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Randomized Controlled Trial

Time to Sustained Recovery Among Outpatients With COVID-19 Receiving Montelukast vs Placebo: The ACTIV-6 Randomized Clinical Trial

Russell L Rothman et al. JAMA Netw Open. .

Abstract

Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate 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: This randomized clinical trial (Accelerating COVID-19 Therapeutic Interventions and Vaccines [ACTIV]-6) was conducted from January 27 through June 23, 2023, during the circulation of Omicron subvariants. Participants aged 30 years or older with confirmed SARS-CoV-2 infection and 2 or more acute COVID-19 symptoms for less than 7 days were included across 104 US sites.

Interventions: Participants were randomized 1:1 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 ≥3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of health care utilization events (hospitalization, urgent care clinic visit, emergency department visit, or death); COVID-19 clinical progression scale score; and difference in mean time unwell. A modified intention-to-treat approach was used for the analysis.

Results: Among 1250 participants who were randomized and received the study drug or placebo, the median age was 53 years (IQR, 42-62 years), 753 (60.2%) were female, and 704 (56.3%) reported receiving 2 or more 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 [AHR], 1.02; 95% credible interval [CrI], 0.92-1.12; P = .63 for efficacy). Unadjusted median time to sustained recovery was 10 days (95% CI, 10-11 days) in both groups. No deaths occurred, and hospitalizations were reported for 2 participants (0.3%) in each group; the composite of health care utilization events was reported for 18 participants (2.9%) in the montelukast group and 18 (2.9%) in the placebo group (AHR, 1.01; 95% CrI, 0.45-1.84; P = .48 for efficacy). Five participants (0.4%) experienced serious adverse events (3 [0.5%] in the montelukast group and 2 [0.3%] in the placebo group).

Conclusions and relevance: In this randomized clinical trial of outpatients with mild to moderate COVID-19, treatment with montelukast did not reduce duration of COVID-19 symptoms. These findings do not support the use of montelukast for the treatment of mild to moderate COVID-19.

Trial registration: ClinicalTrials.gov Identifier: NCT04885530.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rothman reported receiving grants from the National Institutes of Health (NIH), Patient-Centered Outcomes Research Institute (PCORI), Agency for Healthcare Research and Quality, and Centers for Disease Control and Prevention (CDC) during the conduct of the study. Dr Stewart reported receiving a grant from the Duke Clinical Research Institute (DCRI) as a subaward for ACTIV-6 from the NIH during the conduct of the study and receiving personal fees from Eli Lilly for serving on a data monitoring committee for a trial unrelated to COVID-19 outside the submitted work. Dr Garcia reported receiving grants from the NIH during the conduct of the study. Dr Shah reported receiving grants from the NIH during the conduct of the study. Dr Singh reported receiving grant funding from Pfizer for a clinical trial on long COVID, serving on a Gilead advisory committee for an acute COVID-19 clinical trial, and serving on a Regeneron advisory committee for COVID-19 studies outside the submitted work. Dr Williamson reported receiving grants from the NIH during the conduct of the study. Dr Jagannathan reported receiving grants from the NIH during the conduct of the study. Dr Schwasinger-Schmidt reported receiving grants contracted with the University of Kansas Research Institute for serving as principal investigator on clinical trials for the NIH and US Department of Health and Human Services and receiving grants from Eisai, Janssen, Sage Pharmaceuticals, Sarepta, Corcept, Boehringer Ingelheim, AstraZeneca, Sanofi, Axsome, the NIH, the PCORI, Johnson & Johnson, Moderna, Bellus, GSK, Pfizer, and Shaniogi outside the submitted work but received no personal financial benefit by conducting this research. Dr Ginde reported receiving personal fees from the NIH during the conduct of the study and receiving grants from the US Department of Defense (DOD), CDC, Faron Pharmaceuticals, and AbbVie and personal fees from Biomeme and SeaStar outside the submitted work. Dr Castro reported receiving grants from the American Lung Association, Gala Therapeutics, NIH, PCORI, Sanofi-Aventis, and Theravance Biopharma; grants from AstraZeneca and Shionogi for clinical trials; honoraria from AstraZeneca, Amgen, and Regeneron Pharmaceuticals for talks; personal fees from Genentech and GSK for serving on advisory boards; grants from Pulmatrix for clinical trials and serving on the advisory board; honoraria from Sanofi-Aventis for talks and serving on the advisory board; personal fees from Allakos, Amgen, Arrowhead Pharmaceuticals, Blueprint Medicines, Connect BioPharma, Novartis, OM Pharma, Pioneering Medicines, Teva, Third Rock Ventures, and Verona Pharmaceuticals for consulting; personal fees from Merck for serving on the advisory board; and royalties from Aer Therapeutics outside the submitted work. Dr Jayaweera reported receiving grants from Gilead, Janssen, the NIH, and ViiV and personal fees from CCO outside the submitted work. Dr Sulkowski reported receiving personal fees from Aligos, Arbutus, AbbVie, Precision Biosciences, and Virion Therapeutics for serving as a scientific advisory board member; personal fees from Gilead for being a data monitoring committee member; nonfinancial support from Gilead (drug in kind provided to the NIH); and personal fees from Wiley for serving as Editor of the Journal of Viral Hepatitis outside the submitted work. Dr McTigue reported receiving grants from the University of Pittsburgh during the conduct of the study and having a research contract from Pfizer for analyzing vaccines, including COVID-19 vaccine, outside the submitted work. Dr Felker reported receiving grants from the NIH during the conduct of the study. Ms DeLong reported receiving grants from the NIH during the conduct of the study. Ms Wilder reported receiving grants from the NIH during the conduct of the study. Dr Collins reported receiving grants from the NIH during the conduct of the study. Dr Hanna reported receiving grants from the US Biomedical Advanced Research and Development Authority under a contract to Tunnell Government Services for consulting services during the conduct of the study and personal fees from Merck & Co and Abpro outside the submitted work. Dr Hernandez reported receiving personal fees from AstraZeneca, Cytokinetics, Bristol Myers Squibb, and Intellia and grants from Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Verily, and Novo Nordisk outside the submitted work. Dr Naggie reported receiving grants from the NIH during the conduct of the study; receiving grants from Gilead and AbbVie, nonfinancial support from Pardes Biosciences and Silverback Therapeutics for consulting, being a data safety and monitoring board member for Personal Health Insights, serving on the event adjudication committee for BMS-PRA, and receiving personal fees as a prior advisor for and holding stock in Vir Biotechnology outside the submitted work; and serving as deputy editor of Clinical Infectious Diseases. Dr Lindsell reported receiving grants from the NIH, CDC, and DOD to the institution during the conduct of the study and receiving a contract with the institution for research services from bioMérieux, Biomeme, Novartis, Entegrion, Endpoint Health, Baxter, and AstraZeneca outside the submitted work; receiving personal fees from Rocket Pharmaceuticals and Vanderbilt University Medical Center unrelated to the current work; having a patent for risk stratification in sepsis and septic shock issued to Cincinnati Children’s Hospital Medical Center and stock options in Bioscape Digital unrelated to the current work; and serving as editor in chief of the Journal of Clinical and Translational Science. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flow in a Trial of Montelukast for Mild to Moderate COVID-19
Randomization failures occurred when an individual was no longer eligible for inclusion at the time of randomization.
Figure 2.
Figure 2.. Primary Outcome of Time to Sustained Recovery
Sustained recovery was defined as the third of 3 consecutive days without symptoms. Eighteen participants were censored for complete nonresponse and 28 after partial response; all others were followed up until recovery, death, or the end of short-term 28-day follow-up. Median time to sustained recovery was 10 days (95% CI, 10-11 days) in both groups. Shading denotes the pointwise 95% CIs.
Figure 3.
Figure 3.. Posterior Distribution of Treatment Effect Hazard Ratio for Time to Outcomes
Posterior density is the relative likelihood of posterior probability distribution. Outcomes with higher posterior density are more likely than outcomes with lower posterior density. Blue density lines represent kernel density estimates constructed from posterior draws; vertical lines, estimated means of the posterior distribution; shading, the 95% credible interval. Posterior density plots of all the covariates in the primary outcome model are shown in eFigure 10 in Supplement 2.
See this image and copyright information in PMC

Comment in

  • doi: 10.1001/jamanetworkopen.2024.39283

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