Eosinophil-guided Reduction of Inhaled Corticosteroids (COPERNICOS)

Clinical trial on eosinophil-guided time-updated person-specific reduction of inhaled corticosteroid (ICS) therapy and prophylactic azithromycin therapy in patients with severe or very severe chronic obstructive pulmonary disease (COPD) receiving long-acting b-agonist (LABA) / long-acting muscarinic receptor antagonists (LAMA) / ICS treatment.

Study Overview

• Status: Completed
• Conditions: Pneumonia; COPD; COPD Exacerbation; Azithromycin; Inhaled Corticosteroid
• Intervention / Treatment: Drug: ICS; Drug: Azithromycin

Detailed Description

Inhaled corticosteroid (ICS) treatment is recommended by Global Initiative for Obstructive Lung Disease (GOLD) for patients with frequent and/or servere exacerbations and blood eosinophils > 0.3 x 10^9 cells/L and in those with ≥ 0,1 x 109 cells blood-eosinophils and recurrent exacerbations while on bronchodilators. ICS treatment, however, is associated with side effects such as diabetes, osteoporosis and pneumonia which is costly for both patients and society. By studying the effects of a personalized, eoseosinophil-guided approach to direct ICS in COPD patients with frequent AECOPDs through a randomized clinical trial this study will examine the possibilities of reducing ICS overtreatment and thus ICS-related adverse events.

Long term ICS treatment is known for affecting the bacterial load in stable COPD patients. Azithromycin exerts multiple effects on the structure and composition of the lower airway microbiota and has anti-inflammatory effects. This study will, moreover, investigate whether an oral low-dose prophylactic treatment with Azithromycin 250 mg three times weekly can reduce the number of moderate-severe AECOPD and improves time alive and out of hospital.

This study is a randomized, double-blinded, multicentre, four-arm intervention clinical trial and is conducted based on the principles of good clinical practise (GCP).

• Study Type: Interventional
• Enrollment (Actual): 444
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark
    • Aarhus University Hospital
  • Copenhagen, Denmark
    • Hvidovre Hospital
  • Esbjerg, Denmark
    • Sydvestjysk Sygehus Esbjerg
  • Hellerup, Denmark
    • Gentofte Hospital
  • Hillerød, Denmark
    • Nordsjællands Hospital
  • Næstved, Denmark
    • Næstved-Slagelse-Ringsted Sygehus
  • Odense, Denmark
    • Odense University Hospital
  • Roskilde, Denmark
    • Roskilde Sygehus
  • Silkeborg, Denmark
    • Silkeborg Sygehus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• COPD (verified by a specialist in respiratory medicine + spirometry)
• GOLD class E anytime within the last 2 years (corresponding to 2 ≥ AECOPD and/or ≥1 AECOPD leading to hospitalization during a 12 months period within the last 2 years) and/or FEV1<30%.
• Treatment for last 4 weeks including LAMA, LABA and ICS
• Informed consent

Exclusion Criteria:

• Known asthma.
• Male < 40 years.
• Female <40 years, if non-menopausal (had menstruation within the last 12 months) conditioned by a negative urine HCG test
• Severe mental illness which considerably complicates co-operation.
• Language problems that considerably complicate co-operation.
• Current treatment with systemic corticosteroids corresponding to > 5 mg prednisolone per day.
• Systemic antibiotic treatment (if to participate in microbiota sub-study) or systemic corticosteroid treatment within 14 days (also prophylactic Azithromycin).
• Contra-indication to treat with Azithromycin (as listed by the producer).
• Non-bacterial exacerbation per investigator judgement in the last 3 months.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Eosinophil_"Control"/Azithro_"Control"; Azithromycin: patients are given placebo; ICS: The patients are given the usual LAMA/LABA/ICS product in the usual dose.
Experimental: Eosinophil_"Active"/Azithro_"Control": a. Azithromycin: placebo b. ICS: All patients will receive LABA/LAMA medication. The ICS medication will be switched on/off according to the most recent blood eosinophil count (at inclusion + every 3 months): i. If blood eosinophil ≥ 300 cells/μL, ICS in usual dose next 3 months. Blood eosinophils are measured every 3 months. ii. If blood eosinophil <300 cells/μL, ICS is discontinued.	Drug: ICS; All patients will receive LABA/LAMA medication. The ICS medication will be switched on/off according to the most recent blood eosinophil count (at inclusion + every 3 months) vs continued LABA/LAMA/ICS treatment
Experimental: Eosinophil_"Control"/Azithro_"Active" group; Azithromycin: 250 mg azithromycin three times weekly. b. ICS: The patients are given the usual LAMA/LABA/ICS product in the usual dose, where the medical treatment for severe COPD is unchanged throughout the entire project period	Drug: Azithromycin; Prophylactic azithromycin treatment 250 mg three times weekly vs placebo
Experimental: Eosinophil_"Active"/Azithro_"Active": Azithromycin: 250 mg azithromycin three times weekly.; ICS: All patients will receive LABA/LAMA medication. The ICS medication will be switched on/off according to the most recent blood eosinophil count (at inclusion + every 3 months):	Drug: ICS; All patients will receive LABA/LAMA medication. The ICS medication will be switched on/off according to the most recent blood eosinophil count (at inclusion + every 3 months) vs continued LABA/LAMA/ICS treatment; Drug: Azithromycin; Prophylactic azithromycin treatment 250 mg three times weekly vs placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exacerbations, hospital and death	Number of hospitalization-requiring exacerbations within 12 months and/or death within 365 days	365 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative OCS dose	Cumulative dose of systemic corticosteroids within 365 days	365 days
Diabetes mellitus	New diagnosis of diabetes mellitus within 365 days	365 days
Change in HbA1c	Change in HbA1c from baseline to 365 days	365 days
Number of antibiotic requiring infections	Antibiotic-requiring infections within 365 days	365 days
Days alive, out of hospital	Days alive and out of hospital within 365 days after recruitment	365 days
Deaths, uncontrolled AECOPD	Death or uncontrolled AECOPD tendency within 365 days	365 days
Number of exacerbations	Number of moderate/severe exacerbation within 365 days	365 days
Cumulative ICS dose	Cumulative dose of inhaled corticosteroids within 365 days	365 days
Change in FEV1	Change in lung function (ΔFEV1) from baseline to 365 days	365 days
Change in blood eosinophils	Change in blood eosinophils from baseline to 365 days (eosinophilic trajectories)	365 days
Microbiota, abundance and diversity	Difference in respiratory microbiota abundance and diversity from baseline to 12 months between treatment arms	365 days
Microbiota, immunological profile	Difference in immunological profile including cytokines and chemokines in the upper airways from baseline to 12 months between treatment arms	365 days
Change in CAT score	Change in COPD-related quality of life (Based on COPD Assessment Test - CAT) from baseline to 365 days	365 days
Change in MRC dyspnoea score	Number who progress to MRC -dyspnea score from < 3 to ≥3 anytime during follow-up (assessed every 3 months).	365 days
Number of non-invasive ventilation (NIV) or intensive care admissions or death	Number of admission requiring non-invasive ventilation (NIV) treatment or admissions to intensive care within 365 days	365 days
Mortality	Mortality within 365 days	365 days

Collaborators and Investigators

• Sponsor: Chronic Obstructive Pulmonary Disease Trial Network, Denmark

Publications and helpful links

General Publications

• Ronn C, Bonnesen B, Alispahic IA, Tonnesen LL, Kjaergaard JL, Moberg M, Ulrik CS, Harboe ZB, Browatzki A, Jensen TT, Meyer CN, Bodtger U, Bendstrup E, Johansson SL, Kaiser DU, Hyldgaard C, Vestbo J, Sivapalan P, Jensen JS. Study protocol: COPD-eosinophil-guided reduction of inhaled corticosteroids (COPERNICOS) : A randomized, double-blinded, multicenter, four-arm intervention clinical trial on eosinophil-guided time-updated person-specific reduction of inhaled corticosteroid therapy and prophylactic low dose Azithromycin therapy in patients with severe or very severe chronic obstructive pulmonary disease (COPD). Trials. 2025 Sep 2;26(1):335. doi: 10.1186/s13063-025-09032-0.

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2021
• Primary Completion (Actual): November 27, 2024
• Study Completion (Actual): November 19, 2025

Study Registration Dates

• First Submitted: July 14, 2020
• First Submitted That Met QC Criteria: July 17, 2020
• First Posted (Actual): July 22, 2020

Study Record Updates

• Last Update Posted (Actual): January 28, 2026
• Last Update Submitted That Met QC Criteria: January 27, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pathological Conditions, Signs and Symptoms; Pulmonary Disease, Chronic Obstructive; Pneumonia; Organic Chemicals; Macrolides; Lactones; Erythromycin; Polyketides; Azithromycin
• Other Study ID Numbers: COPERNICOS_JUJCPR; 2020-003014-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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