med. 2013;2013:418508. doi: 10.1155/2013/418508. Epub 2013 Apr 16.
PMID: 23690844
citation: Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020 May 12;323(18):1824-1836. doi: 10.1001/jama.2020.6019.
PMID: 32282022
citation: Maruta H, He H. PAK1-blockers: Potential Therapeutics against COVID-19. Med Drug Discov. 2020 Jun;6:100039. doi: 10.1016/j.medidd.2020.100039. Epub 2020 Apr 19.
PMID: 32313880
citation: Serkedjieva J, Manolova N, Bankova V. Anti-influenza virus effect of some propolis constituents and their analogues (esters of substituted cinnamic acids). J Nat Prod. 1992 Mar;55(3):294-302. doi: 10.1021/np50081a003.
PMID: 1593279
citation: Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.
PMID: 32142651
citation: Machado JL, Assuncao AK, da Silva MC, Dos Reis AS, Costa GC, Arruda Dde S, Rocha BA, Vaz MM, Paes AM, Guerra RN, Berretta AA, do Nascimento FR. Brazilian green propolis: anti-inflammatory property by an immunomodulatory activity. Evid Based Complement Alternat Med. 2012;2012:157652. doi: 10.1155/2012/157652. Epub 2012 Dec 19.
PMID: 23320022
citation: Mani JS, Johnson JB, Steel JC, Broszczak DA, Neilsen PM, Walsh KB, Naiker M. Natural product-derived phytochemicals as potential agents against coronaviruses: A review. Virus Res. 2020 Jul 15;284:197989. doi: 10.1016/j.virusres.2020.197989. Epub 2020 Apr 30.
PMID: 32360300
citation: Silveira MAD, Teles F, Berretta AA, Sanches TR, Rodrigues CE, Seguro AC, Andrade L. Effects of Brazilian green propolis on proteinuria and renal function in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled trial. BMC Nephrol. 2019 Apr 25;20(1):140. doi: 10.1186/s12882-019-1337-7.
PMID: 31023272
citation: Cusinato DAC, Martinez EZ, Cintra MTC, Filgueira GCO, Berretta AA, Lanchote VL, Coelho EB. Evaluation of potential herbal-drug interactions of a standardized propolis extract (EPP-AF(R)) using an in vivo cocktail approach. J Ethnopharmacol. 2019 Dec 5;245:112174. doi: 10.1016/j.jep.2019.112174. Epub 2019 Aug 20.
PMID: 31442620
responsible party type: Principal Investigator
investigator affiliation: D'Or Institute for Research and Education
investigator full name: Marcelo Silveira
investigator title: Principal Investigator
mesh term: COVID-19
mesh term: Propolis
sharing ipd: Undecided