Antiviral efficacy of fluoxetine in early symptomatic COVID-19: an open-label, randomised, controlled, adaptive platform trial (PLATCOV)

Background The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine were repurposed for the treatment of early COVID-19 based on their antiviral activity in vitro , and observational and clinical trial evidence suggesting they prevented progression to severe disease. However, these SSRIs have not been recommended in guidelines and their antiviral activity in vivo has not been characterised. Methods PLATCOV is an open-label, multicentre, phase 2, randomised, controlled, adaptive pharmacometric platform trial running in Thailand, Brazil, Pakistan, and Laos. We recruited low-risk adult outpatients aged 18-50 with early symptomatic COVID-19 (symptoms <4 days). Patients were assigned using block randomisation to one of eleven treatment arms including oral fluoxetine (40mg/day for 7 days), or no study drug. Uniform randomisation ratios were applied across the active treatment groups while the no study drug group comprised ≥20% of patients at all times. The primary endpoint was the rate of oropharyngeal viral clearance assessed in a modified intention-to-treat population (>2 days follow-up). The viral clearance rate was estimated under a Bayesian hierarchical linear model fitted to the log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over one week (18 measurements per patient). This ongoing trial is registered at [ClinicalTrials.gov][1] ([NCT05041907][2]). Findings Between 5 April 2022 and 8 May 2023 271 patients were concurrently randomised to either fluoxetine (n=120) or no study drug (n=151). Fluoxetine was well tolerated and accelerated the rate of viral clearance relative to the no study drug arm by 15% (95% credible interval (CrI): 2% to 34%). In a pooled meta-analysis including all unblinded patients the antiviral activity of fluoxetine was substantially less than ritonavir-boosted nirmatrelvir-85% increase in rate of viral clearance (95% CrI: 61 to 112%); and less than remdesivir 35% (14 to 59%), molnupiravir 37% (18 to 60%), and casirivimab/imdevimab 29% (10 to 48%). Interpretation Fluoxetine has in vivo antiviral activity against SARS-CoV-2. Although the level of antiviral efficacy is substantially less than with other currently available antiviral drugs, fluoxetine might still be useful in prophylaxis where less antiviral effect is required. Funding Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator. Evidence before this study The SSRIs fluoxetine and fluvoxamine have been proposed as COVID-19 therapeutics based initially on observational, randomised trial and in vitro evidence. The observational reports suggested that patients taking SSRIs had a reduced probability of developing severe COVID-19 and dying. We searched PubMed and EMBASE for studies in English up until the 30th November 2023 using the search terms “fluoxetine”, “fluvoxamine” and “COVID-19” with the search restricted to randomised controlled trials (RCTs). Eight outpatient fluvoxamine RCTs were identified. There were no fluoxetine RCTs in outpatients. A meta-analysis of available RCTs is compatible with a moderate reduction in hospitalisation and death in COVID-19 patients with an estimated risk ratio of 0.80 (95% CI: 0.62,1.01). Added value of the study We showed that in early COVID-19 illness the SSRI fluoxetine has weak antiviral activity in vivo . This activity is substantially less than other available antivirals such as ritonavir-boosted nirmatrelvir and molnupiravir. The pharmacometric approach described here provides a quantitative measure of in vivo antiviral effects with tractable sample sizes. Implications of available evidence Fluoxetine has weak in vivo antiviral activity in early COVID-19. This is insufficient for treatment but, as less antiviral activity is required to prevent an infection, fluoxetine could still be beneficial in prophylaxis. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT05041907 ### Funding Statement This study was funded by the Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Faculty of Tropical Medicine gave ethical approval for this work Ref: TMEC 21.058 Central Research Ethics Committee, Bangkok, gave ethical approval for this work CREC Ref: CREC048/64BP-MED34. Research Ethics Committee of the Universidade Federal de Minas Gerais gave ethical approval for this work. National Research Ethics Commission, Brazil gave ethical approval for this work Ref: CAAE:51593421.1.0000.5149 National Ethics Committee for Health Research, Laos, gave ethical approval for this work Submission ID 2022.48 IRB of Federal Drug Administration, Laos, gave ethical approval for this work Ethics committee of Faculty of Tropical Medicine gave ethical approval for this work Ref 13066/FDD.12Dec2022 Ethics committee of National Bioethics Committee, Pakistan, gave ethical approval for this work Ref NBC No.4.87/COVID-111/22/842 Ethics Review Committee, Pakistan, gave ethical approval for this work. Ethics committee of the Drug Regulatory Authority of Pakistan, gave ethical approval for this work DRAP Ref: No.03.18/2022.CT (PS) Ethics committee of Oxford University Tropical Research Ethics Committee, gave ethical approval for this work OxTREC Ref: 24.21 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All code and de-identified participant data required for replication of the study’s endpoints are openly accessible via GitHub, as well as the study protocol and statistical analysis plan, from publication date onwards: Individual Patient Data can be requested and may be shared according to the terms defined in the MORU data sharing policy with other researchers to use in the future from the date of publication. Further information on how to apply is found here: . [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05041907&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F18%2F2024.01.16.24301337.atom