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Journal Article Epublish 2 citations

PubMed: 39896880 DOI: 10.1016/j.eclinm.2024.103036

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

EClinicalMedicine 80:103036

Authors: Podjanee Jittamala, Simon Boyd, William H K Schilling, James A Watson, Thundon Ngamprasertchai, Tanaya Siripoon, Viravarn Luvira, Elizabeth M Batty, Phrutsamon Wongnak, Lisia M Esper, Pedro J Almeida, Cintia Cruz, Fernando R Ascencao, Renato S Aguiar, Najia K Ghanchi, James J Callery, Shivani Singh, Varaporn Kruabkontho, Thatsanun Ngernseng, Jaruwan Tubprasert, Wanassanan Madmanee, Kanokon Suwannasin, Amornrat Promsongsil, Borimas Hanboonkunupakarn, Kittiyod Poovorawan, Manus Potaporn, Attasit Srisubat, Bootsakorn Loharjun, Walter R J Taylor, Farah Qamar, Abdul Momin Kazi, M Asim Beg, Danoy Chommanam, Sisouphanh Vidhamaly, Kesinee Chotivanich, Mallika Imwong, Sasithon Pukrittayakamee, Arjen M Dondorp, Nicholas P J Day, Mauro M Teixeira, Watcharapong Piyaphanee, Weerapong Phumratanaprapin, Nicholas J White

Affiliations

  • Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Infectious Diseases Data Observatory, Big Data Institute, Oxford, United Kingdom.
  • Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • Clinical Research Unit, Center for Advanced and Innovative Therapies, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
  • Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
  • Department of Genetics, Ecology and Evolution, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
  • Aga Khan University, Karachi, Pakistan.
  • Department of Medical Services, Ministry of Public Health, Bangkok, Thailand.
  • Laos-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Laos.
  • Pulmonology Department, Mahosot Hospital, Vientiane, Laos.
  • Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Abstract

Background

The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine were repurposed for the treatment of early COVID-19 based on their antiviral activity , and observational and clinical trial evidence suggesting they prevented progression to severe disease. However, these SSRIs have not been recommended in therapeutic guidelines and their antiviral activity 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) between 5 April 2022 and 8 May 2023. Patients were assigned using block randomisation to one of eleven treatment arms including oral fluoxetine (40 mg/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 until day 7. Measurements were taken daily between days 0 and 7 and analysed 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 log viral densities measured in standardised duplicate oropharyngeal swab eluates taken daily over one week (18 measurements per patient). Secondary endpoints were all-cause hospital admission at 28 days, and time to resolution of fever and symptoms. This ongoing trial is registered at ClinicalTrials.gov (NCT05041907).

Findings

271 patients were concurrently randomised to either fluoxetine (n = 120) or no study drug (n = 151). All patients had received at least one COVID-19 vaccine dose and 67% were female (182/271). In the primary analysis, viral clearance rates following fluoxetine were compatible with a small or no increase relative to the no study drug arm (15% increase; 95% credible interval (CrI): -2 to 34%). There were no deaths or hospitalisations in either arm. There were no significant differences in times to symptom resolution or fever clearance between the fluoxetine and the no study drug arms (although only a quarter of patients were febrile at baseline). Fluoxetine was well tolerated, there were no serious adverse events and only one grade 3 adverse event in the intervention arm.

Interpretation

Overall, the evidence from this study is compatible with fluoxetine having a weak antiviral activity against SARS-CoV-2, although the primary endpoint is also compatible with no effect. This level of antiviral efficacy is substantially less than with other currently available antiviral drugs.

Funding

Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.

MeSH

Pharmaceutical Preparations, Fluoxetine, Signs And Symptoms, Drug-Related Side Effects And Adverse Reactions, Covid-19, Therapeutics, Antiviral Agents

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