Participants

On presentation to one of the trial outpatient care clinics, local investigators screened potential participants to identify those who met the eligibility criteria. The key inclusion criteria were patients older than 18 years, presenting to an outpatient care setting with an acute clinical condition consistent with COVID-19 and symptoms beginning within 7 days of the screening date, or positive rapid test for SARS-CoV-2 antigen done at the time of screening or patient with positive SARS-CoV-2 diagnostic test within 7 days of symptom onset. Eligible patients also had at least one additional criterion for high risk: diabetes; systemic arterial hypertension requiring at least one oral medication for treatment; known cardiovascular disease (heart failure, congenital heart disease, valve disease, coronary artery disease, cardiomyopathies being treated, clinically manifested heart disease and with clinical repercussion); symptomatic lung disease or treatment for such (emphysema, fibrosing diseases); symptomatic asthma requiring chronic use of agents to control symptoms; smoking; obesity, defined as body-mass index greater than 30 kg/m² (weight and height information provided by the patient); having had a transplant; stage IV chronic kidney disease or on dialysis; immunosuppression or use of corticosteroid therapy (equivalent to at least 10 mg of prednisone per day) or immunosuppressive therapy; history of cancer in the last 0·5 years or undergoing current cancer treatment or aged 50 years or older; and unvaccinated status.

Patients who met any of the following key criteria were excluded from the trial: diagnostic examination for SARS-CoV-2 negative associated with acute flu-like symptoms (patients with negative test taken early and becoming positive a few days later were eligible, if they were less than 7 days after the onset of flu-like symptoms); acute respiratory condition compatible with COVID-19 treated in primary care and previously requiring hospitalisation; acute respiratory condition owing to other causes; received vaccination for SARS-CoV-2; dyspnoea secondary to other acute and chronic respiratory causes or infections (eg, decompensated chronic obstructive pulmonary disease, acute bronchitis, pneumonia, primary pulmonary arterial hypertension); current use of SSRIs (use of other serotonin reuptake inhibitors were not excluded); uncontrolled psychiatric disorders or suicidal ideation; inability or unwillingness to follow research guidelines and procedures. A full list of exclusion criteria is provided in the trial protocol.

If a patient met the aforementioned eligibility criteria, study personnel obtained written informed consent. After obtaining informed consent a rapid antigen test for COVID-19 (Panbio, Abbott Laboratories Jena, Jena, Germany) and a pregnancy test for women of childbearing age were done. If the COVID-19 test was negative or if the pregnancy test was positive, the participant was not included in the trial. After informed consent, study personnel collected the following data before randomisation: demographics, medical history, concomitant medications, comorbidities, exposure to index case information, WHO clinical worsening scale, and the patient-reported outcomes measurement information (PROMIS) Global Health Scale.

 Randomisation and masking

Participants were randomly assigned by means of a centralised core randomisation process handled by an independent unmasked pharmacist who was not aware of any protocol-related procedures and contracted specifically for this process. Sites requested randomisation by text message to the pharmacist at the coordinating centre. This maintained concealment of allocation. Patients were randomly assigned (1:1) by means of a block randomisation procedure for each participating site, stratified by age (<50 years or ≥50 years). The trial team, site staff, and patients were masked to treatment allocation. The active drugs and the placebo pills were packaged in identically shaped bottles and labelled with alphabet letters corresponding to the active group or placebo group. Only the third-party pharmacist responsible for releasing the randomisation was aware of which letter was associated with which drug or placebo. As this is a multiarm trial and all active interventions have a matching inert placebo, the matching placebo represents the proportion of the control group for the number of arms in the trial at any given time.

 Procedures

All participants received usual standard care for COVID-19 provided by health-care professionals at public health facilities. Patients were randomly assigned to fluvoxamine (Luvox, Abbott) at a dose of 100 mg twice a day for 10 days or corresponding placebo starting directly after randomisation (day 1). Research personnel provided participants with a welcome video, which gave information on the trial, study drug, adverse events, and follow-up procedures. Clinicians providing usual care in public health facilities typically focus on the management of symptoms and provide antipyretics or recommend antibiotics only if they suspect bacterial pneumonia.

Study personnel collected outcome data on days 1, 2, 3, 4, 5, 7, 10, 14, and 28 in person or via telephone contact or social media applications using video-teleconferencing. We collected outcome data irrespective of whether participants took study medication. In case of adverse events, unscheduled visits (during the treatment period) outside of clinical care could occur at any time.

Considering the transmissible characteristics of SARS-CoV-2 and the isolation recommendations of positive individuals, we collected few vital sign data. Cardiac safety was assessed by means of a six-lead electrocardiogram (Kardiamobile, Mountain View, CA, USA) at the baseline visit. The digital recordings were deidentified and transferred to a central facility (Cardresearch, Belo Horizonte, Brazil) for reading. Oxygen status was assessed by means of a pulse oximeter for non-invasive arterial oxygen saturation and pulse (Jumper Medical Equipment, Shenzhen, China), and temperature by means of a standard digital oral thermometer administered by research personnel. Mid-turbinate nasal swab kits and sterile recipient storage were provided for collection of nasopharyngeal swab or sputum–saliva. Nasal swabs for PCR testing was completed on the first quarter of participants enrolled in the trial on days 3 and 7. Viral clearance was assessed to establish whether active drugs showed any antiviral effects.

All serious and non-serious adverse events were reported to study personnel as per local regulatory requirements. Reportable adverse events included serious adverse events, adverse events resulting in study medication discontinuation, and adverse events assessed as possibly related to study medication.

 Outcomes

Our primary outcome was a composite endpoint of medical admission to a hospital setting due to COVID-19-related illness defined as COVID-19 emergency setting visits with participants remaining under observation for more than 6 h or referral to further hospitalisation due to the progression of COVID-19 within 28 days of randomisation. Because many patients who would ordinarily have been hospitalised were prevented from admission due to hospital over-capacity during peak waves, the composite endpoint addresses both hospitalisation and a proxy for hospitalisation, retention in a COVID-19 emergency hospital setting. This region of Brazil implemented hospital-like services in the emergency settings with 50–80 bed units providing services including multiday stays, oxygenation, and mechanical ventilation. The 6 h threshold referred only to periods of time recommended for observation by a clinician and does not include waiting times. Key secondary outcomes include viral clearance, time to clinical improvement, number of days with respiratory symptoms, time to hospitalisation for any cause or due to COVID-19 progression, all-cause mortality and time to death from any causes, WHO clinical worsening scale score, days in hospital and on ventilator and adverse events, adverse reactions to the study medications, and the proportion of participants who are non-adherent with the study drugs. All secondary outcomes were assessed up to 28 days following randomisation.

 Statistical analysis