ICS: All participants 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 ≥ 0.3 x 109 cells/L, ICS is continued in usual dose next 3 months.
ii. If blood eosinophil < 0.3 x 109 cells/L, ICS is discontinued.
A microbiological and immunological study within the framework of the randomized study aims to investigate the respiratory microbiota and immunological profile in participants from the four randomized groups. A total of 40 participants from each group will participate in the sub-study and will undergo tracheal aspirate collection and nasal swabs at baseline and 12 months follow-up. Collection of tracheal aspirates is a routine procedure at participating centres and serious complications are very rare. Nasal swab is not associated with any serious complications. Participants’ data and laboratory specimens will be assigned a coded identification number to maintain participant confidentiality.
Modifications to the protocol which may impact on the conduct of the study, potential affect patient safety, including changes of study objectives, study design, patient population, sample sizes, study procedures, or significant administrative aspects will require a formal amendment to the protocol. Such amendment will be agreed upon COPERNICOS study group and approved by the Clinical Trials Information System (CTIS)prior to implementation.
4.2 Recruitment
Participants for the trial will be recruited through advertisements and announcements on social media, in local newspapers, daily newspapers, and via the Danish Lung Association and its member magazine. Participants can contact trial staff by e-mail or telephone to receive the written participant information. Furthermore, patients at the outpatient clinic at each centre will be consecutively screened for eligibility for the trial. If a patient matches the criteria for the study, the patient will be invited to a screening meeting. The oral information session is given by a medical doctor who is duly qualified, including having knowledge of the trial to be able to provide information about it and answer any questions the subject may have. This meeting will take place in an undisturbed office.
Participants will be thoroughly screened for eligibility, and informed of the right to an assessor and companion at the first contact during an information meeting with trial staff. A 24-hour reflection period will be given to every participant, and informed consent will be obtained upon the signed consent declaration, provided that the participant will participate in the study. Only after receiving oral and written participant information, can informed consent be obtained. It is the primary investigator’s responsibility at each centre to ensure that study personnel are trained, duly authorized, and competent to obtain informed consent. The consent to collect blood samples, tracheal aspirates and nasal swabs to research biobank and future-research biobank is a separate part of the informed consent.
At recruitment health files regarding inclusion and exclusion criteria will be accessed for screening purposes before informed consent is obtained according to the Danish Health Care Act § 46 (1). The following contact to possible participants will be at the next planned visit to the outpatient clinic. During the project health files will be accessed by investigators for the following information:
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Medication
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Hospital admissions
If informed consent is obtained, the study sponsor, investigator, monitor, and the Danish Medicines Agency (Lægemiddelstyrelsen) will have access to health files, including electronic files, as part of the trial surveillance, quality control, etc.
Participants are allocated randomly via REDCap to one of the four arms; prior to randomization the inclusion and exclusion criteria will have been entered.
The azithromycin/placebo tablets are dispensed either as 500 mg tablets with a score line for splitting (patients are instructed to halve each tablet using the provided pill cutter, or as 250 mg capsules that should be swallowed whole without splitting. Patients will therefore be given very detailed instructions on the provided tablets or capsules, and on how to take the medication. The reason for having the medication in two different formulations is that the pharmacy producing the medication, for production reasons, has not been able to supply all the medication in the same formulation. Participants compliance to Azithromycin/placebo are monitored by both medicine diaries and leftover medicine returned at the 12-month examination. Blood eosinophil count will be monitored every 3 months from inclusion and participants will receive a phone call from a nurse every 3 months to ensure that participants have taken ICS according to the physician's prescription and plan the next 3 months treatment according to protocol.
4.3 Inclusion criteria
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COPD (verified by a specialist in respiratory medicine + spirometry).
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GOLD class E anytime within the last 2 years (corresponding to 2 ≥ AECOPD and/or ≥ 1 AECOPD leading to hospitalization during a 12 month period within the last 2 years) and/or FEV1 < 30%.
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Treatment for last 4 weeks including LAMA, LABA and ICS.
4.4 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.
4.5 Examinations
The following clinical tests will be performed during the project cf. figure 2.
Blood tests: Electrolyte parameters (sodium, potassium, albumin, creatinine, hemoglobin), liver parameters (conjugated bilirubin, ALT, alkalic phosphatase, INR, LDH), infection parameters (CRP, white blood cell differential count, thrombocytes), D-dimer and HbA1c.
Questionnaires: Standardized questionnaires are used. CAT and MRC dyspnea scale are short and simple tests that provide an understanding of the severity and impact of COPD on the participant's daily life.
4.6 Data Collection
Data processing, statistical analysis and publication of the data material will be performed by a PhD student (coordinating investigator) together with health professionals (primary and secondary investigators) from the participating pulmonary medical outpatient clinics. The randomized trial started with the inclusion of participants 05JUL2021, and the last participant is expected to be included by 31AUG2025. Data collection ceases 31AUG2026, and the project is scheduled to run until 31AUG2026.
A nurse will be responsible for collecting baseline data, performing lung function measurement, weight and height at baseline and the 12-month follow-up as well as performing blood sampling and questionnaires at three-, six- and nine-month follow-ups, according to Fig. 2. Data will be obtained via the electronic health record. Medical decisions are made by doctors only. Proper handling, storage, and delivery of medication and the primary daily project management is handled by the coordinating investigator. Recruitment, medical examinations, and distribution and accounting of medication will be assisted by primary investigators at each centre.
The data collected will be treated confidentially and only by personnel associated with the project. This includes demographic data, health status, current illnesses, medications, medicinal side effects, hospital admissions, and results from various examinations during the trial. Data will be reported in Electronic Case Report Forms (eCRF) specific for each participant. The data is encrypted, stored in online servers and protected by the Data Protection Authority through various security precautions. The physical copies of the CRF are kept in locked archives on the involved departments for 5 years.
Data in eCRF will be handled by the investigator at each centre and in accordance with the Law for Data Protection and the Danish Law for Privacy Regulation.
4.7 Research Biobank
The purpose of establishing a research biobank is to investigate the frequency of ICS-induced side effects and the changes in respiratory microbiota in different treatment groups. This biobank will clarify the hypotheses and provide biological materials for future research (Providing that future projects can obtain a separate approval from the Danish National Committee on Health Research Ethics).
The research biobank will store blood samples, tracheal aspirate samples, and nasal swabs. Tracheal aspirate and nasal swab samples are taken from 40 participants from each treatment arm, in total 160 participants. Approximately 1-5 ml of tracheal aspirate will be collected from each participant. Blood samples are taken from each participant at inclusion and at follow-up every 3 months during the 12-month study period. Approximately 210 ml of blood will be collected during the entire study period corresponding to a maximum of 36 ml per blood draw. All samples are stored in a freezer at -80 degrees Celsius. The freezers are kept in a locked room at each of the participating pulmonary medicine departments.
All samples are pseudonymized and kept for 15 years in accordance with present legislation and data protection laws. Establishment of this research biobank ends 31AUG2027. Following the end of this study and the research biobank, all surplus biological material will be transferred to a future-research biobank. These samples will also be pseudonymized and kept for 15 years. Permission to store biological material from participants in the research biobank and future-research biobank is a part of the informed consent to participation in the project.
Participants will be randomized using stratified block randomization (REDCap) to ensure equal distribution of participants at the site, age (less than 70 years vs 70 years or more) and number of hospital-requiring exacerbations within the past 12 months (0-1 vs 2 or more).
The trial will have a target of 444 participants, , included in the project within 48 months, and 111 participants will be allocated to each of the four groups to be examined.
Two sample size calculations have been conducted, one for ICS and one for azithromycin, as there are two interventions being tested (factorial design):
A non-inferiority (1-sided) test for ICS.
Type 1 error limit (α) 2.5%, Power (1-β) of 80%. (α = 0.025, β = 0.2)
Control group exacerbation/death: 0.3 (30%)
Expected maximum worsening >11% absolute (up to 0.41)
Sample size 444 (222 x 2)
A 1-sided superiority test for azithromycin.
Type 1 error limit (α) 2.5%, Power (1-β) of 80%. (α = 0.025, β = 0.2)
Control group exacerbation/death: 0.3 (30%)
Expected effect: >10% absolute (up to 0.2)
Sample size 444 (222 x 2)
These two interventions will be published separately in two primary publications, but there will be adjustments in the main analysis to account for whether they received the other intervention. These two analysis teams (separate) will be blinded to an effect estimate of the other intervention.
40 participants from each group will participate in the microbiota sub-study.
Scheduled analyses of data (Interim analysis) will be assessed when half of the participants are recruited. These assessments will be made by the independent Data and Safety Monitoring Board (DSMB) on the two primary endpoints, and for the secondary endpoint “Death or “uncontrolled AECOPD tendency” within 365 days”. Data on primary and secondary power targets will be used for this purpose. DSMB will review the protocol, monitor the guideline, evaluate the trial concerning the recruitment of participants, participants' risk and, based on interim analyses, make recommendations to the investigators on whether to continue or cease the study. DSMB may at any time require an extraordinary interim analysis
5.1 Primary Endpoints
ICS and Azithromycin
The primary outcome targets admissions and death within 365 days of randomization. This is assessed in the following analysis:
- Number of hospitalization-requiring COPD exacerbations and/or death within 365 days (continuous data: analysis with chi squared test)
5.2 Secondary Endpoints
ICS and Azithromycin
- “Days alive and out of hospital within 365 days after recruitment” (continuous data: analysis with T-test)
- Death or “uncontrolled AECOPD tendency”[7][1] within 365 days.
- Number of moderate/severe exacerbation within 365 days
- Cumulative dose of inhaled corticosteroids within 365 days
- Cumulative dose of systemic corticosteroids within 365 days
- Change in lung function (ΔFEV1) from baseline to 365 days
5.3 Exploratory
ICS
- Change in blood eosinophils from baseline to 365 days (eosinophilic trajectories)
- New diagnosis of diabetes mellitus within 365 days
- Change in HbA1c from baseline to 365 days
- Antibiotic-requiring infections within 365 days
ICS and Azithromycin
- Difference in respiratory microbiota abundance and diversity from baseline to 12 months between treatment arms
- Difference in immunological profile including cytokines and chemokines in the upper airways from baseline to 12 months between treatment arms
- Change in COPD-related quality of life (Based on COPD Assessment Test - CAT) from baseline to 365 days
- Number who progress to MRC -dyspnea score from < 3 to ≥3 anytime during follow-up (assessed every 3 months).
- Number of admission requiring non-invasive ventilation (NIV) treatment or admissions to intensive care within 365 days
- Mortality within 365 days
5.3 Data analysis
The four treatment groups will be compared in terms of endpoints at inclusion and follow-up visits every 3 months from trial inclusion with standard statistical tests such as t-test (Dichotomous outcomes), chi-squared test, Fisher’s exact test, and time-to-event analyses.
Recurrence of AECOPD, the period between index AECOPD and the next AECOPD, and number of admission-requiring NIV treatment within 365 days are analyzed using Fisher’s exact test or Chi-squared test. Time to AECOPD within 365 days and number of hospitalization-requiring exacerbations within 365 days will be analyzed with t-test and Cox proportional-hazards regression model (unadjusted and adjusted). Mortality rate within 365 days will be analyzed with Chi-squared test or Fisher’s exact test (unadjusted) and with Cox proportional-hazards regression model (adjusted).
New onset of diabetes during the study period or occurrence of antibiotic-requiring infections within 365 days will be analyzed using Fisher’s exact test or Chi-squared test. Changes in lung function, health-related quality-of-life (CAT), and level of dyspnea (MRC) will be analyzed using analysis of variance (ANOVA). The cumulative ICS dose will be analyzed as mean total cumulative dose from recruitment to end of the study period using t-test, Wilcoxon signed-rank test or Mann-Whitney U test.