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.

Clinical antiviral efficacy of favipiravir in early COVID-19 (PLATCOV): an open- label, randomised, controlled adaptive platform trial (preprint)

Background: Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir has been recommended for the treatment of COVID-19 in some countries. Methods: In a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomised to one of ten treatment arms including high dose oral favipiravir (3.6g on day 0 followed by 1.6g daily to complete 7 days treatment) or no study drug. The primary outcome assessed in a modified intention-to-treat population (mITT) was the rate of viral clearance (derived under a linear mixed-effects model from the daily log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 8 days [18 swabs per patient]). The safety population included all patients who received at least one dose of the allocated intervention. This ongoing adaptive platform trial is registered at ClinicalTrials.gov (NCT05041907). Results: In the final analysis, the mITT population contained data from 114 patients randomised to favipiravir and 126 patients randomised concurrently to no study drug. Under the linear mixed-effects model fitted to all oropharyngeal viral density estimates in the first 8 days from randomisation (4,318 swabs), there was no difference in the rate of viral clearance between patients administered favipiravir and patients receiving no study drug -1% (95% CI: -14 to 14% change). High dose favipiravir was well tolerated. Interpretation: Favipiravir does not accelerate viral clearance in early symptomatic COVID-19.

Clinical antiviral efficacy of remdesivir and casirivimab/imdevimab against the SARS-CoV-2 Delta and Omicron variants (preprint)

BackgroundUncertainty over the therapeutic benefit provided by parenteral remdesivir in COVID-19 has resulted in varying treatment guidelines. Early in the pandemic the monoclonal antibody cocktail, casirivimab/imdevimab, proved highly effective in clinical trials but because of weak or absent in vitro activity against the SARS-CoV-2 Omicron BA.1 subvariant, it is no longer recommended. MethodsIn a multicenter open label, randomized, controlled adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to one of eight treatment arms including intravenous remdesivir (200mg followed by 100mg daily for five days), casirivimab/imdevimab (600mg/600mg), and no study drug. The primary outcome was the viral clearance rate in the modified intention-to-treat population derived from daily log10 viral densities (days 0-7) in standardized duplicate oropharyngeal swab eluates. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907). ResultsAcceleration in mean estimated SARS-CoV-2 viral clearance, compared with the contemporaneous no study drug arm (n=64), was 42% (95%CI 18 to 73%) for remdesivir (n=67). Acceleration with casirivimab/imdevimab was 58% (95%CI: 10 to 120) in Delta (n=13), and 20% (95%CI: 3 to 43) in Omicron variant (n=61) infections compared with contemporaneous no study drug arm (n=84). In a post hoc subgroup analysis viral clearance was accelerated by 8% in BA.1 (95%CI: -21 to 59) and 23% (95%CI: 3 to 49) in BA.2 and BA.5 Omicron subvariants. ConclusionsParenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Despite substantially reduced in vitro activities, casirivimab/imdevimab retains in vivo antiviral activity against COVID-19 infections caused by currently prevalent Omicron subvariants. Brief summaryIn early symptomatic COVID-19 remdesivir accelerated viral clearance by 42% while the monoclonal antibody cocktail casirivimab/imdevimab accelerated clearance by approximately 60% in SARS-CoV-2 Delta variant infections, and by approximately 25% in infections with Omicron subvariants BA.2 and BA.5.

Pharmacometric assessment of the in-vivo antiviral activity of ivermectin in early symptomatic COVID-19 (preprint)

Background: There is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infection. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has significant antiviral activity in vivo is uncertain. Methods: In a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high dose ivermectin (600micrograms/kg daily for seven days), the monoclonal antibodies casirivimab and imdevimab (600mg/600mg), and no study drug. Viral clearance rates were derived from daily duplicate oropharyngeal quantitative PCR measurements. This ongoing trial is registered at ClinicalTrials.gov (NCT05041907). Results: Randomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Compared with the no study drug arm, the mean estimated SARS-CoV-2 viral clearance following ivermectin was 9.1% slower [95%CI -27.2% to +11.8%; n=45 versus n=41], whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster [95%CI +7.0% to +115.1%; n=10 (Delta variant) versus n=41]. Conclusions: High dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Measured in this way viral clearance rate is a valuable

Facilitating safe discharge through predicting disease progression in moderate COVID-19: a prospective cohort study to develop and validate a clinical prediction model in resource-limited settings (preprint)

BackgroundIn locations where few people have received COVID-19 vaccines, health systems remain vulnerable to surges in SARS-CoV-2 infections. Tools to identify patients suitable for community-based management are urgently needed. MethodsWe prospectively recruited adults presenting to two hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 in order to develop and validate a clinical prediction model to rule-out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2 < 94%; respiratory rate > 30 bpm; SpO2/FiO2 < 400; or death. We specified a priori that each model would contain three clinical parameters (age, sex and SpO2) and one of seven shortlisted biochemical biomarkers measurable using near-patient tests (CRP, D-dimer, IL-6, NLR, PCT, sTREM-1 or suPAR), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration and clinical utility of the models in a temporal external validation cohort. Findings426 participants were recruited, of whom 89 (21{middle dot}0%) met the primary outcome. 257 participants comprised the development cohort and 166 comprised the validation cohort. The three models containing NLR, suPAR or IL-6 demonstrated promising discrimination (c-statistics: 0{middle dot}72 to 0{middle dot}74) and calibration (calibration slopes: 1{middle dot}01 to 1{middle dot}05) in the validation cohort, and provided greater utility than a model containing the clinical parameters alone. InterpretationWe present three clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources. FundingMedecins Sans Frontieres, India. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSA living systematic review by Wynants et al. identified 137 COVID-19 prediction models, 47 of which were derived to predict whether patients with COVID-19 will have an adverse outcome. Most lacked external validation, relied on retrospective data, did not focus on patients with moderate disease, were at high risk of bias, and were not practical for use in resource-limited settings. To identify promising biochemical biomarkers which may have been evaluated independently of a prediction model and therefore not captured by this review, we searched PubMed on 1 June 2020 using synonyms of "SARS-CoV-2" AND ["biomarker" OR "prognosis"]. We identified 1,214 studies evaluating biochemical biomarkers of potential value in the prognostication of COVID-19 illness. In consultation with FIND (Geneva, Switzerland) we shortlisted seven candidates for evaluation in this study, all of which are measurable using near-patient tests which are either currently available or in late-stage development. Added value of this studyWe followed the TRIPOD guidelines to develop and validate three promising clinical prediction models to help clinicians identify which patients presenting with moderate COVID-19 can be safely managed in the community. Each model contains three easily ascertained clinical parameters (age, sex, and SpO2) and one biochemical biomarker (NLR, suPAR or IL-6), and would be practical for implementation in high-patient-throughput low resource settings. The models showed promising discrimination and calibration in the validation cohort. The inclusion of a biomarker test improved prognostication compared to a model containing the clinical parameters alone, and extended the range of contexts in which such a tool might provide utility to include situations when bed pressures are less critical, for example at earlier points in a COVID-19 surge. Implications of all the available evidencePrognostic models should be developed for clearly-defined clinical use-cases. We report the development and temporal validation of three clinical prediction models to rule-out progression to supplemental oxygen requirement amongst patients presenting with moderate COVID-19. The models are readily implementable and should prove useful in triage and resource allocation. We provide our full models to enable independent validation.