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

Abstract Background The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine were repurposed for the treatment of early COVID-19 based on their antiviral activityin 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 activityin vivohas 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 &lt;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 (&gt;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<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">ClinicalTrials.gov</jats:ext-link>(<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT05041907">NCT05041907</jats:ext-link>).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 hasin vivoantiviral 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 andin vitroevidence. 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 30thNovember 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 activityin 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 ofin vivoantiviral effects with tractable sample sizes.Implications of available evidence Fluoxetine has weakin vivoantiviral 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..

Medienart:	Preprint

Erscheinungsjahr:	2024
Erschienen:	2024

Enthalten in:	bioRxiv.org - (2024) vom: 22. Jan. Zur Gesamtaufnahme - year:2024

Sprache:	Englisch

Beteiligte Personen:

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

Links:	Volltext [kostenfrei]

Themen:	570 Biology

doi:	10.1101/2024.01.16.24301337

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PPN (Katalog-ID):	XBI042211425