COPD - Eosinophil-guided Reduction of Inhaled Corticosteroids (COPERNICOS)

The primary objective of this study is to evaluate the efficacy of an **eosinophil-guided** administration of inhaled corticosteroids (ICS) in patients with **chronic obstructive pulmonary disease (COPD)** classified as GOLD class E and/or with FEV1 < 30%. The study aims to determine if this regimen maintains treatment efficiency without apparent loss. Additionally, the study investigates the impact of low-dose **Azithromycin** on reducing COPD exacerbations or mortality from all causes within 365 days compared to placebo.

Secondary objectives include:

• Assessing whether eosinophil-guided ICS administration reduces ICS usage by more than 25% in COPD patients classified as GOLD risk class C/D and/or with FEV1 < 30%.
• Evaluating the reduction in ICS-related side effects with eosinophil-guided ICS administration in the same patient group.
• Comparing the composition of the respiratory microbiota, focusing on less pathogenic bacterial species, in patients treated with eosinophil-guided ICS versus continuous triple therapy (ICS/LABA/LAMA).
• Investigating the complexity of the respiratory microbiota in patients on continuous triple therapy compared to those on eosinophil-guided ICS.
• Examining the substantial differences in respiratory microbiota composition when patients are treated with prophylactic low-dose Azithromycin.

The clinical trial involves participants diagnosed with **chronic obstructive pulmonary disease (COPD)**, specifically those classified under GOLD class E and/or with FEV1 < 30%. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants are required to have a history of COPD verified by a specialist in respiratory medicine and spirometry, and must have been receiving LAMA, LABA, and ICS treatments for at least the last four weeks. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified in the available data. Key inclusion criteria include a history of GOLD risk class C/D within the last two years and informed consent. The selection process for the trial population is not detailed in the provided information.

The clinical trial is designed to evaluate the efficacy of **azithromycin** in patients with **chronic obstructive pulmonary disease (COPD)**. The study employs a randomized, double-blind, placebo-controlled design to ensure the reliability and validity of the results. Participants will be randomly assigned to receive either azithromycin or a placebo, with neither the participants nor the investigators aware of the group assignments. The trial is expected to span a duration of 52 weeks, with the primary objective of assessing the reduction in COPD exacerbations or mortality within this period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a verified diagnosis of COPD and a history of exacerbations. Following randomization, participants will attend regular follow-up visits every three months to monitor health status, medication adherence, and any adverse events. These visits will include assessments of lung function, blood eosinophil levels, and quality of life. The end-of-study visit will occur at the conclusion of the 52-week period, where final evaluations will be conducted to assess the primary and secondary endpoints, including hospitalization rates and changes in lung function.

Participant involvement is expected to last for the entire 52-week duration unless specific conditions necessitate early termination. Such conditions include significant adverse reactions to the study medication, withdrawal of consent, or any medical condition that, in the opinion of the investigator, would compromise the participant's safety or the integrity of the study. The trial aims to provide comprehensive data on the potential benefits of azithromycin in managing COPD, contributing valuable insights into treatment strategies for this chronic condition.

The clinical trial involves the administration of **Azithromycin** in various formulations as an experimental treatment. **Azithromycin "Sandoz"** is provided in the form of film-coated tablets, with each tablet containing the active substance **azithromycin**. The maximum daily dose is 250 mg, and the total dose over the treatment period can reach up to 39,000 mg. The tablets are administered orally, and the treatment duration is up to 12 weeks. Compliance with the dosing schedule is monitored throughout the trial.

Another formulation, **Azithromycin "Stada"**, is also used in the study. This product is similarly presented as film-coated tablets containing **azithromycin**. The maximum daily dose is 250 mg, with a total dose of 250 mg over the treatment period. The administration route is oral, and the treatment can last up to 52 weeks. Participant adherence to the dosing regimen is closely observed.

**Azithromycin "Jubilant"** is included as an additional experimental treatment. These film-coated tablets contain **azithromycin** and are administered orally. The maximum daily dose is 250 mg, with a total dose of 39,000 mg over the course of the study. The treatment period extends up to 52 weeks, and participant compliance is monitored to ensure adherence to the prescribed dosing schedule.

The trial also incorporates a **placebo** as a comparator treatment. The placebo is designed to match the appearance of the azithromycin tablets but contains no active substance. It is used to assess the efficacy of the experimental treatments by providing a baseline for comparison. The placebo is administered in a manner consistent with the experimental treatments, ensuring blinding and maintaining the integrity of the study.

Additionally, the study involves the use of **inhaled corticosteroids** as a non-experimental treatment. These are administered via inhalation, with the dosing schedule tailored to the individual needs of the participants. The corticosteroids serve as a standard-of-care therapy, providing a control for evaluating the effects of the experimental treatments on patients with Chronic Obstructive Pulmonary Disease (COPD).

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the number of hospitalization-requiring exacerbations and/or death within 365 days. Secondary endpoints include a range of measures such as death or "uncontrolled AECOPD tendency" within 365 days, the number of moderate/severe exacerbations within 365 days, and cumulative doses of inhaled and systemic corticosteroids within the same period. Additional secondary endpoints involve changes in lung function (ΔFEV1) and blood eosinophils from baseline to 365 days, new diagnoses of diabetes mellitus, changes in HbA1c, antibiotic-requiring infections, and differences in respiratory microbiota abundance and diversity at 12 months between treatment arms.

Further secondary endpoints include changes in COPD-related quality of life, assessed using the COPD Assessment Test (CAT) from baseline to 365 days, the number of patients progressing to an MRC-dyspnea score of ≥3 during follow-up, admissions requiring NIV treatment or admissions to intensive care, mortality within 365 days, differences in immunological profiles including cytokines and chemokines in the upper airways from baseline to 12 months between treatment arms, and "days alive and out of hospital" within 365 days after recruitment.

These efficacy parameters will be measured and collected at specified timepoints, with assessments conducted at baseline and at intervals up to 365 days. The tools and instruments involved in these assessments include validated scales and laboratory tests, ensuring a comprehensive evaluation of the trial's efficacy outcomes.