Eosinophil-guided Reduction of Inhaled Corticosteroids

Study Overview
=================
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.

Official Title
-----------------
Eosinophil-guided Reduction of Inhaled Corticosteroids

Conditions
-----------------
COPD, Inhaled Corticosteroid, Azithromycin, COPD Exacerbation, Pneumonia

Intervention / Treatment
-----------------
* Drug: Azithromycin
* Drug: ICS


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: COPD (verified by a specialist in respiratory medicine + spirometry) GOLD risk class C/D 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%. Must receive at least during last 4 weeks: 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 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.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Eosinophil_Control/Azithro_Control<br>Azithromycin: patients are given placebo ICS: The patients are given the usual LAMA/LABA/ICS product in the usual dose. | |
| Experimental: Eosinophil_Active/Azithro_Control:<br>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. | Drug: ICS<br>* 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<br>|
| Experimental: Eosinophil_Control/Azithro_Active group<br>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 | Drug: Azithromycin<br>* Prophylactic azithromycin treatment 250 mg three times weekly vs placebo<br>|
| Experimental: Eosinophil_Active/Azithro_Active:<br>Azithromycin: 250 mg azithromycin three times weekly. 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): | Drug: Azithromycin<br>* Prophylactic azithromycin treatment 250 mg three times weekly vs placebo<br>Drug: ICS<br>* 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<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days alive | Days alive and out of hospital within 365 days after recruitment | 365 days | 
| Exacerbations, hospital | Number of hospitalization-requiring exacerbations within 12 months | 365 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AECOPD tendency | Death or uncontrolled AECOPD tendency within 365 days | 365 dyas | 
| Number of exacerbations | Number of moderate/severe exacerbation within 12 months | 365 days | 
| Cumulative ICS dose | Cumulative dose of ICS within 365 days | 365 days | 
| Cumulative OCS dose | Cumulative dose of systemic corticosteroids within 365 days | 365 days | 
| Change in FEV1 | Change in lung function (ΔFEV1) from baseline | 365 days | 
| Change in blood eosinophils | Change in blood eosinophils (eosinophilic trajectories) | 365 days | 
| Diabetes mellitus | New diagnosis of diabetes mellitus within 365 days | 365 days | 
| Change in HbA1c | Change in HbA1c from baseline to 365 days | 365 days | 
| Number of antibiotic requiring infections | Antibiotic-requiring infections within 365 days | 365 days | 
| Microbiota | Change in lunge microbiota abundance and diversity | 180 days | 
| Change in CAT score | Change in COPD Assessment Test from baseline to final visit | 365 days | 
| Change in MRC dyspnoea score | MRC-dyspnea score from < 3 to 3 ≥, fron baseline, 3 ,6 ,9 and 12 months | 365 days | 
| Number of non-invasive ventilation (NIV) or intensive care admissions or death | Number of admission-requiring NIV treatment or admissions to intensive care or death within 365 days | 365 days | 
| Mortality | Death within 365 days | 365 days |