Brazilian Green Propolis Extract (EPP-AF) as an Adjunct Treatment for Hospitalized COVID-19 Patients (BeeCovid2)

Overview

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) promotes challenging immune and inflammatory phenomena. Though various therapeutic possibilities have been tested against coronavirus disease 2019 (COVID-19), the most adequate treatment has not yet been established. Among candidate adjunct treatment options, propolis, produced by honey bees from bioactive plant exudates, has shown potential against viral targets and has demonstrated immunoregulatory properties.

Full Title of Study: “The Use of the Standardized Brazilian Green Propolis Extract (EPP-AF) as an Adjunct Treatment for Hospitalized COVID-19 Patients: A Randomized, Double-blind, Placebo-controlled Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: July 30, 2021

Detailed Description

To evaluate the efficacy and safety of oral propolis as an adjunct treatment for SARS-CoV-2 infection, we designed a randomized, double-blind, placebo-controlled trial (Bee-Covid2) (The Use of Brazilian Green Propolis Extract (EPP-AF®) in Patients Affected by COVID-19).

Interventions

  • Drug: Standardized Brazilian Green Propolis Extract
    • 900mg/day of Standardized Brazilian Green Propolis Extract for 10 days.
  • Drug: Placebo
    • 900mg/day of Placebo for 10 days.

Arms, Groups and Cohorts

  • Placebo Comparator: Placebo
    • Patients in the Placebo group will receive an identical number of capsules containing 900 mg / day of placebo (3 capsules of 100 mg each, divided into 3 daily doses); for 10 days.
  • Active Comparator: Propolis
    • Participants in the Propolis group will receive propolis EPP-AF at a dose of 900 mg / day (3 capsules of 100 mg each, divided into 3 daily doses); for 10 days.

Clinical Trial Outcome Measures

Primary Measures

  • Length of hospital stay
    • Time Frame: 1-28 days
    • Hospitalization time after randomization (in days)

Secondary Measures

  • Percentage of participants with adverse events during the use of propolis or placebo
    • Time Frame: 1-28 days
    • We will evaluate the presence or absence of symptoms related to the use of propolis or placebo.
  • Rate and severity of acute kidney injury during the study
    • Time Frame: 1-28 days
    • Assess the degree of acute kidney injury according to KDIGO.
  • Renal replacement therapy.
    • Time Frame: 1-28 days
    • Assess need or not for renal replacement therapy
  • Rate of need for vasopressor use.
    • Time Frame: 1-28 days
    • Describe the time needed for vasopressors in days after randomization.
  • Intensive care unit (ICU) readmission
    • Time Frame: 1-28 days
    • Rate of readmission to the ICU after randomization
  • Invasive oxygenation time
    • Time Frame: 1-28 days
    • Assess the need for mechanical ventilation in days after randomization.
  • Need for Intra-Aortic Balloon Pump
    • Time Frame: 1-28 days
    • Assess the need for Intra-Aortic Balloon Pump in days after randomization.
  • Need for Extracorporeal Oxygenation Membrane (ECMO)
    • Time Frame: 1-28 days
    • Assess the need for Extracorporeal Oxygenation Membrane in days after randomization.

Participating in This Clinical Trial

Inclusion Criteria

  • Older than 18 years; – Diagnosis of coronavirus infection confirmed by polymerase chain reaction – reverse transcriptase testing; – Symptoms started within 14 days of the randomization date Exclusion Criteria:

  • Pregnant or lactating women; – Known hypersensitivity to propolis; – Propolis use less than 30 days from the randomization date; – Active cancer; – Human immunodeficiency virus carriers; – Patients undergoing transplantation of solid organs or bone marrow or who were using immunosuppressive medications; – Bacterial infection at randomization, sepsis or septic shock related to bacterial infection at randomization; – Impossibility of using the medication orally or by nasoenteral tube; – Known hepatic failure or advanced heart failure (New York Heart Association [NYHA] class III or IV). – End Stage Renal Disease (ESRD).

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • D’Or Institute for Research and Education
  • Collaborator
    • Apis Flora Industrial e Comercial Ltda
  • Provider of Information About this Clinical Study
    • Principal Investigator: Marcelo Augusto Duarte Silveira, MD, PhD, Principal Investigator – D’Or Institute for Research and Education
  • Overall Official(s)
    • Marcelo Silveira, MD, PhD, Principal Investigator, D’Or Institute for Research and Education (IDOR)

References

Silveira MAD, Capcha JMC, Sanches TR, de Sousa Moreira R, Garnica MS, Shimizu MH, Berretta A, Teles F, Noronha IL, Andrade L. Green propolis extract attenuates acute kidney injury and lung injury in a rat model of sepsis. Sci Rep. 2021 Mar 15;11(1):5925. doi: 10.1038/s41598-021-85124-6.

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.

MAD Silveira, D De Jong, AA Berretta, et.al. Efficacy of propolis as an adjunct treatment for hospitalized COVID-19 patients: a randomized, controlled clinical trial. MedRxiv preprint doi: https://doi.org/10.1101/2021.01.08.20248932.

Berretta AA, Silveira MAD, Condor Capcha JM, De Jong D. Propolis and its potential against SARS-CoV-2 infection mechanisms and COVID-19 disease: Running title: Propolis against SARS-CoV-2 infection and COVID-19. Biomed Pharmacother. 2020 Nov;131:110622. doi: 10.1016/j.biopha.2020.110622. Epub 2020 Aug 17.

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.

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.

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.

Shimizu T, Hino A, Tsutsumi A, Park YK, Watanabe W, Kurokawa M. Anti-influenza virus activity of propolis in vitro and its efficacy against influenza infection in mice. Antivir Chem Chemother. 2008;19(1):7-13. doi: 10.1177/095632020801900102.

Ito J, Chang FR, Wang HK, Park YK, Ikegaki M, Kilgore N, Lee KH. Anti-AIDS agents. 48.(1) Anti-HIV activity of moronic acid derivatives and the new melliferone-related triterpenoid isolated from Brazilian propolis. J Nat Prod. 2001 Oct;64(10):1278-81. doi: 10.1021/np010211x.

Berretta AA, Nascimento AP, Bueno PC, Vaz MM, Marchetti JM. Propolis standardized extract (EPP-AF(R)), an innovative chemically and biologically reproducible pharmaceutical compound for treating wounds. Int J Biol Sci. 2012;8(4):512-21. doi: 10.7150/ijbs.3641. Epub 2012 Mar 21.

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