Quality of Life and Preference of COPD Patients After Switching From Tiotropium Monotherapy (Spiriva® Handihaler®) to Dual Therapy With Tiotropium Bromide Plus Olodaterol (Spiolto® Respimat®) Under Real Life Conditions in Greece (ELLACTO II Study)
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

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Non-interventional Study Protocol
TITLE PAGE
Document Number:
c29837867-04
BI Study Number:
1237-0098
BI Investigational 
Product(s):
Spiolto® Respimat® (tiotropium bromide plus olodaterol)
Title:
Quality of life and preference of COPD patients after Switching 
from Tiotropium monotherapy (Spiriva® Handihaler®) to dual 
therapy with Tiotropium bromide plus Olodaterol (Spiolto®
Respimat®) under real life conditions in Greece (ELLACTO II 
study)
Brief lay title
Quality of life in Chronic Obstructive Pulmonary Disease (COPD) 
patients after switching to tiotropium plus olodaterol fixed dose 
combination in Greece
Protocol version 
identifier:
Final Version 4.0
Date of last version of 
protocol:
09 Jul 2021
PASS:
No
EU PAS register 
number:
Study not registered
Active substance:
R03AL06 (Tiotropium bromide plus Olodaterol)
Medicinal product:
Spiolto® Respimat® 2.5 microgram/2.5 microgram, inhalation 
solution; tiotropium/olodaterol
Product reference:
NL/H/3157/001/DC
Procedure number:
N/A
Marketing authorisation 
holder(s):
Market Authorization Holder:
Study Initiator:
Joint PASS:
No

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Research question and 
objectives:
The primary objective of this non-interventional study (NIS) is to 
evaluate changes within 3 months in quality of life according to 
health status evaluated with the COPD Assessment Test (CAT) in 
COPD patients who have recently switched (within one week) 
from tiotropium monotherapy (Spiriva® Handihaler®) to dual 
therapy with tiotropium bromide plus olodaterol (Spiolto®
Respimat®), in the Greek private and public sector pulmonary 
offices and clinics.
The secondary objectives are to evaluate change in the proportion 
of patients with CAT ≥10 (representing impaired health status) 
within three-months after the switch, to evaluate changes in 
quality of life (QoL) according to EQ-5D-5L questionnaire within 
three-months after the switch, to describe the 
 
and clinical characteristics of COPD patients who have switched, 
to describe treatment adherence of COPD patients according to 
Simplified Medication Adherence Questionnaire (SMAQ) and 
patients’ satisfaction and preference with inhaler devices 
according to Patient Satisfaction Questionnaire (PASAPQ) before 
and after the switch and to describe patients’ dyspnea status 
according to modified Medical Research Council (mMRC) scale 
within three months after the switch.
Country(-ies) of study:
Greece
Author:
In case of PASS, add:
MAH Contact Person:
N/A
In case of PASS, add:
<EU-QPPV:>
N/A
In case of PASS, add:
<Signature of EU-
QPPV:>
N/A
Date:
09 Jul 2021
Page 1 of 65
Proprietary confidential information
© 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................. 1
1.
TABLE OF CONTENTS ............................................................................................... 3
2.
LIST OF ABBREVIATIONS ........................................................................................ 5
3.
RESPONSIBLE PARTIES............................................................................................. 7
4.
ABSTRACT ................................................................................................................... 8
5.
AMENDMENTS AND UPDATES ............................................................................. 14
6.
MILESTONES ............................................................................................................. 16
7.
RATIONALE AND BACKGROUND ........................................................................ 17
7.1
CURRENT COPD MANAGEMENT AND ASSESSMENT...................................... 17
7.2
TIOTROPIUM BROMIDE PLUS OLODATEROL (SPIOLTO RESPIMAT)........... 18
8.
RESEARCH QUESTION AND OBJECTIVES .......................................................... 20
8.1
RATIONALE FOR PERFORMING THE STUDY..................................................... 20
8.2
STUDY OBJECTIVES ................................................................................................ 20
8.2.1
Primary objective ..................................................................................................... 20
8.2.2
Secondary objectives................................................................................................ 20
9.
RESEARCH METHODS............................................................................................. 22
9.1
STUDY DESIGN ......................................................................................................... 22
Figure 1. Study scheme........................................................................................................... 23
Table 1. Visit flow chart and data collection parameters........................................................ 24
9.2
SETTING...................................................................................................................... 25
9.2.1
Study sites ................................................................................................................ 25
9.2.2
Study population ...................................................................................................... 25
9.2.3
Study visits............................................................................................................... 26
9.2.4
Study discontinuation............................................................................................... 26
9.3
VARIABLES................................................................................................................ 27
9.3.1 List of variables.............................................................................................................. 27
9.3.2 Exposures ....................................................................................................................... 30
9.3.3
Outcomes ................................................................................................................. 30
9.3.3.1 Primary outcome ......................................................................................................... 30
9.3.3.2 Secondary outcomes.................................................................................................... 30

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9.4
DATA SOURCES ........................................................................................................ 31
9.5
STUDY SAMPLE SIZE............................................................................................... 32
9.6
DATA MANAGEMENT ............................................................................................. 32
9.7
DATA ANALYSIS ...................................................................................................... 32
9.7.1
Main analysis ........................................................................................................... 33
9.7.3
Handling of missing data ......................................................................................... 34
9.8
QUALITY CONTROL................................................................................................. 34
9.9
LIMITATIONS OF THE RESEARCH METHODS ................................................... 35
9.10
OTHER ASPECTS .................................................................................................. 35
9.10.1
Data quality assurance...................................................................................... 36
9.10.2
Study records.................................................................................................... 36
9.10.2.1 Source documents ..................................................................................................... 36
9.10.2.2 Direct access to source data and documents ............................................................. 36
9.10.2.3 Completion of study.................................................................................................. 37
10.
PROTECTION OF HUMAN SUBJECTS................................................................... 38
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT .............................................................................................................................. 38
10.2
STATEMENT OF CONFIDENTIALITY............................................................... 38
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE
REACTIONS .......................................................................................................................... 39
11.1
DEFINITIONS OF ADVERSE EVENTS............................................................... 39
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING................................................................................................................. 40
11.3
REPORTING TO HEALTH AUTHORITIES......................................................... 42
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY
RESULTS ............................................................................................................................... 43
13.
REFERENCES............................................................................................................. 44
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS ........................................................ 47
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ........................................ 48
ANNEX 3. ADDITIONAL INFORMATION........................................................................ 55

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special interest
BI
Boehringer Ingelheim
CA
Competent Authority
CAT
COPD Assessment Test
CCDS
Company Core Data Sheet
CI
Confidence Interval
CTM
Clinical Trial Manager
COPD
Chronic Obstructive Pulmonary Disease 
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events 
CTP
Clinical Trial Protocol
eCRF
Electronic Case Report Form
DMP
Data Management Plan
EMA
European Medicines Agency
ENCePP
European Network of Centers for Pharmacoepidemiology and 
Pharmacovigilance
EQ-5D-5L
EuroQoL-5D-5L questionnaire 
EU
European Union
FDA
Food and Drug Administration
FDC
Fix Dose Combination
FEV1
Forced expiratory volume in one second 
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
GVP
Good Pharmacovigilance Practices
GOLD
Global Initiative for Chronic Obstructive Lung Disease 
HCPs
Health Care Professionals
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
ISF
Investigator Site File
LABA
Long-acting beta2 adrenoceptor agonist 
LAMA
Long-acting muscarinic antagonist 
MAH
Marketing Authorization Holder
MedDRA
Medical Dictionary for Drug Regulatory Activities 
mMRC
Modified Medical Research Council
NIS
Non-Interventional Study
PASAPQ
Abbreviated Patient Satisfaction Questionnaire 
PASS
Post-Authorization Safety Study
PGE
Physician’s Global Evaluation

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SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SDV
Source data verification
SMAQ
Simplified Medication Adherence Questionnaire 
SmPC
Summary of Product Characteristics
WHO
World Health Organization

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3.
RESPONSIBLE PARTIES
Study Sponsor
Therapeutic Area Head Respiratory Medicine (TAH)
Team Member Medical Affairs (TM MA)
Team Member Epidemiology (TM Epi)
Head Global Epidemiology (H GEpi)
Therapeutic Area Head Risk Management (TAH RM), 
and Pharmacovigilance Working Group (PVWG)
chairperson

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide plus olodaterol
Protocol date:
04 June 2020
Study number:
1237-0098
Version/Revision:
Final Version 4.0
Version/Revision date:
09 Jul 2021
Title of study:
Quality of life and preference of COPD patients after switching from 
Tiotropium monotherapy (Spiriva® Handihaler®) to dual therapy with 
Tiotropium bromide plus Olodaterol (Spiolto® Respimat®) under real life 
conditiOns in Greece (ELLACTO II study)
Rationale and 
background:
Both pharmacologic and non-pharmacologic therapies in chronic 
obstructive pulmonary disease (COPD) should be guided, mainly, by 
disease severity, although the aim of any treatment is to improve patient 
symptoms, decrease exacerbations, and improve patient function and 
quality of life.
Within the LABA/LAMA combinations, efficacy and safety of tiotropium 
plus olodaterol fixed-dose combination (FDC) compared with the mono-
components was evaluated in patients with moderate to severe COPD in 
clinical trials, and demonstrated significant improvements in lung function 
and health-related quality of life measured by the St George Questionnaire.
The COPD Assessment Tool (CAT) has shown, that it has properties, very 
similar to much more complex health status questionnaires. Only since the 
last years, it has been incorporated as the preferred measure of 
symptomatic impact of COPD into clinical assessment schemes.
Due to the lack of real-world evidence data on LABA/LAMA 
combinations in Greece, this non-interventional study (NIS) plans a 
prospective analysis of the change in the quality of life and health status in 
COPD patients who have recently switched (within one week) from 
tiotropium monotherapy (Spiriva® Handihaler®) to dual therapy with 
tiotropium bromide plus olodaterol (Spiolto® Respimat®) in Greece.

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BI Study Number 1237-0098
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Proprietary confidential information © 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide plus olodaterol
Protocol date:
04 June 2020
Study number:
1237-0098
Version/Revision:
Final Version 4.0
Version/Revision date:
09 Jul 2021
Title of study:
Quality of life and preference of COPD patients after switching from 
Tiotropium monotherapy (Spiriva® Handihaler®) to dual therapy with 
Tiotropium bromide plus Olodaterol (Spiolto® Respimat®) under real life 
conditiOns in Greece (ELLACTO II study)
Research question 
and objectives:
Primary objective
The primary objective of this non-interventional study (NIS) is to evaluate 
changes within 3 months in quality of life according to health status 
evaluated with the COPD Assessment Test (CAT) in COPD patients who 
have recently switched (within one week) from tiotropium monotherapy 
(Spiriva® Handihaler®) to dual therapy with tiotropium bromide plus 
olodaterol (Spiolto® Respimat®), in the Greek private and public sector 
pulmonary offices and clinics.
Secondary objectives
The secondary objectives are 
-
To evaluate change in the proportion of patients with CAT ≥10 
(representing impaired health status) within three months after the 
switch.
-
To evaluate changes in quality of life (QoL) according to EQ-5D-5L 
questionnaire within three-months after the switch.
-
To describe treatment adherence of COPD patients according to 
Simplified Medication Adherence Questionnaire (SMAQ).
-
To describe patients’ satisfaction and preference with inhaler 
devices according to Patient Satisfaction Questionnaire (PASAPQ) 
before and after the switch.
-
To describe patients’ dyspnea status according to modified Medical 
Research Council (mMRC) scale within three months after the 
switch.
Study design:
Non-interventional, 3-months prospective, two visits, single-cohort, 
multicenter, nationwide study in patients with stable COPD under 
maintenance therapy with tiotropium monotherapy (Spiriva® Handihaler®) 
who, according to their treating physician, have recently required a switch 
(within one week) to dual therapy with tiotropium bromide plus olodaterol 
(Spiolto® Respimat®) in the Greek private and public sector pulmonary 
offices and clinics.

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Proprietary confidential information © 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide plus olodaterol
Protocol date:
04 June 2020
Study number:
1237-0098
Version/Revision:
Final Version 4.0
Version/Revision date:
09 Jul 2021
Title of study:
Quality of life and preference of COPD patients after switching from 
Tiotropium monotherapy (Spiriva® Handihaler®) to dual therapy with 
Tiotropium bromide plus Olodaterol (Spiolto® Respimat®) under real life 
conditiOns in Greece (ELLACTO II study)
Population:
COPD patients who have been using tiotropium administered with 
Spiriva® Handihaler® for at least 3 months before the decision to switch to 
a combination therapy with tiotropium bromide plus olodaterol 
administered with Spiolto® Respimat® has been made.
In all cases, the decision to switch the treatment strategy and the initiation 
of the combination therapy with tiotropium bromide plus olodaterol will 
be previous and completely independent from the initiation of this non-
interventional study. Additionally, the decision of the treating physician 
should be taken according to the daily clinical practice in the 
corresponding center.
Variables:
Patient 
COPD history and clinical characteristics (including exacerbations) 
Respiratory comorbidities and allergies
Other comorbidities
Current and past COPD therapies 
Relevant concomitant medications 
COPD Assessment Test (CAT)
Quality of life based on EQ-5D-5L questionnaire 
Simplified Medication Adherence Questionnaire (SMAQ)
Breathlessness based on Modified British Medical Research Council 
(mMRC) Dyspnea Scale
Patient Satisfaction and Preference using the abbreviated Patient 
Satisfaction Questionnaire (PASAPQ)
Assessment of inhaler handling in daily use 
 
Adverse drug reactions (ADRs), fatal adverse events (AEs) and 
pregnancies

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BI Study Number 1237-0098
c29837867-04
Proprietary confidential information © 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide plus olodaterol
Protocol date:
04 June 2020
Study number:
1237-0098
Version/Revision:
Final Version 4.0
Version/Revision date:
09 Jul 2021
Title of study:
Quality of life and preference of COPD patients after switching from 
Tiotropium monotherapy (Spiriva® Handihaler®) to dual therapy with 
Tiotropium bromide plus Olodaterol (Spiolto® Respimat®) under real life 
conditiOns in Greece (ELLACTO II study)
Data sources:
Patient medical records (paper and/or electronically) and patient reported 
outcomes from COPD patients as documented by the treating physician in 
his/her daily practice will be used as data source.
All participating physicians will be obliged to make a note of the patient’s 
participation in the NIS in the patient‘s medical records.
In the event of possible queries, the participating physician must be able to 
identify the patient observed. Medical information on the patient must be 
communicated and analyzed only using the patient number.
During this study the following has to be completed in both study visits: To 
be completed by the physician:
-
Patient 
 (only at Visit 1)
-
Patient 
 files (including comorbidities and concomitant 
medications)
-
  To be completed by the patient at Visit 1 and Visit 2:
-
COPD Assessment Test (CAT)
-
EQ-5D-5L questionnaire
-
Modified Medical Research Council (mMRC) questionnaire
  To be completed by the patient only at Visit 2 (3-month visit):
-
Simplified Medication Adherence Questionnaire (SMAQ)
-     Abbreviated Patient Satisfaction Questionnaire (PASAPQ)
Study size:
Approximately 1500 COPD patients will be recruited by 148 office-based 
pulmonologists and from 2 Hospital pulmonary clinics throughout Greece. 
Each investigator will recruit up to 10 eligible patients in a consecutive 
manner who have recently switched (within one week) from Spiriva®
Handihaler® to Spiolto® Respimat® according to the daily clinical practice 
in the center.

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Non-interventional Study Protocol
BI Study Number 1237-0098
c29837867-04
Proprietary confidential information © 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide plus olodaterol
Protocol date:
04 June 2020
Study number:
1237-0098
Version/Revision:
Final Version 4.0
Version/Revision date:
09 Jul 2021
Title of study:
Quality of life and preference of COPD patients after switching from 
Tiotropium monotherapy (Spiriva® Handihaler®) to dual therapy with 
Tiotropium bromide plus Olodaterol (Spiolto® Respimat®) under real life 
conditiOns in Greece (ELLACTO II study)
Data analysis:
Primary outcome
Mean change in patient’s quality of life (QoL) according to the total CAT 
score within three-months after the switch from Spiriva® Handihaler® to 
Spiolto® Respimat® according to the daily clinical practice.
Secondary outcomes:
1.
Change in the proportion of patients with CAT ≥10 (representing 
impaired health status) within three months after the switch
2.
Mean change from baseline in the total EQ VAS within three-
months after the switch
3.
Proportion of patients that change (improve/worsen) each of the 5 
dimensions of the EQ-5D-5L within three-months after the 
switch
4.
Rate of t adherence to medication of COPD patients according to 
the Simplified Medication Adherence Questionnaire (SMAQ) 
three-months after the switch
5.
Mean total score in abbreviated  Patient Satisfaction Questionnaire 
(PASAPQ; first 13 questions of Part 1) (patients’ satisfaction with 
inhaler devices) three-months after the switch
6.
Mean score of overall satisfaction according to Question 14 of 
PASAPQ (Part 1) three-months after the switch
7.
Proportion of preference (Spiriva® Handihaler® vs Spiolto® 
Respimat®) according to PASAPQ (Part 2) three-months after the 
switch.
8.
Mean score of willingness to continue with inhaler (Spiolto®
Respimat®) according to PASAPQ (Part 2) three-months after the 
switch
9.
Mean change of patients’ dyspnea status according to the modified 
Medical Research Council (mMRC) scale within three- months 
after the switch

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Proprietary confidential information © 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide plus olodaterol
Protocol date:
04 June 2020
Study number:
1237-0098
Version/Revision:
Final Version 4.0
Version/Revision date:
09 Jul 2021
Title of study:
Quality of life and preference of COPD patients after switching from 
Tiotropium monotherapy (Spiriva® Handihaler®) to dual therapy with 
Tiotropium bromide plus Olodaterol (Spiolto® Respimat®) under real life 
conditiOns in Greece (ELLACTO II study)
For the primary outcome, mean  and 95% confidence interval will be 
presented.
Primary and secondary outcome variables will be summarized and 
compared between the baseline visit (based on previous tiotropium 
monotherapy using Spiriva® Handihaler®) and the 3-months study visit 
after the switch to tiotropium bromide plus olodaterol (Spiolto® Respimat
Baseline data analysis will be carried out. Comorbidities, 
 
information and clinical characteristics will be described for the overall 
population.
All categorical variables will be summarized in frequency and percentage.
The continuous variables will be reported by sample statistics: n (number 
of observations), number of missing data, mean, standard deviation (SD), 
minimum, first quartile (Q1), median, third quartile (Q3), and maximum.
For the primary analysis, no treatment of missing data is planned except 
the imputation using the last-observation carried forward [LOCF] method 
if any post-baseline value is available in patients who discontinued before 
three months and for whom the value will be set as the last available 
measure.
 
 
Milestones:
Start of data collection: Feb 2021
End of enrolment period (9 months): Nov 2021 
End of data collection: Feb 2022
Final report of study results: Sep 2022

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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study protocol
Amendment or update
Reason
1
20 July 2020
N/A
EQ-5D-3L questionnaire was replaced by EQ-5D-5L 
questionnaire
Typo error  
2
20 July 2020
N/A
Information about number of patients and sites were 
corrected with  1500 COPD patients from approximately 
150 sites
(around 148 office-based pulmonologists and 2 Hospital 
pulmonary
Compliance in document  
3.
20 July 2020
RESPONSIBLE 
PARTIES
Study SponsorBoehringer-Ingelheim Ellas
Therapeutic Area Head Respiratory Medicine (TAH)
Team Member Medical Affairs (TM MA)
      
Team Member Epidemiology (TM Epi) 
Head Global Epidemiology (H GEpi)
Therapeutic Area Head Risk Management (TAH RM), 
and Pharmacovigilance Working Group (PVWG)
Update with new study’s information

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Number
Date
Section of 
study protocol
Amendment or update
Reason
4.
19 Nov 2020
6.MILESTONES
IRB/IEC approval
January 2021
Start of data collection
January 2021
End of enrolment period
July 2021
End of data collection
October 2021
Final report of study 
results
June 2022
Update with new timelines
5.
09 Jul 2021
6.MILESTONES
IRB/IEC approval
January 2021
Start of data collection
February 2021
End of enrolment period
November
2021
End of data collection
February 2022
Final report of study 
results
September
2022
Update with new timelines

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6.
MILESTONES
The following table estimated timelines for the milestones of this study:
Milestone
Planned Date
IRB/IEC approval
January 2021
Start of data collection
February 2021
End of enrolment period
November 2021
End of data collection
February 2022
Registration in the EU PAS register
N/A
Final report of study results
September 2022

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7.
RATIONALE AND BACKGROUND
7.1
CURRENT COPD MANAGEMENT AND ASSESSMENT
Both pharmacologic and non-pharmacologic therapies in chronic obstructive pulmonary 
disease (COPD) should be guided, mainly, by disease severity, although the aim of any 
treatment is to improve patient symptoms, decrease exacerbations, and improve patient activity 
and quality of life (1).
The contribution of physical inactivity to disability in COPD and its impact on quality of life 
and health status is difficult to be distinguished from disease progression. However, it is clear 
that quality of life and health status is significantly lower in patients with COPD (2,3), 
evidencing that health status should be measured in addition to lung function in those patients 
in order to reach the management goals (2).
COPD prevents patients from carrying out daily activities due to exercise intolerance, which is 
often attributed to limited pulmonary function. Additionally, this inactivity may be related to 
avoidance of exertion as a result of fear of dyspnea. Furthermore, data from a study of 434 
patients with COPD demonstrated that physical inactivity and fatigue is strongly correlated 
with health status and quality of life in its mental and physical components. Moreover, 
multivariate models adjusting for covariates, shown that increased fatigue and decreased 
physical and mental dimensions of health status were all associated to mortality in subjects 
with COPD, but not in non-COPD (4).
Treatment recommendations in GOLD report and NICE guidelines has based on symptoms and 
exacerbation history. GOLD assessment tool has divided COPD patients in four GOLD groups: 
A, B, C and D, which have had different recommendation for medication. Current international 
guidelines for COPD recommended long-acting inhaled bronchodilators, including β2-agonists 
(LABA) and anti-muscarinic antagonists (LAMA) as first choice maintenance therapies in the 
treatment of COPD for GOLD B and C, D groups (1). LABA/LAMA fixed dose combination 
is recommended as a choice for group D (symptomatic frequent exacerbator) and may be 
considered as the initial choice for group B patients who have severe breathlessness.
Most studies with LABA/LAMA combinations have been performed in patients with limited 
rate of exacerbations (5). One study (6) in patients with a history of exacerbations indicated 
that a combination of long-acting bronchodilators is more effective than long-acting 
bronchodilator monotherapy for preventing exacerbations. Another study (7) in patients with a 
history of exacerbations confirmed that a LABA/LAMA decreased exacerbations to a greater
extent than a combination of an inhaled corticosteroid (ICS) and a LABA.
Within the LABA/LAMA combinations, efficacy and safety of tiotropium plus olodaterol 
fixed-dose combination (FDC) compared with the mono-components was evaluated in patients 
with moderate to very severe COPD in two replicate, randomised, double-blind, parallel-group, 
multicentre, phase III trials. These studies demonstrated significant improvements in lung 
function and health-related quality of life (QoL) with once-daily tiotropium plus olodaterol 
FDC versus mono-components over one year in patients with moderate to very severe COPD 
(8).
Besides the efficacy evaluation based on lung function, several instruments and scales have 
been designed to provide a simple and reliable measure of health status in COPD patients to 

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aid their assessment and promote communication between patients and clinicians. The COPD 
Assessment Tool (CAT) has showed that it has properties very similar to much more complex 
health status questionnaires, such as the St George’s Respiratory Questionnaire (SGRQ) (9). A 
recent systematic review confirmed that the CAT provides reliable measurement of health 
status and is responsive to change with treatment and exacerbations (10). Only since the last 
years it has been incorporated as the preferred measure of symptomatic impact of COPD into 
clinical assessment schemes. It has been included in the COPD Foundation guide (11) and in 
the GOLD guideline to healthcare professionals (1).
Together with the CAT and other tools for the evaluation of COPD related health status and 
QoL, the assessment of the adherence to the treatment has an enormous impact on COPD 
patient’s status. Adherence to COPD therapy is still low, despite it has been directly associated 
with up to 10-fold higher risk of exacerbations leading to hospitalization (12). Additionally, 
the specific attributes of inhaler devices and 
 can influence patient 
satisfaction and treatment compliance, and may ultimately impact on clinical outcomes of 
COPD (13).
7.2
TIOTROPIUM BROMIDE PLUS OLODATEROL (SPIOLTO RESPIMAT)
Tiotropium bromide plus olodaterol fix dose combination (FDC) is an aqueous solution of 
tiotropium bromide and olodaterol contained in a cartridge. It is administered by using the 
Respimat® inhaler. Although no clinically relevant differences regarding patient and 
prescribing characteristics were revealed (14), a recent review of tiotropium trials in COPD 
supports the use of the marketed once-daily dose of Respimat® for the maintenance treatment 
of patients with COPD compared with the HandiHaler® inhaler (15). One cartridge is used per 
inhaler, which is inserted into the device prior to first use. In pivotal clinical trials and for the 
marketed product, the clinical dose consists of 5 microgram tiotropium and 5 microgram 
olodaterol given as two puffs once daily, at the same time of the day. The Respimat® inhaler 
uses mechanical energy to create a soft mist which is released over a period of approximately
1.5 seconds.
Tiotropium bromide plus olodaterol FDC 5/5 μg significantly improved FEV1 AUC0-3, FEV1 
AUC0-24, and trough FEV1 response versus the mono-components in two recent studies 
including moderate to very severe COPD patients (p<0.0001 for all comparisons) (8,16). 
Statistically significant improvements in SGRQ total score versus the mono- components were 
also demonstrated for the FDC 5/5 μg (p<0.0001 vs olodaterol and p=0.0001 vs tiotropium) 
(8).
The tiotropium bromide plus olodaterol FDC 5/5 μg has also shown to be safe and well tolerated 
over 1 year in a moderate to very severe COPD population. The overall incidences of adverse 
events (AEs), serious adverse event (SAEs), fatal AEs, frequencies for cardiac events and major 
adverse cardiovascular events in the tiotropium bromide plus olodaterol FDC treatment group 
were similar to the components alone (8). The nature and frequency of AEs in general was
consistent with the disease under study. There were no results in the clinical development 
program suggesting the need for absolute contraindications for the combination product (8).
In conclusion, the clinical trials conducted to date have shown tiotropium bromide plus 
olodaterol FDC to be a safe, well tolerated and efficacious combination therapy according to 
treatment guidelines in a moderate to very severe COPD patient population (8,16). The 
observed incremental bronchodilator response due to the combination compared to the 

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components alone, was translated into clinical benefits that were meaningful to the patient, with 
improvements in several patient centered outcomes. For further information please refer to the 
SmPC of Spiolto® Respimat®.

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8.
RESEARCH QUESTION AND OBJECTIVES
8.1
RATIONALE FOR PERFORMING THE STUDY
The benefits of tiotropium bromide plus olodaterol FDC have been studied in controlled Phase 
III trials, however, data regarding quality of life and health status when treated with Spiolto®
Respimat® in a real world setting is not available, especially in patients that have switched from 
previous monotherapy with tiotropium.
Due to the lack of real-world evidence data on LABA/LAMA combinations in Greece, this 
non-interventional study (NIS) plans a prospective analysis of COPD patients who switch from 
tiotropium monotherapy (Spiriva® Handihaler®) to dual therapy with tiotropium bromide plus 
olodaterol (Spiolto® Respimat®) in the Greek private and public sector pulmonary offices and 
clinics, and specifically to assess the change in the quality of life in relation to health status 
variations in this target population of COPD patients.
The results from this study will be used to scientifically support the improvement on the impact 
of COPD on the patient’s health and quality of life after three months of dual therapy with 
tiotropium bromide plus olodaterol (Spiolto® Respimat®), as well as to understand how switch 
of therapy in COPD patients who initiated this dual therapy after using Spiriva® Handihaler®
is approached by the Greek healthcareproviders.
8.2
STUDY OBJECTIVES
8.2.1
Primary objective
The primary objective of this non-interventional study (NIS) is to evaluate changes within 3 
months in quality of life according to health status evaluated with the COPD Assessment Test 
(CAT) in COPD patients who have recently switched (within one week) from tiotropium 
monotherapy (Spiriva® Handihaler®) to dual therapy with tiotropium bromide plus olodaterol 
(Spiolto® Respimat®), in the Greek private and public sector pulmonary offices and clinics.
8.2.2
Secondary objectives
The secondary objectives are:
-
To evaluate change in the proportion of patients with CAT ≥10 (representing impaired 
health status) within three months after the switch
-
To evaluate changes in quality of life (QoL) according to EQ-5D-5L questionnaire within 
three-months after the switch 
-
To describe treatment adherence of COPD patients according to Simplified Medication 
Adherence Questionnaire (SMAQ) 
-
To describe patients’ satisfaction and preference with inhaler devices according to Patient 
Satisfaction Questionnaire (PASAPQ) before and after the switch
-
To describe patients’ dyspnea status according to modified Medical Research Council 
(mMRC) scale within three months after the switch

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a non-interventional, 3-months prospective, two visits, single-cohort, multicenter, 
nationwide study in patients with stable COPD who have been using maintenance therapy with 
tiotropium monotherapy (Spiriva® Handihaler®) for at least 3 months before, and for whom, 
according to their treating physician, a recent switch (within one week) to dual therapy with 
tiotropium bromide plus olodaterol (Spiolto® Respimat®) have been required, in the Greek 
private and public sector pulmonary offices and clinics.
In all cases, the decision to switch the treatment strategy from Spiriva® Handihaler® to Spiolto®
Respimat® will be previous and completely independent from the initiation of this non-
interventional study. Additionally, the decision of the treating physician will be according to 
the daily clinical practice in the corresponding center.
The intended Health Care Professionals (HCPs) are office-based pulmonologists and practice 
physicians from Hospital pulmonary clinics, who are treating symptomatic COPD patients 
every day, being aware that most of their patients suffer from the physical restrictions induced 
by the disease per se.
Enrolment of patients will not be competitive. Each investigator will recruit up to 10 eligible 
patients in a consecutive manner from those who come to control visits and have been using 
tiotropium administered with Spiriva® Handihaler® for at least 3 months before the decision to 
switch to a combination therapy with tiotropium bromide plus olodaterol administered with 
Spiolto® Respimat® has been made. The enrolment period will last for a maximum of 9 months. 
All centers will stop recruitment once the total sample size of 1500 patients is achieved or, 
alternatively, at the end of the 9-months planned period of enrolment.
The study will collect data from two visits: baseline (within one week after the time of treatment 
switch) and approximately at 3 months (±2 weeks, according to clinical practice) (see Figure 
1). In case of premature discontinuation of Spiolto® Respimat® for any reason (including 
treatment discontinuation, withdrawal of patient willingness to participate, or unexpected 
patient problems to continue with the study), an additional unscheduled visit will be performed, 
if possible according to clinical practice. In this visit, the specific reason for discontinuation 
will be assessed and all the effectiveness and quality of life variables will be collected as 
planned for the regular final visit at 3 months (see Table 1).
Study results will be used to document the effectiveness of Spiolto® Respimat® in reducing the 
impact of COPD on patient’s life. The biggest advantage of the current proposal is that the 
CAT is a well-known and widespread questionnaire, which is also included in the most recent 
GOLD guidelines (1). The CAT questionnaire also exhibits high reproducibility and is 
independent of various languages, as well (17,18).

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Figure 1. Study scheme

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Table 1. Visit flow chart and data collection parameters
Parameter
Visit 1 
(baseline 
visit)
Visit 2
(3 months ±
2 weeks after 
baseline 
visit)1
Unscheduled 
Visit
(in case of 
premature 
disconti-
nuation)
Informed Consent
X
Inclusion / Exclusion Criteria
X
COPD history and clinical characteristics
X
X
X
History of exacerbations in the year before
X
History of exacerbations since baseline
X
X
Past COPD therapies (12 months before Visit 1)
X
COPD related and other relevant concomitant medication
X
X
X
Respiratory comorbidities and allergies
X
X
X
Concomitant diseases / Comorbidities
X
X
X
COPD severity based on GOLD assessment2
X
X
X
COPD Assessment Test (CAT)
X
X
X
EQ-5D-5L questionnaire
X
X
X
Simplified Medication Adherence Questionnaire (SMAQ)
X
X
Modified British Medical Research Council (mMRC) 
questionnaire
X
X
X
Abbreviated Patient Satisfaction Questionnaire (PASAPQ)
X
X
Adverse Drug Reactions (serious and non-serious), fatal AEs, 
pregnancy
X
X
X
Rationale for Spiolto® Respimat® treatment discontinuation 
(if applicable)
X
X
Continuation or discontinuation of treatment with Spiolto®
Respimat® after the study (yes/no)
X
X
1 Premature discontinuation of the study will be considered for any reason including treatment discontinuation, withdrawal 
of patient willingness to participate, or unexpected patient problems to continue with the study.
2 GOLD patient group (B, C or D) will be automatically calculated within the eCRF based on available exacerbation 
history, mMRC and CAT score.

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9.2
SETTING
It is planned that data of approximately 1500 COPD patients from approximately 150 sites 
(around 148 office-based pulmonologists and 2 Hospital pulmonary clinics) throughout Greece 
will be collected. Each investigator will recruit up to 10 eligible patients in a consecutive 
manner who have been using tiotropium administered with Spiriva® Handihaler® for at least 3 
months before the decision to switch to a combination therapy with tiotropium bromide plus 
olodaterol administered with Spiolto® Respimat® has been made, according to the daily clinical 
practice in the corresponding site.
9.2.1
Study sites
Patients will undergo visits 1 and 2 in private practice services and Hospital Pulmonary Clinics 
(centers) disposed by pulmonologists who will participate in the study.
9.2.2
Study population
Approximately 1500 patients with chronic obstructive pulmonary disease (COPD) who have 
recently switched (within one week) from Spiriva® Handihaler® to Spiolto® Respimat®
according to the daily clinical practice in the corresponding site, are to be observed by 
approximately 148 pulmonologists in the setting of private practice and 2 Hospital Pulmonary 
Clinics all over Greece. Hospital Pulmonary Clinics will act as coordinating sites of the study.
The NIS will take place in Greece and sites in urban as well as rural areas will be included. The 
nationwide distribution of the participating pulmonologists as well as the number of patients 
enrolled are intended to ensure that the data collected are representative.
Possible contraindications are to be checked prior to switch treatment to Spiolto® Respimat®. 
See also the latest Summary of Product Characteristics of Spiolto® Respimat®.
Every physician should enroll the first consecutive patients presented for regular control visits 
immediately after the switch to Spiolto® Respimat®. As a consequence, enrolment of patients 
will not be competitive and each investigator will recruit up to 10 eligible patients in a 
consecutive manner up to the moment when the total sample size of 1500 patients is achieved 
or, alternatively, until the end of the 6-months planned period of enrolment.
The decision to treat will be taken independently of participation in this NIS, according to the 
daily clinical practice in the site, and will be made before participation is considered. 
Additionally, enrolled patients in the current NIS have to be already taking the new medication 
before the inclusion in the study is considered by the study investigators.
Inclusion criteria:
1.
Female and male patients ≥40 years of age
2.
Patients diagnosed with COPD who have been using tiotropium administered with 
Spiriva® Handihaler® for at least 3 months before a recent switch (within last week) to 
a combination therapy with tiotropium bromide plus olodaterol administered with 
Spiolto® Respimat® has been made
3.
Written informed consent prior to participation

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4.
Patient should be able to read, comprehend and complete study questionnaires
Exclusion criteria:
1.
Patients with contraindications according to Spiolto® Respimat® SmPC
2.
Patients who have been treated with inhaled corticosteroids (ICS) as maintenance 
therapy* or with a LABA/LAMA combination (free or fixed dose) in the previous 6 
weeks
*Note: patients with temporary corticosteroids (CS) use during acute exacerbations in the 
previous 6 weeks can enter the study
3.
Patients who have been treated with Spiriva® Respimat®, with other LAMA different 
than Spiriva®, or with a combination of Spiriva®+LABA/ICS in the previous 6weeks
4.
Patients diagnosed with asthma or with asthma COPD overlap syndrome (ACO)
5.
Patients for whom availability at the enrolling site during the planned study period of 
approximately 3 months is not possible
6.
Pregnancy and lactation
7.
Patients currently listed for lung transplantation
8.
Current participation in any clinical trial or any other non-interventional study of a 
drug or device.
9.
Patients who initiated the treatment with tiotropium bromide plus olodaterol older 
than 7 days before their enrolment in the present study.
A subject screening log should be kept at the site, recording basic information (e.g. initials, 
gender, date of birth, reason for not enrolling the patient etc.) on all patients who were invited 
to participate in the study, with the information on the eligibility (or reasons for non- eligibility) 
and date of signed informed consent. In the case of refusal, reasons for refusal should be given. 
In addition, a log of all patients included into the study (i.e. having given informed consent) 
will be maintained in the study file at the study site.
9.2.3
Study visits
The enrolment period of the study will last for a maximum of 9 months. Enrolled patients will 
undergo two study visits: visit 1 (baseline visit) during screening and enrolment, and visit 2 
(follow up visit) 3 months (±2 weeks) after the baseline visit. Instead of the regular visit 2 at 3-
months, an unscheduled visit will take place in case of premature discontinuation to assess the 
specific reason for discontinuation, to complete main data collection parameters and to check 
for compliance and safety issues.
9.2.4
Study discontinuation
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
1.
Failure to meet expected enrolment goals overall or at a particular study site.
2.
Emergence of any efficacy/safety information that could significantly affect 
continuation of the study, or any other administrative reasons, i.e. lack of recruitment.
3.
Violation of the protocol, the contract, or applicable laws and regulations for non-
interventional studies, which could disturb the appropriate conduct of the NIS.

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The investigator / the study site will be reimbursed for reasonable expenses incurred in case of 
study termination (except in case of the third reason).
Patients will be automatically discontinued from the study immediately after the treatment of 
interest in the study has been discontinued.
Additional specific withdrawing reasons for discontinuing a patient from this NIS are: 
voluntary discontinuation by the patient who is at any time free to withdraw from the study, 
any situation where the investigator believes that the continuation in the study may be 
detrimental to the patient’s health, and if a patient is included in an interventional clinical trial 
at any time during his/her participation in this NIS.
9.3
VARIABLES
9.3.1 List of variables
In this NIS, the following data collection about the changes after the switch from a maintenance 
therapy with tiotropium monotherapy (Spiriva® Handihaler®) to dual therapy with tiotropium 
bromide plus olodaterol (Spiolto® Respimat®) on quality of life and health status in 1500 COPD 
patients treated in the Greek private and public sector pulmonary offices and clinics will be 
collected in an e-CRF.
The data collection both at the baseline visit (immediately after the switch) and at 3 months
visit (three months later) will consist of the following list of variables:
 
 
 
 
 
COPD history and clinical characteristics at baseline and changes up to 3-months visit: 
Time since COPD diagnosis
COPD severity based on GOLD assessment (B, C, D group), if available 
COPD: Chronic bronchitis/Emphysema/Other COPD
Smoking history and current status
Eosinophilia
FEV1/FVC ratio, if available 
History of exacerbations in the year before baseline visit and between baseline and 3-
months visit
Respiratory comorbidities and allergies at baseline and changes up to 3-months visit:
Pneumonia
Allergic rhinitis
Bronchiectasis

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Lung diseases due to external agents
Comorbidities at baseline and changes up to 3-months visit: 
Diabetes mellitus
Osteoporosis
Cardiovascular diseases (including heart failure, atrial fibrillation and other arrhythmias) 
Malignancies
Anxiety/depression 
Insomnia
Pulmonary artery hypertension 
Sleep apnea
Gastroesophageal reflux disease 
Hemolytic anemia
Atopy 
Sinusitis 
Emphysema
Current and past COPD therapies (in the period of one year before enrolment)
Relevant concomitant medications at baseline and changes up to 3-months visit: 
Use of concomitant inhalers
Other concomitant medications

)
COPD Assessment Test (CAT) (9) (see ANNEX 3)
The CAT is a patient-completed questionnaire assessing globally the impact of COPD 
(cough, sputum, dysnea, chest tighteness) on health status. It is a unidimensional score based 
on 8 items each of them scaling from 0 to 5.
The measurement properties and responsiveness of the instrument were very similar to those 
of the more complex and longer St George's Respiratory Questionnaire (SGRQ). Further 
research has supported these findings and established the CAT as a valuable measure of 
health status in research (9,10,19–21). Following extensive translation and linguistic 
validation, the measurement properties and responsiveness of the CAT have been evaluated 
in many different countries and found to be similar (9,10,19–21).
Range of CAT scores from 0–40. Higher scores denote a more severe impact of COPD on a 
patient’s life. The difference between stable and exacerbation patients was five units. No 
target score represents the best achievable outcome, however, CAT scores <10 
corresponding to mild impact on patients life are usually considered those representing 
patients without impaired health status (21,22).
EQ-5D-5L questionnaire (23,24) (see ANNEX 3)
The EQ-5D-5L questionnaire is a well-established and commonly used tool for the 
measurement of a patients QoL. The EQ-5D-5L essentially consists of two parts: the EQ-

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5D descriptive system and the EQ visual analogue scale (EQ VAS). The questionnaire was 
translated and validated for more than 170 languages.
The EQ-5D-5L descriptive system comprises five dimensions (mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression). Each dimension has three levels (no 
problems, some problems, and extreme problems) and was self-reported by the patient. The 
patient’s decision results into a 1-digit number that expresses the level selected for that 
dimension. 
The EQ VAS records the patient’s self-rated health on a vertical visual analogue scale where 
the endpoints are labelled ‘best imaginable health state’ and ‘worst imaginable health state’. 
The VAS can be used as a quantitative measure of health outcome that reflects the patient’s 
own judgement.
Simplified medication adherence questionnaire (SMAQ) (25) (see ANNEX 3)
This tool is a short and simple questionnaire based on questions posed directly to the patient 
regarding his/her medication-taking habits, which was originally validated for the 
measurement of adherence in patients on anti-retroviral treatment (25). The SMAQ has been 
extensively used for evaluating compliance with treatment for different chronic conditions.
The aim is to assess whether the patient adopts correct attitudes in relation to the treatment 
for his disease. It is assumed that if the attitudes are incorrect, the patient is not compliant. 
It has the advantage that it provides information about the causes of non-compliance. The 
patient is considered as compliant if all questions are answered correctly.
Modified British Medical Research Council (mMRC) Dyspnea Scale (26) (ANNEX 3)
The mMRC Dyspnea Scale quantifies disability attributable to breathlessness, and is useful 
for characterizing baseline dyspnea in patients with respiratory diseases, especially COPD.
It consists of a five-level rating scale based on the patient’s perception of dyspnea in daily 
activities. For patients with COPD, it is a simple and valid tool to assess disability (27), and 
has been reported to be more relevant to patients’ health and psychological status than FEV1
(28).
Patient Satisfaction and Preference (29) (see ANNEX 3)
Patient satisfaction with Respimat® will be measured with the part 1 of the abbreviated 
Patient Satisfaction Questionnaire (PASAPQ) (29). The patient preference Spiriva®
Handihaler® vs Spiolto® Respimat® will be measured using PASAPQ (part 2).
PASAPQ has been proved as a practical, valid, reliable and responsive instrument for 
measuring respiratory device satisfaction (29).
 
 
 
 
Adverse drug reactions (ADRs), fatal adverse events (AEs) and pregnancies

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9.3.2 Exposures
All included patients will be already receiving LAMA/LABA combination treatment with 
Spiolto® Respimat® after a recent switch (within one week) from previous maintenance therapy 
with tiotropium monotherapy (Spiriva® Handihaler®), according to the Greek SmPC. The 
decision of the treating physician to switch the treatment strategy will be previous and 
completely independent from the initiation of this NIS. Additionally, the decision will be 
according to the daily clinical practice in the corresponding center.
The same group of patients at two different time-points (three-months ahead) will be 
considered for the comparison analyses: within one week after the switch of COPD treatment 
from tiotropium monotherapy (Spiriva® Handihaler®) to dual therapy with tiotropium bromide 
plus olodaterol (Spiolto® Respimat®) and three-months after the baseline visit. However, no
minimal exposure will be required. Subjects with premature drug discontinuation for any 
reason will not be excluded from the analysis.
Spiolto® Respimat® contains:
-
The long-acting anticholinergic tiotropium bromide. The dose dispensed is 2.5 
micrograms of tiotropium per puff, equivalent to 3.124 micrograms tiotropium bromide 
monohydrate. The dose dispensed is the quantity available to patients after crossing the
mouthpiece.
-
The selective beta2-adrenoceptor agonist olodaterol. The dose dispensed is 2.5 
micrograms of olodaterol per puff (as olodaterol hydrochloride). The dose dispensed is 
the quantity available to patients after crossing the mouthpiece.
The recommended daily dose of Spiolto® Respimat® for adults is 5 micrograms of tiotropium 
ion (tiotropium) plus 5 micrograms of olodaterol, equivalent to inhaling 2 puffs from the 
Respimat® inhaler once daily at the same time of day.
The Summaries of Product Characteristics on Spiolto® Respimat® is contained in the NIS ISF 
in the “Summary of Product Characteristics” section.
Note: The recommended doses stated in the Summary of Product Characteristics should not 
be exceeded.
9.3.3
Outcomes
9.3.3.1 Primary outcome
The primary outcome of this NIS will be the mean change in patients’ quality of life (QoL) 
according to the total score of COPD Assessment Test (CAT) within three months after the switch 
from Spiriva® Handihaler® to Spiolto® Respimat® according to the daily clinical practice.
9.3.3.2 Secondary outcomes
The secondary outcomes of the NIS include:
-
Change in the proportion of patients with COPD Assessment Test (CAT) ≥10 
(representing impaired health status) within three months after the switch
-
Mean 
-
change from baseline in the total EQ VAS within three- months after the switch
-
Proportion of patients that change (improve/worsen) each of the 5 dimensions of the 

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EQ-5D-5L within three-months after the switch
-
Rate of adherence to medication of COPD patients according to the SMAQ three-
months after the switch
-
Mean total score in abbreviated PASAPQ (first 13 questions of Part 1) (patient 
satisfaction with the inhaler device) approximately three-months after the switch.
-
Mean score of overall satisfaction according to Question 14 of PASAPQ (Part 1)
three-months after the switch.
-
Proportion of preference (Spiriva® Handihaler® vs Spiolto® Respimat®) according 
to PASAPQ (Part 2) three-months after the switch
-
Mean score of willingness to continue with inhaler (Spiolto® Respimat®) according 
to PASAPQ (Part 2) three-months after the switch.
Mean change of patients’ dyspnea status according to the mMRC scale within three-months 
after the switch.
9.4
DATA SOURCES
Patient medical records (paper and/or electronically) and patient reported outcomes from 
COPD patients as documented by the treating physician in his/her daily practice will be used 
as data source.
All participating physicians will be obliged to make a note of the patient’s participation in the 
NIS in the patient‘s medical records.
In the event of possible queries, the participating physician must be able to identify the patient 
observed. Medical information on the patient must be communicated and analyzed only using 
the patient number.
During this study, the following has to be completed: 
To be completed by the physician:
-
-
Patient medical files (including comorbidities and concomitant medications)
-
To be completed by the patient at Visit 1 (baseline) and Visit 2 (3-months visit):
-
COPD Assessment Test (CAT) (9)
-
EQ-5D-5L questionnaire (23,24)
-
Modified Medical Research Council (mMRC) questionnaire (26)
To be completed by the patient only at Visit 2 (3-months visit):

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-
Simplified Medication Adherence Questionnaire (SMAQ) (25)
-
Abbreviated Patient Satisfaction Questionnaire (PASAPQ) (29)
9.5
STUDY SAMPLE SIZE
The sample size determination is not based on a power calculation because no hypotheses will 
be tested. The primary endpoint of change in score of COPD Assessment Test (CAT) within 
three months after the switch from Spiriva® Handihaler® to Spiolto® Respimat® will be 
analysed descriptively by mean and 95% confidence interval. From other studies a mean 
difference in CAT score of 1.0 and standard deviation of 9.0 are expected.
With a sample size of 1310, a two-sided 95% confidence interval for the difference in paired 
mean scores will have an interval that extends by no more than 0.5 from the observed 
difference in means (e.g. an interval from 0.5 to 1.5 for a difference of 1.0), with 90% coverage 
probability, assuming that the true standard deviation of differences is 9.0 and that the 
confidence interval is based on the t statistic. The calculation was performed using the MOC3 
routine from commercial software nQuery Advisor® 7.0 (
 
 [R15-1331]). To account for a 15% dropout rate, 1507 patients will be needed.
Therefore, it was decided to enroll 1500 patients in the study.
9.6
DATA MANAGEMENT
A data management plan (DMP) will be created to describe all functions, processes, and
specifications for data collection, cleaning and validation. The electronic Case Report Forms 
(eCRFs) will include programmable edits to obtain immediate feedback if data are missing 
(also negative answers, unknown), out of range, illogical or potentially erroneous. These rules 
may encompass simple checks such as range validation or presence/absence of data. 
Concurrent manual data review may be performed based on parameters dictated by the DMP. 
Ad hoc queries to the sites may be generated and followed up for resolution. A source data 
quality audit may be initiated to ensure that the data in the database is accurate. Source data 
verification (SDV) will be performed at sites identified by a risk-based approach as needed.
The database will be housed in a physically and logically secure computer system maintained 
in accordance with a written security policy. The system will meet all current legal 
requirements regarding electronic study data handling. Patient confidentiality will be strictly 
maintained.
9.7
DATA ANALYSIS
All patients who were included, fulfilled all selection criteria and have received at least one 
dose of Spiolto® Respimat® will constitute the treated set for the analyses. All analyses will be 
performed on the treated set. If patients have missing values for an outcome, those patients will 
be excluded for that outcome’s analysis, unless otherwise indicated in Section 9.7.3. For
example, if a patient is missing the CAT score at baseline visit and/or at the 3- months visit, 
that patient will be excluded from the analyses for the primary endpoint of COPD related health 
status according to CAT and the secondary endpoint of change in CAT after three months of 
the switch from Spiriva® Handihaler® to Spiolto® Respimat®.
The analyses will relate to the following data:
-
)

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-
COPD history and clinical characteristics
-
Reported exacerbations in the year before and during the 3-months study period
-
Past COPD therapies (12 months before enrolment)
-
COPD related and other relevant concomitant medication
-
Respiratory comorbidities and allergies
-
Concomitant diseases / Comorbidities
-
Respimat® training (Yes/No)
-
COPD severity based on GOLD assessment (if available).
-
COPD impact on patient’s life based on CAT
-
Patient’s QoL based on EQ-5D-5L
-
Adherence to treatment based on SMAQ
-
Breathlessness based on mMRC score
-
Satisfaction and Preference (abbreviated PASAPQ)
-
-
Adverse Drug Reactions (non-serious & serious), fatal AEs, pregnancies
-
Rationale for Spiolto® Respimat® treatment discontinuation (if applicable)
-
Details of treatment continuation / discontinuation
9.7.1
Main analysis
For the primary outcome, mean and 95% confidence interval will be presented.
Secondary outcomes will be evaluated by descriptive statistics:
All categorical variables will be summarized as relative and absolute frequencies. Proportions 
and 95% CI will be presented when appropriate.
The continuous variables will be reported by sample statistics: n (number of observations), 
number of missing data, mean, standard deviation (SD), minimum, first quartile (Q1), median, 
third quartile (Q3), and maximum.

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9.7.3
Handling of missing data
The extent of missing data will be evaluated and described.
For the primary analysis, no treatment of missing data is planned except the imputation using 
the last-observation carried forward [LOCF] method if any post-baseline value is available in 
patients who discontinued before three months and for whom the value will be set as the last 
available measure.
 
 
 
Any removal from the analysis will be documented, stating the site and patient number as well 
as the reason for removal.
9.8
QUALITY CONTROL
To improve and secure data quality, automatic data checks upon data entry will be done within 
the eCRF. In the eCRF, plausible ranges of values for numeric data entries as well as logical 
data entries and listings will be provided for each entry field. Based on this, checks on 
completeness and plausibility will be performed upon data entry in the eCRF.
Validity of data entry thus is ensured by integrated validation checks performed by the system, 
indicating missing or implausible entries to the document list or investigator. All corrections 
will be visible from the systems audit trail.
No regular source data verification is planned in this study. However, in case of decreasing 
compliance (i.e. of missing data, data discrepancies, protocol violations, etc.) a for-cause audit 
or risk-based monitoring visit will be performed.

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9.9
LIMITATIONS OF THE RESEARCH METHODS
The intention of this NIS is to collect new data on the quality of life and health status of COPD 
patients on treatment with Spiolto® Respimat® in a real-world setting.
Per definition, non-interventional studies do not allow randomization or any other procedure 
outside clinical routine that would reduce the risk of biases. No interventions for improving 
follow-up, compliance, event reporting etc. are allowed. Thus, real-life setting studies can only 
deliver data and results that have to be regarded and interpreted in the limits of this context.
One possible concern regarding the classification of the study as observational may be the use 
of patient-reported questionnaires: the COPD Assessment Test for the evaluation of patient’s 
health status, the EQ-5D-5L to measure patient’s QoL, SMAQ for the assessment of treatment 
adherence, and PASAPQ to assess patient’s satisfaction with treatment and the inhaler. Not all 
these tools are routinely used in real world practice. However, according to the European 
Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) document 
“Considerations on the definition of non-interventional trials under the current legislative 
framework” (2011), the following are general principles for interviews and questionnaires to 
still be seen as non-interventional: “they should not lead to a change in behaviour or influence 
treatment and should be as short as needed to reach the objectives of the non-interventional
trial”.
In this study, the inclusion of QoL and satisfaction questionnaires as well as subjects willing to 
complete them might increase compliance with drug and thus overestimate QoL. This 
limitation will be recognized in the potential study publications.
Consecutive enrolment is expected to reduce selection bias. The entry criteria are non-
restrictive which will permit the enrolment of a broad patient population. The choice of 
treatment is at the discretion of the investigator. Also, to be able to discuss the extend of 
selection bias in the publication, a screening log will be completed to describe the number of 
non-recruited subjects who need to start tiotropium bromide plus olodaterol (Spiolto®
Respimat®) after using Spiriva® Handihaler® and the reasons.
Selection bias could occur at the site level and the patient level. Therefore, to reduce the site 
level selection bias, the goal is to have participating pulmonologists/centers that have access to 
all available treatment options, which are approved for use in Greece for the targeted COPD 
patients. Information bias will be minimized by the use of standard eCRF, questionnaire and 
physicians’ training on the study protocol.
There is also a risk of limited internal validity due to the absence of a control group. This could 
lead to overestimation of drug effect due to the “regression to the mean” effect sometimes 
observed in patients with already impaired clinical status. However, the requirement of a 
minimum exposure period with the previous treatment and the collection of exacerbations 
during the previous 12 months can help discussing from a clinical point of view any change 
observed during the follow-up period. Additionally, the use of different tools and scales for the 
measurements of clinical outcomes provides additional validation to the study, if results are 
consistent among them. 
 
9.10 OTHER ASPECTS

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9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or sponsor’s 
designees or by Independent Ethics Committee (IECs) or by regulatory authorities. The quality 
assurance auditor will have access to all medical records, the investigator’s study- related files 
and correspondence, and the informed consent documentation of this study.
9.10.2
Study records
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via remote data 
capture.
9.10.2.1 Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs 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. Answers to the convenience questionnaires will be directly 
noted in the eCRF.
The following documents can be regarded as source data/documents:
-
-
Informed Consent forms
-
Other medical reports
-
Source worksheets
It is expected to have the following information including the source data/documents 
(National legislation regarding the content of subject notes should be followed):
-
-
Medical history and physical examination details
-
AEs and concurrent treatment(s)
-
Visit dates
-
Subject ID
-
Study Number
-
Date when subject signed informed consent
-
Information on the subject’s treatment
9.10.2.2 Direct access to source data and documents
The investigator / institution will permit study-related monitoring, audits, IEC review and 
regulatory inspection, providing direct access to all related source data / documents.
Electronic CRFs and all source documents, including progress notes and copies of laboratory 
and medical test results must be available at all times for review by the sponsor’s clinical study 
monitor, auditor and inspection by health authorities. The Clinical Research Associate (CRA) 
/ Clinical Trial Manager (CTM) and auditor may review all eCRFs, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
Section 9.10.2.1.

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9.10.2.3 Completion of study
The IEC in hospital sites in Greece need to be notified about the end of the study (last 
patient/patient out, unless specified differently in Section 6 of the observational plan) or early 
termination of the trial.

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10.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for Good 
Clinical Practice (GCP) (to the extent applicable to the NIS setting and required by local 
regulations), Good Epidemiological Practice (GEP) (33), 
Guidelines 
for Good 
Pharmacoepidemiology Practice (GPP) (34), and relevant BI Standard Operating Procedures 
(SOPs). Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 
in the responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches of 
the protocol/ICH GCP.
10.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Independent Ethics Committee (IEC) according to current national 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the study, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of Greece. Each signature must be personally dated by each 
signatory and the informed consent and any additional patient-information form retained by the 
investigator as part of the study records. A signed copy of the informed consent and any 
additional patient information must be given to each patient or the patient’s legally accepted
representative.
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of disclosure 
must also be explained to the patient.
The patient must be informed that his/her medical records may be examined by authorized 
monitors (CML/CRA) or Quality Medicine auditors appointed by Boehringer Ingelheim, by 
appropriate IEC members, and by inspectors from regulatory authorities.
10.2 STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate medical 
personnel responsible for the patient’s welfare. Data generated as a result of the study need to 
be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IEC and the regulatory authorities.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1 DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Adverse drug reaction
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is 
noxious and unintended. Response in this context means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility. Adverse reactions 
may arise from use of the product within or outside the terms of the marketing authorization or 
from occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which
-
results in death,
-
is life-threatening,
-
requires in-patient hospitalization, or
-
prolongation of existing hospitalization,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly/birth defect
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are 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 dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
Adverse Event of Special Interest (AESI)
The term Adverse Event of Special Interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 

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and safety assessment within this study, e.g. the potential for AEs based on knowledge from 
other compounds in the same class.
No AESIs have been defined for this study.
11.2 ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorisation. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined.
The following must be collected by the investigator in the eCRF from first dose of Spiolto®
Respimat® until the end of the study, once informed consent is obtained:
-
all adverse drug reactions (ADRs) (serious and non-serious) associated with Spiolto®
Respimat®
-
all AEs with fatal outcome
All ADRs associated with Spiolto® Respimat®, including those persisting after study 
completion must be followed up until they are resolved, have been sufficiently characterized, 
or no further information can be obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse reaction, 
in contrast to an adverse event, is characterized by the fact that a causal relationship between a 
medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history.
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug.
•
The event is known to be caused by or attributed to the drugclass.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced.
•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 

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effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).
•
Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:       Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
The intensity of adverse events should be classified according to the previous criteria and
recorded in the (e)CRF.
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the study, 
after having taken first dose of Spiolto® Respimat®, the investigator must report any drug 
exposure during pregnancy, which occurred in a female subject or in a partner to a male subject 
to the Sponsor by means of Part A of the Pregnancy Monitoring Form. The outcome of the 
pregnancy associated with the drug exposure during pregnancy must be followed up and 
reported by means of Part B of the Pregnancy Monitoring Form.
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines.
Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS AE form from the first dose of 
Spiolto® Respimat®until the end of the study, once informed consent is obtained:

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Type of Report
Timeline
All serious ADRs associated with Spiolto®
Respimat®
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to Spiolto® Respimat®
immediately within 24 hours
All non-serious ADRs associated with 
Spiolto® Respimat®
7 calendar days
All pregnancy monitoring forms
7 calendar days
The same timelines apply if follow-up information becomes available for the respective events. 
In specific occasions the Investigator could inform the Sponsor upfront via telephone. This 
does not replace the requirement to complete and fax the NIS AE form.
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate eCRF pages and the NIS AE form.
Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other than 
Spiolto®
Respimat®(e.g. Spiriva)according to the local regulatory requirements for 
spontaneous AE reporting at the investigator’s discretion by using the locally established routes 
and AE report forms. The term AE includes drug exposure during pregnancy, and, regardless 
of whether an AE occurred or not, any abuse, off-label use, misuse, medication error, 
occupational exposure, lack of effect, and unexpected benefit.
11.3 REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local 
and international regulatory requirements.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The rights of the investigator and of the sponsor with regard to publication of the results of this 
study are described in the investigator contract. As a general rule, no study results should be 
published prior to finalization of the Study Report.

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13.
REFERENCES
1.
Global Strategy for the Diagnosis, Management and Prevention of chronic obstructive 
pulmonary disease: 2018 Report [Internet]. Global Initiative for Chronic Obstructive 
Lung Disease (GOLD). [cited 2018 Jul 30]. Available from: https://goldcopd.org/gold-
reports/
2.
Tsiligianni I, Kocks J, Tzanakis N, Siafakas N, van der Molen T. Factors that influence 
disease-specific quality of life or health status in patients with COPD: a review and 
meta-analysis of Pearson correlations. Prim Care Respir J. 2011 Sep;20(3):257–68.
3.
Carone M, Antoniu S, Baiardi P, Digilio VS, Jones PW, Bertolotti G, et al. Predictors of 
Mortality in Patients with COPD and Chronic Respiratory Failure: The Quality-of-Life 
Evaluation and Survival Study (QuESS): A Three-Year Study. COPD. 2016;13(2):130–
8.
4.
Stridsman C, Skär L, Hedman L, Rönmark E, Lindberg A. Fatigue Affects Health Status 
and Predicts Mortality Among Subjects with COPD: Report from the Population-Based 
OLIN COPD Study. COPD. 2015 Apr;12(2):199–206.
5.
Rodrigo GJ, Price D, Anzueto A, Singh D, Altman P, Bader G, et al. LABA/LAMA 
combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review 
and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2017 Mar 17;12:907–22.
6.
Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sandström T, Taylor AF, et al. 
Analysis of chronic obstructive pulmonary disease exacerbations with the dual 
bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a 
randomised, double-blind, parallel-group study. The Lancet Respiratory Medicine. 2013 
May 1;1(3):199–209.
7.
Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, et al. 
Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med. 
2016 09;374(23):2222–34.
8.
Buhl R, Maltais F, Abrahams R, Bjermer L, Derom E, Ferguson G, et al. Tiotropium 
and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–
4). European Respiratory Journal. 2015 Apr 1;45(4):969–79.
9.
Jones PW, Harding G, Berry P, Wiklund I, Chen W-H, Kline Leidy N. Development 
and first validation of the COPD Assessment Test. Eur Respir J. 2009 Sep;34(3):648–
54.
10.
Gupta N, Pinto LM, Morogan A, Bourbeau J. The COPD assessment test: a systematic 
review. Eur Respir J. 2014 Oct;44(4):873–84.
11.
Barbara P. Yawn MMs, Byron Thomashow MD, David M. Mannino MD, Ravi Kalhan 
MD, MeiLan K. Han MD, Stephen Rennard MD, et al. The 2017 Update to the COPD 
Foundation COPD Pocket Consultant Guide. Chronic Obstructive Pulmonary 
Diseases:Journal of the COPD Foundation. 4(3):177–85.

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12.
Humenberger M, Horner A, Labek A, Kaiser B, Frechinger R, Brock C, et al. 
Adherence to inhaled therapy and its impact on chronic obstructive pulmonary disease 
(COPD). BMC Pulm Med [Internet]. 2018 Oct 19 [cited 2019 Apr 25];18. Available 
from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194635/
13.
 
14.
Schmiedl S, Fischer R, Ibanez L, Fortuny J, Thürmann P, Ballarin E, et al. Tiotropium 
Respimat® vs. HandiHaler®: real-life usage and TIOSPIR trial generalizability. Br J 
Clin Pharmacol. 2016 Feb;81(2):379–88.
15.
Calverley PMA, Könen-Bergmann M, Richard F, Bell S, Hohlfeld JM. Tiotropium 
Respimat® Versus HandiHaler®: Comparison of Bronchodilator Efficacy of Various 
Doses in Clinical Trials. Adv Ther. 2016;33:786–93.
16.
Beeh K-M, Westerman J, Kirsten A-M, Hébert J, Grönke L, Hamilton A, et al. The 24-h 
lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in 
chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2015 Jun;32:53–9.
17.
Jones PW, Brusselle G, Dal Negro RW, Ferrer M, Kardos P, Levy ML, et al. Properties 
of the COPD assessment test in a cross-sectional European study. Eur Respir J. 2011 
Jul;38(1):29–35.
18.
Jones PW. COPD Assessment Test –Rationale, Development, Validation and 
Performance. COPD: Journal of Chronic Obstructive Pulmonary Disease. 2013Mar 
21;10(2):269–71.
19.
Jones P, Harding G, Wiklund I, Berry P, Leidy N. Improving the process and outcome 
of care in COPD: development of a standardised assessment tool. Primary Care 
Respiratory Journal. 2009 Aug 18;18(3):208–15.
20.
Jones PW, Harding G, Wiklund I, Berry P, Tabberer M, Yu R, et al. Tests of the 
Responsiveness of the COPD Assessment Test Following Acute Exacerbation and 
Pulmonary Rehabilitation. CHEST. 2012 Jul 1;142(1):134–40.
21.
Jones PW, Tabberer M, Chen W-H. Creating scenarios of the impact of copd and their 
relationship to copd assessment test (CATTM) scores. BMC Pulmonary Medicine. 2011 
Aug 11;11(1):42.
22.
Jahnz-Różyk K, Szepiel P. Early impact of treatment with tiotropium, long-acting 
anticholinergic preparation, in patients with COPD - real-life experience from an 
observational study. Int J Chron Obstruct Pulmon Dis. 2015;10:613–23.
23.
EuroQol Group. EuroQol--a new facility for the measurement of health-related quality 
of life. Health Policy. 1990 Dec;16(3):199–208.

001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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24.
Miravitlles M, Huerta A, Valle M, García-Sidro P, Forné C, Crespo C, et al. Clinical 
variables impacting on the estimation of utilities in chronic obstructive pulmonary 
disease. Int J Chron Obstruct Pulmon Dis. 2015;10:367–77.
25.
Knobel H, Alonso J, Casado JL, Collazos J, González J, Ruiz I, et al. Validation of a 
simplified medication adherence questionnaire in a large cohort of HIV-infected 
patients: the GEEMA Study. AIDS. 2002 Mar 8;16(4):605–13.
26.
Fletcher C, Clifton M, Fairbairn A, Fry J, Gilson J, Higgins I, et al. Standardized 
Questionaries on Respiratory Symptoms. Br Med J. 1960 Dec 3;2(5213):1665.
27.
Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the 
Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients 
with chronic obstructive pulmonary disease. Thorax. 1999 Jul;54(7):581–6.
28.
Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T, Mishima M. Longitudinal 
deteriorations in patient reported outcomes in patients with COPD. Respir Med. 2007 
Jan;101(1):146–53.
29.
Kozma CM, Slaton TL, Monz BU, Hodder R, Reese PR. Development and validation of 
a patient satisfaction and preference questionnaire for inhalation devices. Treat Respir 
Med. 2005;4(1):41–52.
30.
Ierodiakonou D, Kampouraki M, Poulonirakis I, Papadokostakis P, Lintovoi E, 
Karanassos D, et al. Determinants of frailty in primary care patients with COPD: the 
Greek UNLOCK study. BMC Pulmonary Medicine. 2019 Mar 15;19(1):63.
31.
Zhou A, Zhou Z, Peng Y, Zhao Y, Duan J, Chen P. The role of CAT in evaluating the 
response to treatment of patients with AECOPD. Int J Chron Obstruct Pulmon Dis. 
2018;13:2849–58.
32.
Chen S, Small M, Lindner L, Xu X. Symptomatic burden of COPD for patients 
receiving dual or triple therapy. Int J Chron Obstruct Pulmon Dis. 2018;13:1365–76.
33.
Good Epidemiological Practice (GEP). IEA Guidelines for Proper Conduct of 
Epidemiological Reseach. 2007.
34.
ISPE. Guidelines for good pharmacoepidemiology practices (GPP). Pharmacoepidemiol 
Drug Saf. 2008 Feb;17(2):200–8.

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Not applicable.

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Doc.Ref. EMA/540136/2009
European Network of Centres for 
Pharmacoepidemiology and
Pharmacovigilance
ENCePP Checklist for Study Protocols (Revision 3)
Adopted by the ENCePP Steering Group on 01/07/2016
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) 
welcomes innovative designs and new methods of research. This Checklist has been developed by 
ENCePP to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist is intended to promote 
the quality of such studies, not their uniformity. The user is also referred to the ENCePP Guide on 
Methodological Standards in Pharmacoepidemiology, which reviews and gives direct electronic 
access to guidance for research in pharmacoepidemiology and pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the section number of the protocol where 
this issue has been discussed should be specified. It is possible that some questions do not apply to 
a particular study (for example, in the case of an innovative study design). In this case, the answer 
‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section should be 
used to explain why. The “Comments” field can also be used to elaborate on a “No” answer.
This Checklist should be included as an Annex by marketing authorisation holders when submitting 
the protocol of a non-interventional post-authorisation safety study (PASS) to a regulatory authority 
(see the Guidance on the format and content of the protocol of non-interventional post- authorisation 
safety studies). The Checklist is a supporting document and does not replace the format of the 
protocol for PASS as recommended in the Guidance and Module VIII of the Good pharmacovigilance 
practices (GVP).

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Section 1: Milestones
Yes
No
N/A
Section 
Number
1.1
Does the protocol specify timelines for
1.1.1 Start of data collection1
6
1.1.2 End of data collection2
6
1.1.3 Study progress report(s)
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
6
1.1.6 Final report of study results.
6
Comments:
Section 2: Research question
Yes
No
N/ 
A
Section 
Number
2.1
Does the formulation of the research question
8
7
8
8
9.5
and objectives clearly explain:
2.1.1 Why the study is conducted? (e.g. to address
an important public health concern, a risk identified in
the risk management plan, an emerging safety issue)
2.1.2 The objective(s) of the study?
2.1.3 The target population? (i.e. population or
subgroup to whom the study results are intended to be
generalised)
2.1.4 Which hypothesis(-es) is (are) to be
tested?
2.1.5 If applicable, that there is no a priori
hypothesis?
Comments:
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2 Date from which the analytical dataset is completely available.
The study is not designed to confirm (or refute) any pre-defined hypotheses.
Study title: Quality of life and pReference of COPD patiEnts after Switching from 
Tiotropium monotherApy (Spiriva® Handihaler®) to dual therapy with Tiotropium 
bromide plus Olodaterol (Spiolto® Respimat®) under real life CondiTiOns in 
Greece (ELLACTO II study)
Study reference number: 1237-0098

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Section 3: Study design
Yes
No
N/ 
A
Section 
Number
3.1
Is the study design described? (e.g. cohort, case-
control, cross-sectional, new or alternative design)
9.1
3.2
Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection?
9.1; 9.4
3.3
Does the protocol specify measures of 
occurrence? (e.g. incidence rate, absolute risk)
9.3.3
3.4
Does the protocol specify measure(s) of 
association? (e.g. relative risk, odds ratio, excess risk, 
incidence rate ratio, hazard ratio, number needed toharm 
(NNH) per year)
3.5
Does the protocol describe the approach for the 
collection and reporting of adverse 
events/adverse reactions? (e.g. adverse events that 
will not be collected in case of primary data collection)
11
Comments:
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
9.2.2
4.2
Is the planned study population defined in terms
of:
4.2.1 Study time period?
9.2.3
4.2.2 Age and sex?
9.2.2
4.2.3 Country of origin?
9.2.2
4.2.4 Disease/indication?
9.2.2
4.2.5 Duration of follow-up?
9.2.2
4.3
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria)
9.2.2-4
Comments:
Section 5: Exposure definition and measurement
Yes
No
N/ 
A
Section 
Number
5.1
Does the protocol describe how the study 
exposure is defined and measured?
(e.g. operational details for defining and categorising 
exposure, measurement of dose and duration of drug 
exposure)
9.3.2
5.2
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, use 
of validation sub-study)
9.3.2; 9.9
Statistical analyses will be of exploratory and descriptive in nature.

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Section 5: Exposure definition and measurement
Yes
No
N/ 
A
Section 
Number
5.3
Is exposure classified according to time 
windows? (e.g. current user, former user, non-use)
9.3.2
5.4
Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
9.3.2
Comments:
Section 6: Outcome definition and measurement
Yes
No
N/ 
A
Section 
Number
6.1
Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated?
9.3.3
6.2
Does the protocol describe how the outcomes 
are defined and measured?
9.3.3
6.3
Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, prospective 
or retrospective ascertainment, use of validation sub-study)
9.9
6.4
Does the protocol describe specific endpoints 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services utilisation, 
burden of disease, disease management)
Comments:
Section 7: Bias
Yes
No
N/ 
A
Section 
Number
7.1
Does the protocol describe how confounding will 
be addressed in the study?
9.9
7.1.1. Does the protocol address confounding by 
indication if applicable?
7.2
Does the protocol address:
7.2.1. Selection biases (e.g. healthy user bias)
7.2.2. Information biases (e.g. misclassification of 
exposure and endpoints, time-related bias)
7.3
Does the protocol address the validity of the 
study covariates?
9.7.2; 9.8
Comments:
Section 8: Effect modification
Yes
No
N/ 
A
Section 
Number
There are no Health Technology Assessments planned for this study.

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Section 8: Effect modification
Yes
No
N/ 
A
Section 
Number
8.1
Does the protocol address effect modifiers?
(e.g. collection of data on known effect modifiers, sub-group 
analyses, anticipated direction of effect)
Comments:
Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1
Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview)
9.3.2
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics)
9.3.3
9.1.3 Covariates?
9.3.1
9.2
Does the protocol describe the information 
available from the data source(s) on:
9.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose, number of days of supply prescription, daily 
dosage, prescriber)
9.3.2
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event)
9.3.3
9.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, lifestyle)
9.3.1
9.3
Is a coding system described for:
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System)
9.3.2
9.3.2 Outcomes? (e.g. International Classificationof 
Diseases (ICD)-10, Medical Dictionary for Regulatory 
Activities (MedDRA))
9.3.3
9.3.3 Covariates?
9.3.1
9.4
Is a linkage method between data sources 
described? (e.g. based on a unique identifier orother)
Comments:
Section 10: Analysis plan
Yes
No
N/ 
A
Section 
Number
10.1 Is the choice of statistical techniques described?
9.7
10.2 Are descriptive analyses included?
9.7
10.3 Are stratified analyses included?
9.7

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Section 10: Analysis plan
Yes
No
N/ 
A
Section 
Number
10.4 Does the plan describe methods for adjusting for 
confounding?
10.5 Does the plan describe methods for handling 
missing data?
9.7.3
10.6 Is sample size and/or statistical power 
estimated?
9.5
Comments:
Section 11: Data management and quality
control
Yes
No
N/ 
A
Section 
Number
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
9.8
11.2 Are methods of quality assurance described?
9.8
11.3 Is there a system in place for independent 
review of study results?
9.8
Comments:
Section 12: Limitations
Yes
No
N/ 
A
Section 
Number
12.1 Does the protocol discuss the impact on the 
study results of:
12.1.1 Selection bias?
12.1.2 Information bias?
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods)
9.9
9.9
9.9
12.2 Does the protocol discuss study feasibility?
(e.g. study size, anticipated exposure, duration of follow-up 
in a cohort study, patient recruitment)
9.2
Comments:
Section 13: Ethical issues
Yes
No
N/ 
A
Section 
Number
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described?
9.10.1
13.2 Has any outcome of an ethical review procedure 
been addressed?
13.3 Have data protection requirements been 
described?
10

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Comments:
Section 14: Amendments and deviations
Yes
No
N/ 
A
Section 
Number
14.1 Does the protocol include a section to document 
amendments and deviations?
5
Comments:
Section 15: Plans for communication of study
results
Yes
No
N/ 
A
Section 
Number
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)?
12
15.2 Are plans described for disseminating study 
results externally, including publication?
12
Comments:

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ANNEX 3. ADDITIONAL INFORMATION
COPD Assessment Test (CAT) (9)

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EQ-5D-5L questionnaire (23,24)

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\

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Simplified Medication Adherence Questionnaire (SMAQ) (25)

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Modified Medical Research Council (mMRC) questionnaire (26)
Please circle the number which best describes your grade of breathlessness:
I only get breathless withstrenuous exercise.
0
I get short of breath when hurrying on level ground or walking up a slight hill.
1
On level ground, I walk slower than people of the same age because of
breathlessness, orhave to stop for breath when walking at my own pace.
2
I stop for breath after walking about 100 yards or after a few minutes on level
ground.
3
I am too breathless to leave the house or I am breathlesswhen dressing.
4

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Patient satisfaction and preference questionnaire (PASAPQ) (29)

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PART II: RATING OF PREFERENCE AND WILLINGNESS TO CONTINUE 
WITH INHALER
Comparing the two inhalers that you have used, overall, would you prefer to use Inhaler 1 
or Inhaler 2?
Please check one box
I prefer Inhaler 1
I prefer Inhaler 2
No preference
How would you feel about continuing to use the inhaler?
Please indicate your willingness to continue using the inhaler that you used during the 
study by providing a value between 1 and 100.
0 indicates that you would not be willing to continue using the inhaler and 100 indicates 
that you would definitely be willing to continue.
Please write in a number in the box that is between 0 and 100.
Inhaler 

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