COPD, Inhaled Corticosteroid, Azithromycin, COPD Exacerbation, Pneumonia
Conditions
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).
Interventions
DRUGAzithromycin
Prophylactic azithromycin treatment 250 mg three times weekly vs placebo
DRUGICS
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
Sponsors
Chronic Obstructive Pulmonary Disease Trial Network, Denmark
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
4-arm facultative designed, randomized controlled, multicenter, parallel group, double-blinded (azithromycin), non-inferiority intervention study in patients with severe and very severe COPD study. Participants will be randomly allocated to one of four treatment groups.
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Exacerbations, hospital and death | 365 days | Number of hospitalization-requiring exacerbations within 12 months and/or death within 365 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Days alive, out of hospital | 365 days | Days alive and out of hospital within 365 days after recruitment |
| Deaths, uncontrolled AECOPD | 365 days | Death or uncontrolled AECOPD tendency within 365 days |
| Number of exacerbations | 365 days | Number of moderate/severe exacerbation 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) |
| Diabetes mellitus | 365 days | New diagnosis of diabetes mellitus within 365 days |
| 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 |
| Microbiota, abundance and diversity | 365 days | Difference in respiratory microbiota abundance and diversity from baseline to 12 months between treatment arms |
| 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 |
| 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). |
| 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 |
| Mortality | 365 days | Mortality within 365 days |
Countries
Denmark
Outcome results
None listed