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)

BACKGROUND: Inhaled corticosteroid (ICS) is frequently used for COPD. Based on the considerable adverse effects and the knowledge that many such patients do not gain benefit from this treatment, it remains unresolved whether ICS treatment can be managed with lower doses, or via an ICS-sparing strategy with periods with and without this medicine. The blood eosinophil count is a useful biomarker for steroid-responsive airway inflammation, and we want to investigate whether an individualized and eosinophil-guided approach on ICS treatment reduces ICS over-treatment and side effects. High-dose (500 mg thrice weekly or 250 mg daily) long-term azithromycin has been shown to reduce acute exacerbations of COPD in selected patients. Frequent gastro-intestinal adverse effects remain a challenge, but many patients tolerate lower doses; however, the effect of the treatment at lower doses is unknown, although many physicians prefer such doses. We want to investigate whether oral low-dose prophylactic azithromycin 250 mg three times weekly reduces acute exacerbations of COPD and improves time alive and out of hospital.

METHODS: This is an ongoing, actively recruiting randomized, double-blinded, multicenter, four-arm factorial intervention clinical trial aiming to recruit 444 patients with specialist verified COPD GOLD risk class E and/or FEV1 < 30% who are currently on ICS. The patients are followed for one year and are randomized 1:1:1:1 to one of the four treatment arms: (1) eosinophil-guided ICS-sparing treatment and low-dose azithromycin, (2) eosinophil-guided ICS treatment and placebo, (3) continued ICS treatment and low-dose azithromycin, or (4) continued ICS treatment and placebo. If blood-eosinophils (measured every 3 months) are < 0.3 × 109 cells/L, ICS treatment will be paused in the arms with eosinophil-guided ICS-sparing treatment. Azithromycin/placebo is double-blinded and administered three times weekly. The primary endpoint is the number of hospitalization-requiring COPD exacerbations and/or death within 365 days.

DISCUSSION: Severe ICS-adverse effects like bacterial infections should be reduced. The ICS-sparing intervention, we test, may provide a useful tool to do this safely. Azithromycin low-dose prophylaxis is practiced by many physicians. This trial will provide evidence of whether this is effective.

TRIAL REGISTRATION: ClinTrials.gov. NCT04481555. Registered on 14 AUG 2020, https://clinicaltrials.gov/study/NCT04481555 .