NCT04727424.

Study name	Repurposed approved therapies for outpatient treatment of patients with early‐onset COVID‐19 and mild symptoms
Methods	Trial design: quadruple‐blind RCT with 4 parallel arms, only 2 arms relevant; the third arm investigates fluvoxamine, the fourth arm investigates metformin Type of record: trial register entry Sample size: 2724 Setting: outpatient Country: Brazil Language: English Number of centres: 6 Study purpose (treatment, prevention): treatment Trial registration number: NCT04727424 Date of registration: 27 January 2021
Participants	Inclusion criteria Age > 18 years with the ability to provide free and informed consent Acute influenza‐like symptoms < 7 days At least 1 enhancement factor Age > 50 years Diabetes mellitus requiring oral medication or insulin Systemic arterial hypertension requiring at least 1 oral medication for blood pressure control Known cardiovascular diseases (heart failure, congenital heart disease, valvar heart valve disease, coronary artery disease, cardiomyopathies) Symptomatic lung disease (emphysema, chronic bronchitis) People with symptomatic asthma requiring chronic use of agents for control of symptoms Smoking Obesity, defined as body mass index > 30 kg /m2 bodyweight Received transplant Stage IV chronic kidney disease or receiving dialysis Immunosuppressed/using corticosteroid therapy (equivalent to prednisone ≥ 10 mg/day) or immunosuppressive therapy, or both) History of cancer in the last 5 years or undergoing treatment of a current cancer Chronic renal disease KDIGO (Kidney Disease Improving Global Outcomes) IV or end‐stage renal disease on chronic ambulatory renal replacement therapy Positive rapid test for SARS‐CoV‐2 antigen performed on occasion of the screening or with a positive SARS‐CoV‐2 diagnostic test within 7 days of the onset of symptoms. Willingness to use the proposed investigative treatment and follow the protocol‐related procedures foreseen in the research Exclusion criteria Negative SARS‐CoV‐2 test Influenza‐like symptom onset ≥ 8 days People with COVID‐19 being referred for hospitalization History of SARS‐CoV‐2 vaccine shot Acute respiratory conditions due to other causes Dyspnoea secondary to other acute and chronic respiratory causes or infections (e.g. decompensated COPD, acute bronchitis, pneumonia, primary pulmonary arterial hypertension) Acute influenza‐like condition presenting with ≥ 1 of the criteria below: Respiratory rate > 28 breaths/minute SaO2 < 90% or < 93% in nasal oxygen therapy at 10 L/minute PaO2/FIO2 < 300 mmHg Using serotonin reception inhibitors (donepezil, sertraline) Use of the following medications in the last 14 days Monoamine oxide inhibitors: phenelzine, tranylcypromine, selegiline, isocarboxazide, moclobemide Use of iodinated contrasts during start of treatment through D14 Use of antiretroviral agents Severe psychiatric disorders or major uncontrolled depression or controlled with any of the prohibited drugs above Pregnant or breastfeeding women History of severe ventricular cardiac arrhythmia (ventricular tachycardia, people with ventricular fibrillation recovered) or long QT syndrome History of diabetic ketoacidosis or clinical condition that maintains persistent acidosis Surgical procedure or use of contrast designed to occur during treatment or up to 4 days after the last dose of the study medication Current daily or uncontrolled alcoholism History of seizures in the last month or uncontrolled medical condition Clinical history of liver cirrhosis or Child‐Pugh C classification Known severe degenerative neurological diseases or serious mental disorders Inability of the patient or representative to give consent or adhere to the procedures proposed in the protocol Known hypersensitivity or intolerance to fluvoxamine, ivermectin or metformin Inability to take oral or sublingual medications Inability to follow protocol‐related procedures
Interventions	Details of intervention for relevant arms Type and dose: ivermectin 6 mg, once daily for 3 days Route of administration: oral Treatment details of control group Placebo Concomitant therapy: NA
Outcomes	Primary study outcome Evaluation of emergency department visits and observation unit stay > 6 hours Hospitalization due to COVID‐19 progression within 28 days Relevant review outcomes planned Adverse events at 28 days Additional study outcomes Change in viral load at 3 and 7 days Time to > 50% clinical symptoms changes (self‐reported) within 28 days Number of days with respiratory symptoms since randomization within 28 days All‐cause and COVID‐19 related hospitalizations within 28 days All‐cause mortality at 28 days Cardiovascular death, respiratory death at 28 days Health and functioning after COVID‐19 disease at 14 and 28 days WHO scale for clinical improvement at 28 days Adherence of study drug within 10 days
Starting date	19 January 2021 CARDRESEARCH – Cardiologia Assistencial e de Pesquisa Belo Horizonte, Minas Gerais 30150240 Brazil
Contact information	Gilmar Reis, MD, PhD
Notes	Recruitment status: recruiting Prospective completion date: 1 March 2022 Date last update posted: 24 March 2021 Sponsor/funding: CARDRESEARCH – Cardiologia Assistencial e de Pesquisa