Trial design: randomised, double-blind, placebo-controlled, remote design

Type of publication: journal publication

Setting: non-hospitalised outpatients

Recruitment dates: April to August 2020

Country: USA

Language: English

Number of centres: 2

Trial registration number: NCT04342663

Date of trial registration: 8 April 2020

Number of participants (randomised/analysed): 181/152 (115 completed 15-day assessment)

Age (median, years): fluvoxamine group: 46 (range 20 to 75); control group: 45 (range 21 to 69)

Gender (males, n (%)): fluvoxamine group: 24 (30); control group: 19 (26)

Severity of condition according to study definition: non-hospitalised adults with confirmed COVID-19

Comorbidities: asthma, hypertension, diabetes, high cholesterol, hyperthyroidism, anxiety, osteoarthritis or rheumatoid arthritis, depression

Virus detection performed at baseline (RT-PCR positive at baseline, %): 100%

Inclusion criteria

• outpatients (age 18 and older)

• proven SARS-CoV-2 positive (per lab or physician report)

• currently symptomatic, with at least 1 of the following symptoms: fever, cough, myalgia, mild dyspnoea, diarrhoea, vomiting, anosmia (inability to smell), ageusia (inability to taste), sore throat

Exclusion criteria

• illness severe enough to require hospitalisation or already meeting study’s primary endpoint for clinical worsening

• unstable medical comorbidities (including, but not limited to, severe underlying lung disease)

• decompensated cirrhosis

• congestive heart failure (stage 3 or 4)

• immunocompromised (solid organ transplant, BMT, AIDS, on biologics and/or high dose steroids (> 20 mg prednisone per day))

• currently taking chloroquine, hydroxychloroquine, azithromycin or colchicine.

Details of interventions for relevant arms

• type and dose: fluvoxamine 50 mg (initial dose), then 100 mg (2 times daily, for 2 days as tolerated), then 100 mg (3 times daily, through day 15)

• route of administration: oral

Treatment details of a control group (e.g. type, dose, route of administration)

• placebo (same dose and administration as intervention)

Concomitant medications: all patients received standard care (which was not further defined)

Duration of follow-up: 15 days (after randomisation)

Treatment cross-overs: none

Primary study outcome

• clinical deterioration defined as:

  • presence of dyspnoea or hospitalisation (for dyspnoea) or pneumonia; and

  • decrease in oxygen saturation (< 92%) on room air or supplemental oxygen requirement to maintain oxygen saturation of 92% or greater.

Relevant review outcomes reported

• mortality (all cause)

• serious adverse events

• adverse events (any grade)

• need for non-invasive mechanical ventilation or high flow (ventilator support)

• need for hospitalisation with need for oxygen therapy (by masks or nasal prongs)

Additional study outcomes reported

• clinical deterioration/worsening of clinical status defined by a 7-points scale at day 15:

  • 0 = none, 1 = shortness of breath and oxygen saturation < 92% (no supplemental oxygen), 2 = shortness of breath and oxygen saturation < 92% + supplemental oxygen, 3 = oxygen saturation < 92% + supplemental oxygen and hospitalisation related to dyspnoea or hypoxia, 4 = oxygen saturation < 92% + supplemental oxygen and hospitalisations related to dyspnoea or hypoxia + ventilator support (< 3 days), 5 = oxygen saturation < 92% + supplemental oxygen and hospitalisation related to dyspnoea or hypoxia + ventilator support ( ≥ 3 days), 6 = death

• Post-trial observation events at day 30 (emergency department visit, hospitalisation, or both)

Date of Publication: 12 November 2020

Assessment: remotely

Sponsorship source: Taylor Family Institute for Innovative Psychiatric Treatment and Center for Brain Research in Mood Disorders(Washington University), COVID-19 Early Treatment Fund, Bantly Foundation, and the National Institutes of Health

Conflicts of interest

• Dr Lenze reported receiving grants from the Patient-Centered Outcomes Research Institute, Takeda, Alkermes, Janssen, Acadia, and the Barnes Jewish Hospital Foundation; and receiving consulting fees from Janssen and Jazz Pharmaceuticals;

• Dr Zorumski reported being on the scientific advisory board for and having stock and stock options with Sage Therapeutics, and receiving personal fees from CME Outfitters and JAMA Psychiatry;

• Dr Nicol reported receiving grants from Alkermes, the Center for Brain Research in Mood Disorders, the Center for Diabetes Translational Research, the Institute for Public Health, the McDonnell Center for Neuroscience, and the Barnes Jewish Hospital Foundation; and serving as a consultant to Sunovion, Alkermes, and Elira;

• Mr Miller reported receiving research funding from the Patient-Centered Outcomes Research Institute;

• Dr Avidan reported receiving grants from the COVID-19 Therapeutics Accelerator.

Ethics approval: approved by the institutional review board at Washington University in St Louis

Correspondence with the study authors: request sent (see Table 1)

Trial design: randomised, double-blind placebo-controlled, partly remote design (follow-up was either in person or via telephone contact or social media applications using video-teleconferencing)

Type of publication: journal publication

Setting: non-hospitalised, outpatients

Recruitment dates: January to August 2021

Country: Brazil

Language: English

Number of centres: 11

Trial registration number: NCT04727424

Date of trial registration: 2 June 2020

Number of participants (randomised/analysed): 1497/1497

Age (median, years): fluvoxamine group: 50 (interquartile range 39 to 56); control group: 49 (interquartile range 38 to 56)

Gender (males, n (%)): fluvoxamine group: 332 (45); control group: 303 (40)

Severity of condition according to study definition: confirmed RT-PCR positive for SARS-CoV-2 with a known risk factor for progression to severe disease

Comorbidities: chronic cardiac disease, hypertension, chronic pulmonary disease, asthma, chronic kidney disease, rheumatological disorder, chronic neurological disorder, diabetes (type 1 and 2), autoimmune disease

Virus detection performed at baseline (RT-PCR positive at baseline (%)): rapid test for SARS-CoV-2 antigen (all included participants) after obtaining informed consent; the concordance of COVID-19 positive rapid tests with RT-PCR was evaluated on the group of participants with PCR evaluations and a concordance rate of greater than 99% on both tests collected at baseline was found

Inclusion criteria

• outpatients (age 18 and older) with ≥ 1 enhancement criterion: age > 50 years, diabetes mellitus, systemic arterial hypertension, cardiovascular diseases, symptomatic lung disease, symptomatic asthma patients, obesity, transplanted patients, patient with stage IV chronic kidney disease or on dialysis, immunosuppressed patients, patients undergoing treatment of current cancer, chronic renal disease or end-stage renal disease

Exclusion criteria

• flu-like symptom onset (8 days or more);

• > 14 days of vaccination for SARS-CoV-2;

• acute respiratory conditions;

• dyspnoea due to other causes or infections;

• people with clinical evidence of moderate disease and/or hospitalisation indication;

• people using serotonin reception inhibitors;

• use of antiretroviral agents;

• people with severe psychiatric disorders;

• history of severe ventricular cardiac arrhythmia, symptomatic orthostatic hypotension, postural orthostatic tachycardia syndrome, myocardial infarction, cardiovascular intervention, moderate to severe mitral or aortic stenosis.

Details of intervention for relevant arms

• type and dose: fluvoxamine 100 mg (2 times daily, for 10 days)

• route of administration: oral

Treatment details of control group (e.g. type, dose, route of administration): placebo (same dose and administration as intervention)

Concomitant medications: standard care for COVID-19 provided by healthcare professionals (with a focus on symptom management, antipyretics or antibiotics only as needed); 86/1497 (6%) reported ≥ 1 dose of a COVID-19 vaccine at the end of the trial.

Duration of follow up: 28 days (after randomisation)

Treatment cross‐overs: none

Primary study outcome

• admission to hospital defined as

  • COVID-19 emergency setting visits (participants remaining under observation for > 6 h); or

  • referral to further hospitalisation due to the progression of COVID-19 (within 28 days).

Relevant review outcomes reported

• all-cause mortality (at day 28)

• admission to hospital or death (before hospital submission)

• symptom resolution (mentioned in the study, but no numerical data reported; therefore not further considered in our review see also 'Notes' below)

• serious adverse events

• adverse events (any grade)

• need for mechanical ventilation

• viral clearance (assessed with RT‐PCR for SARS‐CoV‐2) at day 7

Additional study outcomes reported

• respiratory symptoms (number of days)

• time to hospitalisation (for any cause or due to COVID-19 progression)

• time in hospital (number of days)

• mechanical ventilator (number of days)

• adherence (number of participants)

Date of Publication: 28 October 2021

Sponsorship/funding source: FastGrants and the Rainwater Foundation

Conflicts of interest

• Prof. Mills, Dr Glushchenko, Dr. Sprague, have been employed by Platform Life Sciences

• Prof. Mills, Dr Harari and Mrs. Ruton have been employed by Cytel

• Mr Rayner has been employed by Certara;

• Dr Reis has been employed by Cardresearch

• Mrs. Ribeiro Nogueira and Prof. Lenze are co-inventors on a patent application filed by Washington University for methods of treating COVID-19

• No other disclosures were reported.

Ethics approval: local and national ethics boards in Brazil (CONEP CAAE: 41174620.0.1001.5120, approval letter 5.501.284) and the Hamilton Integrated Research Ethics Board (HiREB, approval letter 13390) in Canada

Others: the trial was stopped on 5 August 2021 due to superiority.

Correspondence with the study authors: request sent (see Table 1).