Inhaled Long-acting Bronchodilators With or Without Inhaled Glucocorticosteroids for Preventing Hospitalizations and Death in Elderly Patients With Chronic Obstructive Pulmonary Disease

Study Overview
=================
Brief Summary
-----------------
This will be a phase IV, open label, multicenter, randomized pragmatic study in frail elderly patients with COPD. Participants will be treated with either inhaled LABD alone or LABD combined with inhaled glucocorticosteroids. The main aim of the study is to assess whether, in elderly patients with COPD and one or more cardiac comorbidities (heart failure, and/or ischemic heart disease, and/or atrial fibrillation) recently hospitalized because of an acute exacerbation of COPD, 12 months treatment with LABD(s)+ICS can increase the time to first re-hospitalization (all cause) and/or death for any cause when compared with LABD(s) alone. Patients will be followed-up for 3 months after completion of the 12 month treatment period.

Detailed Description
-----------------
Chronic obstructive pulmonary disease occurs mainly in the elderly and has important comorbidities, particularly cardiovascular, which increase its severity. Chronic obstructive pulmonary disease affects 5% of people globally, increasing to 10% in the elderly. According to data from the World Health Organisation (WHO), there were 384 million cases of COPD in 2010, with a global prevalence of 12% (www.who.int). Deaths due to COPD are 3 million/year globally (GOLD 2018) and >20,000/year in Italy. The investigator speculated that multimorbid elderly COPD patients recently hospitalized due to an acute exacerbation of COPD (AECOPD) and who have concomitant cardiovascular disease may have fewer re-hospitalizations and increased survival in the following year if treated with LABD+ICS rather than with LABD alone. The aim of this study is to examine the efficacy and safety of currently recommended and prescribed inhalation therapies to elderly, frail and multimorbid COPD patients with a recent hospitalization due to an AECOPD. The study involves a group of patients who have never before been selected for a clinical trial and who represent the 5th most common cause of hospitalization and the 3rd most common cause of death in Italy.

Official Title
-----------------
Comparison of 1-year Treatment With Inhaled Long Acting Bronchodilators (LABD) Plus Inhaled Glucocorticosteroids (ICS) Versus LABD Without ICS on Re-hospitalizations and/or Death in Elderly Patients With Chronic Obstructive Pulmonary Disease (COPD) Recently Hospitalized Because of an Acute Exacerbation of COPD (ICS-Life Study).

Conditions
-----------------
Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
-----------------
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents
* Drug: Bronchodilator Agents


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant must be older than 60 years of age, at the time of signing the informed consent. Recently (within 6 months) discharged from hospital with a diagnosis of acute exacerbation of COPD (usually coded as Diagnosis Related Group (DRG) 087 or 088). Participants with a clinical diagnosis of COPD (i.e. previous diagnosis of COPD and/or treatment with short acting bronchodilators (SABD), LABD or LABD+ICS Spirometry confirmed diagnosis of COPD, post-bronchodilator (30 minutes after 400 μg salbutamol) FEV1/FVC ratio <0.7. The diagnostic spirometry test can have been performed up to three years prior to randomization, or if never performed before, should be performed not earlier than 4 weeks since last exacerbation Smokers or ex-smokers with a smoking history of >10 pack years (a pack year is defined as 20 cigarettes smoked every day for a year) Clinical diagnosis documented in the patient's medical records of one or more major chronic cardiac disease (heart failure, ischemic heart disease or atrial fibrillation). Currently receiving at least one of the specified treatments (either alone or in combination, see Appendix 10.5) for heart failure, ischemic heart disease or atrial fibrillation. Participant must be willing and able to perform pulmonary function tests Male or female. Contraception is not considered necessary in this cohort of elderly (> 65 years) patients receiving treatment with commercially available licensed products. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Exclusion Criteria: Patients with a primary discharge diagnosis of DRG 087 or DRG 088 but clearly judged by the clinical investigator to be due to other causes, i.e. patients presenting to the hospital with symptoms of AECOPD but due mainly to other conditions (pulmonary embolism, pneumonia, pneumothorax, anemia, acute kidney failure, decompensated heart failure, acute ischemic heart disease, new onset atrial fibrillation, stroke, etc.) Patients who required invasive mechanical ventilation during hospitalization Patients with Asthma as primary and principal diagnosis Patients with severe cardiovascular (CV) disease who in the opinion of the investigator are unlikely to survive the 15 month study period Patients considered unable to comply with the study procedures and follow-up in the opinion of the investigator (eg, evidence of alcohol or drug abuse, psychiatric disorder, physical disability, social or geographical obstacles) Patients in whom spirometry is contraindicated (eg, hemoptysis, detached retina, active tuberculosis, last trimester of pregnancy) Patients with other mechanical or overt causes of respiratory symptoms, particularly dyspnea (such as pneumothorax, chest wall trauma, lung fibrosis, lung cancer, anemia, severe obesity (BMI >40) or cachexia (BMI <18)) Patients with any major disease which in the opinion of the investigator would prevent study participation, such as dementia, end-stage disease, cachexia, chronically bedridden patient and life expectancy <15 months. Participation in any other interventional study within the last 3 months or concurrent participation in an observational clinical study.

Ages Eligible for Study
-----------------
Minimum Age: 60 Years

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

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

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

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Long-acting beta-agonist (LABA) or LABA/LAMA<br>long-acting bronchodilator agents (LABD, LAMA or LABA/LAMA) but no inhaled steroids plus usual care for comorbidities | Drug: Bronchodilator Agents<br>* Tiotropium<br>* Other names: Spiriva Respimat;Drug: Bronchodilator Agents<br>* Indacaterol<br>* Other names: Onbreez Brezhaler 150;Drug: Bronchodilator Agents<br>* Umeclidinium/vilanterol<br>* Other names: Laventair;Drug: Bronchodilator Agents<br>* Glycopyrronium<br>* Other names: Tovanor Breezhaler;Drug: Bronchodilator Agents<br>* Aclidinium<br>* Other names: Bretaris Genuair;Drug: Bronchodilator Agents<br>* Umeclidinium<br>* Other names: Incruse;Drug: Bronchodilator Agents<br>* Formoterol<br>* Other names: Levovent;Drug: Bronchodilator Agents<br>* Indacaterol glycopyrronium<br>* Other names: Ultibro Breezhaler;Drug: Bronchodilator Agents<br>* Salmeterol<br>* Other names: Serevent;Drug: Bronchodilator Agents<br>* Tiotropium olodaterol<br>* Other names: Spiolto Respimat;Drug: Bronchodilator Agents<br>* Aclidinium/formoterol<br>* Other names: Duaklir Genuair;Drug: Bronchodilator Agents<br>* Olodaterol<br>* Other names: Striverdi Respimat;|
| Experimental: Long-acting muscarinic antagonist (LAMA) and/or LABA plus ICS<br>Bronchodilator agents LAMA and/or LABA with inhaled steroids plus usual care for comorbidities | Drug: Bronchodilator Agents<br>* Fluticasone furoate/vilanterol<br>* Other names: Revinty Ellipta;Drug: Bronchodilator Agents<br>* Fluticasone propionate/salmeterol<br>* Other names: Aliflus Diskus 50/500;Drug: Bronchodilator Agents<br>* Beclometasone dipropionate/formoterol<br>* Other names: Alabaster;Drug: Bronchodilator Agents<br>* Budesonide formoterol<br>* Other names: Fobuler;Drug: Bronchodilator Agents<br>* Formoterol/glycopyrronium bromide/beclometasone dipropionate<br>* Other names: Trimbow;Drug: Bronchodilator Agents<br>* Fluticasone furoate/umeclidinium bromide/vilanterol<br>* Other names: Elebrato Ellipta;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite event of the first time to first re-hospitalization and/or death (all cause) |  | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of moderate/severe COPD exacerbations in the two patient groups |  | 12 months | 
| Number of re-hospitalizations and deaths (all cause) in the two patient groups |  | 12 months | 
| Quality of life (QoL) variation measured as change in COPD Assessment Test (CAT) between the two patient groups |  | 12 months | 
| QoL variation measured using modified Medical Research Council (mMRC) dyspnoea scale between the two patient groups |  | 12 months | 
| Number of pneumonia events |  | 12 months | 
| Number of acute cardiac events |  | 12 months | 
| Number of cardiovascular events |  | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult, drug therapy, combination, bronchodilator agents, male, female