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).
Phase: PHASE4
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Università degli Studi di Ferrara



CONFIDENTIAL 
      Protocol AIFA-ICSLIFE-001 Final 2.0 
Date: 18 Jan 2019 
 
© 2016, 2017 TransCelerate BioPharma 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................6 
1.1. 
Synopsis ............................................................................................................................6 
1.2. 
Schema ............................................................................................................................13 
1.3. 
Schedule of Activities (SoA) ..........................................................................................14 
2. 
Introduction ...................................................................................................................17 
2.1. 
Study Rationale ...............................................................................................................20 
2.2. 
Background .....................................................................................................................21 
2.3. 
Benefit/Risk Assessment ................................................................................................21 
3. 
Objectives and Endpoints ............................................................................................23 
4. 
Study Design ..................................................................................................................24 
4.1. 
Overall Design ................................................................................................................24 
4.2. 
Scientific Rationale for Study Design ............................................................................24 
4.3. 
Justification for Dose ......................................................................................................25 
4.4. 
End of Study Definition ..................................................................................................25 
5. 
Study Population ...........................................................................................................26 
5.1. 
Inclusion Criteria ............................................................................................................26 
5.2. 
Exclusion Criteria ...........................................................................................................26 
5.3. 
Lifestyle Considerations .................................................................................................27 
5.4. 
Screen Failures ................................................................................................................27 
6. 
Study Intervention ........................................................................................................28 
6.1. 
Study Intervention(s) Administered................................................................................28 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................28 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................28 
6.4. 
Study Intervention Compliance ......................................................................................29 
6.5. 
Concomitant Therapy .....................................................................................................29 
6.5.1. 
Rescue Medicine .............................................................................................................29 
6.6. 
Dose Modification ..........................................................................................................30 
6.7. 
Intervention after the End of the Study ...........................................................................30 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................31 
7.1. 
Discontinuation of Study Intervention ............................................................................31 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................31 
7.3. 
Lost to Follow Up ...........................................................................................................31 
8. 
Study Assessments and Procedures.............................................................................33 
8.1. 
Efficacy Assessments .....................................................................................................38 
8.1.1. 
Assessment of re-hospitalizations and deaths (all cause) ...............................................38 
8.1.2. 
Assessment of moderate/severe COPD exacerbations ...................................................38 
8.1.3. 
Assessment of number of pneumonia events ..................................................................39 
8.1.4. 
Acute cardiac events .......................................................................................................39 
8.1.5. 
Cardiovascular death .......................................................................................................39 
8.1.6. 
Quality of Life.................................................................................................................39 

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      Protocol AIFA-ICSLIFE-001 Final 2.0 
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8.1.7. 
Spirometry.......................................................................................................................39 
8.2. 
Safety Assessments .........................................................................................................40 
8.2.1. 
Physical Examinations ....................................................................................................40 
8.2.2. 
Vital Signs .......................................................................................................................40 
8.2.3. 
Electrocardiograms .........................................................................................................40 
8.2.4. 
Chest x-ray ......................................................................................................................40 
8.2.5. 
Clinical Safety Laboratory Assessments ........................................................................41 
8.3. 
Adverse Events and Serious Adverse Events .................................................................41 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................41 
8.3.2. 
Monitoring of AEs ..........................................................................................................41 
8.3.3. 
Clinical Laboratory Abnormalities .................................................................................41 
8.3.4. 
Recording of AEs and SAEs ...........................................................................................42 
8.3.5. 
Prompt Reporting of SAEs to Sponsor ...........................................................................42 
8.3.6. 
Follow-up of AEs and SAEs ...........................................................................................43 
8.3.7. 
Expeditable Events..........................................................................................................43 
8.3.8. 
Pregnancy ........................................................................................................................43 
8.3.9. 
Disease Related Events and/or Disease Related Outcomes not 
Qualifying as AEs or SAEs.............................................................................................44 
8.4. 
Treatment of Overdose ...................................................................................................44 
8.5. 
Pharmacokinetics ............................................................................................................44 
8.6. 
Pharmacodynamics .........................................................................................................44 
8.7. 
Genetics ..........................................................................................................................44 
8.8. 
Biomarkers ......................................................................................................................44 
8.9. 
Medical Resource Utilization and Health Economics ....................................................44 
9. 
Statistical Considerations .............................................................................................44 
9.1. 
Statistical Hypotheses .....................................................................................................44 
9.2. 
Sample Size Determination ............................................................................................45 
9.3. 
Populations for Analyses ................................................................................................45 
9.4. 
Statistical Analyses .........................................................................................................45 
9.4.1. 
Descriptive Statistics .......................................................................................................46 
9.4.2. 
Participant Accountability ..............................................................................................46 
9.4.3. 
Description of Baseline Characteristics ..........................................................................46 
9.4.4. 
Missing Data ...................................................................................................................46 
9.4.5. 
Principles of Statistical Analysis ....................................................................................46 
9.4.6. 
Efficacy Analyses ...........................................................................................................47 
9.4.7. 
Safety Analyses ...............................................................................................................47 
9.4.8. 
Other Analyses ................................................................................................................48 
9.5. 
Interim Analyses .............................................................................................................48 
9.5.1. 
Data Monitoring Committee (DMC) ..............................................................................48 
10. 
Supporting Documentation and Operational Considerations ..................................49 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................49 
10.1.1. Regulatory and Ethical Considerations ...........................................................................49 

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      Protocol AIFA-ICSLIFE-001 Final 2.0 
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10.1.2. Financial Disclosure........................................................................................................49 
10.1.3. Informed Consent Process ..............................................................................................49 
10.1.4. Data Protection................................................................................................................50 
10.1.5. Committees Structure......................................................................................................50 
10.1.6. Dissemination of Clinical Study Data.............................................................................50 
10.1.7. Data Quality Assurance ..................................................................................................51 
10.1.8. Source Documents ..........................................................................................................51 
10.1.9. Study and Site Closure ....................................................................................................51 
10.1.10. Publication Policy ...........................................................................................................52 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................53 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................54 
10.4. 
Appendix 4: Abbreviations .............................................................................................60 
10.5. 
Appendix 5: List of Cardiovascular Drugs .....................................................................62 
11. 
References ......................................................................................................................64 
 

CONFIDENTIAL 
      Protocol AIFA-ICSLIFE-001 Final 2.0 
Date: 18 Jan 2019 
 
© 2016, 2017 TransCelerate BioPharma 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol 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). 
Short Title:  
Inhaled long-acting bronchodilators with or without inhaled glucocorticosteroids for preventing 
hospitalizations and death in elderly patients with chronic obstructive pulmonary disease. 
Rationale: 
Chronic obstructive pulmonary disease occurs mainly in the elderly and has important 
comorbidities, particularly cardiovascular, which increase its severity (Roversi et al 2016). 
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 (Ministero Della Salute 
www.salute.gov.it). 
Acute exacerbation of COPD is one of the most common clinical diagnoses in patients presenting 
to the hospital with increased dyspnoea and hypoxemia as chief complaints or signs. In Italy, 
patients with a main diagnosis of AECOPD are primarily classified under the diagnosis related 
group (DRG) code 087 (pulmonary oedema and respiratory failure). In Italy, DRG 087 is the 5th 
most common cause of admission to the hospital; 139,000 patients classed as DRG 087 were 
discharged in 2014 (Ministero Della Salute www.salute.gov.it). Patients hospitalized due to 
exacerbations of respiratory symptoms are mostly elderly (average age 75 years), frail, and have 
multiple comorbidities (Shah et al 2016). Up to 20% of patients hospitalized for AECOPD are re-
hospitalized (Shah et al 2016) or even die (Serra-Picamal et al 2018) within 30 days, and >30% 
are re-hospitalized or die within a year (Tokgoz et al 2016). The most important risk factors for 
re-hospitalization and death after AECOPD are comorbidities (Shah et al 2016, Vanflateren et al 
2016), particularly HF/IHD/AF (Roversi et al 2016). Thus, re-hospitalizations and death are a 
major risk for the patient and a major burden on society, particularly in the year following the first 
hospitalization due to AECOPD (Shah et al 2016, Tokgoz et al 2016). 
Compared to randomized clinical trials conducted in younger patients with milder cases of chronic 
obstructive pulmonary disease (COPD) (Calverley et al 2007, Vestbo et al 2016(a)), meta-analyses 
and registry studies suggest that long-acting bronchodilators plus inhaled steroids (LABD+ICS) 
reduce hospitalizations and mortality in elderly, frail patients (Gershon et al 2014, Sin et al 2005) 
with COPD.  

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      Protocol AIFA-ICSLIFE-001 Final 2.0 
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According to the Global Initiative for Obstructive Lung Disease (www.goldcopd.org), for GOLD 
D patients, GOLD recommends LABD either alone (LAMA or LABA) or in combination 
(LAMA+LABA), mainly to reduce symptoms and exacerbations (Wedzicha et al 2016). GOLD 
also recommends adding ICS to LABD, but only if patients are young and/or have eosinophilia 
and/or a history of asthma, mainly because LABA+ICS is the most prescribed treatment in these 
patients. 
We 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. 
 

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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
 to demonstrate that in elderly COPD 
patients with one or more cardiac 
comorbidities (heart failure, and/or 
ischemic heart disease, and/or atrial 
fibrillation) who have been recently 
hospitalized due to AECOPD, 1-years 
treatment with LABD+ICS will 
prolong the time to first re-
hospitalization and/or the death for 
any cause when compared to 1-years 
treatment with LABD alone 
 composite event of the time to first re-
hospitalization and/or death (all cause) 
Secondary 
 
 to compare the number of 
moderate/severe exacerbations of 
COPD in the two patient groups 
 to compare the number of re-
hospitalizations and deaths (all cause) 
in the two patient groups 
 to compare quality of life (QoL) 
scores measured using the COPD 
Assessment Test (CAT) and mMRC 
dyspnoea scale between the two 
patient groups 
 to verify if one year of treatment with 
combination therapy including ICS 
increases the risk of pneumonia 
 to compare the number of acute 
cardiac events in this frail, elderly 
COPD population 
 to compare the incidence of deaths 
due to cardiovascular events 
 to compare changes in lung function 
 number of moderate/severe COPD 
exacerbations 
 number of re-hospitalizations and 
deaths (all cause) 
 QoL variation measured as change in 
CAT total score from baseline to end 
of treatment period. 
 change in mMRC dyspnea score from 
baseline to end of treatment period. 
 number of pneumonia events 
 number of acute cardiac events 
 number of cardiovascular deaths 
 change in FEV1 from baseline to the 
end of treatment period 
 change in FVC from baseline to the 
end of treatment period 
 
Overall Design: 

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      Protocol AIFA-ICSLIFE-001 Final 2.0 
Date: 18 Jan 2019 
 
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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 choice of the specific LABD and ICS to be used 
will be left to the discretion of the clinical investigator, according to the treatments available from 
their pharmacy department. 
The center will be considered as a unique stratifying factor, so the study will have a balanced-
block center-stratified design. 
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. 
Randomization to treatment will occur after screening. 
A Data Monitoring Committee (DMC) will periodically review and evaluate the accumulated 
study data for safety, study conduct and progress, scientific validity and integrity. The DMC will 
monitor the progress of the study, enrollment, study performance in terms of data management 
metrics and will undertake a review of the safety data including adverse events. 
Participants will be recruited according to the following inclusion and exclusion criteria: 
Inclusion criteria 
1. Participant must be older than 60 years of age, at the time of signing the informed 
consent. 
2. Recently (within 6 months) discharged from hospital with a diagnosis of acute 
exacerbation of COPD (usually coded as DRG 087 or DRG 088). 
3. 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 
4. 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 
5. 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) 
6. 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).  
7. 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.  
8. Participant must be willing and able to perform pulmonary function tests 
9. Male or female. Contraception is not considered necessary in this cohort of elderly (> 60 
years) patients receiving treatment with commercially available licensed products. 

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10. 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 
1. 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.) 
2. Patients who required invasive mechanical ventilation during hospitalization 
3. Patients with Asthma as primary and principal diagnosis 
4. Patients with severe cardiovascular (CV) disease who in the opinion of the investigator are 
unlikely to survive the 15 month study period 
5. 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) 
6. Patients in whom spirometry is contraindicated (eg, hemoptysis, detached retina, active 
tuberculosis, last trimester of pregnancy) 
7. 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)) 
8. 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. 
9. Participation in any other interventional study within the last 3 months or concurrent 
participation in an observational clinical study. 
 
Number of Participants: 
The aim is to randomize 464 participants to each intervention group 
Adjusting for an expected 10% dropout rate, a total of 516 patients per group will need to be 
randomized. 
 The study will be performed at 39 centers in Italy. 
Intervention Groups and Duration: 
In this study patients will be randomised to receive one of the following two treatment regimens 
for up to 12 months:  
1) 
Usual and optimized treatment for concomitant cardiovascular (CV) diseases plus inhaled 
long acting bronchodilator(s) (LABD(s)) 

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      Protocol AIFA-ICSLIFE-001 Final 2.0 
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2) 
Usual and optimized treatment for concomitant CV diseases plus inhaled long acing 
bronchodilator(s) and inhaled glucocorticosteroids (ICS).  
The choice of the specific LABD(s) and/or ICS for each patient will be left to the discretion of the 
clinical investigator. All treatments will be administered at licensed dosages. During the study, the 
doses of all medications may be adjusted by the investigator according to licensed dosages. Both 
study groups will receive prescriptions for study medication, which will be collected by the 
patients from their local pharmacy or hospital pharmacy department. Prescription data will be 
captured on the electronic case report form (eCRF). 
All diagnostic procedures and medical treatments will be performed according to best medical 
practice (Percorsi Diagnostico Terapeutici Assistenziali (PDTA) at the study centre. Best medical 
practice is usually based on the most recent and credited international guidelines for these chronic 
diseases such as the ESC guidelines for cardiac diseases (www.esc.org) and GOLD guidelines 
(www.goldcopd.org) for COPD. 
Additional therapeutic or diagnostic procedures (i.e. use of concomitant medication) will be 
performed according to local guidelines (PDTA). 
Both study groups will receive prescriptions for study medication, which will be collected by the 
patients from their local pharmacy or hospital pharmacy department. Study treatments will be 
stored and dispensed by the pharmacy in accordance with normal dispensing practice. 
The total duration of study participation for each participant will be 15 months (12 month treatment 
period and 3 month follow-up) plus up to an additional 10 days for the study screening to be 
completed. 
Participants will be instructed in the correct method of using the inhaler device(s) at the 
randomization visit and their technique will be checked at each follow-up visit to ensure that they 
are using the device(s) correctly. 
Participants will be requested to bring their medication when they attend for their next visit and 
the investigator will make an assessment of the participant’s compliance with their treatment from 
the quantity of medication returned and by directly asking the participant about their compliance 
with their COPD treatment. 
During the study, the doses of all medications can be adjusted by the investigator according to 
licensed dosages.  
Treatment with ICS in the only LABDs group will be permitted if, on clinical Investigators 
judgement, it would be necessary for patient temporary conditions for at maximum 15 days in case 
of patient treated at home or for 15 days (at maximum) after hospital discharge in case of 
hospitalised patient. If the ICS treatment will surpass these periods, the patient will be considered 
being switched to the LABD + ICS group and considered as protocol violator 
Statistical Considerations 
Sample Size 
The sample size calculation is based on the superiority criteria of the LABD+ICS group vs. LABD 
alone group in terms of re-hospitalization and/or death. With 464 patients in each group, the 

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      Protocol AIFA-ICSLIFE-001 Final 2.0 
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© 2016, 2017 TransCelerate BioPharma 
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percentage of patients experiencing the composite event (re-hospitalization and/or death) is 
expected to be 9% in the LABD+ICS group and 15% in the LABD alone group. A log-rank test 
(two-sided 5% significance level) will have 80% power to detect a difference between treatment 
groups in terms of time to first re-hospitalization and/or death (primary efficacy endpoint).  
Statistical Hypothesis 
The superiority of the LABD(s)+ICS group vs. LABD(s) group in terms of time to first re-
hospitalization and/or death will be tested. The following hypothesis scheme will be considered: 
H0: there is no difference in the time to first re-hospitalization and/or death between the two 
treatment groups. 
H1: there is a difference in the time to first re-hospitalization and/or death between the two 
treatment groups 
Patient Populations 
The following populations will be considered for the analysis: 
 Randomized population: all randomized patients. 
 Safety population: all randomized patients who receive at least one administration of the 
study treatment in a given treatment period. 
 Intention-to-Treat population (ITT): all randomized patients from the safety population 
with at least one available post-baseline efficacy evaluation during the treatment period. 
 Per-protocol population (PP): all randomized patients from the ITT population without 
any major protocol deviations (e.g., wrong inclusions, forbidden concomitant medications, 
etc.). The exact definition of major protocol deviations will be discussed with the clinical 
team case by case during the review of the data and will be described in the Data Review 
Report. 
The primary efficacy variable will be analysed both in the ITT and in the PP populations. As this 
is a superiority study, the primary analysis population will be the ITT. All the other efficacy 
variables will be analysed in the ITT population only.  
Analysis of safety variables will be performed on the safety population. 
The primary efficacy variable will be analyzed using the Kaplan-Meier estimator. Comparison 
between treatment groups will be performed using the log-rank test stratified by center. A Kaplan-
Meier plot for time to first re-hospitalization and/or death will also be presented by treatment 
group. 
The LABD(s)+ICS group will be declared to prolong time to first re-hospitalization and/or death, 
compared to the LABD(s) group, if the difference between the two treatments is significantly in 
favour of LABD(s)+ICS (i.e. the p-value from the log-rank test is ≤ 0.050). 
A detailed Statistical Analysis Plan (SAP) will be described in a separate document to be 
completed after the protocol is finalised and before database lock. 
Data Monitoring Committee: Yes 
 

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1.2. 
Schema 
 
 
 

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1.3. 
Schedule of Activities (SoA) 
 
Procedure 
Screening  
(up to 10 days 
before Day 1) 
Intervention Period [months] 
Follow-up 
(3 months 
after last 
study 
treatment) 
Notes 
 
day 1 
(randomiz
ation) 
 
3 months 
 
6 months 
 
9 months 
 
12 months 
(or early 
withdrawal) 
Visit number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
Recheck clinical status 
before randomization 
and/or 1st dose of study 
medication. 
Spirometry* 
 
X 
 
 
 
X 
 
Participant must have a 
diagnosis of COPD 
confirmed by spirometry 
(performed within the last 
3 years) prior to 
randomization.  
COPD assessment test (CAT) 
X 
X 
X 
X 
X 
X 
X 
 
mMRC dyspnea scale 
X 
X 
X 
X 
X 
X 
X 
 
Demography 
X 
 
 
 
 
 
 
 
Physical examination including height 
and weight 
X 
X 
X 
X 
X 
X 
X 
 
Medical history (including substance 
usage (review and update after 
screening if necessary)*  
X 
X 
X 
X 
X 
X 
 
X 
Substances: alcohol, 
tobacco, and caffeine 
Medical history will be 
reviewed and updated at 
the follow-up visits 

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Procedure 
Screening  
(up to 10 days 
before Day 1) 
Intervention Period [months] 
Follow-up 
(3 months 
after last 
study 
treatment) 
Notes 
 
day 1 
(randomiz
ation) 
 
3 months 
 
6 months 
 
9 months 
 
12 months 
(or early 
withdrawal) 
Visit number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
 
History of COPD and cardiovascular 
disease (particularly HF, IHD or AF) 
X 
X 
X 
X 
X 
X 
 
X 
Participants must have 
concomitant CV disease 
(HF, IHD or AF) and must 
be receiving treatment 
(see Appendix 10.5) to be 
eligible for the study 
Past and current medical conditions   
X 
 
 
 
 
 
 
Participants must have  at 
least one concomitant 
major CV condition (HF, 
IHD or AF) 
Laboratory assessments 
X 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
 
X 
 
For stable patients a 
previous ECG recording 
(within the last 3 months) 
can be used 
Chest x-ray 
X (Optional) 
 
 
 
 
 
 
Chest x-ray data will be 
collected if available 
Vital signs (blood pressure and heart 
rate) 
X 
X 
X 
X 
X 
X 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Study treatment checked and 
prescribed 
 
X 
X 
X 
X 
 
 
 
Assessment of symptoms and 
hospitalizations 
 
 
X 
X 
X 
X 
X 
Also assessed via monthly 
telephone contact between 
visits 

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Procedure 
Screening  
(up to 10 days 
before Day 1) 
Intervention Period [months] 
Follow-up 
(3 months 
after last 
study 
treatment) 
Notes 
 
day 1 
(randomiz
ation) 
 
3 months 
 
6 months 
 
9 months 
 
12 months 
(or early 
withdrawal) 
Visit number 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
 
Vaccination check (to be recorded in 
concomitant form) 
 
X 
X 
X 
X 
 
 
Anti-influenza and anti-
pneumococci. To be 
checked also during 
monthly telephone call 
Adverse event review 
 
X 
X 
X 
X 
X 
 
 
Serious adverse event review 
 
X 
X 
X 
X 
X 
X 
 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
 
CV = cardiovascular, HF = heart failure, IHD = ischemic heart disease, AF = atrial fibrillation, CAT = COPD Assessment Test, mMRC = modified Medical Research Council. 
* Participants with a diagnosis of COPD confirmed by spirometry within the last 3 years, will be immediately eligible for the study after hospital discharge. Participants without a 
previous spirometric confirmation must have a spirometry test, which must be performed not earlier than 4 weeks since last exacerbation.  If confirmed then they can be recruited 
to the study. 
**Participants will be contacted by telephone each month, by the clinical investigator or by a research staff member, to check compliance with the study procedures and treatment. 
Information about any hospitalizations or any unexpected medical events, particularly moderate exacerbations treated with antibiotics and/or steroids will be collected Information 
on anti-influenza and anti-pneumococci vaccination will also be collected. 
 

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2. 
Introduction 
Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory 
symptoms and airflow limitation caused mostly by cigarette smoking. In up to 30% of patients, 
COPD is punctuated by acute exacerbations that may cause hospitalization and death. 
Chronic obstructive pulmonary disease occurs mainly in the elderly and has important 
comorbidities, particularly cardiovascular, which increase its severity (Roversi et al 2016). 
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 (Ministero Della Salute 
www.salute.gov.it). 
With the increase in smoking and aging populations, the global prevalence of COPD is expected 
to rise over the next 14 years, with >4.5 million expected deaths/year in 2030 from COPD and 
related conditions. Hospitalizations for acute exacerbations of COPD (AECOPD) are estimated to 
cost about 25% ($13.2 billion) of the total direct costs of COPD in the U.S. ($50 billion). Acute 
exacerbations of COPD and hospitalizations are a significant burden on the healthcare system 
(May et al 2015), particularly due to comorbidities (Lisspers et al 2018). 
Severe acute respiratory symptoms, in particular, dyspnoea, are important causes of 
hospitalization, healthcare resource utilization, and death. They are mainly due to AECOPD but 
may be due to other causes such as cardiac failure, ischaemic heart disease, acute kidney failure, 
anaemia, or pulmonary thromboembolisms (Roca et al 2013, Wedzicha et al 2014, Vanfleteren, et 
al 2016; GOLD 2018). 
Acute exacerbations of COPD are defined as acute episodes characterized by a significant 
worsening of respiratory symptoms, particularly dyspnoea, cough, and sputum that can become 
purulent, that force a change in medication, use of healthcare resources, or hospitalization. Acute 
exacerbations of COPD are complex events usually associated with increased airway 
inflammation, increased mucus production and marked air trapping, which contribute to dyspnoea 
in particular. Sputum purulence and volume, together with increased cough and wheezing, may 
also be present (Anthonisen et al 1987, GOLD 2018), and possibly specifically distinguish 
exacerbations of respiratory symptoms due to AECOPD from the many other causes that may 
worsen dyspnoea (Roca et al 2013). 
As comorbidities are common in COPD patients, exacerbations of dyspnoea must be differentiated 
clinically from other causes of acute dyspnoea, such as acute heart failure (HF) and/or ischemic 
heart disease (IHD) and/or atrial fibrillation (AF), anaemia, pulmonary embolism, pneumonia and 
others (Roca et al 2013). 
Acute exacerbation of COPD is one of the most common clinical diagnoses in patients presenting 
to the hospital with increased dyspnoea and hypoxemia as chief complaints or signs. In Italy, 
patients with a main diagnosis of AECOPD are primarily classified under the diagnosis related 
group (DRG) code 087 (pulmonary oedema and respiratory failure). In Italy, DRG 087 is the 5th 
most common cause of admission to the hospital; 139,000 patients classed as DRG 087 were 

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discharged in 2014 (Ministero Della Salute www.salute.gov.it). Patients hospitalized due to 
exacerbations of respiratory symptoms are mostly elderly (average age 75 years), frail, and have 
multiple comorbidities (Shah et al 2016). Up to 20% of patients hospitalized for AECOPD are re-
hospitalized (Shah et al 2016) or even die (Serra-Picamal et al 2018) within 30 days, and >30% 
are re-hospitalized or die within a year (Tokgoz et al 2016). The most important risk factors for 
re-hospitalization and death after AECOPD are comorbidities (Shah et al 2016, Vanflateren et al 
2016), particularly HF/IHD/AF (Roversi et al 2016). Thus, re-hospitalizations and death are a 
major risk for the patient and a major burden on society, particularly in the year following the first 
hospitalization due to AECOPD (Shah et al 2016, Tokgoz et al 2016). 
The global initiative for chronic obstructive lung disease (GOLD) guidelines recommend 
pharmacological and non-pharmacological treatments with the main aims of reducing symptoms, 
exacerbations and hospitalizations, and improving quality of life (www.goldcopd.org Apart from 
long-term oxygen treatment and smoking cessation, no treatment so far has been shown to reduce 
COPD hospitalizations or mortality. The most important limit of the GOLD guidelines, as with all 
guidelines for chronic diseases, is that they are based on randomized clinical trials (RCT) 
conducted in patients who are usually younger, with less severe symptoms and fewer comorbidities 
compared to patients treated in the general population (NICE Guidelines 2016, Fried et al 2012, 
Tinetti et al 2012). In particular, no properly powered RCT has ever been conducted in elderly, 
frail, multimorbid COPD patients after a recent hospitalization due to AECOPD, a large population 
at particular risk of re-hospitalization and death (vide supra). 
For GOLD D patients, GOLD recommends LABD either alone (LAMA or LABA) or in 
combination (LAMA+LABA), mainly to reduce symptoms and exacerbations (Wedzicha et al 
2016). GOLD also recommends adding ICS to LABD, but only if patients are young and/or have 
eosinophilia and/or a history of asthma, mainly because LABA+ICS is the most prescribed 
treatment in these patients. 
While patients with COPD are at increased risk of cardiovascular diseases (Sin et al 2003) new 
initiation of LABAs or LAMAs in patients with COPD is associated with an increased severe 
cardiovascular risk (Wang et al 2018), particularly in the elderly (Gershon et al, 2013). Previous 
studies (Macie et al 2006) meta-analyses (Sin et al 2005) and registry studies (Gershon et al 2014) 
have suggested that treatment of COPD including ICS in addition to LABD may reduce mortality 
and hospitalizations, particularly in elderly, frail patients with severe COPD and multimorbidities. 
Two randomized clinical trials conducted in non-hospitalized, younger patients with milder COPD 
(Calverley et al 2007, Vestbo et al 2016(a)) resulted in a barely significant (Calverley et al 2007) 
or non-significant (Vestbo et al 2016(a)) reduction of mortality. In these studies, patients were 
treated for 4 years (Calverley et al 2007) and up to 3 years (Vestbo et al 2016(a)) with a 
combination of a LABA (salmeterol or vilanterol) and an ICS (fluticasone propionate or 
fluticasone furoate), respectively. Interestingly, the study by Vestbo et al was the first ever 
conducted in patients with COPD and concomitant cardiovascular disease or at risk for 
cardiovascular disease (Vestbo et al 2016(a), but the patients were relatively milder and younger 
compared to the usual COPD population. The study showed a non-significant reduction in 
mortality, but 1) patients were relatively young (mean age, 65 years), 2) airflow limitation was 
moderate (mean FEV1, 60% of predicted), and most importantly, 3) only 15% of patients had a 
previous history of hospitalization. Nonetheless, the 3-year treatment with the LABA+ICS 

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combination (vilanterol/fluticasone furoate) was associated with a non-significant 11.8% reduction 
of mortality for all causes as compared with 9% with the LABA vilanterol alone and a 22% 
reduction of hospitalizations as compared to 15% with vilanterol alone (Vestbo et al 2016(a). By 
contrast, a more recent RCT showed that, compared to a LABA/LAMA combination in a single 
inhaler, both a triple LABA/LAMA/ICS combination and a LABA/ICS combination in a single 
inhaler reduced all-cause mortality in symptomatic patient with COPD and history of 
exacerbations, with a marginally increased risk of pneumonia (Lipson et al 2018). A similar even 
if smaller head-to-head study showed not only superiority of LABA/LAMA/ICS over 
LABA/LAMA in reducing AECOPD but also an interesting reduction in some major 
cardiovascular adverse events (Papi et al 2018).  
We speculated that multimorbid elderly COPD patients recently hospitalized due to AECOPD may 
have reduced re-hospitalizations and increased survival in the following year if treated with 
LABD+ICS rather than LABD without ICS. 
The 2017 revision of the GOLD guidelines introduced an interesting refinement of the previous 
ABCD assessment tool that separates spirometric grades (GOLD 1, 2, 3, 4) depending on the 
percentage of predicted FEV1: post-bronchodilator FEV1/FVC <0.7 and FEV1 >80% (GOLD 1), 
FEV1 50-80% (GOLD 2), FEV1 30-50% (GOLD 3), or FEV1<30% (GOLD 4) from clinical 
severity GOLD A,B,C,D groups, that were defined only by symptom severity and frequency of 
exacerbations/hospitalizations 
in 
the 
previous 
year 
(www.goldcopd.org). 
Treatment 
recommendations are no longer based on spirometric severity but only on clinical GOLD A, 
GOLD B, GOLD C and GOLD D severity. 
Thus pharmacological treatment recommendations are mainly based on results of RCTs assessing 
the effects on patient related outcomes, i.e. 
patient symptoms and history of 
exacerbation/hospitalization. 
For GOLD D patients, GOLD recommends LABD either alone (LAMA or LABA) or in 
combination (LAMA+LABA), mainly to reduce symptoms and exacerbations (Wedzicha et al 
2016). GOLD also recommends adding ICS to LABD, but only if patients are young and/or have 
eosinophilia and/or a history of asthma, mainly because LABA+ICS is the most prescribed 
treatment in these patients. 
The reasons for limiting combinations including ICS are 1) that they may be equally effective 
(Magnussen et al 2014) or even less effective (Wedzicha et al 2016), than LABA+LAMA without 
ICS and, more importantly, 2) because ICS are associated with the risk of pneumonia (Jannella et 
al 2016). Finally, in GOLD D patients, GOLD recommends stepping up to triple therapy 
(LAMA+LABA+ICS) only when the above mentioned options are not effective enough (GOLD 
2018). This recommendation is today supported by at least four recent studies that clearly show 
that LAMA+LABA+ICS in a single inhaler is superior to LABA+ICS (Singh et al 2016), to 
LAMA alone (Vestbo et al 2017), and to LABA+LAMA (Papi et al 2018, Lipson et al 2018). 
Interestingly, neither of these studies on triple therapy (Singh et al 2016, Vestbo et al 2017) nor a 
recent large, real-life study confirming reduction of exacerbations by adding LABA+ICS to usual 
care (Vestbo et al 2016(b)), showed a clinically relevant increased risk of pneumonia, thus 
lessening concerns associated with the use of ICS (Jannella et al 2016). No or marginal risk of 

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pneumonia has been reported in two recent studies comparing triple with LABA/LAMA (Papi et 
al 2018, Lipson et al 2018 
As previously mentioned, however, these recommendations are based on RCTs conducted in 
relatively young (average age 65 years) patients with less severe and less comorbid COPD, along 
with a very small (<1%) cohort of elderly frail patients with multimorbid COPD who had recent 
hospitalizations. 
For this reason, considering the potential beneficial effects of ICS in this population, we propose 
to conduct a real-life study in which we will randomize elderly frail, multimorbid COPD patients 
recently hospitalized due to AECOPD to one of two regimens: 1) usual and optimized treatment 
for concomitant chronic diseases plus LABD but no ICS, and 2) usual and optimized treatment for 
concomitant chronic diseases plus LABD+ICS. The choice of the particular LABD and ICS will 
be left to the discretion of the clinical investigator. Thus, the proposed study will be a real-life but 
randomized study with a 12 month treatment period and 3 months follow-up. All diagnostic 
procedures and medical treatments will be performed according to best medical practice (PDTA) 
which is usually based on the most recent and credited international guidelines for both of these 
chronic diseases, e.g., European Society of Cardiology (ESC) guidelines for cardiac diseases 
(www.esc.org) and GOLD guidelines (www.goldcopd.org) for COPD. 
2.1. 
Study Rationale 
Re-hospitalizations and death are major concerns for patients hospitalized due to AECOPD. By 
limiting this study to include only patients admitted to the hospital because of exacerbation of 
respiratory symptoms and discharged with the DRG 087 (pulmonary edema or respiratory failure), 
we are referring to a population that in 2014 accounted for about 139,000 hospitalizations in Italy 
(Vestbo et al 2016(b), Ministero della Salute www.salute.gov.it). Many AECOPD may also be 
included in other DRG codes, such as DRG 127 (cardiac failure and shock, 190,000), DRG 89 
(pneumonia, 73,000), DRG 125 (other cardiovascular diseases, 63,000) and DRG 088 (COPD, 
42,000) (Roca et al 2013, Vanfleteren et al 2016). 
The reason why AECOPD are coded as DRG 087 and not DRG 088 (COPD) is administrative, as 
reimbursement is much higher if COPD patients are admitted for respiratory failure than for stable 
disease. In the last 15 years there has been a significant decrease in admissions with DRG 088 and 
a simultaneous increase in DRG 087. 
Compared to randomized clinical trials conducted in younger patients with milder cases of COPD 
(Calverley et al 2007, Vestbo et al 2016(a)), meta-analyses and registry studies suggest that, while 
new initiation of LABAs or LAMAs in patients with COPD is associated with an increased severe 
cardiovascular risk (Wang et al 2018) particularly in the elderly (Gershon et al 2013), long-acting 
bronchodilators plus inhaled steroids (LABD+ICS) reduce hospitalizations and mortality in 
elderly, frail patients (Macie et al 2006, Sin et al 2005, Gershon et al 2014) with COPD. 
For GOLD D patients, GOLD recommends LABD either alone (LAMA or LABA) or in 
combination (LAMA+LABA), mainly to reduce symptoms and exacerbations (Wedzicha et al 
2016). GOLD also recommends adding ICS to LABD, but only if patients are young and/or have 
eosinophilia and/or a history of asthma, mainly because LABA+ICS is the most prescribed 
treatment in these patients. 

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We speculated that elderly COPD patients recently hospitalized due to AECOPD 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. 
2.2. 
Background 
For GOLD D patients, GOLD recommends LABD either alone (LAMA or LABA) or in 
combination (LAMA+LABA), mainly to reduce symptoms and exacerbations (Wedzicha et al 
2016). GOLD also recommends adding ICS to LABD, but only if patients are young and/or have 
eosinophilia and/or a history of asthma, mainly because LABA+ICS is the most prescribed 
treatment in these patients. 
We speculate that multimorbid elderly COPD patients recently hospitalized with an AECOPD and 
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.  
In this study patients will be randomised to one of two treatment regimens:  
1) Usual and optimized treatment for concomitant chronic diseases plus LABD(s) but no ICS 
2) Usual and optimized treatment for concomitant chronic diseases plus LABD(s)+ICS.  
The choice of the particular LABD(s); (1 or 2) and ICS will be left to the discretion of the clinical 
investigator. Thus, the proposed study will be a real-life but randomized study with a 12 month 
treatment period followed by 3 months follow-up. All diagnostic procedures and medical 
treatments will be performed according to best medical practice (Percorsi Diagnostico Terapeutici 
Assistenziali (PDTA)) at the study centre. Best medical practice is usually based on the most recent 
and credited international guidelines for these chronic diseases such as the ESC guidelines for 
cardiac diseases (www.esc.org) and GOLD guidelines (www.goldcopd.org) for COPD. 
2.3. 
Benefit/Risk Assessment 
The key 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 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. 
The main objective of this  study is to determine whether a long-term inhalation treatment 
including LABD(s) and ICS, that is currently recommended and shown to reduce symptoms and 
exacerbations, may also reduce re-hospitalizations and/or death in elderly, frail and multimorbid 
COPD patients with a recent hospitalization due to AECOPD. 

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Despite attempts to define the risk of re-hospitalization and death in this population, we could not 
go beyond an estimated re-hospitalization rate of 20% at 1 month in severe AECOPD (Shah et al 
2016), and a re-hospitalization/death rate of 30% at 1 year (Tokgoz et al 2016). However, these 
estimates were obtained from retrospective studies reported in the literature (Shah et al 2016, 
Tokgoz et al 2016) that included patients with respiratory failure if they required non-invasive as 
well as invasive ventilation. In addition, as previously mentioned, the characterization of AECOPD 
in real life is quite inaccurate, not only as to the nature of the exacerbation of respiratory symptoms 
(Roca et al 2013) but also in confirming the diagnosis of COPD by spirometry. 
For all these reasons, we estimated that by selecting patients with a diagnosis of COPD confirmed 
by spirometry, even if elderly, frail and with comorbidities, particularly the main chronic heart 
diseases (CHF, IHD, AF); excluding patients with respiratory failure requiring invasive 
mechanical ventilation, up to 20% of whom are expected to be re-hospitalized within the first 
month after a hospitalized AECOPD; and optimizing diagnosis and treatment at the beginning of 
the study, the rate of re-hospitalization or death will decrease to a maximum of 15% in patients 
treated with usual care plus LABD(s) but no ICS, whereas we expect that this number will decrease 
to 9% (40% reduction) by treating them with LABD(s)+ICS. 
This reduction would be considered clinically relevant, a reduction of about 60 cases in the study 
that would translate to a hypothetical population of 100,000 similar patients in Italy, and a 
reduction of 6,000 hospitalizations/deaths in 1 year (Vestbo et al 2016(b), Ministero della Salute 
www.salute.gov.it). 
In addition to the above-mentioned advantages, the study will provide a unique learning exercise 
for the 39 hospital centers planned to participate in the study, enabling them to improve their ability 
to characterize and treat this difficult population of patients who are often encountered not only in 
hospital pulmonary units but also in many hospital internal medicine units. 
Since this will be a pragmatic real-life study, there are no anticipated additional risks to the 
standard medical procedures for patients who agree to participate in this study. The choice of the 
specific LABD(s) and ICS used to treat each patient will be left to the discretion of the clinical 
investigator, according to the ICS and LABD(s) treatments available in their pharmacy 
department.  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of the study interventions may be found in the study Participant 
Information Sheet. Information may also be found in the Patient Information Leaflet and Summary 
of Product Characteristics for the specific licensed products prescribed for the individual 
participants. 

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3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
 to demonstrate that in elderly COPD 
patients with one or more cardiac 
comorbidities (heart failure, and/or 
ischemic heart disease, and/or atrial 
fibrillation) who have been recently 
hospitalized due to AECOPD, 1-years 
treatment with LABD+ICS will 
prolong the time to first re-
hospitalization and/or the death for 
any cause when compared to 1-years 
treatment with LABD alone 
 composite event of the time to first re-
hospitalization and/or death (all cause) 
Secondary 
 
 to compare the number of 
moderate/severe exacerbations of 
COPD in the two patient groups 
 to compare the number of re-
hospitalizations and deaths (all cause) 
in the two patient groups 
 to compare quality of life (QoL) 
scores measured using the COPD 
Assessment Test (CAT) and mMRC 
dyspnoea scale between the two 
patient groups 
 to verify if one year of treatment with 
combination therapy including ICS 
increases the risk of pneumonia 
 to compare the number of acute 
cardiac events in this frail, elderly 
COPD population 
 to compare the incidence of deaths 
due to cardiovascular events 
 to compare changes in lung function 
 number of moderate/severe COPD 
exacerbations 
 number of re-hospitalizations and 
deaths (all cause) 
 QoL variation measured as change in 
CAT total score from baseline to end 
of treatment period. 
 change in mMRC dyspnea score from 
baseline to end of treatment period. 
 number of pneumonia events 
 number of acute cardiac events 
 number of cardiovascular deaths 
 change in FEV1 from baseline to the 
end of treatment period 
 change in FVC from baseline to the 
end of treatment period 
 

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4. 
Study Design 
4.1. 
Overall Design 
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 choice of the specific LABD and ICS to be used 
will be left to the discretion of the clinical investigator, according to the treatments available from 
their pharmacy department. 
The center will be considered as a unique stratifying factor, so the study will have a balanced-
block center-stratified design. 
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. 
4.2. 
Scientific Rationale for Study Design 
This is a pragmatic, randomized, open study. Pragmatic studies are designed to evaluate the 
effectiveness of different treatment strategies in real-life clinical practice.  
The key 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 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. The main objective is to determine whether a 
long-term inhalation treatment including LABD(s) and ICS, can reduce re-hospitalizations and/or 
death in elderly, frail and multimorbid COPD patients with a recent hospitalization due to 
AECOPD. 
The pragmatic study design means that the choice of the particular LABD(s) and ICS to be 
prescribed for each patient will be left to the discretion of the clinical investigator and all diagnostic 
procedures and medical treatments will be performed according to best medical practice at the 
study centre. 
The randomized pragmatic design of this study will help to provide information about treatment 
choices in real clinical practice and the results will help physicians to make informed choices about 
the most appropriate treatments in frail elderly COPD patients with multiple comorbidities. The 
study will also provide a unique learning exercise for the study centers, enabling them to improve 
their ability to characterize and treat this difficult population of patients. 
 

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4.3. 
Justification for Dose 
The choice of the specific LABD(s) and ICS used to treat each patient will be left to the discretion 
of the clinical investigator. All COPD treatments will be administered using licenced dosages. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit (Visit 7). 
The end of the study is defined as the date of the last visit of the last participant in the study. 
 

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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be older than 60 years of age, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Recently (within 6 months) discharged from hospital with a diagnosis of acute exacerbation 
of COPD (usually coded as DRG 087 or DRG 088). 
3. 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 
4. 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 randomisation, or if never performed before, should 
be performed not earlier than 4 weeks since last exacerbation 
5. 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) 
6. Clinical diagnosis documented in the patient’s medical records of one or more major 
chronic cardiac disease (heart failure, ischaemic heart disease or atrial fibrillation).  
7. 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.  
8. Participant must be willing and able to perform pulmonary function tests 
Sex 
9. Male or female. Contraception is not considered necessary in this cohort of elderly (> 60 
years) patients receiving treatment with commercially available licensed products.  
Informed Consent 
10. 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. 
 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 

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1. 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, anaemia, acute kidney failure, decompensated heart failure, 
acute ischemic heart disease, new onset atrial fibrillation, stroke, etc.) 
2. Patients who required invasive mechanical ventilation during hospitalization 
3. Patients with Asthma as primary and principal diagnosis 
4. Patients with severe cardiovascular (CV) disease who in the opinion of the investigator are 
unlikely to survive the 15 month study period 
5. 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) 
6. Patients in whom spirometry is contraindicated (eg, haemoptysis, detached retina, active 
tuberculosis, last trimester of pregnancy) 
7. Patients with other mechanical or overt causes of respiratory symptoms, particularly 
dyspnoea (such as pneumothorax, chest wall trauma, lung fibrosis, lung cancer, anaemia, 
severe obesity (BMI >40) or cachexia (BMI <18)) 
8. 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. 
Prior/Concurrent Clinical Study Experience 
9. Participation in any other interventional study within the last 3 months or concurrent 
participation in an observational clinical study 
5.3. 
Lifestyle Considerations 
No lifestyle restrictions are required. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) can be 
rescreened at a later date.  

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6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
 
6.1. 
Study Intervention(s) Administered 
In this study patients will be randomised to receive one of the following two treatment regimens 
for up to 12 months:  
1) 
Usual and optimized treatment for concomitant cardiovascular (CV) diseases plus inhaled 
long acting bronchodilator(s) (LABD(s)) 
2) 
Usual and optimized treatment for concomitant CV diseases plus inhaled long acing 
bronchodilator(s) and inhaled glucocorticosteroids (ICS).  
The choice of the specific LABD(s) and/or ICS for each patient will be left to the discretion of the 
clinical investigator. All treatments will be administered at licensed dosages. During the study, the 
doses of all medications may be adjusted by the investigator according to licensed dosages. Both 
study groups will receive prescriptions for study medication, which will be collected by the 
patients from their local pharmacy or hospital pharmacy department. Prescription data will be 
captured on the electronic case report form (eCRF). 
6.2. 
Preparation/Handling/Storage/Accountability 
Participants enrolled in the study will receive medication dispensed from the local pharmacy or 
hospital pharmacy department in the usual way, there are no additional preparation, handling, or 
storage requirements. 
Participants will be requested to bring any unused medication and the used empty device inhalers  
when they attend for their next visit and the investigator will make an assessment of the 
participant’s compliance with treatment from the quantity of medication returned and by directly 
asking the participant about their compliance with the prescribed COPD treatment. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All participants will be centrally assigned to randomized study intervention using an Interactive 
Web Response System (IWRS). Before the study is initiated, the log in information and 
instructions for the IWRS will be provided to each site. 
The center will be considered as a unique stratifying factor, so the randomization will follow a 
balanced-block center-stratified design. 
Study intervention will be dispensed at the study visits summarized in the SoA.  
This is an open-label study; however, the specific intervention to be taken by a participant will be 
assigned using an IWRS. The site will contact the IWRS prior to the start of study intervention 

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administration for each participant. The site will record the intervention assignment on the 
applicable case report form.  
Potential bias will be reduced by using central randomization. 
Since this is an open label study, no unblinding procedures are foreseen. 
6.4. 
Study Intervention Compliance 
Participants will be instructed in the correct method of using the inhaler device(s) at the 
randomization visit (Visit 2) and their technique will be checked at each follow-up visit to ensure 
that they are using the device(s) correctly. 
Participants will be requested to bring their medication when they attend for their next visit and 
the investigator will make an assessment of the participant’s compliance with their treatment from 
the quantity of medication returned, including the empty drug device inhalers and by directly 
asking the participant about their compliance with their COPD treatment. The investigator will 
then provide a response to the following question in the eCRF: “Has the subject been compliant 
with the study medication up to this visit?” 
6.5. 
Concomitant Therapy 
Additional therapeutic or diagnostic procedures (i.e. use of concomitant medication) will be 
performed according to local guidelines (PDTA). 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the participant is receiving at the time of enrollment or receives during 
the study must be recorded in the eCRF at each visit. Information recorded will include: 
 Name of medication 
 Reason for use 
 Dates of administration including start and end dates 
 Dosage information including dose and frequency 
Treatment with ICS in the only LABDs group will be permitted if, on clinical Investigators 
judgement, it would be necessary for patient temporary conditions for at maximum 15 days in case 
of patient treated at home or for 15 days (at maximum) after hospital discharge in case of 
hospitalised patient. If the ICS treatment will surpass these periods, the patient will be considered 
being switched to the LABD + ICS group and considered as protocol violator. 
6.5.1. 
Rescue Medicine 
The study site can prescribe inhaled short acting beta agonists (SABAs) as rescue medication to 
be taken on an as required (prn) basis. Rescue medications that may be used include: 
1. salbutamol 
2. terbutaline 
Use of rescue medication is forbidden 6 hours before visits when lung function is assessed; if 
already taken, spirometry can be postponed to 6 hours after last inhalation 

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6.6. 
Dose Modification 
During the study, the doses of all medications can be adjusted by the investigator according to 
licensed dosages, providing they remain in the correct treatment arm (see also paragraph 6.5). 
6.7. 
Intervention after the End of the Study 
This is a pragmatic study, so participants will be treated according to consolidated standards of 
care. On completion of the randomized treatment period, patients will not be withdrawn from the 
treatment but will continue to be treated according to accepted standards of care based on their 
clinical (respiratory and non-respiratory) condition and lung function. Patients will continue with 
their treatment. 

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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1. 
Discontinuation of Study Intervention  
Participants who are hospitalized during the study period will be allowed to continue in the study 
until the end at the discretion of the principal investigator and/or the participant. The investigator/ 
participant can decide to discontinue the study drug for safety or efficacy reasons. 
Albeit we will invite patients and doctors to stick to the initial treatment unless required by changed 
medical condition, the specific COPD treatment regimen (LABD(s) without ICS or LABD(s) + 
ICS) can be changed at any point during the study. Treatment with ICS in the only LABDs group 
will be permitted if, on clinical Investigators judgement, it would be necessary for patient 
temporary conditions for at maximum 15 days in case of patient treated at home or for 15 days (at 
maximum) after hospital discharge in case of hospitalised patient. If the ICS treatment will surpass 
these periods, the patient will be considered being switched to the LABD + ICS group and 
considered as protocol violator. 
See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
 A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
 If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
 See SoA for data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
 The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
 Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 

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equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
 

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8. 
Study Assessments and Procedures 
 Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions 
are not allowed. 
 Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness, to determine if the participant should continue or discontinue study intervention. 
 Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to record 
details of all participants screened and to confirm eligibility or record reasons for screening 
failure, as applicable.  
 Procedures conducted as part of the participant’s routine clinical management (such as 
spirometry, ECG and chest x-ray) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures meet the protocol-specified criteria 
and were performed within the time frame defined in the SoA. 
Identification of suitable participants 
In order to identify suitable participants, investigators at each centre will screen the medical 
records of all patients hospitalized in their department during the 6 month period before the 
beginning of the study, who were discharged with a diagnosis of pulmonary oedema/respiratory 
failure (usually, but not limited to DRG 087 or DRG 088). 
Potential participants identified through this search of the medical records will be contacted by the 
research staff in person or over the phone to ascertain if they are eligible and whether they are 
interested in participating in the study. If the potential participant is eligible and willing to take 
part, the investigator or the research staff member will provide a copy of the informed consent 
form (ICF) for the potential participant to review or will proceed to schedule a time for the 
participant to come to the clinic to review the informed consent and for the screening visit (Visit 
1). 
Visit 1: Screening 
Eligibility to participate will be assessed from the study inclusion and exclusion criteria. 
Eligible participants will be asked to read the Participant Information Sheet and ICF. The 
participant will be given time to ask questions. Signed informed consent must be obtained from 
each participant before any study specific procedures are initiated. A copy of the signed consent 
form and the Participant Information Sheet will be given to each participant to keep. 
Participants will be asked to complete both the CAT and mMRC dyspnoea scale questionnaires.  
The participant’s demography and medical history (including drug, alcohol, tobacco, and caffeine 
usage) will be recorded.  
A physical examination including height and weight will be performed.  
Past and current medical conditions, including the participant’s history of COPD and the presence 
of concomitant cardiovascular diseases (in particular HF, IHD and AF) and all related treatment 

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will be recorded. To be eligible for recruitment into the study the participant must be receiving at 
least one of the CV treatments specified in Appendix 10.5. 
Information about any moderate/severe exacerbations of COPD in the previous year, in addition 
to the index severe exacerbation, should also be recorded on the eCRF. This information should 
be assessed from the participant’s clinical records and prescription history. 
A blood sample will be taken for measurement of baseline laboratory parameters as described in 
Appendix 2. 
A medical examination, including measurement of vital signs (blood pressure and heart rate), will 
be performed. A 12-lead ECG will also be performed unless a previous ECG recording (taken 
within the previous 3 months) is available and the participant is also considered to be in a stable 
condition. 
If available, a chest x-ray taken within the last year when the participant was in a stable condition 
(and at least 4 weeks before the current acute COPD exacerbation) will be used for the screening 
assessment. In case of no x-ray available, it will be a discretionary choice of each centre to perform 
a chest x-ray at the screening visit (the chest x-ray must be performed at least 4 weeks after the 
most recent acute exacerbation of COPD). 
Concomitant medications will be reviewed and updated if necessary (at the discretion of the 
investigator). Doses of all COPD medications can be adjusted by the clinical investigator 
according to licenced dosages for each inhaled drug, at any time during the study. 
Visit 2: Randomization 
The randomisation visit can be completed on the same day as the screening visit (in which case 
tests do not need to be repeated) or up to 10 days afterwards.  
Vital signs, including blood pressure and heart rate, will be measured. 
If the randomisation visit is completed on a different day to the screening visit the patient’s 
eligibility to participate will be reassessed again prior to randomization, vital signs will be recorded 
and concomitant medications will be reviewed again. Participants will be asked to complete the 
CAT and mMRC questionnaires. 
All participants will undergo a spirometry test at the randomization visit, this will be the baseline 
value. 
The diagnostic spirometry test (to confirm the presence of COPD and eligibility to enter the study) 
can have been performed up to three years prior to randomization. For participants who have not 
had a diagnostic spirometry test within the last 3 years, the spirometry test performed at the 
randomization visit will also be the diagnostic test. The diagnostic spirometry test must be 
performed at least 4 weeks after discharge from hospital following hospitalization for an acute 
moderate to severe exacerbation of COPD. 
Spirometry will be performed in accordance with American Thoracic Society (ATS) and European 
Respiratory Society (ERS) guidelines (Miller et al 2005). The spirometry test will be performed 
before and 30 minutes after bronchodilation (4 inhalations of 100 µg salbutamol). The key 

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objective diagnostic criterion for COPD is a FEV1/FVC ratio <0.7 after bronchodilation. If this 
criterion is not met the patient cannot be recruited into the study.  
The participant’s medical history including details of COPD and CV diseases will be reviewed 
and updated as necessary. 
Participants will be questioned about the occurrence of any pre-treatment adverse events or serious 
adverse events and details will be recorded on the eCRF. 
The participant will be randomized to receive the study treatment for a period of 12 months. 
Participants in both study intervention groups will receive prescriptions for study medication, 
which will be collected from the local pharmacy or hospital pharmacy department. Prescription 
data will be captured on the eCRF. Participants will be instructed in the correct method of using 
the inhaler device(s). 
The participant will be given a study participation card which will include details about the study 
and emergency contact information for the investigational site. Participants will be instructed to 
contact the centre in case of worsening of the clinical conditions, particularly for acute 
exacerbations of respiratory symptoms. 
Concomitant medications will be reviewed. Doses of all COPD medications can be adjusted by 
the clinical investigator according to licenced dosages for COPD for each inhaled drug, at any time 
during the study.  
Information on anti-influenza and anti-pneumococci vaccine will be recorded. 
Participants will be contacted by telephone each month, by the clinical investigator or by a research 
staff member, to check compliance with the study procedures and treatment (including any anti-
influenza and anti-pneumococci vaccinations). Information about any hospitalizations or any 
unexpected medical events, particularly moderate exacerbations treated with antibiotics and/or 
steroids will be collected. 
 
Visit 3: Follow-up after 3 months of treatment 
Participants will be asked to complete the CAT and mMRC questionnaires. 
Vital signs, including blood pressure and heart rate, will be measured. 
Medical history and history of COPD and CV disease will be reviewed and updated as necessary. 
Participants will be asked to bring back all the unused medication and the empty drug devices and 
they will also be asked about their compliance with the study procedures and treatment. Inhaler 
use and technique will be checked to ensure that the participant is using the device(s) correctly.  
Information about any hospitalizations or any unexpected medical events, particularly moderate 
exacerbations treated with antibiotics and/or steroids will be collected. Information will be 
obtained by reviewing the patient’s medical records and prescribed medication and also from direct 
questioning of the participant. Participants will also be contacted by telephone each month between 
the study visits (by the clinical investigator or by a research staff member) to assess this 
information. 

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The participant’s ongoing treatments (concomitant medications, including any anti-influenza and 
anti-pneumococci vaccinations) will be reviewed and updated as necessary both for COPD and 
CV comorbidities, particularly HF, IHD and/or AF. Details of all concomitant medications will be 
recorded. Doses of all COPD medications can be adjusted by the clinical investigator according to 
licenced dosages for COPD for each inhaled drug, at any time during the study.  
Participants will be questioned about the occurrence of any adverse events and details will be 
recorded on the eCRF. 
Prescriptions for further supplies of the study medication, for collection from the local pharmacy 
or hospital pharmacy department, will be issued. Prescription data will be captured on the eCRF. 
Visit 4: Follow-up after 6 months of treatment 
Participants will be asked to complete the CAT and mMRC questionnaires. 
Vital signs, including blood pressure and heart rate, will be measured. 
Medical history and history of COPD and CV disease will be reviewed and updated as necessary. 
Participants will be asked to bring back all the unused medication and the empty drug devices and 
they will also be asked about their compliance with the study procedures and treatment. Inhaler 
use and technique will be checked to ensure that the participant is using the device(s) correctly.  
Information about any hospitalizations or any unexpected medical events, particularly moderate 
exacerbations treated with antibiotics and/or steroids will be collected. Information will be 
obtained by reviewing the patient’s medical records and prescribed medication and also from direct 
questioning of the participant. Participants will also be contacted by telephone each month between 
the study visits (by the clinical investigator or by a research staff member) to assess this 
information. 
The participant’s ongoing treatments (concomitant medications including any anti-influenza and 
anti-pneumococci vaccinations) will be reviewed and updated as necessary both for COPD and 
CV comorbidities, particularly HF, IHD and/or AF. Details of all concomitant medications will be 
recorded. Doses of all COPD medications can be adjusted by the clinical investigator according to 
licenced dosages for COPD for each inhaled drug, at any time during the study.  
Participants will be questioned about the occurrence of any adverse events and details will be 
recorded on the eCRF. 
Prescriptions for further supplies of the study medication, for collection from the local pharmacy 
or hospital pharmacy department, will be issued. Prescription data will be captured on the eCRF. 
Visit 5: Follow-up after 9 months of treatment 
Participants will be asked to complete the CAT and mMRC questionnaires. 
Vital signs, including blood pressure and heart rate, will be measured. 
Medical history and history of COPD and CV disease will be reviewed and updated as necessary. 
Participants will be asked to bring back all the unused medication and the empty drug devices and 
they will also be asked about their compliance with the study procedures and treatment. Inhaler 
use and technique will be checked to ensure that the participant is using the device(s) correctly.  

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Information about any hospitalizations or any unexpected medical events, particularly moderate 
exacerbations treated with antibiotics and/or steroids will be collected. Information will be 
obtained by reviewing the patient’s medical records and prescribed medication and also from direct 
questioning of the participant. Participants will also be contacted by telephone each month between 
the study visits (by the clinical investigator or by a research staff member) to assess this 
information. 
The participant’s ongoing treatments (concomitant medications including any anti-influenza and 
anti-pneumococci vaccinations) will be reviewed and updated as necessary both for COPD and 
CV comorbidities, particularly HF, IHD and/or AF. Details of all concomitant medications will be 
recorded. Doses of all COPD medications can be adjusted by the clinical investigator according to 
licenced dosages for COPD for each inhaled drug, at any time during the study.  
Participants will be questioned about the occurrence of any adverse events and details will be 
recorded on the eCRF. 
Prescriptions for further supplies of the study medication, for collection from the local pharmacy 
or hospital pharmacy department, will be issued. Prescription data will be captured on the eCRF. 
Visit 6: End of Study after 12 months of treatment or early withdrawal 
Participants will be asked to complete the CAT and mMRC questionnaires. 
Spirometry will be performed in accordance with ATS and ERS guidelines (Miller et al 2005). 
The spirometry test will be performed before and 30 minutes after bronchodilation (4 inhalations 
of 100 µg salbutamol). 
Vital signs, including blood pressure and heart rate, will be measured. A 12-lead ECG will also be 
performed. 
Medical history and history of COPD and CV disease will be reviewed and updated as necessary. 
Participants will be asked to bring back all the unused medication and the empty drug devices and 
they will also be asked about their compliance with the study procedures and treatment. 
Information about any hospitalizations or any unexpected medical events, particularly moderate 
exacerbations treated with antibiotics and/or steroids will be collected. Information will be 
obtained by reviewing the patient’s medical records and prescribed medication and also from direct 
questioning of the participant. 
Participants will be questioned about the occurrence of any adverse events and details will be 
recorded on the eCRF. 
For participants who are withdrawn before the end of the study the reason for early withdrawal 
will be recorded on the eCRF. 
Participants who complete the 12 month randomized treatment period will continue to be 
prescribed the most appropriate treatment for their condition at the discretion of the investigator. 
Doses of all COPD medications can be adjusted by the clinical investigator according to licenced 
dosages for COPD for each inhaled drug, at any time during the study. 
Visit 7: Follow-up 3 months after End of Study 

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Participants will be asked to complete the CAT and mMRC questionnaires. 
Medical history and history of COPD and CV disease will be reviewed and updated as necessary. 
Participants will be asked about treatment. Information about any hospitalizations or any 
unexpected medical events, particularly moderate exacerbations treated with antibiotics and/or 
steroids will be collected. Information will be obtained by reviewing the patient’s medical records 
and prescribed medication and also from direct questioning of the participant. 
The participant’s ongoing treatments (concomitant medications) will be reviewed and updated as 
necessary both for COPD and CV comorbidities, particularly HF, IHD and/or AF. Details of all 
concomitant medications will be recorded.  
Participants will be questioned about the occurrence of any serious adverse events and details will 
be recorded on the eCRF. 
8.1. 
Efficacy Assessments  
At each follow-up visit, participants will be questioned about any hospitalizations or any 
unexpected medical events, particularly moderate exacerbations treated with antibiotics and/or 
steroids and all information will be collected on the eCRF. In addition, the participant’s medical 
records will be reviewed and details of any relevant medical events and any medication prescribed 
will be recorded in the eCRF. Participants will also be contacted by telephone each month between 
the study visits (by the clinical investigator or by a research staff member) to assess this 
information. 
An emergency telephone number contact will be set up in each center, in case the patients require 
hospitalization, particularly for acute exacerbations of respiratory symptoms. 
8.1.1. 
Assessment of re-hospitalizations and deaths (all cause) 
Information on deaths (all cause) will be collected from the participant’s medical records. 
Information on re-hospitalizations (all cause) will be collected by reviewing the participant’s 
medical records, from direct questioning of the participant during the follow-up visits and during 
monthly phone calls with the participant. 
8.1.2. 
Assessment of moderate/severe COPD exacerbations 
Moderate/ severe exacerbations of COPD will be recorded based on the clinical evaluation. 
A moderate/ severe COPD exacerbation is defined as a sustained worsening of respiratory 
symptoms that requires treatment with systemic corticosteroids, antibiotics (moderate) , or hospital 
admission (or any combination thereof). Events are classified as moderate or severe according to 
the European Medicines Agency Guideline 2012. Moderate exacerbations are those that require 
treatment with additional rescue bronchodilators systemic corticosteroids and/or antibiotics. 
Severe exacerbations are defined as those requiring treatment with additional rescue 
bronchodilators systemic corticosteroids and/or antibiotics. Hospital admission, or resulting in 
death. 

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8.1.3. 
Assessment of number of pneumonia events 
Pneumonia events will be recorded based on the clinical diagnosis and will be confirmed by 
chest x-ray where possible. 
8.1.4. 
Acute cardiac events 
Acute cardiac events will be recorded based on the clinical evaluation. 
Acute CV events are defined as an inpatient or emergency department visit with a primary 
diagnosis of any of the following conditions (International Classification of Diseases, 9th 
Revision, Clinical Modification (ICD-9-CM) codes are also shown). Coronary heart disease (ICD-
9-CM codes 410–414), cardiac arrhythmia (ICD-9-CM code 427), heart failure (ICD-9-CM code 
428), or ischemic stroke (ICD-9-CM codes 433-434) (Wang et al 2018). 
8.1.5. 
Cardiovascular death 
Cause of death will be assessed based on the coded cause of death recorded in the participant’s 
records. Cardiovascular death will be defined as death resulting from an acute myocardial 
infarction, sudden cardiac death, heart failure, stroke, cardiovascular procedure, cardiovascular 
hemorrhage, or death due to other cardiovascular causes. (Hicks et al 2015) 
8.1.6. 
Quality of Life 
Participants will be asked to provide responses to the CAT questionnaire and the mMRC dyspnoea 
scale which will be completed by the investigator. 
The CAT questionnaire measures the impact of COPD on the participant’s wellbeing and daily 
life. It includes 8 questions which are rated on a 6-point scale of 0 to 5. Participants are assigned 
an overall score ranging from 0 to 40. Higher scores indicate a poorer quality of life. 
The mMRC dyspnoea scale rates the participant’s breathlessness on a scale of 0 to 4, with higher 
scores indicating worse symptoms. 
8.1.7. 
Spirometry 
Participants must have their diagnosis of COPD confirmed by spirometry. The key objective 
diagnostic criterion for COPD is a FEV1/FVC ratio <0.7 after bronchodilation. If this criterion is 
not met the patient cannot be recruited into the study. 
The diagnostic spirometry test (to confirm the presence of COPD and eligibility to enter the study) 
can be performed up to three years prior to randomization. For participants who have not had a 
diagnostic spirometry test within the last 3 years, the spirometry test performed at the 
randomization visit will be the diagnostic test. The diagnostic spirometry test must be performed 
not earlier than 4 weeks since last exacerbationor discharge from hospital following 
hospitalization for an acute COPD episode. 
All participants will undergo a pre- and post-bronchodilator spirometry test at the randomization 
visit, this will be the baseline value. 
A spirometry test will also be performed at the end of the study (Visit 6).  

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Spirometry tests will be performed in accordance with ATS and ERS guidelines (Miller et al 2005). 
The test will be performed before and 30 minutes after bronchodilation (4 inhalations of 100 µg 
salbutamol). 
The following parameters will be recorded: 
 Forced vital capacity (FVC) 
 Forced expiratory volume in one second (FEV1) 
 The FEV1/FVC ratio will be calculated 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
 A physical examination will be performed at each visit. 
 The physical examination will include, as a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. 
Vital Signs 
 Vital signs will be measured at the screening visit, random visit and at each of the follow-
up visits during the treatment period (Visits 2-6). 
 Blood pressure and pulse measurements can be assessed using a completely automated 
device or manual techniques  
 Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
8.2.3. 
Electrocardiograms 
 A 12-lead electrocardiogram (ECG) will be performed at the screening visit. 
 If the patient is in a “stable condition” at the screening visit and has an ECG which was 
recorded within the last 3 months no further ECG measurements will be recorded. 
 For unstable patients and patients with no previous ECG recording available, an ECG test 
will be performed at the screening visit. 
 A 12-lead ECG will also be performed at Visit 6 which will be completed after 12 months 
treatment or following early withdrawal of the participant from the study. 
8.2.4. 
Chest x-ray 
 A chest x-ray taken within the last year when the participant was in a stable condition (and 
at least 4 weeks before the current acute COPD exacerbation) can be used for the screening 
assessment. 
 Optionally (centre choice) , for all other participants a chest x-ray will be performed at the 
screening visit (the chest x-ray must be performed at least 4 weeks after the most recent 
acute exacerbation of COPD). 

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 In case of suspected pneumonia occurring during the study, the investigator is invited to 
confirm the diagnosis with a chest x-ray. 
8.2.5. 
Clinical Safety Laboratory Assessments 
 Laboratory tests will be performed for screening purposes only.  
 All tests will be performed by the local hospital laboratory. 
 See Appendix 2 for the list of clinical laboratory tests to be performed.  
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Section 10.3 (Appendix 3). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information  
All AEs (serious and non-serious) will be collected and registered by the investigator in the CRF, 
from the start of study treatment until the last follow up visit at the time points specified in the 
SoA (Section 1.3). SAEs will be collected starting from Informed Consent signature (see 8.3.2). 
Investigators are not obligated to actively seek AEs after conclusion of the study participation. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event to be reasonably related to the 
study intervention or study participation, the investigator must promptly notify the sponsor. 
8.3.2. 
Monitoring of AEs 
Patients will be monitored throughout the study for AEs to the study treatment. AEs will be 
documented and collected on an on-going basis during the treatment period and the relevant follow 
up period. The Investigator will instruct the patient how to communicate any AEs occurred in this 
period. Medical events fulfilling one or more criteria of seriousness and occurring after the 
informed consent has been signed, must be immediately (within maximum 24 hours) reported to 
the Sponsor using an SAE form (separate paper forms will be supplied to the investigators), even 
if the study treatment administration has not been started yet.  
Serious adverse events occurring before the initiation of the study treatment, must also be recorded 
on the “Medical History/Current Medical Conditions” pages of the CRF (but not in the AE page),  
The Investigator has to follow all AEs until resolution, stabilization, further investigation results 
are obtained, or the participant is lost to follow-up. 
SAEs still present at the end of the study period and for the subsequent 30 days must be followed 
until a final outcome (that is any outcome different from “on-going”) is determined. 
An AE that is initially reported as non-serious and later on meets the criteria for an SAE must be 
reported as an SAE as soon as the information regarding the presence of one or more seriousness 
criteria become known to the investigator. 
8.3.3. 
Clinical Laboratory Abnormalities 
Clinically significant abnormal laboratory findings or other abnormal assessments that are detected 
during the study or are present at baseline and significantly worsen following the start of the study 

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will be reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or 
other abnormal assessments that are associated with a disease reported in the medical history, 
unless judged by the Investigator as more severe than expected for the subject’s condition, or that 
are present or detected at the start of the study and do not worsen, will not be reported as AEs or 
SAEs.  
The Investigator will exercise his or her medical and scientific judgement in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. 
8.3.4. 
Recording of AEs and SAEs 
During the study, site personnel will evaluate and record any change in the pre-existing 
condition(s) and/or the occurrence of any AEs. 
Subjects will be questioned for the occurrence of any new or worsening sign or symptom at each 
study visit. The Investigator or designee will enquire about AEs by asking non-leading questions, 
such as in the following examples: 
At the first scheduled AE enquiry on Day 0 (pre-dose) subjects will be asked: 
“How are you feeling?” 
At subsequent scheduled intervals subjects will be asked: 
“Since you were last asked, have you felt unwell or different from usual?” 
Out of range laboratory results arising once study treatment has begun, will be reviewed by the 
Investigator. The Investigator will determine whether the signs and symptoms represent clinically 
significant changes from the subject’s baseline, and if so, they should be recorded as an AE.  
The Investigator will evaluate all AEs as to: 
• 
Seriousness: See definition in Appendix 3 
• 
Severity: See definition in Appendix 3. 
• 
Causal Relationship to study drug: See definition in Appendix 3. 
• 
Outcome. 
All AEs, serious and non-serious, must be recorded in the AE section of the CRF. SAEs must 
also be reported to the Sponsor in 24 hours though the SAE form. 
After the end of study period, including follow-ups, only if a SAE is believed to be related to the 
study drug administration should it be reported to the Sponsor. 
Adverse Events causing treatment discontinuation 
If a subject is withdrawn from the study as a consequence of an AE, this must be recorded and 
reasoned in the CRF, and the subject must be followed up until the AE outcome resolution. 
8.3.5. 
Prompt Reporting of SAEs to Sponsor 
Once an Investigator becomes aware that an SAE has occurred in a study subject, he/she will 
immediately (within 24 hours from being aware of an SAE) notify the Sponsor: 

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-- 
by phone (TEL: 0532/236835)  
- 
or by e-mail (a.marra@ospfe.it) to notify and transmit  SAEs.  
In case of Serious Adverse Events, the Investigator will transmit electronically if applicable or fill 
in an SAE form and will transmit it within 24 hours since becoming aware of the event, to Sponsor. 
The SAE form must be completed as thoroughly as possible with all details available at that time 
point and signed by the Investigator (or appropriately qualified designee). 
If the Investigator does not have all information regarding an SAE he/she will not wait to receive 
additional information before notifying the Sponsor of the event and completing the form. The 
form will be updated when additional information is received (follow up reports).  
The Investigator will always provide an assessment of causality at the time of the initial report.  
If follow up data obtained after having already reported an SAE indicates that the assessment of 
causality is incorrect, then a follow up SAE form will  be filled in with the amended information,  
signed and dated, and resubmitted to the Sponsor. 
In accordance with local Independent Ethics Committee (IEC) requirements, the Investigator must 
also notify IEC of any SAEs according the guidelines of the Ethics Committee. 
The Investigator, and others responsible for subject care, should institute any supplementary 
investigations of SAEs based on their clinical judgement of the likely causative factors. This may 
include seeking further opinion from a specialist in the field of the AE. The Sponsor may also 
request extra tests. If a subject dies, any post-mortem findings, including histopathology will be 
provided to the Sponsor if available. No medical help, diagnosis, or advice should be withheld 
from the subject due to an inability to contact the Sponsor 
 
8.3.6. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts, in order to collect all relevant information. Particularly, all SAEs will 
be followed until resolution, stabilization, further investigation results are obtained, or the 
participant is lost to follow-up. Further information on follow-up procedures is given in Appendix 
3. 
8.3.7. 
Expeditable Events 
Expeditable events are those AEs that are causally related to the study product, and that are both 
serious and unexpected (Serious Unexpected Suspected Adverse Reaction- SUSAR), see 
Appendix 3.  
8.3.8. 
Pregnancy 
Any pregnancy where the fetus may have been exposed to study drug, should be notified by the 
Investigator to the Sponsor, by filling in the “Pregnancy Form” and sending it, within 24 hours of 
its knowledge, to the Sponsor: 

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- 
 by e-mail (a.marra@ospfe.it)  
• 
Outcome of the pregnancy (normal or abnormal) must be followed up and recorded. 
• 
Abnormal pregnancy outcome must be notified on an expedited basis (i.e. within 24 
hours of the Investigator becoming aware of the abnormal pregnancy outcome) using the SAE 
form. This refers especially to congenital anomalies in the fetus/child, fetal death and 
spontaneous abortion, and adverse reactions in the neonate that are classified as serious. 
• 
Pregnancy will be recorded as an AE in all cases.  It will be qualified as an SAE only if it 
fulfils SAE criteria (see above). 
8.3.9. 
Disease Related Events and/or Disease Related Outcomes not Qualifying as AEs 
or SAEs 
Not applicable 
 
8.4. 
Treatment of Overdose 
The investigator should consult the product label of the licensed study medication for advice on 
treatment of overdose. 
8.5. 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 
9. 
Statistical Considerations   
9.1. 
Statistical Hypotheses 
The superiority of the LABD(s)+ICS group vs. LABD(s) group in terms of time to first re-
hospitalization and/or death will be tested. The following hypotheses scheme will be considered: 

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H0: there is no difference in the time to first re-hospitalization and/or death between the two 
treatment groups. 
H1: there is a difference in the time to first re-hospitalization and/or death between the two 
treatment groups 
9.2. 
Sample Size Determination  
The sample size calculation is based on the superiority criteria of the LABD+ICS group vs. LABD 
alone group in terms of re-hospitalization and/or death. With 464 patients in each group, the 
percentage of patients experiencing the composite event (re-hospitalization and/or death) is 
expected to be 9% in the LABD+ICS group and 15% in the LABD alone group. A log-rank test 
(two-sided 5% significance level) will have 80% power to detect a difference between treatment 
groups in terms of time to first re-hospitalization and/or death (primary efficacy endpoint). 
Adjusting for an expected 10% dropout rate, a total of 516 patients per group will need to be 
randomized. 
9.3. 
Populations for Analyses 
The following populations will be considered for the analysis: 
 Randomized population: all randomized patients. 
 Safety population: all randomized patients who receive at least one administration of the 
study treatment in a given treatment period. 
 Intention-to-Treat population (ITT): all randomized patients from the safety population 
with at least one available post-baseline efficacy evaluation during the treatment period. 
 Per-protocol population (PP): all randomized patients from the ITT population without 
any major protocol deviations (e.g., wrong inclusions, forbidden concomitant medications, 
etc.). The exact definition of major protocol deviations will be discussed with the clinical 
team case by case during the review of the data and will be described in the Data Review 
Report. 
The statistical analysis will be performed after database lock.  
The primary efficacy variable will be analysed both in the ITT and in the PP populations. As this 
is a superiority study, the primary analysis population will be the ITT. All the other efficacy 
variables will be analysed in the ITT population only.  
Analysis of safety variables will be performed on the safety population. 
 
9.4. 
Statistical Analyses 
All statistical analyses will be undertaken by CROS NT S.r.l. (Verona, Italy) using SAS software, 
release 9.4 or higher (SAS Institute, Cary, NC, USA). 
The following describes the statistical analysis as it is foreseen at the time of planning the trial. 

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A detailed Statistical Analysis Plan (SAP) will be described in a separate document to be 
completed after the protocol is finalised and before database lock. 
9.4.1. 
Descriptive Statistics 
Descriptive statistics will be provided in summary tables by treatment group according to the 
type of variable summarized: 
• 
Quantitative variables will be summarized using n (sample size), arithmetic mean, 
standard deviation (SD), median, minimum and maximum; 
• 
Categorical variables will be summarized using frequency count and percent 
distribution. 
9.4.2. 
Participant Accountability 
Disposition of patients, patient status and patients excluded from analysis sets will be 
summarized by treatment group. 
9.4.3. 
Description of Baseline Characteristics 
The baseline demographic characteristics will be summarized by treatment group by means of 
descriptive statistics for the ITT population. 
The following parameters will be presented:  
 demographics; 
 medical history (including CV diseases); 
 previous and concomitant medications (including CV medications); 
 physical examination; 
 vital signs; 
 efficacy parameters. 
9.4.4. 
Missing Data 
The number of patients with missing data will be presented under the “Missing” category, if 
present. Missing values will be included in the denominator count when computing percentages. 
When continuous data are being summarized, only the non-missing values will be evaluated for 
computing summary statistics. Further details on dealing with missing data, along with the 
handling of possible outliers, will be described in the SAP.  
Other critical missing data will be discussed prior to database lock, if any. Decisions will be taken 
during the data review of the data and will be fully documented in the Data Review Report 
9.4.5. 
Principles of Statistical Analysis 
For all inferential analyses, p-values will be rounded to three decimal places. Statistical 
significance will be declared if the rounded p-value is ≤ 0.05. No adjustment for multiple testing 
is planned. 

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9.4.6. 
Efficacy Analyses 
Primary Efficacy Variable 
The primary efficacy variable is the time from baseline (Visit 2) to first re-hospitalization and/or 
death. If the patient discontinues/completes the treatment period and no re-hospitalization and/or 
death is observed, then the time to first re-hospitalization and/or death is treated as right censored 
at the end of treatment period (i.e. date of Visit 6) or at the time of the withdrawal during the 
treatment period (i.e. the date of discontinuation). 
The primary efficacy variable will be analyzed using the Kaplan-Meier estimator. Comparison 
between treatment groups will be performed using the log-rank test stratified by center. A Kaplan-
Meier plot for time to first re-hospitalization and/or death will also be presented by treatment group. 
The LABD(s)+ICS group will be declared to prolong time to first re-hospitalization and/or death, 
compared to the LABD(s) group, if the difference between the two treatments is significantly in 
favour of LABD(s)+ICS (i.e. the p-value from the log-rank test is ≤ 0.050). 
In addition, a Cox proportional hazards regression analysis will be performed as well, presenting 
the treatment effect as a hazard ratio with the associated 95% confidence interval with center, age 
and treatment group as factors. The inclusion of any other potential confounding factors in the 
model will be evaluated during the Data Review, verifying the homogeneity of factors distributions 
among treatment groups. 
A sensitivity analysis will be also carried out excluding efficacy data (i.e. hospitalization and 
death) collected after the crossover occurrence (i.e. patients that switch from one treatment group 
to the other adding or stopping ICS). The crossover patients that do not experience any 
hospitalization or death will be considered as censored at the time of cross-over start. Kaplan-
Meier, log-rank test and Cox model will be repeated on this modified analysis dataset. 
Secondary Efficacy Variables 
The number of re-hospitalizations and deaths (all cause) will be analysed using a Poisson 
regression model. The model will include the number of events as dependent variable and 
treatment group, age and center as factors. Log-time on study will be used as an offset. The over 
dispersion parameter based on the deviance will be considered in order to account for between-
patient variability in the events rate and standard errors will be estimated allowing for extra-
Poisson variation.  
All the other counting variables will be analysed with the same model. 
All the continuous variables will be summarized at each visit by means of descriptive statistics. 
Mean change from baseline value and the 95% confidence intervals will be calculated. P-values 
of paired t-tests will be provided for mean changes from baseline.  
Change in continuous variables will also be analysed using an ANCOVA model, with treatment 
group, centre and age as factors and baseline as covariate.  
9.4.7. 
Safety Analyses 
The number and the percentage of patients experiencing adverse events, adverse drug reactions, 
serious adverse events, severe adverse events and adverse events leading to study withdrawal will 

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be summarized by treatment group. Adverse events will also be summarized by System Organ 
Class (SOC) and Preferred Term (PT) using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary and comparison between treatments will be performed using a Chi-square 
test or Fisher's exact test, as appropriate. 
Any other safety variables to be summarized by treatment group using descriptive statistics will 
be detailed in the SAP. 
9.4.8. 
Other Analyses  
A subgroup analysis will be performed by considering the patients randomized with Triple 
Therapy (LAMA+LABA+ICS) or LAMA+LABA. The analysis of primary endpoint and the 
number of re-hospitalizations and deaths (all cause) secondary analysis will be performed on this 
subset of patients. 
Other subgroup analyses may be performed for efficacy and safety endpoints based on baseline 
disease characteristics which could provide evidence to assess effectiveness, adherence levels and 
the true value of adding ICS treatment to LABD. 
 
9.5. 
Interim Analyses  
Not foreseen. 
9.5.1. 
Data Monitoring Committee (DMC) 
The Data Monitoring Committee will periodically review and evaluate the accumulated study 
data for safety, study conduct and progress, scientific validity and integrity. 
The DMC will monitor the progress of the study, enrollment, study performance in terms of data 
management metrics and will undertake a review of the safety data including adverse events.  

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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
 This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 Applicable ICH Good Clinical Practice (GCP) Guidelines 
 Applicable laws and regulations 
 The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
 Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
 The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
 The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.  
 Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 

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Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
 The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
 Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
 A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
 Participants who are rescreened are required to sign a new ICF 
10.1.4. 
Data Protection 
 Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
 The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant.  
 The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
The study will be coordinated by a Scientific Steering Committee composed of highly qualified 
and experienced clinical investigators. 
The study will be monitored by a Data Monitoring Committee, which will monitor the following: 
1. Participant safety, burden, confidentiality 
2. Study performance and all aspects of quality control 
3. Study productivity 
The DMC will monitor the progress of the study, enrolment, study performance in terms of data 
management metrics and review of safety data like adverse events. 
The Committees will have regular teleconferences and will meet at least twice a year in person 
with the Principal Investigators. 
10.1.6. 
Dissemination of Clinical Study Data 
A clinical study report describing the results of this study will be written by CROS NT S.r.l. 
(Verona, Italy). The study report will be written within one year after the end of the study. 
The investigators plan to write a paper describing the results of this study for publication in an 
appropriate peer reviewed medical journal. 

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10.1.7. 
Data Quality Assurance 
 All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
 The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
 The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
 The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 7 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.  
10.1.8. 
Source Documents 
 Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
 Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
10.1.9. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 

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 Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of participants by the investigator 
 Discontinuation of further study intervention development 
10.1.10. 
Publication Policy 
 The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.  
 The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
 Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
The following blood tests will be performed for screening purposes only at the local hospital 
laboratory. 
 full blood count (to include hemoglobin, hematocrit, mean corpuscular volume (MCV), 
mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration 
(MCHC), red blood cell (RBC) count, white blood cell (WBC) count and differential 
(platelets, neutrophils, lymphocytes, monocytes, eosinophils and basophils) 
 fibrinogen 
 NT-BNP  or B-type natriuretic peptide (BNP)  
 lipid profile (to include total cholesterol, high density lipoprotein (HDL) cholesterol, low 
density lipoprotein (LDL) cholesterol and triglycerides) 
 creatinine 
 sodium 
 potassium 
 calcium 
 glucose 
 C- reactive protein (CRP) 
 alanine amino transferase (ALT) 
 gamma glutamyl transferase 
* 
 
 

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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Adverse event (AE) definition 
AE Definition 
 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated 
with the use of study intervention. 
Serious adverse event (SAE) definition 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 

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e. 
Is a congenital anomaly/birth defect 
f. 
Important medical event 
 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 
SAE not requiring immediate reporting   
The following reasons for hospitalisations will not to be managed as SAEs but just 
recorded in the CRF: 
 
Hospitalization planned before entry into the clinical study which is part of the 
normal treatment or monitoring of the studied indication and not associated with any 
deterioration in condition; 
 
Hospitalization for routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition; 
 
Hospitalization for treatment, which was elective or pre-planned, for a pre-existing 
condition that is unrelated to the indication under study and did not worsen. 
 
 
AE and SAE Recording 
 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
 
The investigator will then record all relevant AE/SAE information in the CRF. 
 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the sponsor’s representative in lieu of completion of the AE/SAE 
CRF page. 
 
There may be instances when copies of medical records for certain cases are 
requested by the sponsor’s representative In this case, all participant identifiers, with 

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the exception of the participant number, will be redacted on the copies of the medical 
records before submission to the sponsor’s representative. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
 
 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:  
 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
 
To ensure no confusion or misunderstanding of the difference between the terms 
"serious" and "severe", which are not synonymous, the following note of 
clarification is provided: 
The term "severe" is often used to describe the intensity (severity) of a specific 
event; the event itself, however, may be of relatively minor medical significance 
(such as severe headache).  This is not the same as "serious," which is based on 
patient/event outcome or action criteria usually associated with events that pose a 
threat to a patient's life or functioning.  Seriousness (not severity) serves as a guide 
for defining regulatory reporting obligations. An event is defined as ‘serious’ when it 
meets at least one of the predefined outcomes as described in the definition of an 
SAE, NOT when it is rated as severe. 
 
 
 
Assessment of Causality 
The investigator must assess the relationship between study treatment and each AE/SAE. 
He/she will use the following definitions for any adverse event being collected in the 
study and for all serious adverse events, to assess the relationship of the adverse event to 
the use of study treatment:  

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 
“Reasonable possibility” that the AE is related to the study drug. For example, when 
an adverse event has a strong temporal relationship to study drug or recurs on re-
challenge and another etiology is unlikely or significantly less likely or a more likely 
alternative etiology does not exists. 
 
“Not reasonable possibility” that the AE is related to the study drug. For example, 
when an adverse event is due to an underlying or concurrent illness or effect of 
another drug and is not related to the study drug (e.g., has no temporal relationship to 
study drug or has a much more likely alternative etiology), or an adverse event has 
little or no temporal relationship to the study drug and/or a more likely alternative 
etiology exists. 
The investigator will use clinical judgment to determine the relationship. 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor’s representative. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor’s 
representative. 
The investigator may change his/her opinion of causality in light of follow-up 
information and in this case will send an SAE follow-up report with the updated causality 
assessment. 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Assessment of Expectedness 
The expectedness is assessed by the Sponsor versus the Reference Safety Information 
identified for the study treatment (IB or SmPC). 
An adverse event should be assessed as “expected” from the perspective of events 
previously observed, not on the basis of what might be anticipated from the 
pharmacological properties of a medicinal product. 
An “unexpected” adverse event is an AE, the nature or severity of which is not consistent 
with the applicable product information (e.g. Investigator’s brochure or summary of 
product characteristics). 
 
Follow-up of AEs and SAEs 
 
The investigator must perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 

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sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
 
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide upon request the Sponsor with a copy of any 
post-mortem findings including histopathology.  
 
New or updated information will be recorded in the originally completed CRF. 
 
The investigator will submit any updated SAE form to the sponsor within 24 hours 
of being aware of the new information. 
 
SAE Reporting by the investigator to the sponsors via Paper SAE form 
 
Facsimile transmission of the SAE paper form  is the preferred method to transmit 
this information to the sponsor. 
 
Notification by email is also acceptable. 
 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE form pages within the designated reporting time frames. 
 
Contacts for SAE reporting can be found in section 8.3. 
 
 
SUSAR  reporting by the sponsor 
SUSAR Reporting to Competent Authorities/Ethic Committees 
SUSARs are subject to expedited electronic reporting by the Sponsor to EudraVigilance 
Clinical Trial Module (EVCTM) and to the concerned Ethics Committees. SUSARs must 
be reported, within the timelines reported below, by the Sponsor or a suitably qualified 
designee.  
The clock for expedited initial reporting (day 0) starts as soon as the information 
containing the minimum reporting criteria has been received by the sponsor. 
The minimum information includes, at least, all of the following: 
— valid EudraCT number (where applicable), 
— sponsor study number, 
— one identifiable coded subject , 
— one identifiable reporter, 
— one SUSAR, 

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— one suspect IMP (including active substance name- code), 
— a causality assessment. 
 
Reporting Timelines: 
Adverse event type 
EU Regulatory Deadlines (within) 
Related, unexpected serious reports of 
death or life-threatening 
7 calendar days from day 0 for initial 
safety reports 
15 calendar days from the day 0 for 
follow-up safety reports 
Any other serious related unexpected 
reports  
 
15 calendar days from day 0 
 
SUSAR reporting to Investigators 
Periodically, the Sponsor will distribute to all Investigators involved in the study, line 
listings and or individual safety reports in order to inform all of them about the suspected 
unexpected serious adverse reactions (SUSARs) which have occurred in the study. 
 
 
 
 
 

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10.4. 
Appendix 4: Abbreviations 
 
AECOPD 
acute exacerbation of chronic obstructive pulmonary disease 
AE 
 
adverse event 
AF 
 
atrial fibrillation 
ATS 
 
American Thoracic Society (ATS)  
CAT  
COPD Assessment Test 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
COPD  
chronic obstructive pulmonary disease 
CRP 
 
C reactive proteine 
CV 
 
cardiovascular 
DRG  
diagnosis related group 
eCRF  
electronic case report form 
ERS 
 
European Respiratory Society 
ESC 
 
European Society of Cardiology 
FEV1  
forced expiratory volume in 1 second 
FVC  
forced vital capacity 
GOLD  
Global Initiative for Chronic Obstructive Lung Disease 
GCP  
Good Clinical Practice 
HDL  
high density lipoprotein 
HF 
 
heart failure 
HIPPA  
Health Insurance Portability and Accountability Act 
IB 
 
 investigators brochure 
ICF 
 
informed consent form 
ICH 
 
International Conference on Harmonization 
ICS 
 
inhaled glucocorticosteroids 
IEC 
 
Independent Ethics Committee 
IHD 
 
ischaemic heart disease 
IRB 
 
Institutional Review Board 
LABA  
long-acting beta2-agonist 

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LABD  
long acting bronchodilators 
LAMA 
long acting antimuscarinic 
LDL 
 
low density lipoprotein 
MCV  
mean corpuscular volume 
MCH  
 mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MedDRA 
Medical Dictionary for Regulatory Activities 
mMRC 
modified Medical Research Council 
PDTA  
Percorsi Diagnostico Terapeutici Assistenziali (best medical practice) 
PT 
 
preferred term 
QoL 
 
quality of life 
RBC  
red blood cell 
SABA  
short acting beta agonist 
SABD  
short acting bronchodilator 
SAE 
 
serious adverse event 
SoA 
 
schedule of activities 
SOC  
system order class 
RCT 
 
Randomised controlled trial 
WBC  
white blood cell 
WHO  
World Health Organisation 
 
 

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10.5. 
Appendix 5: List of Cardiovascular Drugs 
To be eligible for recruitment into the study the participant must be receiving at least one of the 
CV treatments listed below given alone or in combination. 
 
Treatments for atrial fibrillation 
Calcium channel blockers (such as diltiazem, verapamil) 
Beta-blockers 
Cardiac glycosides 
Anti-arrhythmics (such as amiodarone, dronedarone, sotalol, dofetilide) 
Anti-arrhythmics (such as flecainide, propafenone) 
Anti-arrhythmics (such as quinidine, disopyramide) 
Drugs for pharmacological cardioversion (such as flecainide, amiodarone or propafenone) 
 
Treatments for heart failure 
Angiotensin-converting enzyme inhibitors (ACE-inhibitors) 
Angiotensin receptor blockers (ARBs) 
Angiotensin receptor-nephrilysin inhibitors (ARNIs) (such as valsartan/sacubitril) 
Ivabradine 
Beta blockers  
Aldosterone antagonists 
Isosorbide dinitrate or hydralazine 
Nitrates  
Phosphodiesterase-3 inhibitors (such as milrinone, inamrinone (formerly amrinone), cilostazol) 
Diuretics (thiazide, loop, or natriuretic peptides) 
Cardio-stimulatory or inotropic drugs which stimulate contractility (such as digitalis, beta-
agonists, sympathomimetic drugs) 
 
Treatments for ischemic heart disease 
Alpha-adrenoceptor antagonists (alpha-blockers) (such as prazosin, terazosin, etc) 
Angiotensin converting enzyme (ACE) inhibitors (such as benazepril; captopril; enalapril; 
fosinopril; lisinopril; moexipril; quinapril; ramipril, etc) 

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Angiotensin receptor blockers (ARBs) (such as candesartan, eprosartan, irbesartan, losartan; 
olmesartan, telmisartan, azilsartan, valsartan) 
Beta-2-adrenoceptor agonists (β2-agonists) 
Calcium-channel blockers (CCBs) 
Centrally acting sympatholytics (such as clonidine, α-methyldopa) 
Direct acting vasodilators (such as hydralazine) 
Endothelin receptor antagonists (such as bosentan) 
Nitrodilators (such as isosorbide dinitrate, isosorbide mononitrate, nitroglycerine, etc) 
Phosphodiesterase inhibitors 
Potassium-channel openers (such as minoxidil) 
Renin inhibitors (such as aliskiren) 
 
 
 

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