Clinical trial NCT04695704: Efficacy of Montelukast in Mild-moderate Respiratory Symptoms in Patients With Long-COVID-19:
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Covid19
SARS (Disease)
Keywords: SARS-CoV-2
Montelukast
Leukotriene Antagonists
Primary Health Care
Clinical Trial
Quality of Life
Long Term Covid
Lead sponsor: Fundacio d'Investigacio en Atencio Primaria Jordi Gol i Gurina
Sponsor class: OTHER
Collaborators: name: Institut Català de la Salut
First posted: 2021-01-05
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blind randomized placebo-controlled clinical trial,.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: COP Assessment Test Scale (CAT)
timeFrame: 7, 14, 21 and 28 days
Secondary outcomes:
measure: 1min sit-to-stand test
timeFrame: 14 and 28 days
measure: O2 desaturation
timeFrame: 14 and 28 days
measure: Visual Analogical Scale (VAS)
timeFrame: 7, 14, 21 and 28 days
measure: All-cause mortality
timeFrame: 7, 14, 21 and 28 days
measure: Number of visits to primary care
timeFrame: 28 days
measure: Number of visits to the emergency room
timeFrame: 28 days
measure: Number of hospital admissions.
timeFrame: 28 days
measure: Medication side effects
timeFrame: 7, 14, 21 and 28 days
measure: Days of sick leave
timeFrame: 28 days
measure: 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)
timeFrame: 0 and 28 days
Other outcomes:
Locations:
city: Corbera De Llobregat
country: Spain
facility: Primaty health Center Corbera
state: Barcelona
city: Cornellà De Llobregat
country: Spain
facility: Primary Health Center Jaume Soler
state: Barcelona
city: El Prat De Llobregat
country: Spain
facility: Primary Health Center 17 Setember
state: Barcelona
city: Sant Boi De Llobregat
country: Spain
facility: Primary Health Center Camps Blancs
state: Barcelona
city: Sant Boi De Llobregat
country: Spain
facility: Primary Health Center Molí Nou
state: Barcelona
city: Sant Boi De Llobregat
country: Spain
facility: Primary Health Center Vinyets
state: Barcelona
city: Sant Feliu De Llobregat
country: Spain
facility: Primary Health Center ElPla
state: Barcelona
city: Barcelona
country: Spain
facility: Primary Health Center Raval nord
Study officials:
affiliation: Institut Català de la Salut
name: Jesus Almeda Ortega, PhD
role: STUDY_CHAIR
affiliation: Institut Català de la Salut
name: Sara Bonet Monne, PhD
role: STUDY_CHAIR
affiliation: Institut Català de la Salut
name: Betlem Salvador Gonzalez, PhD
role: STUDY_CHAIR
affiliation: Institut Català de la Salut
name: Francisco Mera Cordero, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.