COPD - Eosinophil-guided Reduction of Inhaled COrticoSteroids (COPERnICOS)

INTERVENTION: Trade Name: Azithromycin Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Azithromycin Other descriptive name: AZITHROMYCIN Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 250‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Trade Name: Inhaled coticosteroid Pharmaceutical Form: CONDITION: Clinicaltrial on eosinophil‐guided time‐updated person‐specific reduction of inhaled corticosteroid therapy and prophylactic azithromycin therapy in patients with severe or very severe chronic obstructive pulmonary disease (COPD) ; MedDRA version: 21.1 Level: LLT Classification code 10010952 Term: COPD System Organ Class: 100000004855 Therapeutic area: Diseases [C] ‐ Parasitic Diseases [C03] PRIMARY OUTCOME: Main Objective: 1. ICS; • Whether a strategy of "time‐updated, eosinophil‐guided administration of inhaled corticosteroids" in patients with severe/very severe COPD and frequent AECOPD´s can lead to non‐inferior treatment responses to standard treatment with combined ICS, LAMA, and LABA (same number of AECOPD, but with substantially lower exposure to corticosteroids).; • Whether the side effects of ICS can be reduced with the time‐updated, eosinophil‐guided administration of inhaled corticosteroids ; 2. Azithromycin: Whether the use of azithromycin can reduce the time hospitalized with AECOPD (or other cause) in severe COPD patients; Primary end point(s): 1. “Days alive and out of hospital within 365 days after recruitment” (Continuous data: Analysis with T‐test); 2. Number of hospitalization‐requiring exacerbations within 12 months (Continuous data: Analysis with T‐test) ; Secondary Objective: 1. ICS: ; • The microbiota changes that happen in the airways of a patient with COPD, when the patient is receiving inhaled corticosteroids continuously, compared to when a corticosteroid‐sparing, biomarker‐guided administration is used.; 2. Azithromycin: ; • The influence of the macrolide antibiotic azithromycin on the respiratory microbiota in patients with COPD.; Timepoint(s) of evaluation of this end point: 12 months SECONDARY OUTCOME: Secondary end point(s): • Death within 12 months (Death equates to 3 exacerbations in data analysis when an exacerbation is not antecedent to death) ; • Number of moderate/severe exacerbation within 12 months ; • Number of mild exacerbations within 12 months ; • The cumulative ICS dose ; • Change in blood eosinophils (eosinophilic trajectories) ; • Change in lunge microbiome abundance and diversity over 12 months ; • Antibiotic‐requiring infections within 90 days (0 vs. 1) ; • Need for treatment with systemic corticosteroids ; • Change in lung function (?FEV1) from baseline ; • One or more ICS‐induced side effects as listed below ; o Debut or worsening of diabetes mellitus (At baseline and 3 months follow‐ups) ; ? HbA1c = 6.5% (does not apply to patients with chronic renal failure, recent transfusion or haematological disorders) * or ; ? Venous fasting plasma glucose = 7.0 mmol / l * or ; ? Initiation or intensification of antidiabetic therapy ; o Pulmonary infections ; ; • Change in following from baseline ; o Body mass index (of more than 1 unit) over 12 months ; o MRC‐dyspnea score from < 3 to 3 =, over 3 months ; o COPD‐related quality of life (Based on COPD Assessment Test ‐ CAT) ; • Treatment failure: Recurrence of COPD leading to emergency room visit, hospitalization or need to intensify pharmacological treatment within 30 days ; • Mortality within 365 days (Access via patient journal) ; • Worsening of COPD symptoms (approach via patient journal and questionnaire). This endpoint is analyzed as: ; o Recurrence of COPD exacerbation or death within 30 days ; o Time to exacerbation or death within 30 days ; o Number of admission‐requiring NIV treatment or admissions to intensive care or death within 30 days ; Timepoint(s) of evaluation of this end point: At baseline and 12 months, except blood samples, CAD and MRC every 3 month (baseline, 3, 6, 9 and 12 months) INCLUSION CRITERIA: • COPD (verified by a specialist in respiratory medicine + spirometry) • GOLD risk class C/D or FEV1<30% • Must receive at least during last 4 weeks: LAMA, LABA and ICS • Informed consent Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 44 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 400