A systematic review and meta-analysis, investigating dose and time of fluvoxamine treatment efficacy for COVID-19 clinical deterioration, death, and Long-COVID complications.
(E)‐5‐methoxy‐1‐[4‐(trifluoromethyl)phenyl]pentan‐1‐one O‐2‐aminoethyl oxime)
Antidepressant
Coronavirus
Drug repurposing
Pandemic
SARS-CoV-2
Sigma-1 receptor (σ1R)
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
12 Jun 2024
12 Jun 2024
Historique:
received:
12
03
2024
accepted:
06
06
2024
medline:
12
6
2024
pubmed:
12
6
2024
entrez:
11
6
2024
Statut:
epublish
Résumé
There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as of January 2024. In the early stages of the pandemic, there was an urgent need to reduce the severity of the disease and prevent the need for hospitalization to avoid stress on healthcare systems worldwide. The repurposing of drugs to prevent clinical deterioration of COVID-19 patients was trialed in many studies using many different drugs. Fluvoxamine (an SSRI and sigma-1 receptor agonist) was initially identified to potentially provide beneficial effects in COVID-19-infected patients, preventing clinical deterioration and the need for hospitalization. Fourteen clinical studies have been carried out to date, with seven of those being randomized placebo-controlled studies. This systematic review and meta-analysis covers the literature from the outbreak of SARS-CoV-2 in late 2019 until January 2024. Search terms related to fluvoxamine, such as its trade names and chemical names, along with words related to COVID-19, such as SARS-CoV-2 and coronavirus, were used in literature databases including PubMed, Google Scholar, Scopus, and the ClinicalTrials.gov database from NIH, to identify the trials used in the subsequent analysis. Clinical deterioration and death data were extracted from these studies where available and used in the meta-analysis. A total of 7153 patients were studied across 14 studies (both open-label and double-blind placebo-controlled). 681 out of 3553 (19.17%) in the standard care group and 255 out of 3600 (7.08%) in the fluvoxamine-treated group experienced clinical deterioration. The estimated average log odds ratio was 1.087 (95% CI 0.200 to 1.973), which differed significantly from zero (z = 2.402, p = 0.016). The seven placebo-controlled studies resulted in a log odds ratio of 0.359 (95% CI 0.1111 to 0.5294), which differed significantly from zero (z = 3.103, p = 0.002). The results of this study identified fluvoxamine as effective in preventing clinical deterioration, and subgrouping analysis suggests that earlier treatment with a dose of 200 mg or above provides the best outcomes. We hope the outcomes of this study can help design future studies into respiratory viral infections and potentially improve clinical outcomes.
Identifiants
pubmed: 38862591
doi: 10.1038/s41598-024-64260-9
pii: 10.1038/s41598-024-64260-9
doi:
Substances chimiques
Fluvoxamine
O4L1XPO44W
Selective Serotonin Reuptake Inhibitors
0
Types de publication
Journal Article
Meta-Analysis
Systematic Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
13462Subventions
Organisme : the Ratchadaprisk Sompoch Endowment Fund (2023) Chulalongkorn University
ID : Sys_66_007_3700_001
Informations de copyright
© 2024. The Author(s).
Références
Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 5, 536–544, https://doi.org/10.1038/s41564-020-0695-z (2020).
World-Health-Organization. WHO Coronavirus (COVID-19) Dashboard. WHO Coronavirus (COVID-19), https://data.who.int/dashboards/covid19/deaths (2023).
Feehan, J. & Apostolopoulos, V. Is COVID-19 the worst pandemic?. Maturitas 149, 56–58. https://doi.org/10.1016/j.maturitas.2021.02.001 (2021).
doi: 10.1016/j.maturitas.2021.02.001
pubmed: 33579552
pmcid: 7866842
Suryasa, I. W., Rodríguez-Gámez, M. & Koldoris, T. The COVID-19 pandemic. Int. J. Health Sci. 5 (2021).
Wannigama, D. L. et al. Tracing the new SARS-CoV-2 variant BA. 2.86 in the community through wastewater surveillance in Bangkok, Thailand. Lancet Infect. Dis. 23, e464–e466 (2023).
Rad, S. A. H., Wannigama, D. L., Hirankarn, N. & McLellan, A. D. The impact of non-synonymous mutations on miRNA binding sites within the SARS-CoV-2 NSP3 and NSP4 genes. Sci. Rep. 13, 16945 (2023).
doi: 10.1038/s41598-023-44219-y
pubmed: 37805621
pmcid: 10560223
Wannigama, D. L. et al. COVID-19 monitoring with sparse sampling of sewered and non-sewered wastewater in urban and rural communities. Iscience 26, 107019 (2023).
doi: 10.1016/j.isci.2023.107019
pubmed: 37351501
pmcid: 10250052
Brown, R. L. et al. Pathophysiology, diagnosis, and management of neuroinflammation in covid-19. bmj 382 (2023).
Hashimoto, K. Overview of the potential use of fluvoxamine for COVID-19 and long COVID. Discov. Mental Health 3, 9 (2023).
doi: 10.1007/s44192-023-00036-3
Chen, T.-B. et al. Neuroimmunological effect of vitamin D on neuropsychiatric Long COVID syndrome: A review. Nutrients 15, 3802 (2023).
doi: 10.3390/nu15173802
pubmed: 37686834
pmcid: 10490318
Omori, I. M. et al. Fluvoxamine versus other anti-depressive agents for depression. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD006114.pub2 (2010).
doi: 10.1002/14651858.CD006114.pub2
pubmed: 20238342
Lenze, E. J. et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: A randomized clinical trial. JAMA 324, 2292–2300. https://doi.org/10.1001/jama.2020.22760 (2020).
doi: 10.1001/jama.2020.22760
pubmed: 33180097
pmcid: 7662481
Hashimoto, Y., Suzuki, T. & Hashimoto, K. Mechanisms of action of fluvoxamine for COVID-19: A historical review. Mol. Psychiatry 27, 1898–1907 (2022).
doi: 10.1038/s41380-021-01432-3
pubmed: 34997196
pmcid: 8739627
Friesland, M., Mingorance, L., Chung, J., Chisari, F. V. & Gastaminza, P. Sigma-1 receptor regulates early steps of viral RNA replication at the onset of hepatitis C virus infection. J. Virol. 87, 6377–6390 (2013).
doi: 10.1128/JVI.03557-12
pubmed: 23536676
pmcid: 3648129
Vasallo, C. & Gastaminza, P. Cellular stress responses in hepatitis C virus infection: Mastering a two-edged sword. Virus Res. 209, 100–117 (2015).
doi: 10.1016/j.virusres.2015.03.013
pubmed: 25836277
Gordon, D. E. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583, 459–468 (2020).
doi: 10.1038/s41586-020-2286-9
pubmed: 32353859
pmcid: 7431030
Ishikawa, M. et al. High occupancy of sigma-1 receptors in the human brain after single oral administration of fluvoxamine: A positron emission tomography study using [11C] SA4503. Biol. Psychiatry 62, 878–883 (2007).
doi: 10.1016/j.biopsych.2007.04.001
pubmed: 17662961
Ozonoff, A. et al. Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: Results from the IMPACC study. Nat. Commun. 15, 216. https://doi.org/10.1038/s41467-023-44090-5 (2024).
doi: 10.1038/s41467-023-44090-5
pubmed: 38172101
pmcid: 10764789
Groff, D. et al. Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: A systematic review. JAMA Netw. Open 4, e2128568–e2128568 (2021).
doi: 10.1001/jamanetworkopen.2021.28568
pubmed: 34643720
pmcid: 8515212
Puelles, V. G. et al. Multiorgan and renal tropism of SARS-CoV-2. N. Engl. J. Med. 383, 590–592 (2020).
doi: 10.1056/NEJMc2011400
pubmed: 32402155
Rhea, E. M. et al. The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice. Nat. Neurosci. 24, 368–378 (2021).
doi: 10.1038/s41593-020-00771-8
pubmed: 33328624
Reis, G. 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. Lancet Glob. Health 10, e42–e51. https://doi.org/10.1016/s2214-109x(21)00448-4 (2022).
doi: 10.1016/s2214-109x(21)00448-4
pubmed: 34717820
Bramante, C. T. et al. Randomized trial of metformin, ivermectin, and fluvoxamine for Covid-19. N. Engl. J. Med. 387, 599–610. https://doi.org/10.1056/NEJMoa2201662 (2022).
doi: 10.1056/NEJMoa2201662
pubmed: 36070710
pmcid: 9945922
McCarthy, M. W. 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 329, 296–305. https://doi.org/10.1001/jama.2022.24100 (2023).
doi: 10.1001/jama.2022.24100
pubmed: 36633838
pmcid: 9857647
Seo, H. et al. Fluvoxamine treatment of patients with symptomatic COVID-19 in a community treatment center: A Preliminary result of randomized controlled trial. Infect. Chemother. 54, 102–113. https://doi.org/10.3947/ic.2021.0142 (2022).
doi: 10.3947/ic.2021.0142
pubmed: 35384422
pmcid: 8987178
Stewart, T. G. et al. Higher-Dose fluvoxamine and time to sustained recovery in outpatients with COVID-19: The ACTIV-6 randomized clinical trial. JAMA 330, 2354–2363. https://doi.org/10.1001/jama.2023.23363 (2023).
doi: 10.1001/jama.2023.23363
pubmed: 37976072
pmcid: 10656670
Reiersen, A. M. et al. The STOP COVID 2 Study: Fluvoxamine vs placebo for outpatients with symptomatic COVID-19, a fully remote randomized controlled trial. Open Forum Infect. Dis. 10, ofad419, https://doi.org/10.1093/ofid/ofad419 (2023).
Calusic, M. et al. Safety and efficacy of fluvoxamine in COVID-19 ICU patients: An open label, prospective cohort trial with matched controls. Br. J. Clin. Pharmacol. 88, 2065–2073. https://doi.org/10.1111/bcp.15126 (2022).
doi: 10.1111/bcp.15126
pubmed: 34719789
Pineda, E. et al. Impact of fluvoxamine on outpatient treatment of COVID-19 in Honduras in a prospective observational real-world study. Front. Pharmacol. 13, 1054644. https://doi.org/10.3389/fphar.2022.1054644 (2022).
doi: 10.3389/fphar.2022.1054644
pubmed: 36532727
pmcid: 9748291
Seftel, D. & Boulware, D. R. Prospective Cohort of fluvoxamine for early treatment of coronavirus disease 19. Open Forum Infect. Dis. 8, ofab050. https://doi.org/10.1093/ofid/ofab050 (2021).
Kirenga, B. J. et al. Association of fluvoxamine with mortality and symptom resolution among inpatients with COVID-19 in Uganda: A prospective interventional open-label cohort study. Mol. Psychiatry https://doi.org/10.1038/s41380-023-02004-3 (2023).
doi: 10.1038/s41380-023-02004-3
pubmed: 36869228
pmcid: 9982784
Tsiakalos, A., Ziakas, P. D., Polyzou, E., Schinas, G. & Akinosoglou, K. Early fluvoxamine reduces the risk for clinical deterioration in symptomatic outpatients with COVID-19: A real-world, retrospective, before-after analysis. Microorganisms. https://doi.org/10.3390/microorganisms11082073 (2023).
doi: 10.3390/microorganisms11082073
pubmed: 37630633
pmcid: 10459506
Wannigama, D. L., et al. Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: A randomized clinical trial. EClinicalMedicine 70 (2024).
Siripongboonsitti, T. et al. Efficacy of combination therapy of fluvoxamine and favipiravir vs favipiravir monotherapy to prevent severe COVID-19 among mild to moderate COVID-19 patients: Open-label randomized controlled trial (EFFaCo study). Int. J. Infect. Dis. 134, 211–219. https://doi.org/10.1016/j.ijid.2023.06.018 (2023).
doi: 10.1016/j.ijid.2023.06.018
pubmed: 37393041
Oskotsky, T. et al. Mortality risk among patients with COVID-19 prescribed selective serotonin reuptake inhibitor antidepressants. JAMA Netw. Open 4, e2133090. https://doi.org/10.1001/jamanetworkopen.2021.33090 (2021).
doi: 10.1001/jamanetworkopen.2021.33090
pubmed: 34779847
pmcid: 8593759
Brimson, J. M. et al. The effectiveness of Bacopa monnieri (Linn.) Wettst. as a nootropic, neuroprotective, or antidepressant supplement: analysis of the available clinical data. Sci. Rep. 11, 1–11 (2021).
doi: 10.1038/s41598-020-80045-2
Jadad, A. R. et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary?. Controlled Clin. Trials 17, 1–12 (1996).
doi: 10.1016/0197-2456(95)00134-4
pubmed: 8721797
The Jamovi project. v. Jamovi (Version 2.3) ( https://www.jamovi.org , 2023).
Viechtbauer, W. Bias and efficiency of meta-analytic variance estimators in the random-effects model. J. Educ. Behav. Statistics 30, 261–293 (2005).
doi: 10.3102/10769986030003261
Reiersen, A. M., Zorumski, C. F. & Lenze, E. J. Fluvoxamine and long COVID: Post-acute recovery. Rev. Med. Virol. 34(4), e2557. https://doi.org/10.1002/rmv.2557 (2024).
doi: 10.1002/rmv.2557
pubmed: 38825753
Bramante, C. T. et al. Outpatient treatment of Covid-19 with metformin, ivermectin, and fluvoxamine and the development of Long Covid over 10-month follow-up. medRxiv. https://doi.org/10.1101/2022.12.21.22283753 (2022).
Farahani, R. H., Ajam, A. & Naeini, A. R. Effect of fluvoxamine on preventing neuropsychiatric symptoms of post COVID syndrome in mild to moderate patients, a randomized placebo-controlled double-blind clinical trial. BMC Infect. Dis. 23, 197. https://doi.org/10.1186/s12879-023-08172-5 (2023).
doi: 10.1186/s12879-023-08172-5
pubmed: 37003990
pmcid: 10064948
Sidky, H. et al. Assessing the effect of selective serotonin reuptake inhibitors in the prevention of post-acute sequelae of COVID-19. medRxiv (2022).
Hashimoto, K. Overview of the potential use of fluvoxamine for COVID-19 and long COVID. Discov. Ment. Health 3, 9. https://doi.org/10.1007/s44192-023-00036-3 (2023).
doi: 10.1007/s44192-023-00036-3
pubmed: 36968793
pmcid: 10029802
Ishima, T., Fujita, Y. & Hashimoto, K. Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells. Eur. J. Pharmacol. 727, 167–173 (2014).
doi: 10.1016/j.ejphar.2014.01.064
pubmed: 24508523
Khani, E. & Entezari-Maleki, T. Fluvoxamine and long COVID-19: A new role for sigma-1 receptor (S1R) agonists. Mol. Psychiatry 27, 3562–3562 (2022).
doi: 10.1038/s41380-022-01545-3
pubmed: 35388182
pmcid: 8985056
Hashimoto, Y., Suzuki, T. & Hashimoto, K. Comments to “Fluvoxamine and long COVID-19: A new role for sigma-1 receptor (S1R) agonists” by Khani and Entezari-Maleki. Mol. Psychiatry 27, 3563–3564 (2022).
doi: 10.1038/s41380-022-01546-2
pubmed: 35388183
pmcid: 8985059
Fenton, C. & Lee, A. Antidepressants with anti-inflammatory properties may be useful in long COVID depression. Drugs Therapy Perspect. 39, 65–70 (2023).
doi: 10.1007/s40267-022-00975-x
French, G. et al. Impact of hospital strain on excess deaths during the COVID-19 pandemic—United States, July 2020–July 2021. Morb. Mortal. Wkly. Rep. 70, 1613 (2021).
doi: 10.15585/mmwr.mm7046a5
Rodebaugh, T. L. et al. Acute symptoms of mild to moderate COVID-19 are highly heterogeneous across individuals and over time. Open Forum Infect Dis 8, ofab090, https://doi.org/10.1093/ofid/ofab090 (2021).
Griffin, D. O. et al. The importance of understanding the stages of COVID-19 in treatment and trials. AIDS Rev. 23 (2021).
Wannigama, D. L. & Jacquet, A. NOD2-dependent BCG-induced trained immunity: A way to regulate innate responses to SARS-CoV2?. Int. J. Infect. Dis. 101, 52–55 (2020).
doi: 10.1016/j.ijid.2020.09.1429
pubmed: 32980554
pmcid: 7832069
Tay, M. Z., Poh, C. M., Rénia, L., MacAry, P. A. & Ng, L. F. The trinity of COVID-19: immunity, inflammation and intervention. Nat. Rev. Immunol. 20, 363–374 (2020).
doi: 10.1038/s41577-020-0311-8
pubmed: 32346093
pmcid: 7187672
Merad, M. & Martin, J. C. Pathological inflammation in patients with COVID-19: A key role for monocytes and macrophages. Nat. Rev. Immunol. 20, 355–362 (2020).
doi: 10.1038/s41577-020-0331-4
pubmed: 32376901
pmcid: 7201395
Davis, H. E., McCorkell, L., Vogel, J. M. & Topol, E. J. Long COVID: Major findings, mechanisms and recommendations. Nat. Rev. Microbiol. 21, 133–146 (2023).
doi: 10.1038/s41579-022-00846-2
pubmed: 36639608
pmcid: 9839201
Batool, S. et al. Efficacy and safety of favipiravir in treating COVID-19 patients: A meta-analysis of randomized control trials. Cureus 15 (2023).
Shah, P. L. et al. Favipiravir in patients hospitalised with COVID-19 (PIONEER trial): A multicentre, open-label, phase 3, randomised controlled trial of early intervention versus standard care. Lancet Respir. Med. 11, 415–424 (2023).
doi: 10.1016/S2213-2600(22)00412-X
pubmed: 36528039
Knoops, K. et al. SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLoS Biol. 6, e226 (2008).
doi: 10.1371/journal.pbio.0060226
pubmed: 18798692
pmcid: 2535663
Maier, H. J. et al. Infectious bronchitis virus generates spherules from zippered endoplasmic reticulum membranes. MBio 4 (2013).
Reggiori, F. et al. Coronaviruses Hijack the LC3-I-positive EDEMosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication. Cell Host Microbe 7, 500–508 (2010).
doi: 10.1016/j.chom.2010.05.013
pubmed: 20542253
pmcid: 7103375
Fung, T. S. & Liu, D. X. Coronavirus infection, ER stress, apoptosis and innate immunity. Front. Microbiol. 5, 296 (2014).
doi: 10.3389/fmicb.2014.00296
pubmed: 24987391
pmcid: 4060729
Fung, T. S. & Liu, D. X. The ER stress sensor IRE1 and MAP kinase ERK modulate autophagy induction in cells infected with coronavirus infectious bronchitis virus. Virology 533, 34–44. https://doi.org/10.1016/j.virol.2019.05.002 (2019).
doi: 10.1016/j.virol.2019.05.002
pubmed: 31082732
Singh, K. K., Chaubey, G., Chen, J. Y. & Suravajhala, P. Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis. Am. J. Physiol. Cell Physiol. (2020).
Gatti, P., Ilamathi, H. S., Todkar, K. & Germain, M. Mitochondria targeted viral replication and survival strategies—Prospective on SARS-CoV-2. Front. Pharmacol. 11 (2020).
Song, P., Li, W., Xie, J., Hou, Y. & You, C. Cytokine storm induced by SARS-CoV-2. Clin. Chim. Acta (2020).
Pedersen, S. F. & Ho, Y.-C. SARS-CoV-2: a Storm is raging. J. Clin. Investig. 130 (2020).
Rosen, D. A. et al. Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci. Transl. Med. 11, eaau5266. https://doi.org/10.1126/scitranslmed.aau5266 (2019).
Härtter, S., Grözinger, M., Weigmann, H., Röschke, J. & Hiemke, C. Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clin. Pharmacol. Ther. 67, 1–6 (2000).
doi: 10.1067/mcp.2000.104071
pubmed: 10668847
Demisch, K. et al. Melatonin and cortisol increase after fluvoxamine. Br. J. Clin. Pharmacol. 22, 620–622. https://doi.org/10.1111/j.1365-2125.1986.tb02947.x (1986).
doi: 10.1111/j.1365-2125.1986.tb02947.x
pubmed: 3098271
pmcid: 1401188
Gordon, D. E. et al. Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 370, eabe9403. https://doi.org/10.1126/science.abe9403 (2020).
Vela, J. M. Repurposing sigma-1 receptor ligands for COVID-19 therapy? Front. Pharmacol. https://doi.org/10.3389/fphar.2020.582310 (2020).
Papadopoulos, K. I., Sutheesophon, W. & Aw, T. C. Anti-SARS-CoV-2 action of fluvoxamine may be mediated by endothelial nitric oxide synthase. Pharmacopsychiatry 55, 57. https://doi.org/10.1055/a-1641-0357 (2022).
doi: 10.1055/a-1641-0357
pubmed: 34555857
Papadopoulos, K. I., Papadopoulou, A. & Aw, T. C. Beauty and the beast: Host microRNA-155 versus SARS-CoV-2. Hum Cell 36, 908–922. https://doi.org/10.1007/s13577-023-00867-w (2023).
doi: 10.1007/s13577-023-00867-w
pubmed: 36847920
pmcid: 9969954
Papadopoulos, K. I., Papadopoulou, A. & Aw, T. C. Anexelekto (AXL) no more: microRNA-155 (miR-155) controls the “Uncontrolled” in SARS-CoV-2. Hum. Cell 37, 582–592. https://doi.org/10.1007/s13577-024-01041-6 (2024).
doi: 10.1007/s13577-024-01041-6
pubmed: 38472734
Kugler, N., Klein, K. & Zanger, U. M. MiR-155 and other microRNAs downregulate drug metabolizing cytochromes P450 in inflammation. Biochem. Pharmacol. 171, 113725. https://doi.org/10.1016/j.bcp.2019.113725 (2020).
doi: 10.1016/j.bcp.2019.113725
pubmed: 31758923
Wang, X. et al. MiR-155 is involved in major depression disorder and antidepressant treatment via targeting SIRT1. Biosci Rep. https://doi.org/10.1042/bsr20181139 (2018).
Papadopoulos, K. I., Papadopoulou, A. & Aw, T. C. Selective serotonin reuptake inhibitors may influence COVID-19 prognosis through antioxidant and cytoprotective pathways mediated by sigma 1 receptor agonism. Pharmacopsychiatry 55, 305–306. https://doi.org/10.1055/a-1909-2198 (2022).
doi: 10.1055/a-1909-2198
pubmed: 35981550
Trkulja, V. Why we should not recommend or offer fluvoxamine to COVID-19 patients?. Eur. J. Clin. Pharmacol. 79, 321–322. https://doi.org/10.1007/s00228-022-03447-3 (2023).
doi: 10.1007/s00228-022-03447-3
pubmed: 36550263
Reis, G. et al. Oral fluvoxamine with inhaled budesonide for treatment of early-onset COVID-19: A randomized platform trial. Ann. Intern. Med. 176, 667–675 (2023).
doi: 10.7326/M22-3305
pubmed: 37068273