Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) is uncertain. Objective: To assess the effectiveness of montelukast compared with placebo, in treating outpatients with mild to moderate COVID-19. Design, Setting, and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate the effectiveness of repurposed medications in treating mild to moderate COVID-19. Between January 27, 2023, and June 23, 2023, 1250 participants >=30 years of age with confirmed SARS-CoV-2 infection and >=2 acute COVID-19 symptoms for <=7 days, were included across 104 US sites to evaluate the use of montelukast. Interventions: Participants were randomized to receive montelukast 10 mg once daily or matched placebo for 14 days. Main Outcomes and Measures: The 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 clinical progression scale; and difference in mean time unwell. Results: Among participants who were randomized and received study drug, the median age was 53 years (IQR 42-62), 60.2% were female, 64.6% identified as Hispanic/Latino, and 56.3% reported >=2 doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR] 1.02; 95% credible interval [CrI] 0.92-1.12; P(efficacy) = 0.63]). Unadjusted median time to sustained recovery was 10 days (95% confidence interval 10-11) in both groups. No deaths were reported and 2 hospitalizations were reported in each group; 36 participants reported healthcare utilization events (a priori defined as death, hospitalization, emergency department/urgent care visit); 18 in the montelukast group compared with 18 in the placebo group (HR 1.01; 95% CrI 0.45-1.84; P(efficacy)=0.48). Five participants experienced serious adverse events (3 with montelukast and 2 with placebo). Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with montelukast does not reduce duration of COVID-19 symptoms.

Rothman: Reports grants from NIH, PCORI, AHRQ, CDC, during the conduct of the study. Spouse owns stock in Moderna unrelated to the current work. Stewart: Reports grants from NIH NCATS during the conduct of the study; Grants from NIH outside the submitted work. Boulware: Reports grants from NIH during the conduct of the study. Singh: Research support from NIH, AHRQ, and Pfizer, Inc.; advisor to Regeneron and Gilead. Schwasinger-Schmidt: Served as principal investigator for clinical trials sponsored by Eisai, Janssen, Boehringer Ingelheim, Bellus, Shionogi, AstraZeneca, Axsome, Johnson & Johnson, Moderna, Pfizer, Acumen, and GlaxoSmithKline. All clinical trial and study contracts were with and payments were made to the University of Kansas Medical Center Research Institute, which is a research institute affiliated with Kansas University School of Medicine-Wichita. Ginde: Reports grants from NIH during the conduct of the study; Grants from NIH, CDC, DoD, AbbVie (investigator-initiated), and Faron Pharmaceuticals (investigator-initiated) outside the submitted work; Paid consulting with Seastar and Biomeme outside the submitted work. Castro: Reports institutional grant funding from NIH, ALA, PCORI, AstraZeneca, GSK, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi; Speaker/Consultant fees from Grant Funding, Genentech, Teva, Sanofi-Aventis; Consultant fees from Merck, Novartis, Arrowhead, OM Pharma, Allakos; Speaker honorarium from Amgen, AstraZeneca, GSK, Regeneron; Royalties from Elsevier all outside the submitted work. Jayaweera: Reports grants from NCATS PI-Ralph Sacco during the conduct of the study; Grants from Gilead, Pfizer, Janssen, and Viiv; Consulting fees from Theratechnologies outside the submitted work. Sulkowski: Reports advisory board fees from AbbVie, Gilead, GSK, Atea, Antios, Precision Bio, Viiv, and Virion; Institutional grants from Janssen outside the submitted work. Sulkowski: Reports advisory board fees from AbbVie, Gilead, GSK, Atea, Antios, Precision Bio, Viiv, and Virion; Institutional grants from Janssen outside the submitted work. Gentile: Reports personal fees from Duke University for protocol development and oversight during the conduct of the study; grants from NIH outside the submitted work. McTigue: Reports grants from NIH Research Subcontract to the University of Pittsburgh during the conduct of the study; Research contract to the University of Pittsburgh from Pfizer, and Janssen outside the submitted work. Felker: Reports institutional research grants from NIH during the conduct of the study and from Novartis outside the submitted work. DeLong: Reports institutional research funding from the National Center for Advancing Translational Sciences (3U24TR001608) during the conduct of the study. Wilder: Reports institutional research funding from the National Center for Advancing Translational Sciences (3U24TR001608) during the conduct of the study. Collins: Reports grant funding from NHLBI and personal fees from Vir Biotechnology during the conduct of the study. Adam: Reports other from US Government Funding through Operation Warp Speed during the conduct of the study. Hanna: Reports grants from US Biomedical Advanced Research & Development Authority contract to Tunnell Government Services for consulting services during the conduct of the study; Personal fees from Merck & Co. and AbPro outside the submitted work. Hernandez: Reports grants from American Regent, Amgen, Boehringer Ingelheim, Merck, Verily, Somologic, and Pfizer; Personal fees from AstraZeneca, Boston Scientific, Cytokinetics, Bristol Myers Squibb, and Merck outside the submitted work. Naggie: Reports grants from NIH, the sponsor for this study, during the conduct of the study; Institutional research grants from Gilead Sciences, AbbVie; Consulting fees from Pardes Biosciences; Scientific advisor/Stock options from Vir Biotechnology; Consulting with no financial payment from Silverback Therapeutics; DSMB fees from Personal Health Insights, Inc; Event adjudication committee fees from BMS/PRA outside the submitted work. Lindsell: Reports institutional grants from NCATS during the conduct of the study; Institutional grants from NIH, CDC, and DoD; Contract with institution for research services from Endpoint Health, bioMerieux, Entegrion Inc, Abbvie, and Astra Zeneca, Biomeme, and Novartis outside the submitted work; Dr Lindsell has a patent for risk stratification in sepsis and septic shock issued to Cincinnati Children's Hospital Medical Center. All other authors have nothing to report.

NCT04885530

ACTIV-6 is funded by the National Center for Advancing Translational Sciences (NCATS) (3U24TR001608-06S1). Additional support for this study was provided by the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority (Contract No.75A50122C00037). The Vanderbilt University Medical Center Clinical and Translational Science Award from NCATS (UL1TR002243) supported the REDCap infrastructure.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

WCG IRB gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

ACTIV-6 is a platform trial using shared placebos. On completion of the platform trial, when there is no risk of unblinding across study arms, the data will be made publicly available by depositing it in an approved data repository such as NHLBI BioData Catalyst.