Antiviral efficacy of fluoxetine in early symptomatic COVID-19: an open-label, randomised, controlled, adaptive platform trial (PLATCOV)
MD Podjanee Jittamala, MBBS Simon Boyd, MBBS William Hk Schilling, James A Watson, MD Thundon Ngamprasertchai, MD Tanaya Siripoon, MD Viravarn Luvira, PhD Elizabeth M Batty, PhD Phrutsamon Wongnak, Lisia M Esper, Pedro J Almeida, MD Cintia Cruz, Fernando R Ascencao, Renato S Aguiar, PhD Najia K Ghanchi, James J Callery, MBBS Shivani Singh, PhD Varaporn Kruabkontho, MBA Thatsanun Ngernseng, Pharm.D Jaruwan Tubprasert, Wanassanan Madmanee, Kanokon Suwannasin, Amornrat Promsongsil, MD Borimas Hanboonkunupakarn, MD Kittiyod Poovorawan, MD Manus Potaporn, MD Attasit Srisubat, MD Bootsakorn Loharjun, Walter Rj Taylor, Farah Qamar, Abdul Momin Kazi, M Asim Beg, Danoy Chommanam, Sisouphanh Vidhamaly, PhD Kesinee Chotivanich, PhD Mallika Imwong, MBBS Sasithon Pukrittayakamee, Arjen M Dondorp, Nicholas Pj Day, MD Mauro M Teixeira, MD Watcharapong Piyaphanee, MD Weerapong Phumratanaprapin, Nicholas J White
doi:10.1101/2024.01.16.24301337
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 lowrisk adult outpatients aged 18-50 with early symptomatic COVID-19 (symptoms <4 days). Patients
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.
Contributors PJ-investigation, methodology, project administration, supervision, validation, and writingoriginal 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. JAW-conceptualisation, data curation, formal analysis, funding acquisition, methodology, visualisation, and writing-original draft. TN, TS, VL-Investigation, methodology, supervision. EMB-data curation, formal analysis, visualisation. PW-data curation, formal analysis, visualisation, and writing-original draft. RA, FA, NG-formal analysis, investigation. LE, PA, CC, JJC, SS, VK, TN, JT, FQ, AMK -methodology, investigation, project administration. WM, KS, AP-investigation, methodology. BH, KP-
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'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The '
'selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine were repurposed '
'for the treatment of early COVID-19 based on their antiviral activity<jats:italic>in '
'vitro</jats:italic>, 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<jats:italic>in vivo</jats:italic>has not been '
'characterised.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p><jats:p>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<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>).</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>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%).</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Fluoxetine '
'has<jats:italic>in vivo</jats:italic>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.</jats:p></jats:sec><jats:sec><jats:title>Funding</jats:title><jats:p>Wellcome '
'Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics '
'Accelerator.</jats:p></jats:sec><jats:sec><jats:title>Evidence before this '
'study</jats:title><jats:p>The SSRIs fluoxetine and fluvoxamine have been proposed as COVID-19 '
'therapeutics based initially on observational, randomised trial and<jats:italic>in '
'vitro</jats:italic>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 30<jats:sup>th</jats:sup>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).</jats:p></jats:sec><jats:sec><jats:title>Added value of '
'the study</jats:title><jats:p>We showed that in early COVID-19 illness the SSRI fluoxetine '
'has weak antiviral activity<jats:italic>in vivo</jats:italic>. 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<jats:italic>in '
'vivo</jats:italic>antiviral effects with tractable sample '
'sizes.</jats:p></jats:sec><jats:sec><jats:title>Implications of available '
'evidence</jats:title><jats:p>Fluoxetine has weak<jats:italic>in vivo</jats:italic>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.</jats:p></jats:sec>',
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