Antiviral efficacy of fluoxetine in early symptomatic COVID-19: an open-label, randomised, controlled, adaptive platform trial (PLATCOV)
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
eClinicalMedicine, doi:10.1016/j.eclinm.2024.103036
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 therapeutic 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) 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 10 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).
Ethics The trial was approved in Thailand by the Faculty of Tropical Medicine Ethics Committee (Mahidol University, FTMEC Ref: TMEC 21-058) and the Central Research Ethics Committee (CREC, Bangkok, Thailand, CREC Ref: CREC048/64BP-MED34), in Brazil by the Research Ethics Committee of the Universidade Federal de Minas Gerais (COEP-UFMG, Minas Gerais, Brazil, COEP-UFMG) and National Research Ethics Contributors PJ-investigation, methodology, project administration, supervision, validation, and writing-original draft. SB-investigation, methodology, project administration, writing-original draft. PJ and SB contributed equally. WHKS-funding acquisition, investigation, methodology, project administration, supervision, validation, and writing-original draft. JAWconceptualisation, data curation, formal analysis, funding acquisition, methodology, visualisation, and writing-original draft. TN, TS, and VL-Investigation, methodology, supervision. EMB-data curation, formal analysis, visualisation. PW-data curation, formal analysis, visualisation, and writing-original draft. RSA, FRA, and NKG-formal analysis, investigation. LME, PJA, CC, JJC, SS, VK, TN, JT, FQ, and AMK-methodology, investigation, project administration. WM, KS, and AP-investigation, methodology. BH and KP-methodology, investigation, supervision. MP, AS, and BL-resources. WRJT-methodology, supervision. KC and MI-formal analysis, investigation, resources, supervision. SP, AMD, MAB, MMT, WaP, WeP, DC, and SV-methodology,..
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