Procedures
Trial randomization was stratified based on clinical parameters related to the need for supplemental oxygen as follows: no use of oxygen, catheter ≤ 5 L/min, nasal catheter > 5 L/min or non-rebreather mask, continuous positive airway pressure (CPAP), or high-flow nasal cannula. Randomization was carried out from permuted blocks listed on the REDCap platform. The permuted block (four patients per block) randomization sequence, including stratification, was prepared by a statistician not involved in the trial. To minimize bias, design and allocation concealment were performed by a trained professional who is not connected to the study.Eligible patients were randomly assigned at a 1:1 ratio to receive Propomax® capsules produced with dehydrated standardized Brazilian green propolis extract, EPP-AF®, for 10 days at 900 mg/day (three 100-mg capsules, three times per day) or placebo (three capsules, three times per day). Hard gelatin capsules with magnesium stearate (1%), silicon dioxide (0.1%), and microcrystalline cellulose qsp (320 mg) were prepared as placebo formulations. Placebo packages had the same labelling of the active product. They were also opaque and had a security system to prevent improper opening. All capsules had the same organoleptic characteristics, making propolis and placebo capsules indistinguishable. The study was double-blinded, so neither the patients, the healthcare providers nor the principal investigator knew to which group the patients were allocated.Both groups received standard-of-care treatment that could include supplemental oxygen, noninvasive or invasive ventilation, corticosteroids, antibiotics and/or antivirals, vasopressor support, renal replacement therapy, intra-aortic balloon pump (IABP), and extracorporeal membrane oxygenation (ECMO), as needed. Supportive treatment was freely selected at the sole discretion of assisting clinical teams in accordance with individual needs of patients, without any kind of interference from researchers.The propolis extract used in this study was prepared from a single batch to guarantee uniformity. High performance liquid chromatography (HPLC) was performed in the propolis batch before the manufacturing of capsules. The standardized Brazilian green propolis extract, which is composed mainly of green propolis produced in southeastern Brazil and processed with specific extraction and drying processes, was selected for this study due to its batch-to-batch reproducibilityPatients were evaluated daily during hospitalization, from days 1 to 28. Patients who were discharged in less than 10 days have completed treatment at home and were followed up by telephone as a means to obtain relevant safety data on the study medication.