Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19

Reis, Gilmar; Silva, Eduardo Augusto dos Santos Moreira; Silva, Daniela Carla Medeiros; Thabane, Lehana; Campos, Vitoria Helena de Souza; Ferreira, Thiago Santiago; Santos, Castilho Vitor Quirino dos; Nogueira, Ana Maria Ribeiro; Almeida, Ana Paula Figueiredo Guimarães de; Savassi, Leonardo Cançado Monteiro; Neto, Adhemar Dias de Figueiredo; Bitarães, Carina; Milagres, Aline Cruz; Callegari, Eduardo Diniz; Simplicio, Maria Izabel Campos; Ribeiro, Luciene Barra; Oliveira, Rosemary; Harari, Ofir; Wilson, Lindsay A.; Forrest, Jamie I; Ruton, Hinda; Sprague, Sheila; McKay, Paula; Guo, Christina M.; Guyatt, Gordon; Rayner, Craig R.; Boulware, David R.; Ezer, Nicole; Lee, Todd C.; McDonald, Emily G.; Bafadhel, Mona; Butler, Christopher Collett; Silva, Josue Rodrigues; Dybul, Mark; Mills, Edward J.

doi:10.7326/m22-3305

Cited by 25 publications

(19 citation statements)

References 20 publications

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“…5 A follow-up TOGETHER trial (n = 1476) testing fluvoxamine 100 mg twice daily with inhaled budesonide in a majority-vaccinated population demonstrated a 50% reduction in the same composite end point. 8 In contrast, the COVID-OUT and ACTIV-6 trials studying fluvoxamine 50 mg twice daily did not identify a benefit for fluvoxamine. 2 Among these studies, ACTIV-6 is the only trial with a primary outcome of patient-reported sustained recovery and, in this trial of fluvoxamine 100 mg twice daily for 13 days, there was no evidence of benefit.…”

Section: Discussionmentioning

confidence: 98%

“…The TOGETHER trial was stopped early for superiority of fluvoxamine 100 mg twice daily, compared with placebo, with a 32% reduction in the primary composite end point of hospitalization or extended care in an emergency setting . A follow-up TOGETHER trial (n = 1476) testing fluvoxamine 100 mg twice daily with inhaled budesonide in a majority-vaccinated population demonstrated a 50% reduction in the same composite end point . In contrast, the COVID-OUT and ACTIV-6 trials studying fluvoxamine 50 mg twice daily did not identify a benefit for fluvoxamine .…”

Section: Discussionmentioning

confidence: 99%

“…There are important opportunities to learn from the success of the ACTIV platform, including its decentralized approach that intentionally integrated clinical research into clinical care. 8 There is also its spirit of collaboration that brought hundreds of geographically diverse recruitment sites together in partnership. Additionally, its leadership has focused on minimizing bureaucratic barriers while protecting patients, such as the use of centralized institutional review boards.…”

Section: Conflict Ofmentioning

confidence: 99%

“…Fluvoxamine at doses of 100 mg 2 or 3 times daily have demonstrated a reduction in emergency department visits and hospitalizations, although tolerability may be a limitation. A lower dose of 50 mg twice daily had improved tolerability, but this lower dose was not efficacious in 2 clinical trials …”

Section: Introductionmentioning

confidence: 99%

“…A lower dose of 50 mg twice daily had improved tolerability, 6 but this lower dose was not efficacious in 2 clinical trials. 2,5,7,8 The ongoing Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial evaluates repurposed medications in the outpatient setting. 7 A previous trial from ACTIV-6 randomly assigned 1331 adults with mild to moderate COVID-19 to receive fluvoxamine, 50 mg twice daily, or placebo for 10 days.…”

mentioning

confidence: 99%

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Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19

Stewart,

Rebolledo,

Mourad

et al. 2023

JAMA

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ImportanceThe effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain.ObjectiveTo assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19.Design, Setting, and ParticipantsThe ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less.InterventionsParticipants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607).Main Outcomes and MeasuresThe primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28.ResultsAmong 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy = .40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit): 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy = .86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths.Conclusions and RelevanceAmong outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms.Trial RegistrationClinicalTrials.gov Identifier: NCT04885530

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Conflict Ofmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19

Stewart,

Rebolledo,

Mourad

et al. 2023

JAMA

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Matched vs Nonmatched Placebos in a Randomized Trial of COVID-19 Treatments

Reis,

Savassi,

Ferreira

et al. 2024

JAMA Netw Open

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ImportanceMatched placebo interventions are complex and resource intensive. Recent evidence suggests matched placebos may not always be necessary. Previous studies have predominantly evaluated potential bias of nonmatched placebos (ie, differing on dose, frequency of administration, or formulation) in pain and mental health, but to date no systematic examination has been conducted in infectious disease.ObjectiveTo test for differences between nonmatched and matched placebo arms with respect to clinical outcome measures across multiple therapeutics for COVID-19.Design, Setting, and ParticipantsIn a comparative effectiveness research study, a post hoc analysis was conducted of data on individual patients enrolled in a large, multiarm, platform randomized clinical trial in symptomatic adult outpatients with COVID-19 between January 15, 2021, to September 28, 2023, in which the outcomes of both matched and nonmatched placebo groups were reported. Bayesian and frequentist covariate-adjusted techniques were compared with 7 intervention-placebo pairs.ExposuresSeven matched and nonmatched placebo pairs (for a total of 7 comparisons) were evaluated throughout the primary platform trial. Comparisons were made between treatment and its associated matched (concurrent) placebo, as well as with nonmatched placebo (alone and in combination) assessed at a similar time point.Main Outcomes and MeasuresOutcomes assessed included hospitalizations, EuroQol 5-Dimension 5-level scores, and PROMIS Global-10 scores.ResultsA total of 7 intervention-control pairs (N = 2684) were assessed, including 1620 (60.4%) women, with mean (SD) age, 47 (15.2) years; the most common comorbidities were obesity (41.9%) and hypertension (37.9%). In a meta-analysis with decoupled SEs, accounting for overlapping placebo patients, the overall odds ratio (OR) of nonmatched compared with matched placebo was 1.01 (95% credible interval, 0.77-1.32), with posterior probability of equivalence, defined as 0.8 ≤ OR ≤ 1.2 (a deviation from perfect equivalence ie, OR = 1, by no more than 0.2) of 85.4%, implying no significant difference. Unadjusted analysis of the event rate difference between all nonmatched and matched placebo groups did not identify any notable differences across all 7 treatment-placebo combinations assessed. Similar analysis that was conducted for patient-reported quality of life outcomes did not yield statistically significant differences.Conclusions and RelevanceIn this post hoc study of a randomized clinical platform trial, pooling matched and nonmatched placebo patient data did not lead to inconsistencies in treatment effect estimation for any of the investigational drugs. These findings may have significant implications for future platform trials, as the use of nonmatched placebo may improve statistical power, or reduce barriers to placebo implementation.

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Outpatient randomized controlled trials to reduce COVID‐19 hospitalization: Systematic review and meta‐analysis

Sullivan,

Focosi,

Hanley

et al. 2023

Journal of Medical Virology

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This COVID‐19 outpatient randomized controlled trials (RCTs) systematic review compares hospitalization outcomes amongst four treatment classes over pandemic period, geography, variants, and vaccine status. Outpatient RCTs with hospitalization endpoint were identified in Pubmed searches through May 2023, excluding RCTs <30 participants (PROSPERO‐CRD42022369181). Risk of bias was extracted from COVID‐19‐NMA, with odds ratio utilized for pooled comparison. Searches identified 281 studies with 61 published RCTs for 33 diverse interventions analyzed. RCTs were largely unvaccinated cohorts with at least one COVID‐19 hospitalization risk factor. Grouping by class, monoclonal antibodies (mAbs) (OR = 0.31 [95% CI = 0.24−0.40]) had highest hospital reduction efficacy, followed by COVID‐19 convalescent plasma (CCP) (OR = 0.69 [95% CI = 0.53−0.90]), small molecule antivirals (OR = 0.78 [95% CI = 0.48−1.33]), and repurposed drugs (OR = 0.82 [95% CI: 0.72−0.93]). Earlier in disease onset interventions performed better than later. This meta‐analysis allows approximate head‐to‐head comparisons of diverse outpatient interventions. Omicron sublineages (XBB and BQ.1.1) are resistant to mAbs Despite trial heterogeneity, this pooled comparison by intervention class indicated oral antivirals are the preferred outpatient treatment where available, but intravenous interventions from convalescent plasma to remdesivir are also effective and necessary in constrained medical resource settings or for acute and chronic COVID‐19 in the immunocompromised.

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Oral Fluvoxamine With Inhaled Budesonide for Treatment of Early-Onset COVID-19

Cited by 25 publications

References 20 publications

Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19

Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19

Matched vs Nonmatched Placebos in a Randomized Trial of COVID-19 Treatments

Outpatient randomized controlled trials to reduce COVID‐19 hospitalization: Systematic review and meta‐analysis

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