COPD
Conditions
Keywords
COPD, ERDOSTEINE
Brief summary
Chronic obstructive pulmonary disease (COPD) remains a major contributor to global morbidity and mortality, exposing healthcare systems to a significant economical and social load. Indeed, acute severe COPD exacerbations are the events that contribute most to the overall disease burden. Current management strategies are aimed at maximizing symptom-free periods, reduce hospitalizations, improve exercise tolerance, overall health status, and quality of life. Key pathophysiological mechanisms involved in COPD exacerbations (defined as acute worsening of respiratory symptoms) include oxidative stress, acute on chronic inflammation, and mucus hypersecretion. Agents with antioxidant, anti-inflammatory, and mucolytic properties can help reduce exacerbation frequency. Erdosteine is a new-generation mucoactive molecule developed to overcome the limitations associated with traditional mucolytics. In fact, in addition to its mucolytic effects, erdosteine exhibits antioxidant and anti-inflammatory activities and may reduce bacterial adhesion to airway surfaces - features that may be beneficial in the prevention and management of exacerbations. Preliminary clinical findings (EQUALIFE and RESTORE studies) suggest that erdosteine, in add-on to chronic inhaled therapy, can reduce exacerbation rates, shorten hospital stay, and improve health-related quality of life in patients with COPD. However, studies that have investigated the pathobiological mechanisms behind such clinical effects are lacking. The present study was constructed in order to investigate the mechanism of action of erdosteine on inflammation, oxidative stress pathways and immune response in patients with COPD. The secondary objectives of the study are to evaluate the effect of erdosteine on lung function tests in patients with COPD; to explore the effect of erdosteine on respiratory and COPD-related symptoms in patients with COPD; to assess the effect of erdosteine on exercise tolerance in patients with COPD. In order to do so, the investigator designed a pragmatic, low intervention, two-arms, monocenter, open-label, prospective, randomized, controlled trial, set in clinical practice. A total of 30 patients will be randomized by means of a 1:1 random allocation. The active group (15 patients) will be assigned to Treatment Arm A (Erdosteine \[Esteclin®\] 300 mg, 1 tablet twice daily for 30 days), while the control group (15 patients) will be assigned to Treatment Arm B (Standard of Care - current standard inhalation therapy in use).
Interventions
DRUGErdosteine
Erdosteine tablets 300 mg, 1 tablet orally every 12 hours (twice daily) for 30 days
DRUGStandard of Care (SOC)
Long acting beta-2 agonists and Long acting muscarinic antagonists in association (LABA/LAMA) with or without inhaled corticosteroids (LABA/LAMA/ICS) depending on the chronic inhaled home treatment. Dosage and posology will change depending on the molecules and the devices (once daily in case of umeclidinium bromide/vilanterol 55/22 mcg or fluticasone/umeclidinium bromide/vilanterol 92/55/22 or twice daily in case of budesonide/formoterol/glycopyrronium 160/7.2/4.8 mcg and beclometasone/formoterol/glycopyrronium 87/5/9 mcg)
Sponsors
Pierachille Santus, MD, PhD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 45 years 2. A confirmed COPD diagnosis at least 12 months prior to enrollment 3. Stable clinical conditions, defined as no exacerbations or respiratory infections of any severity in the last 3 months before enrollment 4. Moderate to Severe airflow obstruction (FEV1 30-80 %predicted post bronchodilation. 5. No hospitalizations for any cause in the 3 months prior to enrollment 6. Ability to perform repeatable pulmonary function tests 7. Chronic inhaled therapy with LAMA/LABA or LAMA/LABA/ICS with no changes in dosage in the last 3 before enrollment
Exclusion criteria
1. NYHA class III and IV heart failure 2. Unstable arrythmia 3. Active malignancy (solid or blood) 4. Chronic treatment with systemic corticosteroids or immunosuppressants 5. Immune depression 6. Known hypersensitivity to erdosteine 7. Pregnancy or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in transcriptomics of pro-inflammatory and anti-inflammatory cytokines in COPD patients exposed to erdosteine. | 4 weeks | Peripheral blood will be analyzed for immunological profiling in patients treated with standard of care only and patients also exposed to Erdosteine at baseline and after 4 weeks of treatment. Cytokine/chemokine profiles will be quantified in cell culture supernatants using the Bio-Plex Pro Human Cytokine 27-plex Assay. RNA extraction from whole blood will be performed to identify expression levels of molecules involved in immune response: CARD6, CASP1, CASP4, CCL2, HLA-A, IFITM1, IFNA1, IFNAR1, IL1β, IL6, IL8, IL10, IL17, IL18, IL22, ISG20, TGF-β, NLRP3, NLRP4, VCAM1. Betaactin (ACTB) and glyceraldeyde-3-phosphate dehydrogenase (GAPDH) will be used as housekeeping genes. The results for the gene expression analyses will be presented as the average of the relative expression units (%) to an internal reference sample and normalized to the housekeeping genes GAPDH and ACTB. |
| Changes in transcriptomics of oxidative stress signaling pathways in COPD patients exposed to erdosteine. | 4 weeks | Peripheral blood will be analyzed for oxidative stress profiling in patients treated with standard of care only and patients also exposed to Erdosteine at baseline and after 4 weeks of treatment. Oxidative stress will be quantified in cell culture supernatants using the Bio-Plex Pro Human Cytokine 27-plex Assay. RNA extraction from whole blood will be performed to identify expression levels of molecules involved in oxidative stress: APOE, CAT, DUSP1, GPX2, GPX3, MPO, NOS2, NOX4, NUDT1, SOD2. Betaactin (ACTB) and glyceraldeyde-3-phosphate dehydrogenase (GAPDH) will be used as housekeeping genes. The results for the gene expression analyses will be presented as the average of the relative expression units (%) to an internal reference sample and normalized to the housekeeping genes GAPDH and ACTB. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To assess the effect of erdosteine on mMRC dyspnea scale in patients with COPD | 4 weeks | Patiens will undergo the Modified British Medical Research Council Questionnaire (mMRC) at baseline and after 4 weeks of treatment with erdosteine or placebo. Modified British Medical Research Council Questionnaire (mMRC) assesses the patient's degree of chronic dyspnea with a score ranging from 0 (no dyspnea) to 4 (too much dyspnea to leave the house). The results will be expressed as absolute and relative difference in dyspnea score. |
| To assess the effect of erdosteine on distance covered during the six minute walk test in patients with COPD | 4 weeks | Patiens will undergo the Six Minutes Walk Test (6MWT) at study enrolment and after 4 weeks of treatment with erdosteine or placebo. The 6MWT will be conducted according to the 2002 American Thoracic Society (ATS) statement. For patients requiring exertional oxygen therapy, the test will be performed with supplemental oxygen. Patients will be asked to walk for 6 minutes on a flat surface, wearing a pulse oximeter. Before starting, the following parameters will be recorded: perceived dyspnoea level using the Borg scale (0-10 score), peripheral oxygen saturation (SpO2), heart rate (beats/min), and respiratory rate (breaths/min). The same parameters will be measured again at the end of the test. The distance walked, and any exercise-induced desaturation (SpO2 drop ≥4 points) will also be noted. The distance covered at the 6MWT will be measured in meters, and results will be expressed as absolute and relative difference from baseline. |
| To assess the effect of erdosteine on CAT (COPD assessment test) in patients with COPD | 4 weeks | Patiens will undergo the CAT (COPD assessment test) at baseline and after 4 weeks of treatment with erdosteine or placebo. COPD assessment test (CAT) aims to assess the impact of COPD on health status through a patient-completed questionnaire consisting of 8 items, each scored from 0 to 5. The total score ranges from 0 to 40, with higher scores indicating a greater impact of the disease on the patient's quality of life. The results will be expressed as absolute and relative difference in CAT total score. |
Countries
Italy
Contacts
CONTACTPierachille Santus Professor, MD, PhD
CONTACTDejan Radovanovic, MD, PhD
Outcome results
None listed