Double-blind placebo-controlled randomized clinical trial to assess the efficacy of montelukast in mild to moderate respiratory symptoms of patients with long COVID: E-SPERANZA COVID Project study protocol

Francisco Mera-Cordero, Sara Bonet-Monne, Jesús Almeda-Ortega, Ana García-Sangenís, Oriol Cunillera-Puèrtolas, Sara Contreras-Martos, Gemma Alvarez-Muñoz, Ramon Monfà, Marina Balanzo-Joué, Rosa Morros, Betlem Salvador-Gonzalez, Francisco Mera-Cordero, Sara Bonet-Monne, Jesús Almeda-Ortega, Ana García-Sangenís, Oriol Cunillera-Puèrtolas, Sara Contreras-Martos, Gemma Alvarez-Muñoz, Ramon Monfà, Marina Balanzo-Joué, Rosa Morros, Betlem Salvador-Gonzalez

Abstract

Background: The coronavirus disease 2019 (COVID-19) pandemic continues to affect the globe. After 18 months of the SARS-CoV-2 emergence, clinicians have clearly defined a subgroup of patients with lasting, disabling symptoms. While big strides have been made in understanding the acute phase of SARS-CoV-2 infection, the pathophysiology of long COVID is still largely unknown, and evidence-based, effective treatments for this condition remain unavailable.

Objectives: To evaluate the efficacy of 10 mg oral montelukast every 24 h versus placebo in improving quality of life associated with mild to moderate respiratory symptoms in patients with long COVID as measured with the COPD Assessment Test (CAT) questionnaire. The secondary objectives will evaluate the effect of montelukast versus placebo on improving exercise capacity, COVID-19 symptoms (asthenia, headache, mental confusion or brain fog, ageusia, and anosmia), oxygen desaturation during exertion, functional status, and mortality.

Methods and analysis: Phase III, randomized, double-blind clinical trial. We will include 18- to 80-year-old patients with SARS-CoV-2 infection and mild to moderate respiratory symptoms lasting more than 4 weeks. Participants will be randomly allocated in a 1:1 ratio to the intervention (experimental treatment with 10 mg/day montelukast) or the control group (placebo group), during a 28-day treatment. Follow-up will finish 56 days after the start of treatment. The primary outcome will be health-related quality of life associated with respiratory symptoms according to the COPD Assessment Test 4 weeks after starting the treatment. The following are the secondary outcomes: (a) exercise capacity and oxygen saturation (1-min sit-to-stand test); (b) Post-COVID-19 Functional Status Scale; (c) other symptoms: asthenia, headache, mental confusion (brain fog), ageusia, and anosmia (Likert scale); (d) use of healthcare resources; (e) mortality; (f) sick leave duration in days; and (g) side effects of montelukast.

Ethics and dissemination: This study has been approved by the Clinical Research Ethics Committee of the IDIAPJGol (reference number 21/091-C). The trial results will be published in open access, peer-reviewed journals and explained in webinars to increase awareness and understanding about long COVID among primary health professionals.

Trial registration: ClinicalTrials.gov NCT04695704 . Registered on January 5, 2021. EudraCT number 2021-000605-24. Prospectively registered.

Keywords: COVID-19; Dyspnea; Health status; Long COVID; Montelukast; Primary care; Quality of life; Randomized controlled trial; SARS-CoV-2.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Summary and steps for the E-COVID study. IC, informed consent; CAT, COPD Assessment Test; PCFS, Post-COVID-19 Functional Status Scale; 1MSTS, 1-min sit-to-stand test

References

    1. Informe n° 85. Situación de COVID-19 en España. Informe COVID-19. 30 de junio de 2021. Equipo COVID-19. RENAVE. CNE. CNM (Instituto de Salud Carlos III).
    1. Lechien JR, Chiesa-Estomba CM, Place S, Van Laethem Y, Cabaraux P, Mat Q. et al; COVID-19 Task Force of YO IFOS. Clinical and epidemiological characteristics of 1420 European patients with mild-to-moderate coronavirus disease 2019. J Intern Med. 2020;288(3):335–344. doi: 10.1111/joim.13089.
    1. Carfì A, Bernabei R, Landi F. Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients after acute COVID-19. JAMA. 2020;324(6):603–605. doi: 10.1001/jama.2020.12603.
    1. Navabi N. Long COVID: how to define it and how to manage it. BMJ webinar. BMJ. 2020;370:m3489. doi: 10.1136/bmj.m3489.
    1. Yelin D, Wirtheim E, Vetter P, Kalil AC, Bruchfeld J, Runold M, Guaraldi G, Mussini C, Gudiol C, Pujol M, Bandera A, Scudeller L, Paul M, Kaiser L, Leibovici L. Long term consequences of COVID-19: research needs. Lancet Infect Dis. 2020;20(10):1115–1117. doi: 10.1016/S1473-3099(20)30701-5.
    1. COVID-19 rapid guideline: managing the long-term effects of COVID-19. NICE guideline [NG188] . National Institute for Health and Care Excellence, Royal College of General Practitioners, HealthcareImprovementScotland/SIGN. Published date: 18 December 2020
    1. Editorial. Meeting the challenge of long COVID. Nat Med. 2020 Dec;26(12):1803.
    1. COVID symptom study. How long does COVID last? June 6, 2020.
    1. Davis HR, Assaf GS, McCorkell L, Wei H, Low RJ, Re’em Y, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;15:101019. doi: 10.1016/j.eclinm.2021.101019.
    1. Ostrosky T, Perelman C, Sepulveda R, Rebolledo P, Cuapio A, et al. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. medRxiv [Preprint] 2021;30:2021.01.27.21250617.
    1. Michelen M, Manoharan L, Elkheir N, Cheng V, Dagens D, Hastie C, et al. Characterising long-term COVID-19: a rapid living systematic review. medRxiv [Preprint] 2020.12.08.20246025.
    1. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;46(4):586–590. doi: 10.1007/s00134-020-05985-9.
    1. Song P, Li W, Xie J, Hou Y, You C. Cytokine storm induced by SARS-CoV-2. Clin Chim Acta. 2020;509:280–287. doi: 10.1016/j.cca.2020.06.017.
    1. Gazzaruso C, Carlo Stella N, Mariani G, Nai C, Coppola A, Naldani D, Gallotti P. High prevalence of antinuclear antibodies and lupus anticoagulant in patients hospitalized for SARS-CoV-2 pneumonia. Clin Rheumatol. 2020;39(7):2095–2097. doi: 10.1007/s10067-020-05180-7.
    1. Das UN. Can bioactive lipids inactivate coronavirus (COVID-19)? Arch Med Res. 2020;51(3):282–286. doi: 10.1016/j.arcmed.2020.03.004.
    1. Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, Ruiz C, Melguizo-Rodríguez L. SARS-CoV-2 infection: the role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev. 2020;54:62–75. doi: 10.1016/j.cytogfr.2020.06.001.
    1. Pedersen SF, Ho YC. SARS-CoV-2: a storm is raging. J Clin Invest. 2020;130(5):2202–2205. doi: 10.1172/JCI137647.
    1. Tamada T, Ichinose M. Leukotriene receptor antagonists and antiallergy drugs. Handb Exp Pharmacol. 2017;237:153–169. doi: 10.1007/164_2016_72.
    1. Copertino DC, Duarte RRR, Powell TR, Rougvie MM, Nixon DF. Montelukast drug activity and potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) J Med Virol. 2021;93(12):187–189. doi: 10.1002/jmv.26299.
    1. Davino-Chiovatto JE, Oliveira-Junior MC, MacKenzie B, Santos-Dias A, Almeida-Oliveira AR, Aquino-Junior JCJ, Brito AA, Rigonato-Oliveira NC, Damaceno-Rodrigues NR, Oliveira APL, Silva AP, Consolim-Colombo FM, Aimbire F, Castro-Faria-Neto HC, Vieira RP. Montelukast, leukotriene inhibitor, reduces LPS-induced acute lung inflammation and human neutrophil activation. Arch Bronconeumol (Engl Ed). 2019;55(11):573–580. doi: 10.1016/j.arbres.2019.05.003.
    1. Bhattacharyya D. Reposition of montelukast either alone or in combination with levocetirizine against SARS-CoV-2. Med Hypotheses. 2020;144:110046. doi: 10.1016/j.mehy.2020.110046.
    1. Barré J, Sabatier JM, Annweiler C. Montelukast drug may improve COVID-19 prognosis: a review of evidence. Front Pharmacol. 2020;11:1344. doi: 10.3389/fphar.2020.01344.
    1. Fidan C, Aydoğdu A. As a potential treatment of COVID-19: montelukast. Med Hypotheses. 2020;142:109828. doi: 10.1016/j.mehy.2020.109828.
    1. Almerie MQ, Kerrigan DD. The association between obesity and poor outcome after COVID-19 indicates a potential therapeutic role for montelukast. Med Hypotheses. 2020;143:109883. doi: 10.1016/j.mehy.2020.109883.
    1. Khan AR, Misdary C, Yegya-Raman N, Kim S, Narayanan N, Siddiqui S, et al. Montelukast in hospitalized patients diagnosed with COVID-19. J Asthma. 2021:1–7. 10.1080/02770903.2021.1881967.
    1. Wilchesky M, Tranmer G, Grad R. The COVID-19 Symptom Montelukast Trial (COSMO). Identifier: NCT04389411. Fecha de consulta [12.02.2021]. Disponible en:
    1. Investigation of the effect of montelukast in COVID-19. A national, multi-center, open-label, three-arm, phase II study to investigate the effect of montelukast between emergency room visits and hospitalizations in COVID-19 pneumonia in comparison with standard treatment. Fecha de consulta [12.02.2021]. Disponible en:
    1. Mera Cordero F, Salvador González B, Morros R, Bonet Monne S, Cos FX, Almeda OJ. Effectiveness of montelukast against exuberant immune activation in “long COVID”. Biomed J Sci & Tech Res. 2021;33(2):25750–25751. doi: 10.26717/BJSTR.2021.33.005385.
    1. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Leidy NK. Development and first validation of the COPD Assessment Test. Eur Resp J. 2009;34(3):648–654. doi: 10.1183/09031936.00102509.
    1. Kon SS, Canavan JL, Jones SE, Nolan CM, Clark AL, Dickson MJ, et al. Minimum clinically important difference for the COPD Assessment Test: a prospective analysis. Lancet Respir Med. 2014;2(3):195–203. doi: 10.1016/S2213-2600(14)70001-3.
    1. Greenhalgh T, Javid B, Knight M, Inada-Kim M. What is the efficacy and safety of rapid exercise test for exertional desaturation in COVID-19?
    1. Klok FA, Boon GKAM, Barco S, Endres M, Geelhoed JJM, Knauss S, et al. The Post-COVID-19 Functional Status Scale: a tool to measure functional status over time after COVID-19. Eur Respir J. 2020;56(1):2001494. doi: 10.1183/13993003.01494-2020.
    1. Cañadas I, Sánchez-Bruno A. Categorías de respuesta en escalas tipo Likert. Psicothema. 1998;10(3):623–631.
    1. Wang J, Guo S, Zeng M, Yu P, Mo W. Observation of the curative effect of device-guided rehabilitation on respiratory function in stable patients with chronic obstructive pulmonary disease. Medicine. 2019;98(8):e14034. doi: 10.1097/MD.0000000000014034.
    1. Fletcher CM, Elmes PC, Fairbairn MB, Wood CH. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. Br Med J. 1959;2(5147):257–266. doi: 10.1136/bmj.2.5147.257.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) – a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–381. doi: 10.1016/j.jbi.2008.08.010.
    1. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, et al. REDCap Consortium. The REDCap Consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208. doi: 10.1016/j.jbi.2019.103208.

Source: PubMed

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