The efficacy and safety of fluvoxamine in patients with COVID-19: A systematic review and meta-analysis from randomized controlled trials.

BACKGROUND: Recently, several randomized controlled trials (RCTs) of fluvoxamine have been successfully conducted for the treatment of patients with coronavirus disease 2019 (COVID-19). This systematic review and meta-analysis was to evaluate the efficacy and safety of fluvoxamine in patients with COVID-19. METHODS: MEDLINE, EMBASE, Cochrane Library and clinicaltrials.gov were searched for RCTs which were performed to evaluate fluvoxamine and placebo up to January 31, 2024. Review Manager 5.3 was used to perform meta-analysis. The risk ratio (RR) and mean difference (MD) was analyzed and calculated with a random effect model. RESULTS: We pooled 4,711 participants from six RCTs (2,382 in the fluvoxamine group and 2,329 in the placebo group). Compared to the placebo group, the fluvoxamine group had a significantly lower rate of clinical deterioration (RR, 0.73; P = 0.004; 95% CI, 0.59 to 0.90; I2 = 0%) and hospitalization (RR, 0.76; P = 0.04; 95% CI, 0.59 to 0.99; I2 = 0%). In the meantime, compared with the placebo group, fluvoxamine group did not show any higher risk of AEs (P = 0.13 and 0.91, respectively) in safety outcomes analysis. The subgroup analysis showed that fluvoxamine treatment performed more than 200 mg daily appears to be more effective than those performed less than 200 mg daily in reducing clinical deterioration and hospitalization risks, while not exhibiting higher AE and SAE risks than placebo group. CONCLUSION: Fluvoxamine for patients with COVID-19, especially those who take 200 mg or more daily, is superior to the placebo group in reducing clinical deterioration and hospitalization, and did not show any higher risk of AEs and SAEs in safety concerns, which might be a promising intervention for COVID-19.

Evaluating fluvoxamine for the outpatient treatment of COVID-19: A systematic review and meta-analysis.

This systematic review and meta-analysis of randomised controlled trials (RCTs) aimed to evaluate the efficacy, safety, and tolerability of fluvoxamine for the outpatient management of COVID-19. We conducted this review in accordance with the PRISMA 2020 guidelines. Literature searches were conducted in MEDLINE, EMBASE, International Pharmaceutical Abstracts, CINAHL, Web of Science, and CENTRAL up to 14 September 2023. Outcomes included incidence of hospitalisation, healthcare utilization (emergency room visits and/or hospitalisation), mortality, supplemental oxygen and mechanical ventilation requirements, serious adverse events (SAEs) and non-adherence. Fluvoxamine 100 mg twice a day was associated with reductions in the risk of hospitalisation (risk ratio [RR] 0.75, 95% confidence interval [CI] 0.58-0.97; I 2  = 0%) and reductions in the risk of healthcare utilization (RR 0.68, 95% CI 0.53-0.86; I 2  = 0%). While no increased SAEs were observed, fluvoxamine 100 mg twice a day was associated with higher treatment non-adherence compared to placebo (RR 1.61, 95% CI 1.22-2.14; I 2  = 53%). In subgroup analyses, fluvoxamine reduced healthcare utilization in outpatients with BMI ≥30 kg/m2 , but not in those with lower BMIs. While fluvoxamine offers potential benefits in reducing healthcare utilization, its efficacy may be most pronounced in high-risk patient populations. The observed non-adherence rates highlight the need for better patient education and counselling. Future investigations should reassess trial endpoints to include outcomes relating to post-COVID sequelaes. Registration: This review was prospectively registered on PROSPERO (CRD42023463829).

In outpatients with mild to moderate COVID-19, low-dose fluvoxamine did not reduce time to sustained recovery.

SOURCE CITATION: McCarthy MW, Naggie S, Boulware DR, et al. Effect of fluvoxamine vs placebo on time to sustained recovery in outpatients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2023;329:296-305. 36633838.

Efficacy and Safety of Fluvoxamine as Outpatient Treatment for Patients With Covid-19: A Systematic Review and Meta-analysis of Clinical Trials.

BACKGROUND: Fluvoxamine may be beneficial for the management of coronavirus disease 2019 (Covid-19) because of its effect on the sigma-1 receptor. Available evidence from randomized clinical trials (RCTs) has shown conflicting results. OBJECTIVE: This study sought to analyze the efficacy and safety of fluvoxamine as an outpatient treatment for Covid-19. METHODS: Using specific keywords, we comprehensively go through the potential articles on PubMed, Scopus, Europe PMC, and ClinicalTrials.gov sources until February 1, 2023. We collected all published clinical trials on fluvoxamine and Covid-19. We were using Review Manager 5.4 to conduct statistical analysis. RESULTS: We include a total of 6 trials. Our pooled analysis revealed that fluvoxamine did not offer any significant benefit when compared with placebo in reducing the risk of clinical deterioration (risk ratio [RR] = 0.83; 95% CI: 0.65-1.06, P = 0.14, I2 = 29%), and hospitalization (RR = 0.80; 95% CI: 0.62-1.04, P = 0.09, I2 = 0%) of Covid-19 outpatients. The serious adverse events did not differ significantly between the 2 groups. CONCLUSIONS AND RELEVANCE: This study indicates that although safe, fluvoxamine was not effective for outpatient treatment of Covid-19. Until more evidence can be obtained from larger RCTs, our study did not encourage the use of fluvoxamine as routine management for patients with Covid-19.

Trial Sequential Analysis and Updated Meta-Analysis of Fluvoxamine on Clinical Deterioration in Adult Patients with Symptomatic COVID-19 Infection.

Preliminary meta-analyses suggested that fluvoxamine was effective in treating COVID-19 infection. However, the reliability of this evidence has not yet been examined. MEDLINE, CENTRAL, EMBASE, PsycINFO, and ClinicalTrials.gov were searched to identify any randomized controlled trials (RCTs) from the inception of the databases to 5 February 2023. We used trial sequential analysis (TSA) to examine the reliability of the current existing evidence on the benefits of fluvoxamine on COVID-19 infection. The primary outcome was clinical deterioration, as defined in the original study (reported as odds ratio (OR), with 95% confidence intervals), and the secondary outcome was hospitalization. In the TSA, we used the relative risk reduction thresholds of 10, 20, and 30%. The updated meta-analysis of the five RCTs showed that fluvoxamine was not associated with lower odds of clinical deterioration when compared with a placebo (OR: 0.81; 0.59-1.11). The effect of fluvoxamine lay within the futility boundary (i.e., lack of effect) when using a 30% relative risk reduction threshold. The effect estimates lay between the superiority and futility boundary using the 10% and 20% threshold, and the required size of information was not reached for these two thresholds. The effect of fluvoxamine on the odds of hospitalization was not statistically significant (0.76; 0.56-1.03). In conclusion, there is no reliable evidence that fluvoxamine, when compared to a placebo, reduces the relative risk of clinical deterioration among adult patients with COVID-19 infection by 30%, and a relative risk reduction of 20% or 10% is still uncertain. The role of fluvoxamine as a COVID-19 treatment cannot be justified.

Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

Importance: The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear. Objective: To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US. Interventions: Participants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28. Results: Among 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Rhabdomyolysis in a male adolescent associated with monotherapy of fluvoxamine.

Rhabdomyolysis is a syndrome resulting from striated muscular breakdown, which may occur due to drug therapy with agents such as selective serotonin reuptake inhibitors (SSRIs). Although studies have shown that fluvoxamine can rarely cause myalgia, there are no reported cases of rhabdomyolysis due to fluvoxamine monotherapy. Here we describe a case of rhabdomyolysis due to fluvoxamine monotherapy for obsessive-compulsive disorder. The young adolescent developed pain in the extremities, and an increase in serum creatine kinase (CK) and myoglobin during fluvoxamine treatment. These adverse reactions were reversed immediately after the medicine was changed to another SSRI-sertraline. This is the first reported case of fluvoxamine-associated rhabdomyolysis. It is advisable to determine serum CK levels before starting fluvoxamine treatment, and then at regular intervals, to avoid the occurrence of severe acute kidney injury with possible life-threatening complications.

Pharmacogenetic Aspects of COVID-19 Management and Post-COVID-19 Depression Treatment with Fluvoxamine.

BACKGROUND: Quarantine measures with self-isolation of varying duration have been significant psychosocial stressors in the context of the COVID-19 pandemic. The serotonin selective reuptake inhibitor fluvoxamine has been considered as a prophylaxis against depression in early COVID-19 patients, with additional benefits apparently arising from its antiviral activity. In this narrative review, we draw attention to the body of evidence showing efficacy of fluvoxamine in protecting against depressive disorders in COVID-19 patients, while also attenuating the severity of COVID-19 disease, with a notable reduction in the need for intubation and lower mortality. We consider this potential two-fold action of fluvoxamine in the light of its pharmacogenetic and pharmacological profiles. SUBJECTS AND METHODS: Full-text publications in English and Russian in Google Scholar, PubMed, NCBI, Web of Science, and E-Library databases were selected by keywords, solitary and in combination (fluvoxamine, COVID-19, depression, anxiety, antidepressants, adverse reactions) for the period from March 01, 2020 to June 06, 2022. We also analyzed the full-text publications in English and Russian language reporting adverse reactions caused by fluvoxamine use for the period from 2012 to 2022. RESULTS: The literature search yielded 10 papers reporting on the efficacy fluvoxamine in relieving depressive symptoms in COVID-19 patients, and 3 papers on its effect on medical outcome. The preponderance of data indicated a dual therapeutic action of fluvoxamine, and our further literature investigation was informative about drug-drug interactions and genetic factors moderating the antidepressant efficacy of fluvoxamine. CONCLUSIONS: Patients with COVID-19 seeking psychopharmacological treatment for depressive symptoms must be informed of the benefits and risks of fluvoxamine use. Several lines of findings indicate this agent to possess an additional antiviral action. However, optimal dosage regimens and the trade-off with drug-drug interactions remain unclear. Pharmacogenetic testing may assist in evidence-based optimization of fluvoxamine dosages in the context of COVID-19 infection with comorbid depression.

Evidence of pharmacogenetics-based fluvoxamine use as an add-on to clozapine treatment in psychiatry.

Pharmacological treatments used for psychiatric disorders, such as clozapine, demonstrate large interindividual variability in terms of possible adverse effects and therapeutic benefit. This variability can be explained by multiple factors, including pharmacogenetic factors. Clozapine efficacy can be impacted by CYP polymorphisms. A growing body of literature on pharmacogenetics suggests the clinical benefit of concomitant use of clozapine and fluvoxamine to improve global pharmacotherapeutic management. This article reviews and discusses available clinical and pharmacological data and limitations of clozapine augmentation with fluvoxamine based on pharmacogenetic rationale and clinical experience. The aim is to provide an updated approach on how to use the pharmacological and pharmacogenetic profile to improve clozapine efficacy and tolerance in severely ill patients.

Efficacy and tolerability of pharmacotherapy for obsessive-compulsive personality disorder: a systematic review of randomized controlled trials.

INTRODUCTION: Although obsessive-compulsive personality disorder (OCPD) is one of the most prevalent personality disorders, it is one of the least studied. There is debate as to whether pharmacotherapy is efficacious for OCPD. We aimed to systematically evaluate the efficacy and tolerability of pharmacotherapy for OCPD. AREAS COVERED: This systematic review found two randomized controlled trials investigating pharmacotherapy of OCPD. In a study of major depression (n = 308) with comorbid OCPD (n = 71), citalopram was more effective for OCPD than sertraline with fewer drop-outs from treatment. In a small study of OCPD (n = 24), fluvoxamine was more effective than placebo, and there was a low drop-out rate. Risk of bias and quality assessment of these studies was not possible, and findings have very low levels of certainty. EXPERT OPINION: Two studies provide preliminary evidence in support of citalopram and fluvoxamine for OCPD. Further randomized controlled trials are required before firm conclusions can be drawn regarding efficacy of pharmacotherapy for OCPD.

A Disproportionality Analysis of Drug-Drug Interactions of Tizanidine and CYP1A2 Inhibitors from the FDA Adverse Event Reporting System (FAERS).

INTRODUCTION: Tizanidine is primarily metabolized via cytochrome P450 (CYP) 1A2 and therefore medications that inhibit the enzyme will affect the clearance of tizanidine, leading to increased plasma concentrations of tizanidine and potentially serious adverse events. OBJECTIVES: Our aim was to study the occurrence of adverse events reported in the FDA Adverse Event Reporting System (FAERS) involving the combination of tizanidine and drugs that inhibit the metabolic activity of CYP1A2. METHODS: A disproportionality analysis of FAERS reports from 2004 quarter 1 through 2020 quarter 3 was conducted to calculate the reporting odds ratio (ROR) of reports mentioning tizanidine in a suspect or interacting role or having any role, a CYP1A2 inhibitor, and the following adverse events: hypotension, bradycardia, syncope, shock, cardiorespiratory arrest, and fall or fracture. RESULTS: A total of 89 reports were identified mentioning tizanidine, at least one CYP1A2 inhibitor, and one of the adverse events of interest. More than half of the reports identified tizanidine as having a suspect or interacting role (n = 59, 66.3%), and the reports more frequently involved women (n = 58, 65.1%). The median age was 56.1 years (standard deviation 17.1). Some of the important safety signals included interactions between tizanidine in a suspect or interacting role and ciprofloxacin (ROR for hypotension 28.1, 95% confidence interval [CI] 19.2-41.2) or fluvoxamine (ROR for hypotension 36.9, 95% CI 13.1-103.4), and also when reported in "any role" with ciprofloxacin (ROR for hypotension 6.3, 95% CI 4.7-8.5), fluvoxamine (ROR for hypotension 11.4, 95% CI 4.5-28.8), and zafirlukast (ROR for falls 16.0, 95% CI 6.1-42.1). CONCLUSIONS: Reports involving tizanidine and a CYP1A2 inhibitor have higher odds of reporting hypotension. This study suggests that concurrent use of tizanidine with CYP1A2 inhibitors may lead to serious health consequences associated with low blood pressure such as falls and fractures.

Antidepressants for COVID-19: A systematic review.

OBJECTIVE: To systematically examine the efficacy and safety of antidepressants for the treatment of coronavirus disease 2019 (COVID-19). METHODS: A systematic search was performed independently by two researchers based on Chinese Journal Net, WanFang, PsycINFO, Cochrane Library, PubMed, and EMBASE. RESULTS: Seven studies (n = 92,947) including three retrospective studies (n = 91,083), two randomized clinical trials (RCTs, n = 1649), two prospective cohort study (n = 215) involving (n = 92,947) patients with COVID-19 were examined. For RCTs, fluvoxamine outperformed placebo in reducing clinical deterioration and hospitalisation for COVID-19 patients. For retrospective studies, antidepressants (2 studies) and fluoxetine (1 study) possibly reduced the risk of mortality in patients with COVID-19. Results from two remaining studies supported the superiority of fluvoxamine in reducing risk of mortality in COVID-19 patients. The two RCTs that examined the safety of fluvoxamine for COVID-19 patients found inconsistent results but no significant group differences in the dropout rate. CONCLUSION: This systematic review found emerging evidence for fluvoxamine in reducing the risk of mortality and hospitalisation in COVID-19 patients, but inconsistent evidence for the safety of fluvoxamine in COVID-19 patients. More studies are needed to determine the efficacy and safety of antidepressants for the treatment of COVID-19.

Identifying Antidepressants Less Likely to Cause Hyponatremia: Triangulation of Retrospective Cohort, Disproportionality, and Pharmacodynamic Studies.

Antidepressants are known to cause hyponatremia, but conflicting evidence exists regarding specific antidepressants. To identify antidepressants less likely to cause hyponatremia, we conducted a triangulation study integrating retrospective cohort, disproportionality, and pharmacodynamic studies. In the retrospective cohort study of patients (≥ 60 years) in Nihon University School of Medicine's Clinical Data Warehouse (2004-2020), a significant decrease in serum sodium levels was observed within 30 days after initiation of a selective serotonin reuptake inhibitor (SSRI; mean change -1.00 ± 0.23 mmol/L, P < 0.001) or serotonin-noradrenaline reuptake inhibitor (SNRI; -1.01 ± 0.31 mmol/L, P = 0.0013), whereas no decrease was found for a noradrenergic and specific serotonergic antidepressant (mirtazapine; +0.55 ± 0.47 mmol/L, P = 0.24). Within-class comparison revealed no decrease in serum sodium levels for fluvoxamine (+0.74 ± 0.75 mmol/L, P = 0.33) among SSRIs and milnacipran (+0.08 ± 0.87 mmol/L, P = 0.93) among SNRIs. In the disproportionality analysis of patients (≥ 60 years) in the Japanese Adverse Drug Event Report database (2004-2020), a significant increase in hyponatremia reports was observed for SSRIs (reporting odds ratio 4.41, 95% confidence interval 3.58-5.45) and SNRIs (5.66, 4.38-7.31), but not for mirtazapine (1.08, 0.74-1.58), fluvoxamine (1.48, 0.94-2.32), and milnacipran (0.85, 0.45-1.62). Finally, pharmacoepidemiological-pharmacodynamic analysis revealed a significant correlation between the decrease in serum sodium levels and binding affinity for serotonin transporter (SERT; r = -0.84, P = 0.02), suggesting that lower binding affinity of mirtazapine, fluvoxamine, and milnacipran against SERT is responsible for the above difference. Although further research is needed, our data suggest that mirtazapine, fluvoxamine, and milnacipran are less likely to cause hyponatremia.

Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19：a meta-analysis.

BACKGROUND: The coronavirus disease (COVID-19) epidemic has not been completely controlled. Although great achievements have been made in COVID-19 research and many antiviral drugs have shown good therapeutic effects against COVID-19, a simple oral antiviral drug for COVID-19 has not yet been developed. We conducted a meta-analysis to investigate the improvement in mortality or hospitalization rates and adverse events among COVID-19 patients with three new oral antivirals (including molnupiravir, fluvoxamine and Paxlovid). METHODS: We searched scientific and medical databases, such as PubMed, Web of Science, Embase and Cochrane Library for relevant articles and screened the references of retrieved studies on COVID-19. RESULTS: A total of eight studies were included in this study. The drug group included 2440 COVID-19 patients, including 54 patients who died or were hospitalized. The control group included a total of 2348 COVID-19 patients, including 118 patients who died or were hospitalized. The overall odds ratio (OR) of mortality or hospitalization was 0.33 (95% confidence interval [CI], 0.22-0.49) for COVID-19 patients in the drug group and placebo group, indicating that oral antiviral drugs were effective for COVID-19 patients and reduced the mortality or hospitalization by approximately 67%. CONCLUSIONS: This study showed that three novel oral antivirals (molnupiravir, fluvoxamine and Paxlovid) are effective in reducing the mortality and hospitalization rates in patients with COVID-19. In addition, the three oral drugs did not increase the occurrence of adverse events, thus exhibiting good overall safety. These three oral antiviral drugs are still being studied, and the available data suggest that they will bring new hope for COVID-19 recovery and have the potential to be a breakthrough and very promising treatment for COVID-19.KEY MESSAGESMany antiviral drugs have shown good therapeutic effects, and there is no simple oral antiviral drug for COVID-19 patients.Meta-analysis was conducted for three new oral antivirals to evaluate the improvement in mortality or hospitalization rates and adverse events among COVID-19 patients.We focussed on three new oral Coronavirus agents (molnupiravir, fluvoxamine and Paxlovid) and hope to provide guidance for the roll-out of oral antivirals.

Safety and efficacy of fluvoxamine in COVID-19 ICU patients: An open label, prospective cohort trial with matched controls.

AIMS: Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) and sigma-1 receptor agonist, has so far shown promise in the prevention of COVID-19 progression as an early treatment option in three trials. The aim of this study was to evaluate the safety and efficacy of fluvoxamine in COVID-19 patients if administered later in the course of the disease. METHODS: The study was designed as an open-label, prospective cohort trial with matched controls. In April and May 2021, 51 ICU COVID-19 patients hospitalised in the University Hospital Dubrava and University Hospital Centre Zagreb, Croatia, were treated with fluvoxamine 100 mg three times daily for 15 days in addition to standard therapy and they were prospectively matched for age, gender, vaccination against COVID-19, disease severity and comorbidities with 51 ICU controls. RESULTS: No statistically significant differences between groups were observed regarding the number of days on ventilator support, duration of ICU or total hospital stay. However, overall mortality was lower in the fluvoxamine group, 58.8% (n = 30/51), than in the control group, 76.5% (n = 39/51), HR 0.58, 95% CI (0.36-0.94, P = .027). CONCLUSION: Fluvoxamine treatment in addition to the standard therapy in hospitalised ICU COVID-19 patients could have a positive impact on patient survival. Further studies on the effects of fluvoxamine in COVID-19 patients are urgently required.

Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.

BACKGROUND: Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19. METHODS: This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation. Our primary outcome was a composite endpoint of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high level adherence (>80%). We used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at ClinicalTrials.gov (NCT04727424) and is ongoing. FINDINGS: The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18-102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 [11%] of 741 vs 119 [16%] of 756); relative risk [RR] 0·68; 95% Bayesian credible interval [95% BCI]: 0·52-0·88), with a probability of superiority of 99·8% surpassing the prespecified superiority threshold of 97·6% (risk difference 5·0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0·69, 95% BCI 0·53-0·90) and larger in the per-protocol analysis (RR 0·34, 95% BCI, 0·21-0·54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0·68, 95% CI: 0·36-1·27). There was one death in the fluvoxamine group and 12 in the placebo group for the per-protocol population (OR 0·09; 95% CI 0·01-0·47). We found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups. INTERPRETATION: Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital. FUNDING: FastGrants and The Rainwater Charitable Foundation. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.