Looking for Treatments for Mild to Moderate COVID-19 (2025)

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Invited Commentary

Infectious Diseases

October18, 2024

John C.O’Horo,MD, MPH1,2

Author Affiliations Article Information

¹Division of Public Health, Infectious Diseases and Occupational Medicine, Mayo Clinic, Rochester, Minnesota
²Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota

JAMA Netw Open. 2024;7(10):e2439283. doi:10.1001/jamanetworkopen.2024.39283

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Original Investigation Time to Sustained Recovery From COVID-19 After Montelukast vs Placebo
Russell L.Rothman,MD, MPP; Thomas G.Stewart,PhD; AhmadMourad,MD; David R.Boulware,MD, MPH; Matthew W.McCarthy,MD; FlorenceThicklin; Idania T.Garcia del Sol,MD; Jose LuisGarcia,MD; Carolyn T.Bramante,MD, MPH; Nirav S.Shah,MD, MPH; UpinderSingh,MD; John C.Williamson,PharmD; Paulina A.Rebolledo,MD, MSc; PrasannaJagannathan,MD; TiffanySchwasinger-Schmidt,MD, PhD; Adit A.Ginde,MD, MPH; MarioCastro,MD, MPH; DushyanthaJayaweera,MD; MarkSulkowski,MD; NinaGentile,MD; KathleenMcTigue,MD; G. MichaelFelker,MD, MHS; AllisonDeLong,BS; RhondaWilder,MS; SeanCollins,MD, MSci; Sarah E.Dunsmore,PhD; Stacey J.Adam,PhD; George J.Hanna,MD; ElizabethShenkman,PhD; Adrian F.Hernandez,MD, MHS; SusannaNaggie,MD, MHS; Christopher J.Lindsell,PhD; Accelerating COVID-19 Therapeutic Interventions and Vaccines–6 Study Group and Investigators; GeorgeHanna; RyanFraser; MarkWard; JenniferGamboa Jackson; M. PatriciaMcAdams; JuliaVail; Kayla Korzekwinski; MartinaOyelakin; JulieChopp; DesmonRandle; SamanthaDockery; RodneyAdkins; Matthew Crow; ErinNowell; KadieWells; AliciaHerbert; AllegraStone; HeatherHeavlin; LinleyBrown; TinaHarding; Amanda Harrington; MeaghanBeauchaine; KellyLindblom; Andrea Burns; DavidAamodt; JessCollins; SheriDixon; YueGao; JohnGraves; JamesGrindstaff; FrankHarrell; JessicaLai; VickyLiao; ItzelLopez; ElizabethManis; KalleyMankowski; JessicaMarlin; AlyssaMerkel; SamNwosu; SavannahObregon; DirkOrozco; NelsonPrato; MaxRhode; JanaShirey-Rice; KristaVermillion; JacobSmith; Hsi-nienTan; MeghanVance; MariaWeir; RayBianchi; JenPremas; MadhuGupta; GregKarawan; SantiaLima; CareyZiomek; JosephArena; SonalyDeAlmeida; AnujMalik; JaneBryce; SarahSwint; SoroushRamin; JayaNataraj; JulienDeider; RicardoCruz; Ana MariaRamirez; LoriHenault; JosephMarcus; AlexisSouthwell; GeniceJacques; CedarSexton; BrianTiffany; CharlotteTanner; AllegraSahelian; ConstanceGeorge-Adebayo; AdeoluAdebayo; JoseZapatero; JulieClement; TheresaRonan; AshleyWoods; ChristopherGallegos; TamaraFlys; OliviaSloan; AnthonyOlofintuyi; JoshuaSamraj; AlmaVasbinder; AmayaAverett; AlexSlandzicki; JessicaWallen; ClaudiaVogel; SebastianMunoz; DavidKavtaradze; CasandraWatson; DavidSingleton; MarcusSevier; MariaRivon; ArnoldDel Pilar; AmberSpangler; SohailRao; LuisCantu; ArvindKrishna; HeidiDaugherty; BrandiKerr; KathyEvans; RobertSpees; MailynMarta; RowenaDolor; LorraineVergara; JackieJordan; ValenciaBurruss; TerriHurst; IghoOfotokun; CeciliaZhang; JessicaTraenkner; Mary M.Atha; RajeshPrabhu; KrystalKlicka; AmberLightfeather; VickieJames; MarcellaRogers; ChukwuemekaOragwu; NgoziOguego; RajeshPillai; AhabGabriel; EmadGhaly; MarianMichal; MichelleVasquez; AngelaMamon; MichelleSheets; GammalHassanien; SamahIsmail; YehiaSamir; AndrewMeltzer; SoroushShahamatdar; Ryan S. Heidish; AdityaLoganathan; ScottBrehaut; AngelinaRoche; ManishaMehta; NicoleKoppinger; JoseBaez; IvonePagan; DallalAbdelsayed; MinaAziz; PhilipRobinson; GraceLozinski; JulieNguyen; AlvinGriffin; MichaelMorris; NicoleLove; BonnieMattox; RaykelMartin; VictoriaPardue; TeddyRowland; JuanRuiz-Unger; LionelReyes; YadiraZamora; NavilaBacallao; JohnCienki; JonathanCohen; YingYuan; JennyLi; JeremySzeto; LaurenStelmash; SaraMekhael; LedularMorales Castillo; AnyaGutierrez; SabrinaPrieto; ArchAmon; AndrewBarbera; AndrewBugajski; WalterWillis; KellceeJacklin; DerylLamb; AmronHarper; ElmerStout; MerischiaGriffin; NancyPyram-Bernard; ArlenQuintero; NinaClark; MaryBarsanti-Sekhar; ChristinaCarbrera-Mendez; Mary RoseEvans; EftimAdhami; GiovanniCarillo; JosetteMaria; DikshaPaudel; OksanaRaymond; JeffreySummers; TammyTurner; LeslieLenert; EbonyPanaccione; ElizabethSzwast; AmyReynolds; AhsanAbdulghani; PravinVasoya; ConradMiller; HawaWiley; AustinChan; SaadiaKhizer; OluwadamilolaAdeyemi; Wei NingChi; JulyChen; MelissaMorton-Jost; JulieCastex; AliQuirch; HrishikeshBelani; RosarioMachicado; BjornBjornsson; JacquelineOlivo; MariaMaldonado; AnthonyVecchiarelli; DianaGaytan-Alvarez; VijayaCherukuri; RadicaAlicic; Allison A.Lambert; CarissaUrbat; JoniBaxter; AnnCooper; DawnLinn; LauraFisher; VijayPatel; RoshanTalati; PritiPatel; LeonardEllison; AngeeRoman; JeffreyHarrison; JamesMoy; DinaNaquiallah; BinodShah; OrlandoQuintero; JakeScott; YasminJazayeri; AndrewO'Donnell; DivyaPathak; AnitaGupta; N.Chandrasekar; CliffordCurtis; BrianaWhite; MarthaDockery; TabithaFortt; AnisaFortt; IngridJones-Ince; AlixMcKee; JasonWilson; JackieMarcelin; BrendaFarlow; CaseyGrady; RandallRichwine; PennyPazier; EdwardMichelson; SusanWatts; DilumaKariyawasam; LeannRodriguez; IsmarysManresa; Angel A.Achong; Mari C.Garcia; SangeetaKhetpal; FaithPosey; ArvindMahadevan; MartinGnoni; CarlaVan de Weerd; JeffreyLowenkron; EricaSappington; MitchellRoberts; JenniferWang; MelissaAdams; XinyiDing; MaryCo; MarkD'Andrea; StephenLim; WayneSwink; EmilyBozant; MadelineYoung; MichaelWilson; CarlyEastin; AllysonCheathem; AhadNadeem; CrystalWalters; MargaretPowers-Fletcher; DouglasBrown; DeliaMiller; SylvereMukunzi; BrittneyManning; MelissaTerry-White; Maria ChristinaCrizaldo; CarmenIsache; JenniferBowman; AngeliqueCallaghan-Brown; DebraMartin; AshleyAst; BrentDuran; AshlieCornejo; AllieArcher; MariaAlmanzar; VanessaMotel; Matt Pullen; BlakeAnderson; Neeta Bhat; DanielaParra; PaulaCampora; Matthew Robinson; MichelleSeithel; LizKendrick; DyannHelming; KellyPollock; AkiraSekikawa; EmilyKlawson; JonathanArnold; NathanWeiland; LuisOstrosky-Zeichner; BelaPatel; VirginiaUmana; LauraNielsen; Carolyn Z.Grimes; Thomas F.Patterson; RobinTragus; Bridgette T.Soileau; TimothyHeath; ErikHinjosa; CesarGutierrez; Patrick E.H.Jackson; CarolineHallowell; Heather M.Haughey; BhavnaVaidya-Tank; CameronGould; ParulGoyal; SueSommers; HaleyPangburn; CarlyJones; LoriMichalowski; BrittanyWortham; RicaAbbott; UnwanaUmana; CandaceAlleyne; BrittaWitting; EddieArmas; Ramon O.Perez Landaburo; MichelleDe La Cruz; MarthaBallmajo; JorgeAlvarez

JAMA Network Open

Mild COVID-19 therapeutics with guideline support currently are limited to options for those who are at high risk of disease progression and have a lower certainty of benefit overall than previous therapeutics.¹^,2 This makes the study by Rothman et al³ very timely. Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) has provided broad based trial evaluation of promising and plausible therapeutics for COVID-19, and here,³ evaluated montelukast in patients older than 30 years with symptomatic COVID-19 not requiring hospitalization. Montelukast was identified as a potential candidate for protease and polymerase inhibition and perhaps symptomatic relief of some of the inflammatory pathways implicated in COVID-19 symptomatology. Unfortunately, no significant reduction in symptoms was seen.³

Most of the COVID-19 pandemic was marked by a scramble for treatments for severe disease. In a remarkably short amount of time, studies and guidelines clarified who may benefit from steroids, remdesivir, interleukin-6 inhibitors, and convalescent plasma. While the recommendations for each of these treatments and an understanding of who benefits have evolved throughout the pandemic,¹^,2 all of these treatments were preferentially studied and recommended primarily for severe or critically ill patients. The combined effects of prior vaccinations, infections, and possibly lower virulence of circulating variants has decreased the proportion of patients experiencing severe disease over the course of the pandemic,⁴ making the treatment of the mild and moderate cases a more pressing question.

ACTIV-6 has brought rigor to the assessment of several repurposed medication treatments of COVID-19.⁵ Montelukast can now be added to the list of failed therapeutics, but the importance of even negative results in this space cannot be overstated. All therapeutics come with potential harms and knowing that the risks outweigh putative benefits is crucial as outpatient management of COVID-19 becomes more important.

Evaluating impact among the mild to moderate cases is inherently difficult. As noted by the authors in this study,³ any event tended to be rare in this population. Early in the pandemic, when hospitalizations trended toward more severe illness, it was comparatively easy to demonstrate a benefit of a proposed therapeutic and balance it against harms in a critically ill population. The safety profile needed for mild outpatient therapy is substantially more conservative and makes finding a cost-effective therapeutic more challenging. The ACTIV-6 platform has opted to look at existing medications, recognizing the cost-effectiveness challenges of novel therapeutics in this arena. Unfortunately, none have panned out so far, although further study drugs are still being analyzed.

Present directed options for mild to moderate infection are limited and expensive. Remdesivir, ritonavir-boosted nirmatrelvir, and molnupiravir have all shown some efficacy in reducing disease progression, although the magnitude of those benefits is now being brought into question, and the cost of these therapeutics is high. Monoclonal antibodies are no longer available, and the indications for convalescent plasma have been shrinking.¹^,2

Mild to moderate COVID-19 is currently reverting to our treatments of other upper respiratory tract infection symptom–based therapy in the absence of directed therapeutics. Given the duration of illness, propensity toward progression and potential for postacute sequelae for COVID-19, it is inevitable that we will see more therapeutic candidates advanced. Montelukast cannot be added to our therapeutic armamentarium, but the search cannot stop here. Until a new option becomes available, we will all have to hold our breath.

Article Information

Published: October 18, 2024. doi:10.1001/jamanetworkopen.2024.39283

Corresponding Author: John C. O’Horo, MD, MPH, Division of Public Health, Infectious Diseases, and Occupational Medicine, 200 First St SW, Rochester, MN, 55902 (ohoro.john@mayo.edu).

Conflict of Interest Disclosures: None reported.

References

National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. Published April 21, 2024. Accessed July 10, 2024. https://www.ncbi.nlm.nih.gov/books/NBK570371/

Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America guidelines on the treatment and management of patients with COVID-19 (September 2022). Clin Infect Dis. 2024;78(7):e250-e349. doi:10.1093/cid/ciac724 PubMed Google Scholar Crossref

Rothman RL, Stewart TG, Mourad A, et al; Accelerating COVID-19 Therapeutic Interventions and Vaccines–6 Study Group And Investigators. Time to sustained recovery among outpatients with COVID-19 receiving montelukast vs placebo: the ACTIV-6 randomized clinical trial. JAMA Netw Open. 2024;7(10):e2439332. doi:10.1001/jamanetworkopen.2024.39332Google Scholar

Hedberg P, Parczewski M, Serwin K, et al. In-hospital mortality during the wild-type, alpha, delta, and omicron SARS-CoV-2 waves: a multinational cohort study in the EuCARE project. Lancet Reg Health Eur. 2024;38:100855. doi:10.1016/j.lanepe.2024.100855 PubMed Google Scholar Crossref

Accelerating Covid-19 Therapeutic Interventions and Vaccines (ACTIV)-6 Study Group. ACTIV-6: Operationalizing a decentralized, outpatient randomized platform trial to evaluate efficacy of repurposed medicines for COVID-19. J Clin Transl Sci. 2023;7(1):e221. doi:10.1017/cts.2023.644 PubMed Google Scholar Crossref

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O’Horo JC. Holding Our Breath—Looking for Treatments for Mild to Moderate COVID-19. JAMA Netw Open. 2024;7(10):e2439283. doi:10.1001/jamanetworkopen.2024.39283

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