Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial

Question  Does 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, shorten symptom duration among adult (aged ≥30 years) outpatients with symptomatic mild to moderate COVID-19?

Findings  In this platform randomized clinical trial conducted during a period of predominance for the Delta and Omicron variants in the US, including 1288 adult outpatients with COVID-19 treated with fluvoxamine vs placebo, the hazard ratio was 0.96 (95% credible interval, 0.86-1.06) for time to sustained recovery with a posterior P = .21 for the probability of improvement. This did not meet the prespecified threshold of greater than 0.95 for posterior probability.

Meaning  These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19.

Importance  The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear.

Objective  To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US.

Design, Setting, and Participants  The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US.

Interventions  Participants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo.

Main Outcomes and Measures  The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28.

Results  Among 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups.

Conclusions and Relevance  Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19.

Trial Registration  ClinicalTrials.gov Identifier: NCT04885530

There remains a need for oral therapies to prevent progression to severe COVID-19.¹ Novel oral antivirals have demonstrated a clinical benefit in unvaccinated persons; however, the efficacy of the currently recommended therapies for mild to moderate COVID-19 among vaccinated patients is unclear and may be lower than what was reported among unvaccinated populations.^2,3 Repurposing approved drugs developed for other conditions presents an attractive strategy to identify new treatment options and expand access to potentially lifesaving care.^4,5

Fluvoxamine is a selective serotonin reuptake inhibitor approved by the US Food and Drug Administration in 1994 for the treatment of obsessive-compulsive disorder and is now used to treat a variety of psychiatric conditions, including social anxiety disorder and depression.⁶ Fluvoxamine also has been noted to activate the σ-1 receptor, which may decrease inflammation by reducing endoplasmic reticulum stress and downregulating the expression of inflammatory genes. Early COVID-19 studies reported improved clinical outcomes in participants receiving fluvoxamine.^7-9

A placebo-controlled, randomized, adaptive platform trial (TOGETHER trial)¹⁰ of 1497 symptomatic adults in Brazil who had confirmed SARS-CoV-2 and a known risk factor for progression to severe COVID-19 found treatment with 100 mg of fluvoxamine twice daily for 10 days reduced the need for hospitalization (defined as retention in an emergency setting or transfer to a tertiary hospital). However, tolerability has been identified as a potential limiting factor for use of this dose of fluvoxamine, with 74% of participants in the fluvoxamine group reporting completion of more than 80% of possible doses.

The STOP COVID 2 trial,¹¹ in which participants were randomized to receive 100 mg of fluvoxamine twice daily or placebo for 15 days, was stopped for futility in May 2021 after an interim analysis found that the low event rate (for hypoxia or hospitalization due to COVID-19) seen in the trial with the original sample size was associated with a conditional probability of less than 10% for demonstrating efficacy of fluvoxamine. A subsequent meta-analysis⁷ of 3 clinical trials found a high probability (94.1%-98.6%) that fluvoxamine was associated with a reduced risk of hospitalization for COVID-19 with a risk ratio of 0.75 (95% CI, 0.58-0.97). Given these conflicting results, regulatory authorities and guideline committees have not recommended fluvoxamine as an early treatment for COVID-19. In addition, uncontrolled observational data suggested a lower 50-mg dose would be more tolerable.¹²

The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial is investigating the use of repurposed drugs (a 50-mg, twice-daily dose of fluvoxamine for 10 days vs placebo in this report) among nonhospitalized adults with mild to moderate COVID-19.

This ongoing double-blind, placebo-controlled platform randomized clinical trial is being conducted using a decentralized approach, allowing for use in a wide range of settings within health care systems and the community. The study has enrolled outpatients with mild to moderate COVID-19 and a confirmed positive polymerase chain reaction or antigen test for SARS-CoV-2 infection, including positive results from home-based testing. The trial protocol and the statistical analysis plan appear in Supplement 1.

The trial protocol was approved by each site’s institutional review board. Informed consent was obtained from each participant either via written or electronic consent. An independent data and safety monitoring committee oversaw participant safety, efficacy, and trial conduct.

Recruitment into the platform trial opened on June 11, 2021, and is ongoing. Participants were enrolled into the fluvoxamine group or the placebo group between August 6, 2021, and May 27, 2022, at 91 sites in the US. The 2 groups (fluvoxamine and matching placebo) were closed after meeting the prespecified accrual goal. Participants were identified by investigators at trial sites or were self-identified by contacting a central study telephone hotline. Participants without a local site were managed via interactions with the coordinating call center or website.

The trial sites verified eligibility criteria, including (1) age of 30 years or older, (2) confirmed SARS-CoV-2 infection for 10 days or less, and (3) whether experiencing 2 or more COVID-19 symptoms for 7 days or less from the time of consent (the full eligibility criteria appear in Supplement 1). Symptoms included the following: fatigue, dyspnea, fever, cough, nausea, vomiting, diarrhea, body aches, chills, headache, sore throat, nasal symptoms, and loss of sense of taste or smell. Receipt of a SARS-CoV-2 vaccine was not an exclusion criterion. Use of standard COVID-19 therapies available under US Food and Drug Administration approval or emergency use authorization was permissible.

Exclusion criteria included hospitalization, known allergies or contraindications (including to prohibited concomitant medications), and use of fluvoxamine within 14 days of enrollment.

Within the platform trial, drugs could be added or removed according to the adaptive design, emerging evidence, or both. During the period that randomization to the fluvoxamine group was open, participants were assigned using a random number generator to 1 of the drugs actively enrolling, which included 50 mg of fluvoxamine twice daily for 10 days, 400 μg/kg/d of oral ivermectin for 3 days, and 200 μg of inhaled fluticasone furoate once daily for 14 days, or to a matching placebo. Because multiple study drugs were available, randomization occurred based on the appropriateness of each drug for the participant as determined by the eligibility criteria (Figure 1). Participants could choose to opt out of being randomized to specific drugs during the consent process.

At the first step of randomization, participants were assigned to receive either placebo or active drug in a ratio of 1:m, where m is the number of study drug groups for which participants were eligible. The more study groups for which a participant was eligible, the greater the chance of receiving the active study drug. Subsequently, participants were randomized among the m study groups with equal probability. The trial was designed to share information and participants who were randomized to receive placebo contributed data to all of the placebo groups for which eligibility to the matching study drug was met (Figure 1).

Participants received a 10-day supply of either fluvoxamine or placebo matching fluvoxamine in bottles provided by the manufacturer (Apotex) via direct home delivery from a central pharmacy. Participants self-administered 50 mg of fluvoxamine or matching placebo twice daily for 10 consecutive days. For the alternative active drugs (ivermectin or inhaled fluticasone furoate), packaging for the matching placebo was identical to that of the associated drug.

The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). This was selected a priori from among the 2 coprimary outcomes that remained available to the other drugs (additional information about the other drugs in this platform trial appears in Supplement 1). By definition, participants who died did not recover regardless of reported freedom from symptoms.

There were 7 secondary outcomes, including hospitalization or death by day 28; the mean amount of time spent feeling unwell; COVID Clinical Progression Scale scores on days 7, 14, and 28; mortality through day 28; and the composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28. The final secondary outcome, the PROMIS-29 (Patient-Reported Outcomes Measurement Information System 29) profile, was to be assessed through day 90 and is not reported here because of the longer follow-up.

The study was designed as a decentralized trial and all study visits were planned as remote. Screening and eligibility were self-reported by the participants and confirmed by the investigators at the study sites. A positive SARS-CoV-2 test result was verified by the investigators at the study sites prior to randomization. For the screening visit, participants self-reported demographic information, eligibility criteria, medical history, concomitant medications, COVID-19 symptoms, and completed quality-of-life questionnaires.

A central investigational pharmacy distributed the drugs (either active or placebo) to residential addresses provided by the participants, and shipping and delivery were tracked. Confirmation that the drugs were delivered to the participant’s address was required for the participant to be included in the analysis. Receipt of the study drug was defined as day 1.

Participants were asked to complete assessments and report safety events daily through the first 14 days. From days 15 to 28, participants continued to report if they had symptoms until they had experienced 3 consecutive days without symptoms. Follow-up visits occurred at days 28 and 90. At each study assessment, participants self-reported symptoms and severity, health care visits, and whether they were taking any new medications. Additional details appear in Supplement 2.

This platform trial was designed to be analyzed with the possibility of adding and dropping drug groups as the trial progresses. Regression modeling was the general analytical approach used. Proportional hazard regression was used for the time-to-event analysis. Cumulative probability ordinal regression models were used for the ordinal outcomes. The mean time spent unwell was estimated using a longitudinal ordinal regression model as a quantification of benefit (additional information appears in the statistical analysis plan in Supplement 1).

The planned primary outcome analysis was a Bayesian proportional hazards model. The primary inferential, decision-making quantity was the posterior distribution for the treatment assignment hazard ratio (HR), with an HR greater than 1 indicating benefit. If the posterior probability of benefit exceeded 0.95 at any of the interim or final analyses, the trial would conclude efficacy of the intervention. To preserve a type I error rate of less than 0.05, the prior used for the treatment effect parameter on the log_e relative hazard scale was a normal distribution centered at 0 and scaled to an SD of 0.1. All other parameter priors were noninformative using the software default of 2.5 times the ratio of the SD of the outcome divided by the SD of the predictor variable. The study design was estimated to have 80% power to detect an HR of 1.2 for the primary outcome.

In addition to randomization assignment, the primary outcome model included the following predictor variables: age (as a restricted cubic spline), sex, duration of symptoms prior to receipt of study drug, calendar time (as a restricted cubic spline), vaccination status, geographic region (Midwest, Northeast, South, and West), call center indicator, and baseline symptom severity. The proportional hazards assumption of the primary outcome was evaluated by generating visual diagnostics such as the log-log plot and plots of time-dependent regression coefficients for each predictor in the model (a diagnostic that indicates deviations from proportionality if the time-dependent coefficients are not constant in time).

The secondary outcomes were analyzed with Bayesian regression models (either proportional hazards or proportional odds). Noninformative priors were used for all parameters. The secondary outcomes were not used for formal decision-making and no decision threshold was selected. The findings for the analyses of the secondary outcomes should be interpreted as exploratory because of the potential for type I error due to multiple comparisons. The same set of covariates used in the primary outcome model was used in the analysis of the secondary outcomes, provided the outcome accrued enough events to be analyzed with covariate adjustment.

To achieve the sample size in this ongoing platform trial, once 1200 participants had been randomized to the drug group or matching placebo and had received the drug, the choice for additional participants in the drug group was removed from the platform. Some participants had already consented to participate but had not yet been randomized or received the drug at the time of the drug group closure, and these participants were allowed to continue in the trial. As a platform trial, the primary analysis is implemented separately for each drug group. The placebo group consists of all randomized participants who meet the eligibility criteria for the study drug and includes those who received the fluvoxamine-matched placebo and those who received the placebo matching an alternative drug (ivermectin or inhaled fluticasone furoate).

Based on the experience of other remotely conducted trials,^13,14 it was recognized that medication delivery (placebo or drug) may not always occur (eg, delivery failure, participant withdrawal, or hospitalization). For this trial, the full analysis set for the primary outcome analysis included all participants who received fluvoxamine or placebo and the participants were analyzed as randomized. All available data were used to compare each active study drug vs placebo control, regardless of adherence to the trial protocol after randomization. In both the analyses for the primary and secondary outcomes, missing data among covariates were addressed with conditional mean imputation because the amount of missing covariate data was small (<5%).

A prespecified analysis tested for differential treatment effects as a function of preexisting participant characteristics. The analysis of heterogeneity for the treatment effect included age, the number of days with symptoms, body mass index (BMI), symptom severity on day 1, calendar time (surrogate for the circulating SARS-CoV-2 Delta or Omicron variant), sex, and vaccinations status. The continuous variables were modeled as such without creating subgroups.

The analyses were performed using R version 4.1 (R Foundation for Statistical Computing) and the following primary packages: rstanarm, rmsb, and survival.¹⁵ Additional details appear in Supplement 2.

Of the 1331 participants who were randomized, 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group; Figure 1). Of the 614 participants receiving placebo, 326 (53%) received placebo matching fluvoxamine and 288 (47%) received placebo matching an alternative drug (ivermectin or inhaled fluticasone furoate).

The median age of the participants was 47 years (IQR, 38-57 years) and 42% were aged 50 years or older (Table 1). The population was 57% female, 6.4% identified as Asian, 7.5% identified as Black or African American, 17% reported being of Hispanic or Latino ethnicity, and 81% identified as White. Although not required for enrollment, high-risk comorbidities were prevalent, including a BMI (calculated as weight in kilograms divided by height in meters squared) greater than 30 (36.4%), diabetes (9.2%), hypertension (24.4%), and asthma (13.2%). Overall, 67% of participants reported receiving at least 2 doses of a SARS-CoV-2 vaccine.

The median time from symptom onset to receipt of study drug was 5 days (IQR, 4-7 days); 80% received fluvoxamine within 7 days of symptom onset and 77% received placebo (eFigure 1 in Supplement 2). Baseline symptom prevalence and severity are described in eTable 1 in Supplement 2. Although allowable per the trial protocol (Supplement 1), COVID-19 therapeutics approved or authorized for emergency use by the US Food and Drug Administration were uncommonly used (remdesivir by 0.08%, monoclonal antibodies by 2.9%, and ritonavir-boosted nirmatrelvir by 1%; Table 1).

The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (HR, 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]) (Table 2 and Figure 2A). The posterior probability of the primary outcome was below the prespecified threshold of 0.95. No statistical evidence of a treatment benefit remained when using a noninformative prior, no prior, and various approaches for imputing missing symptom data (Table 2 and Figure 3).

For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]; Table 2). There was only 1 hospitalization in the fluvoxamine group and there were 2 hospitalizations in the placebo group; there were no deaths in either group (Table 2 and eFigures 2A and 2B in Supplement 2). Thus, the HR on this composite outcome was uninformative.

The mean difference in the amount of time spent feeling unwell was 0.06 days (95% CrI, −0.33 to 0.43 days) in favor of placebo (Table 2 and Figure 2C). The posterior probability of any benefit observed with the COVID Clinical Progression Scale at days 7, 14, and 28 also did not meet prespecified thresholds for beneficial treatment effect (Table 2 and Supplement 2). For example, by day 7, 92.3% (542/587) of the fluvoxamine group and 93.4% (512/548) of the placebo group were not hospitalized and did not report any limitation of activities (eFigure 3 in Supplement 2).

There was no evidence of a treatment effect with fluvoxamine compared with placebo for vaccine status, timing of symptom onset, severity of symptoms, age, sex, or calendar time. There was evidence for possible differential treatment effect on time to recovery for BMI (P = .01 for heterogeneity of treatment effect), with a suggestion of increasing treatment benefit with increasing BMI (eFigure 4 in Supplement 2).

Among participants who reported taking either fluvoxamine or placebo at least once, adverse events were uncommon and similar in both groups (4.7% [29/615] with fluvoxamine vs 5.3% [30/565] with placebo) (eTable 2 in Supplement 2).

Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery in this large trial of 1288 participants. There was no treatment effect for the secondary outcomes, including for the composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28. Hospitalizations and deaths were uncommon in this largely vaccinated study population. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19.

There are numerous conflicting trials for the use of fluvoxamine, and some of the differences may be attributable to dosage.^7,8,10,16 Compared with the largest published trial to date (the TOGETHER trial¹⁰), the current trial has some similarities and differences. The TOGETHER trial¹⁰ used a higher dose of fluvoxamine (100 mg twice daily) compared with 50 mg twice daily in the current trial. The timing of the trial also was different. The TOGETHER trial¹⁰ reported randomization to fluvoxamine between January 20, 2021, and August 5, 2021, predating the arrival of the SARS-CoV-2 Omicron variant and the associated subvariants. By contrast, the current trial was conducted during the Delta and Omicron variant surges. In addition, the 2 trials enrolled different populations. The participants in the fluvoxamine group in the TOGETHER trial¹⁰ were unvaccinated, high-risk, symptomatic adults living in Brazil with a known risk factor for clinical progression to severe COVID-19. The current trial enrolled adults in the US regardless of COVID-19 risk factors or vaccination status. In fact, the majority (67%) of patients enrolled in this trial reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Similar null results were observed in the COVID-OUT trial,¹⁶ which also tested 50 mg of fluvoxamine twice daily vs placebo in a population with the majority of participants who were vaccinated and who were overweight or obese.

This trial has several strengths. As a nationwide trial in the US, it is generalizable for all adults aged 30 years or older with COVID-19. This trial enrolled patients rapidly during the Delta and Omicron variant surges and included individuals who had been vaccinated, thus remaining a highly relevant population for the present time.

This trial has several limitations. First, due to the broadly inclusive study population, few clinical events occurred, resulting in an inability to study the treatment effect on clinical outcomes such as hospitalization.

Second, due to the remote nature of the trial, the median time from symptom onset to receipt of study drug was 5 days, which is at the upper limit of the recommend start of antiviral medicines (≤5 days). However, significant interactions with respect to the time from symptom onset to study drug receipt were not observed, consistent with other trials.^10,16

Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19.

Corresponding Author: Susanna Naggie, MD, MHS, Duke Clinical Research Institute, Duke University School of Medicine, 300 W Morgan St, Ste 800, Durham, NC 27701 ([email protected]).

Correction: This article was corrected October 24, 2023, to fix the description of how the medications were distributed and the name of the manufacturer in the Methods section.

Accepted for Publication: December 13, 2022.

Published Online: January 12, 2023. doi:10.1001/jama.2022.24100

Author Contributions: Drs Naggie and Hernandez had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: McCarthy, Naggie, Boulware, Lindsell, Stewart, Felker, Gentile, Wilson, Remaly, Collins, Dunsmore, Adam, Thicklin, Ginde, Hernandez.

Acquisition, analysis, or interpretation of data: Naggie, Boulware, Lindsell, Stewart, Felker, Jayaweera, Sulkowski, Bramante, Singh, Dolor, Ruiz-Unger, DeLong, Remaly, Wilder, Dunsmore, Hanna, Ginde, Castro, McTigue, Shenkman, Hernandez.

Drafting of the manuscript: McCarthy, Naggie, Stewart, Remaly, Thicklin, Shenkman.

Critical revision of the manuscript for important intellectual content: Naggie, Boulware, Lindsell, Stewart, Felker, Jayaweera, Sulkowski, Gentile, Bramante, Singh, Dolor, Ruiz-Unger, Wilson, DeLong, Wilder, Collins, Dunsmore, Adam, Hanna, Ginde, Castro, McTigue, Hernandez.

Statistical analysis: Lindsell, Stewart.

Obtained funding: Naggie, Collins, Shenkman, Hernandez.

Administrative, technical, or material support: McCarthy, Naggie, Boulware, Singh, DeLong, Remaly, Wilder, Dunsmore, Adam, Thicklin, Hanna, Shenkman, Hernandez.

Supervision: Naggie, Lindsell, Felker, Jayaweera, Singh, Ruiz-Unger, Wilson, Remaly, Collins, Castro, Hernandez.

Conflict of Interest Disclosures: Dr Naggie reported receiving grants from Gilead Sciences and AbbVie; receiving personal fees from Pardes Biosciences and Personal Health Insights; serving as a scientific advisor and having stock options in Vir Biotechnology; having stock options and receiving nonfinancial support from Silverback Therapeutics; and serving on committees for Bristol Myers Squibb and PRA. Dr Lindsell reported receiving grants from the US Centers for Disease Control and Prevention and the US Department of Defense; receiving research services from Endpoint Health, bioMerieux, Entegrion, AbbVie, and AstraZeneca; and having a patent for risk stratification in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center. Dr Stewart reported receiving grants from Duke University. Dr Jayaweera reported receiving grants from the Biomedical Advanced Research and Development Authority, Janssen, ViiV Healthcare Ltd, and Gilead and serving as a consultant to Theratechnologies. Dr Sulkowski reported serving on advisory boards and receiving personal fees from AbbVie, Atea, Antios, Gilead, GlaxoSmithKline, Janssen, Precision Bio, Virion, and ViiV Healthcare Ltd. Dr Bramante reported receiving research support from Apotex. Dr Collins reported receiving personal fees from Vir Biotechnology and Enanta Pharmaceuticals. Dr Hanna reported receiving grants from Biomedical Advanced Research and Development Authority and receiving personal fees from Merck & Co and AbPro. Dr Ginde reported receiving grants from the National Institutes of Health, the US Centers for Disease Control and Prevention, Faron Pharmaceuticals, AbbVie, and the US Department of Defense. Dr Castro reported receiving grants from the National Institutes of Health, the American Lung Association, the Patient-Centered Outcomes Research Institute, AstraZeneca, Gala Therapeutics, GlaxoSmithKline, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi, Theravance; receiving personal fees from Genentech, Teva, Sanofi-Aventis, Merck, Novartis, Arrowhead Pharmaceuticals, Allakos, Amgen, OM Pharma, Pfizer, Pioneering Medicines, and GlaxoSmithKline; having a patent with Aer Therapeutics; and receiving royalties from Elsevier. Dr McTigue reported receiving grants from the University of Pittsburgh, Pfizer, and Janssen Pharmaceuticals. Dr Hernandez reported receiving personal fees from AstraZeneca, Boston Scientific, Bristol Myers Squibb, Merck, and Cytokinetics and receiving grants from Amgen, Bayer, Boehringer Ingelheim, American Regent, Verily, Merck, Somologic, and Pfizer. No other disclosures were reported.

Funding/Support: This trial was supported by grant 3U24TR001608-06S1 from the National Center for Advancing Translational Sciences. Additional support was provided by contract 75A50122C00037 from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority; translational science award UL1TR002243 from the National Center for Advancing Translational Sciences (awarded to Vanderbilt University Medical Center); the REDCap infrastructure; and grant U24TR001579 from the National Center for Advancing Translational Sciences (awarded to the Vanderbilt University Medical Center Recruitment Innovation Core).

Role of the Funder/Sponsor: The National Center for Advancing Translational Sciences (Samuel Bozzette, MD, PhD, and Eugene Passamani, MD) had a role in the trial design and development of the trial protocol. The funders/sponsors had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The members of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group and Investigators appear in Supplement 3.

Data Sharing Statement: See Supplement 4.