Summary of COVID-19 fluvoxamine studies

1. Wannigama et al., Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial

498 patient fluvoxamine early treatment RCT: 98% lower ventilation (p<0.0001), 89% lower need for oxygen therapy (p<0.0001), 94% lower hospitalization (p<0.0001), and 40% lower PASC (p<0.0001).
RCT 995 outpatients showing significantly lower progression with early treatment within 48 hours using fluvoxamine, fluvoxamine+bromhexine, fluvoxamine+cyproheptadine, and niclosamide+bromhexine. 70% of patients received treatment within 12 hours of symptom onset. Treatments groups showed significantly lower long COVID (PASC). The combined treatment groups showed significantly lower viral load as early as day 3. The 3 combination arms were superior to fluvoxamine alone. The study was open-label. 593 out of 1,900 randomized participants did not receive the treatment, mostly due to inability to confirm eligibility, however baseline characteristics were similar for these patients. There was a very high hospitalization rate in the control arm. Authors note that the majority of cases were mild - the threshold for hospitalization may have been very low (in some places/times all cases were hospitalized). Authors also note that the patients requiring high flow oxygen all had the delta/alpha..
Mar 2024, eClinicalMedicine, 10.1016/j.eclinm.2024.102517, https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00096-8/fulltext, https://c19p.org/wannigama

2. Lenze et al., Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial

152 patient fluvoxamine early treatment RCT: 93% lower progression (p=0.009) and 82% lower hospitalization (p=0.009).
RCT 152 outpatients, 80 treated with fluvoxamine showing lower progression with treatment (0 of 80 versus 6 of 72 control).
Nov 2020, JAMA, https://jamanetwork.com/journals/jama/fullarticle/2773108, https://c19p.org/lenze

3. Pineda et al., Impact of fluvoxamine on outpatient treatment of COVID-19 in Honduras in a prospective observational real-world study

657 patient fluvoxamine early treatment study: 94% lower mortality (p=0.01), 73% lower need for oxygen therapy (p=0.0002), and 51% lower hospitalization (p=0.04).
Prospective study of 657 COVID+ outpatients in Honduras, 594 accepting fluvoxamine treatment, showing significantly lower mortality and hospitalization with treatment.
Oct 2022, Frontiers in Pharmacology, https://www.frontiersin.org/articles/10.3389/fphar.2022.1054644/full, https://c19p.org/pineda

4. Kirenga et al., Association of fluvoxamine with mortality and symptom resolution among inpatients with COVID-19 in Uganda: a prospective interventional open-label cohort study

316 patient fluvoxamine late treatment study: 68% lower mortality (p<0.0001) and 53% improved recovery (p=0.04).
Prospective study of 316 hospitalized patients in Uganda, 94 receiving fluvoxamine, showing significantly lower mortality and improved recovery with treatment.
Mar 2023, Molecular Psychiatry, https://www.nature.com/articles/s41380-023-02004-3, https://c19p.org/kirenga2

5. Stewart et al., Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19

1,175 patient fluvoxamine late treatment RCT: 31% lower progression (p=0.34), 34% improved recovery (p=0.32), and 49% lower hospitalization (p=0.59).
Late treatment low risk population RCT showing lower progression to hospitalization or urgent care/ER visits with fluvoxamine, without statistical significance. There was no mortality and only three hospitalizations. Authors provide no details on the cause of hospitalization, but they appear to be unrelated to COVID-19. eFigure 5 shows no COVID-19 clinical progression to hospitalization (note that a hospitalization can be seen in the equivalent plot for the low dose arm), and the text indicates that the "COVID clinical progression scale simplified into a self-reported evaluation of home levels (limited vs not)". Note that the urgent care/ER visit outcome is also likely diluted due to inclusion of all-cause events, and could be statistically significant for only COVID-19 events. The sustained recovery outcome, which shows no difference, was a post-hoc creation used to hide efficacy for ivermectin, and is not logical for evaluating efficacy in this trial. The..
Sep 2023, JAMA, https://jamanetwork.com/journals/jama/fullarticle/2812204, https://c19p.org/stewart8

6. Seftel et al., Prospective cohort of fluvoxamine for early treatment of COVID-19

125 patient fluvoxamine early treatment study: 72% lower mortality (p=0.38), 84% lower combined mortality/ICU admission (p=0.15), 94% lower hospitalization (p=0.003), and 99% improved recovery (p<0.0001).
Prospective quasi-randomized (patient choice) study with 125 outpatients, 77 treated with fluvoxamine, showing lower death/ICU admission (0 of 77 vs. 2 of 48), lower hospitalization (0 of 77 vs. 6 of 48), and faster recovery with treatment. Note that 12 treatment patients were added but are not reflected in the table in the paper (because the numbers had been previously published and the IRB did not allow updating the table).
Jan 2021, Open Forum Infectious Diseases, https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofab050/6124100, https://c19p.org/seftel

7. Tsiakalos et al., Early Fluvoxamine Reduces the Risk for Clinical Deterioration in Symptomatic Outpatients with COVID-19: A Real-World, Retrospective, before–after Analysis

103 patient fluvoxamine early treatment study: 84% lower hospitalization (p=0.06) and 86% lower progression (p=0.02).
Retrospective 103 outpatients in Greece, showing lower risk of progression with fluvoxamine 100mg bid for 10 days. 2 patients (4%) in the fluvoxamine group had clinical deterioration compared to 8 patients (16%) in the standard care group (p<0.05). After adjusting for confounders, fluvoxamine was associated with a lower risk of clinical deterioration (adjusted OR 0.12, p=0.02). Fluvoxamine was also associated with improved lymphocyte count. Control patients were during Sep-Nov 2021, and treatment patients Nov-Dec 2021, introducing potential confounding by time due to changes in variants, although the change in risk during this period is expected to be relatively low.
Aug 2023, Microorganisms, https://www.mdpi.com/2076-2607/11/8/2073, https://c19p.org/tsiakalos

8. Calusic et al., Safety and efficacy of fluvoxamine in COVID-19 ICU patients: an open label, prospective cohort trial with matched controls

102 patient fluvoxamine ICU PSM study: 42% lower mortality (p=0.03).
Prospective PSM study of 51 COVID-19 ICU patients in Croatia and 51 matched controls, showing significantly lower mortality with treatment.
Oct 2021, British J. Clinical Pharmacology, https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15126, https://c19p.org/calusic

9. Diaz et al., Protective Effect of Fluvoxamine for COVID-19 in Obsessive-Compulsive Disorder

82,069 patient fluvoxamine prophylaxis PSM study: 28% fewer cases (p<0.0001).
TriNetX PSM retrospective 82,069 OCD patients, showing lower risk of COVID-19 with fluvoxamine use.
Oct 2022, The Primary Care Companion For CNS Disorders, https://www.psychiatrist.com/pcc/ocd/protective-effect-fluvoxamine-covid-19-obsessive-compulsive-disorder-real-world-case-control-study/, https://c19p.org/diaz3

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

1,497 patient fluvoxamine late treatment RCT: 30% lower mortality (p=0.24), 22% lower ventilation (p=0.33), 22% lower hospitalization (p=0.1), and 32% fewer combined hospitalization/ER visits (p=0.004).
Together Trial showing significantly lower hospitalization/extended ER visits with fluvoxamine treatment. Adherence was only 73.2%. Symptom onset was unspecified or >= 4 days for 57% of patients. The schedule of study activities specifies treatment administration only one day after randomization, adding an additional day delay. Overall mortality is high for the patient population. Results may be impacted by late treatment, poor SOC, and may be specific to local variants [science.sciencemag.org, thelancet.com]. Per-protocol analysis shows significantly improved results in this trial, however this may be subject to bias - the probability of adherence may be related to the probability of the outcome. Regarding the combined hospitalization/extended ER observation outcome, authors have noted that at the study sites, extended medical observation was essentially equivalent to being hospitalized. “These were not standard emergency rooms but instead were COVID-19 emergency centers that were..
Aug 2021, The Lancet Global Health, https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00448-4/fulltext, https://c19p.org/reis2

11. Farahani et al., Effect of fluvoxamine on preventing neuropsychiatric symptoms of post COVID syndrome in mild to moderate patients, a randomized placebo-controlled double-blind clinical trial

100 patient fluvoxamine long COVID RCT: 51% lower PASC (p=0.06).
RCT 100 mild/moderate COVID-19 outpatients in Iran, showing lower post COVID symptoms 12 weeks after infection, statistically significant only for fatigue with the small sample size. All symptoms may occur for non-COVID-19 reasons, smell/taste disorder may be the most likely to be related to COVID-19 infection. Fluvoxamine 100mg daily for 10 days.
Mar 2023, BMC Infectious Diseases, https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-023-08172-5, https://c19p.org/farahani

12. Siripongboonsitti et al., The Real-World Effectiveness of Fluvoxamine Therapy in Mild to Moderate COVID-19 Patients; a Historical Cohort Study (Fluvoxa Trial)

752 patient fluvoxamine early treatment study: 67% higher need for oxygen therapy (p=0.02), 42% lower progression (p=0.08), 34% improved recovery (p<0.0001), and 4% worse viral clearance (p=0.66).
Retrospective 752 patients in Thailand showing mixed results with 50mg fluvoxamine bid. Authors note that trials showing benefit mostly used 100mg bid.
Oct 2023, J. Infection and Public Health, https://www.sciencedirect.com/science/article/pii/S1876034123003374, https://c19p.org/siripongboonsitti5

14. Trkulja et al., Outpatients prescribed with fluvoxamine around the time of COVID-19 diagnosis are not at a reduced risk of subsequent hospitalization and death compared to their non-prescribed peers: population-based matched cohort study

32,085 patient fluvoxamine prophylaxis PSM study: 27% lower mortality (p=0.41) and 37% higher hospitalization (p=0.5).
Retrospective COVID+ patients in Croatia, showing no significant difference in outcomes with fluvoxamine prophylaxis.
Nov 2022, European J. Clinical Pharmacology, https://link.springer.com/10.1007/s00228-023-03479-3, https://c19p.org/trkulja2

16. Reis et al., Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19

1,476 patient fluvoxamine early treatment RCT: 12% lower hospitalization (p=1) and 50% lower progression (p=0.04).
Low-risk (1% hospitalization) outpatient RCT with 738 fluvoxamine + budesonide patients and 738 placebo patients, showing significantly lower hospitalization/ER visits with treatment.
Apr 2023, Annals of Internal Medicine, https://www.acpjournals.org/doi/epdf/10.7326/M22-3305, https://c19p.org/reis10

17. Bramante et al., Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19

653 patient fluvoxamine early treatment RCT: 11% higher combined mortality/hospitalization (p=0.88), 16% higher progression (p=0.68), and 2% lower hospitalization (p=1).
COVID-OUT remotely operated RCT, showing no significant difference in outcomes. Results for other treatments are listed separately - metformin , ivermectin . The "control" group includes patients receiving metformin, which is known to be beneficial for COVID-19 1 . Authors note that the dosage used in the trial is lower than that of other trials 2 . Control arm results are very different between treatments, for example considering hospitalization/death, this was 1.0% for ivermectin vs. 2.7% for overall control, however it was 1.3% for the ivermectin-specific control. 394 control patients are shared. The rate for the non-shared 261 metformin control patients is 5%, compared to 1.3% for ivermectin control patients. The metformin arm started earlier, however it is unclear why the difference in outcomes is so large. Results were delayed for 6 months with no explanation, with followup ending Feb 14, 2022. Multiple outcomes are missing, for example time to recovery (where ACTIV-6 showed..
Aug 2022, NEJM, https://www.nejm.org/doi/10.1056/NEJMoa2201662, https://c19p.org/covidoutf

19. Visos-Varela et al., Repurposing selective serotonin reuptake inhibitors for severity of COVID-19: A population-based study

86,602 patient fluvoxamine prophylaxis study: 395% higher ICU admission (p=0.24), 40% lower hospitalization (p=0.39), and 12% fewer cases (p=0.6).
Retrospective 86,602 patients in Spain, showing lower COVID-19 risk SSRIs citalopram and paroxetine. There were no significant difference for fluvoxamine, which few patients were taking.
Apr 2023, European Neuropsychopharmacology, https://www.sciencedirect.com/science/article/pii/S0924977X23000639, https://c19p.org/visosvarela

20. Siripongboonsitti et al., Efficacy of Combination Therapy of Fluvoxamine and Favipiravir versus Favipiravir Monotherapy to Prevent Severe COVID-19 among Mild to Moderate COVID-19 Patients: Open-label Randomized Controlled Trial (EFFaCo Study)

327 patient fluvoxamine early treatment RCT: 2% higher need for oxygen therapy (p=1) and 22% higher hospitalization (p=0.77).
RCT 327 outpatients in Thailand, showing no significant difference with 50mg fluvoxamine bid added to favipiravir. Authors note that trials showing benefit mostly used 100mg bid.
Jun 2023, Int. J. Infectious Diseases, https://www.ijidonline.com/article/S1201-9712(23)00641-0/fulltext, https://c19p.org/siripongboonsitti2

21. Reiersen et al., The STOP COVID 2 study: Fluvoxamine vs placebo for outpatients with symptomatic COVID-19, a fully-remote randomized controlled trial

547 patient fluvoxamine early treatment RCT: 201% higher need for oxygen therapy (p=0.5), 9% lower hospitalization (p=1), and 12% lower progression (p=0.85).
Remote RCT 547 outpatients a median of 5 days from onset, showing no significant differences with fluvoxamine. The trial was stopped early and underpowered due to low event rates. The trial does not report outcomes that may not be underpowered like time to recovery. Authors note that treatment may have been too late.
Aug 2021, Open Forurm Infectious Diseases, https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofad419/7238414, https://c19p.org/reiersen

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