Eosinophil-guided Reduction of Inhaled Corticosteroids

Phase 4

Recruiting

• Conditions: COPD; Inhaled Corticosteroid; COPD Exacerbation; Azithromycin; Pneumonia
• Interventions: Drug: Azithromycin; Drug: ICS

• Registration Number: NCT04481555
• Lead Sponsor: Chronic Obstructive Pulmonary Disease Trial Network, Denmark

Brief Summary

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.

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 Timeline

• Study First Submitted: 2020-07-14
• Study First Submitted QC: 2020-07-17
• Study First Posted: 2020-07-22
• Study Start: 2021-06-28
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-04
• Last Update Posted: 2024-03-05
• Primary Completion: 2024-12-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 444

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Eosinophil_"Active"/Azithro_"Active":	Azithromycin	1. Azithromycin: 250 mg azithromycin three times weekly. 2. 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):
Eosinophil_"Active"/Azithro_"Active":	ICS	1. Azithromycin: 250 mg azithromycin three times weekly. 2. 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):
Eosinophil_"Active"/Azithro_"Control":	ICS	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.
Eosinophil_"Control"/Azithro_"Active" group	Azithromycin	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

Primary Outcome Measures

Name	Time	Method
Exacerbations, hospital and death	365 days	Number of hospitalization-requiring exacerbations within 12 months and/or death within 365 days

Secondary Outcome Measures

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

Trial Locations

Locations (9)

Silkeborg Sygehus; 🇩🇰 Silkeborg, Denmark

Aarhus University Hospital; 🇩🇰 Aarhus, Denmark

Hvidovre Hospital; 🇩🇰 Copenhagen, Denmark

Sydvestjysk Sygehus Esbjerg; 🇩🇰 Esbjerg, Denmark

Gentofte Hospital; 🇩🇰 Hellerup, Denmark

Nordsjællands Hospital; 🇩🇰 Hillerød, Denmark

Næstved-Slagelse-Ringsted Sygehus; 🇩🇰 Næstved, Denmark

Odense University Hospital; 🇩🇰 Odense, Denmark

Roskilde Sygehus; 🇩🇰 Roskilde, Denmark