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

BackgroundThe 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. MethodsPLATCOV 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 (NCT05041907). FindingsBetween 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%). InterpretationFluoxetine 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. FundingWellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator. Evidence before this studyThe 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 studyWe 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 evidenceFluoxetine 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.

Temporal changes in SARS-CoV-2 clearance kinetics and the optimal design of phase 2 antiviral studies (preprint)

BackgroundEffective antiviral drugs prevent hospitalisation and death in COVID-19. Antiviral efficacy can be assessed efficiently in-vivo by measuring rates of SARS-CoV-2 clearance estimated from serial viral densities measured in nasopharyngeal or oropharyngeal swab eluates. The changing epidemiology of SARS-CoV-2 infection has substantially affected viral clearance kinetics and thus the optimal design and interpretation of antiviral pharmacometric evaluations. MethodsSerial viral density data were analysed from patients enrolled in a large multicentre randomised adaptive pharmacodynamic platform trial (PLATCOV) comparing antiviral interventions for SARS-CoV-2. Viral clearance rates over one week were estimated and boot-strap re-sampling was used to assess the optimal duration of follow-up for pharmacometric assessment, where optimal is defined as maximising the expected z-score. ResultsBetween 29 September 2021 and 20 October 2023, 1264 patients were randomised. Unblinded data were available from 800 patients (16,818 oropharyngeal viral qPCR measurements). SARS-CoV-2 viral clearance was biphasic (bi-exponential). The first phase () was accelerated by effective interventions. For all the effective interventions studied, maximum discriminative power (maximum expected z-score) was obtained when evaluating serial data from the first 5 days after enrolment. Over the two year period studied, median viral clearance half-lives estimated over 7 days have shortened from 16.8 hours in September 2021 to 9.3 hours in October 2023 in patients receiving no antiviral drugs, equivalent to a relative reduction of 44% [95% credible interval (CrI): 17 to 67%]. A parallel trend was observed in treated patients. In the ritonavir-boosted nirmatrelvir arm the median clearance half-life declined from 6.6 hours in June 2022 to 4.8 hours in October 2023, a relative reduction of 26% [95%CrI: -4 to 42%]. ConclusionsSARS-CoV-2 viral clearance kinetics in symptomatic vaccinated individuals have accelerated substantially over the past two years. Antiviral efficacy in COVID-19 can now be assessed efficiently in-vivo using serial qPCRs from duplicate oropharyngeal swab eluates taken daily for 5 days after drug administration. FundingWellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.