Efficacy of Montelukast in Mild-moderate Respiratory Symptoms in Patients With Long-COVID-19: (E-SPERANZA)

Double-blind Randomized Clinical Trial, Placebo-controlled to Assess the Efficacy of Montelukast in Mild-moderate Respiratory Symptoms in Patients With Long-COVID-19: E-SPERANZA COVID-19 PROJECT

Recently, a new clinical presentation called "long covid" has been reported, for patients with symptoms lasting for more than 4 weeks from the onset of the disease. Typically, the symptoms comprise dyspnea, cough, headache, arthralgia, fever, abdominal pain, asthenia and skin manifestations This project aims to evaluate the efficacy of Montelukast in improving the quality of life associated with respiratory symptoms in patients with persistent COVID-19 symptoms. The main objective is to compare the efficacy of low-dose Montelukast versus placebo to improve respiratory symptoms in patients with persistent COVID-19 symptoms.

Study Overview

• Status: Recruiting
• Conditions: Covid19; SARS (Disease)
• Intervention / Treatment: Drug: Montelukast; Other: placebo

Detailed Description

In December 2019, the first case of a new coronavirus causing pneumonia was described in Wuhan (China), designated as SARS-CoV-2 by the World Health Organization.

From the start of the SARS-CoV-2 alert until May 21st, 2020, 250,287 cases of coronavirus disease (COVID-19) were reported in Spain. The importance of the COVID-19 pandemic with its high humanitarian and economic cost, urgently requires effective therapies to reduce the severity, complications and mortality associated with this infection.

As the number of cases of COVID-19 increases, so does information regarding the management and evolution of the disease. More recently, a new clinical presentation called "long COVID-19" has been reported, for patients with symptoms lasting for more than 4 weeks from the onset of the disease. Typically, the symptoms comprise dyspnea, cough, headache, arthralgia, fever, abdominal pain, asthenia and skin manifestations.

The inflammatory process produced at the pulmonary and extra pulmonary level, and the immune response triggered have been identified as important mechanisms in the pathophysiology of COVID-19.

Coronavirus infection activates the cytokine cascade at the immune level, in which leukotriene are possibly involved in the development of respiratory symptoms in patients with persistent symptoms after infection by SARS-CoV-2.

Leukotriene antagonists (LTRAs) have a bronchodilator action and inhibit inflammation of the airways, resulting in a significant improvement in asthma symptoms and allergic rhinitis. In asthma, they improve respiratory function, inhalation rate of inhaled β2 agonist, airway inflammation, airway hyper responsiveness, inhaled corticosteroid dosage, and reduce exacerbations.

Regarding the treatment of acute SARS-CoV-2 infection, to date, the available evidence is limited; there are few conclusive clinical trials that allow recommendations based on scientific evidence.

To date, no treatment has been evaluated in long COVID-19. The hypothesis of using Montelukast would be based on the pathophysiological response of the disease mediated by the immune system against the SARS-CoV-2 infection.

Montelukast blocks the action of substances such as leukotriene C4, D4 and E4 by binding to the CysLT1 receptor in the lungs and bronchi. This reduces the bronchoconstriction caused by leukotriene and results in less inflammation.

Montelukast effectively attenuated both lung inflammation induced by Lipopolysaccharides in a mouse model with Acute Respiratory Distress Syndrome, as in human neutrophils.

Individuals affected by long COVID-19 have self-organized to gain visibility. They have made a self-completed form to describe the characteristics of the disease. The "Persistent COVID19" network in Catalonia currently gathers more than 3000 people.

From the contact with the "Persistent COVID19 association" in Catalonia, and in search of a response to this symptomatology, which can be very disabling, a pilot study was carried out in patients with persistent COVID-19 symptoms with off-label use of Montelukast.

Empirical treatment with Montelukast at a dose of 10 mg / day for 14 days was started in 13 patients with long COVID-19, some with symptoms of more than a month of evolution since the beginning of the COVID-19 clinic. The patients were followed up to evaluate the improvement of the symptoms with a numerical scale from 0 to 100 and COPD Assessment Test Scale (CAT), 3 weeks after starting treatment.

An improvement in symptoms was observed a few days after treatment and a good evolution of the sensation of dyspnea, chest pain, symptoms of discomfort, dry cough, and nasal symptoms. Likewise, the incorporation of the patients to their work activity during that period was observed. To date, the improvement continues to exist, without evidence of clinical deterioration.

• Study Type: Interventional
• Enrollment (Anticipated): 284
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Francisco M Mera Cordero, MD; Phone Number: +34699942492; Email: franmcor@hotmail.com
• Study Contact Backup: Name: Rosa Morros Pedrós, PhD; Phone Number: +34934824124; Email: rmorros@idiapjgol.org

Study Locations

• Spain
  • Barcelona, Spain, 08001
    • Recruiting
    • Primary Health Center Raval nord
    • Contact: Laura Romera, PiD MD
  • Barcelona
    • Corbera De Llobregat, Barcelona, Spain, 08757
      • Recruiting
      • Primaty health Center Corbera
      • Contact: Arnau Segura, MD
    • Cornellà De Llobregat, Barcelona, Spain, 08940
      • Recruiting
      • Primary Health Center Jaume Soler
      • Contact: Maria Jesus Gallardo, M.D
    • El Prat De Llobregat, Barcelona, Spain, 08820
      • Recruiting
      • Primary Health Center 17 Setember
      • Contact: Calero Xavier, MD
    • Sant Boi De Llobregat, Barcelona, Spain, 08830
      • Recruiting
      • Primary Health Center Camps Blancs
      • Contact: Zully Karin Amaya, MD
    • Sant Boi De Llobregat, Barcelona, Spain, 08830
      • Recruiting
      • Primary Health Center Molí Nou
      • Contact: Marta Via, MD
    • Sant Boi De Llobregat, Barcelona, Spain, 08830
      • Recruiting
      • Primary Health Center Vinyets
      • Contact: Cristina Armengol, MD
    • Sant Feliu De Llobregat, Barcelona, Spain, 08980
      • Recruiting
      • Primary Health Center ElPla
      • Contact: Silvia Plaza

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients 18 to 80 years old with SARS-CoV-2 infection (positive CRP <10 days from the onset of symptoms) treated in Primary Health Care.
• Persistent respiratory symptoms (more than 1 and <12 months of evolution)
• Mild-moderate dyspnea: score at the beginning of the study according to the modified Medical Research Council (mMRC) scale from 0 to 3
• The patient must be competent to complement the follow-up evaluations.
• The patient agrees to participate in the study and take assigned medication during the 4 weeks.
• Sign the informed consent

Exclusion Criteria:

• Severity criteria: fever> 38ºC, or O2 saturation <93%.
• Patients with SARS-Cov-2 pneumonia in the acute / subacute phase.
• Patients who have required hospital admission for SARS-Cov-2.
• Chronic Obstructive Pulmonary Disease (COPD), asthma, bronchiectasis, pulmonary fibrosis, obstructive sleep apnea syndrome (OSAS), chronic respiratory failure from any cause, home oxygen therapy.
• Use of montelukast or zafirlukast ≤ 30 days prior to inclusion
• Use of any dose of systemic corticosteroids ≤ 30 days prior to inclusion
• Use of gemfibrocil.
• Hypersensitivity to montelukast or to any of the excipients included (e.g. lactose.
• Any condition (including the inability to swallow pills) that, in the opinion of the researcher, would prevent the completion of taking the medication.
• Active malignancy, current or recent chemotherapy treatment (<6 months).
• Medical history of infection by the Human Immunodeficiency Virus (HIV) or any serious immunocompromised state.
• Pregnancy, planning to get pregnant or patients of childbearing age not undergoing birth control methods.
• Breastfeeding mother.
• Any other condition for which, in the opinion of the principal investigator, it is considered that the subject does not fit the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Montelukast; 10mg oral montelukast once daily for 28 days.	Drug: Montelukast; 10 mg oral montelukast once daily for 28 days; Other Names: antileukotriene
Placebo Comparator: Placebo; oral placebo once daily for 28 days.	Other: placebo; 10 mg oral placebo once daily for 28 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
COP Assessment Test Scale (CAT)	Quality of life of respiratory symptoms according to COPD Assessment Test (CAT The COPD Assessment Test (CAT) is a questionnaire for people with COPD, designed to measure the impact of COPD on a person's life, and how this changes over time.Quality of life of respiratory symptoms according to COPD Assessment Test (CAT). This is a validated self-administered scale to quantify and monitor the impact of COPD on well-being and daily life. It consists of 8 items (from 0 to 5 points), and a total score of 0-40 (0-9 mild, 10-20 moderate, 21-30 severe and 31-40 very severe), being higher scores worse outcome. A difference of 2 or more points in health status is considered clinically significant.	7, 14, 21 and 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1min sit-to-stand test	Exercise capacity: number of repetitions performed in the 1min sit-to-stand test	14 and 28 days
O2 desaturation	O2 desaturation ≥ 4% with effort (1min sit-to-stand test)	14 and 28 days
Visual Analogical Scale (VAS)	Symptoms evaluated using numeric Visual Analogical Scale (VAS): asthenia, headache, ageusia, anosmia, and rhinitis . It is numbered from 0-10, where 0 is the absence and 10 the greatest intensity, meaning higher scores worse outcome. The patient selects the number that best evaluates the intensity of the symptom.	7, 14, 21 and 28 days
All-cause mortality	Mortality from any cause during the study	7, 14, 21 and 28 days
Number of visits to primary care	Number of visits of any kind to primary health care settings (phone visit or face to face visit) during the study period.	28 days
Number of visits to the emergency room	Number of visits to emergency room form primary health o hospital settings during the study period.	28 days
Number of hospital admissions.	Number of hospital admissions during the study period.	28 days
Medication side effects	Number and type of adverse reactions during the study period related to medication.	7, 14, 21 and 28 days
Days of sick leave	Number of days of incapacity for work (sick leave) during the study period.	28 days
Factors of inflamatory and prothrombotic processes: D-Dimer, N-terminal prohormone of brain natriuretic peptide (NT Pro-BNP), C-reactive protenin and Antinuclear antibodies (ANA)	To analyze wether the factors of inflamatory and prothrombotic processes (D-Dimer, Pro-BNP, C-reactive protein, and ANA) at the begining of the study are response predictors to the treatment.	0 and 28 days

Collaborators and Investigators

• Sponsor: Jordi Gol i Gurina Foundation
• Collaborators: Institut Català de la Salut
• Investigators: Study Chair: Jesus Almeda Ortega, PhD, Institut Català de la Salut; Study Chair: Sara Bonet Monne, PhD, Institut Català de la Salut; Study Chair: Betlem Salvador Gonzalez, PhD, Institut Català de la Salut; Principal Investigator: Francisco Mera Cordero, MD, Institut Català de la Salut

Publications and helpful links

General Publications

• Mera-Cordero F, Bonet-Monne S, Almeda-Ortega J, Garcia-Sangenis A, Cunillera-Puertolas O, Contreras-Martos S, Alvarez-Munoz G, Monfa R, Balanzo-Joue M, Morros R, Salvador-Gonzalez B. 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. Trials. 2022 Jan 6;23(1):19. doi: 10.1186/s13063-021-05951-w. Erratum In: Trials. 2022 Feb 9;23(1):130.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2021
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): August 31, 2023

Study Registration Dates

• First Submitted: January 4, 2021
• First Submitted That Met QC Criteria: January 4, 2021
• First Posted (Actual): January 5, 2021

Study Record Updates

• Last Update Posted (Actual): June 3, 2022
• Last Update Submitted That Met QC Criteria: June 1, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Quality of Life; Primary Health Care; Clinical Trial; Montelukast; Leukotriene Antagonists; Long Term Covid
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Signs and Symptoms, Respiratory; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Asthmatic Agents; Respiratory System Agents; Leukotriene Antagonists; Hormone Antagonists; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Montelukast
• Other Study ID Numbers: 4R21/006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No