Non-interventional, Cross-sectional, Multicenter Study to Describe the Exacerbations Profile of COPD Patients Treated With ICS in a Real-life Primary Care Population in Spain. OPTI Study.
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
    TITLE PAGE
Non-interventional Study Protocol
TITLE PAGE
Document Number:
c19714253-01
BI Study Number:
1237- 0070
BI Investigational
Product(s):
Spiolto® Respimat®
Title:
Non-interventional, cross-sectional, multicenter study to describe 
the exacerbations profile of COPD patients Treated with ICS in 
a real-life primary care population in Spain. OPTI Study.
Brief lay title
The OPTI study in Spain looks at the history flare-ups in patients 
with Chronic Obstructive Pulmonary Disease (COPD) treated 
with inhaled steroids.
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
19 September 2017
PASS:
No
EU PAS register 
number:
The study will be registered in EU PAS Register (ENCePP) and 
clinicaltrials.gov
Active substance:
R03AL06
Tiotropium bromide + Olodaterol
Medicinal product:
Spiolto® Respimat® 2.5 microgram/2.5 microgram, inhalation 
solution; tiotropium/olodaterol
Product reference:
NL/H/3157/001/DC
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
MAH:
This study is initiated, managed and sponsored by:
Joint PASS:
No

Boehringer Ingelheim
Page 2 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Research question and 
objectives:
Primary objective: To describe the patient profile for patients 
treated with ICS at the time of study visit.
The secondary objectives are: 
-
To describe the patient profile for patients not treated with 
ICS at the time of study visit
-
To assess the proportion and the number (count) of 
patients with COPD treated with ICS at the time of study 
visit with or without moderate-to-severe exacerbations,
both in the previous 1 year and previous 2 years before 
the study visit.
-
To assess the proportion and the number (count) of 
patients with COPD not treated with ICS at the time of 
study 
visit 
with
or 
without 
moderate-to-severe 
exacerbations, both in the previous 1 year and previous 2 
years before the study visit.
-
Use of rescue medication.
-
Adherence to treatment recommendations according 
GesEPOC guidelines.
-
To describe ICS-related adverse events.
Country(-ies) of study:
Spain
Author:
Mobile: 
Marketing authorisation 
holder(s):
Date:
19 September 2017
Page 2 of 41
Proprietary confidential information
© 2017 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

Boehringer Ingelheim
Page 3 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
1.
TABLE OF CONTENTS
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 6
4.
ABSTRACT........................................................................................................... 7
5.
AMENDMENTS AND UPDATES..................................................................... 12
6.
MILESTONES..................................................................................................... 13
7.
RATIONALE AND BACKGROUND................................................................ 14
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 15
9.
RESEARCH METHODS .................................................................................... 16
9.1
STUDY DESIGN............................................................................................ 16
9.2
SETTING........................................................................................................ 16
9.2.1
Study sites ............................................................................................... 16
9.2.2
Study population ..................................................................................... 16
9.2.3
Study visits .............................................................................................. 17
9.2.4
Study discontinuation.............................................................................. 17
9.3
VARIABLES .................................................................................................. 17
9.3.1
Exposures ................................................................................................ 17
9.3.2
Outcomes................................................................................................. 18
9.3.2.1
Primary outcomes............................................................................. 18
9.3.2.2
Secondary outcomes......................................................................... 18
9.3.3
Covariates................................................................................................ 19
9.4
DATA SOURCES........................................................................................... 20
9.5
STUDY SIZE.................................................................................................. 20
9.6
DATA MANAGEMENT................................................................................ 21
9.7
DATA ANALYSIS......................................................................................... 21
9.7.1
Main analysis........................................................................................... 22
9.7.2
Further analysis ....................................................................................... 22
9.8
QUALITY CONTROL................................................................................... 23
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 24
9.10
OTHER ASPECTS ......................................................................................... 24
9.10.1
Data quality assurance............................................................................. 24
9.10.2
Study records........................................................................................... 24

Boehringer Ingelheim
Page 4 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.10.2.1
Source documents ............................................................................ 24
9.10.2.2
Direct access to source data and documents .................................... 25
9.10.3
Completion of study................................................................................ 25
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 26
10.1
Study approval, patient information, and informed consent........................... 26
10.2
Statement of confidentiality............................................................................ 26
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 28
11.1
Definitions of adverse events.......................................................................... 28
11.2
Adverse event and serious adverse event collection and reporting................. 29
11.3
Reporting to health Authorities....................................................................... 31
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 32
13.
REFERENCES .................................................................................................... 33
13.1
PUBLISHED REFERENCES......................................................................... 33
13.2
UNPUBLISHED REFERENCES................................................................... 33
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 34
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 35
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 41

Boehringer Ingelheim
Page 5 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
2.
LIST OF ABBREVIATIONS
ACOS
Asthma COPD overlap syndrome
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special interest
ANOVA
Analysis of Variance
BMI
Body Mass Index
CA
Competent Authority
CI
Confidence Interval
CML
Clinical Monitor Local
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
DMP
Data Management Plan
CTP
Clinical Trial Protocol
eCRF
Electronic Case Report Form
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1st second
FVC
Forced vital capacity
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
GVP
Good Pharmacovigilance Practices
IB
Investigator’s Brochure
ICS
Inhaled corticosteroid
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File
LABD
Long-acting bronchodilators
mMRC
Modified Medical Research Council
MAH
Marketing Authorisation Holder
NIS
Non-Interventional Study
PASS
Post-Authorization Safety Study
QoL
Quality of Life
TCM
Trial Clinical Monitor
TMMA
Team Member Medical Affairs
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan

Boehringer Ingelheim
Page 6 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
3.
RESPONSIBLE PARTIES
Team Member Medical Affairs (TM MA)
Trial Statistician (TSTAT)
Medical Advisor
Trial Clinical Monitor (TCM)
 
Coordinating Investigator
 
Coordinating Investigator
Coordinating Investigator

Boehringer Ingelheim
Page 7 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide + Olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
19 September 2017
1237- 0070
Version 1.0
Title of study:
Non-interventional, cross-sectional, multicenter study to describe the 
exacerbations profile of COPD patients Treated with ICS in a real-life 
primary care population in Spain. OPTI Study.
Rationale and 
background:
Chronic obstructive pulmonary disease (COPD) is essentially 
characterized by chronic airflow limitation that is not fully reversible
and mainly associated with tobacco smoke. It is an underdiagnosed 
disease with high morbidity and mortality and is a very significant 
public health problem. 
COPD is a complex disease with a very heterogeneous clinical 
presentation. Within what we know as COPD, different phenotypes 
can be defined that have clinical, prognostic and therapeutic 
repercussions. 
GesEPOC guidelines identify four clinical phenotypes with differential 
treatment: non-exacerbator, mixed COPD - asthma syndrome (ACOS), 
exacerbator with emphysema and exacerbator with chronic bronchitis 
(1). Exacerbation is defined as an acute episode of clinical instability 
that occurs in the natural course of the disease and is characterized by a 
sustained deterioration of respiratory symptoms that goes beyond their 
daily variations. The main symptoms referred to are worsening of the 
dyspnoea, cough, increased volume and / or changes in the colour of 
the sputum. (1).
Different clinical practice guidelines (2) recognize the usefulness of 
using inhaled corticosteroid (ICS) in patients who present frequent
exacerbations despite optimal bronchodilator treatment, and their use 
associated with long-acting bronchodilators (LABD) produces a 
significant decrease in the number of exacerbations and an improved 
quality of life, even though they have not been shown to have a 
beneficial effect on mortality (3). However, clinical evidence has
showed a higher prevalence and incidence of side effects when ICS is 
long-term used (such as pneumonias) (2).
According to the new GOLD 2017 report (2) patients with 0-1 
exacerbations (not leading to hospital admission – group A/B) 
treatment with ICS is not recommended and for patients with ≥ 2 
exacerbations or ≥ 1 exacerbation leading to hospital admission (group 

Boehringer Ingelheim
Page 8 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide + Olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
19 September 2017
1237- 0070
Version 1.0
C/D) the preferred option is Long acting bronchodilation. It is known 
that almost 2/3 of the COPD patients are non-exacerbators (4). In these 
patients, an inhaled corticosteroids (ICS) therapy is not recommended 
and despite of this, 61% of these patients are being treated with ICS 
(4). Additionally, a Spanish consensus in the use of ICS in COPD 
patients recommends that the ICS therapy should be withdrawn in 
those patients without evidence of exacerbations in the previous two 
years (5). However there are discrepancies between guidelines and 
real-life practice, as ICS are still being overused.
Research question 
and objectives:
Primary objective: To describe the patient profile for patients treated 
with ICS at the time of study visit.
The secondary objectives are: 
a)
To describe the patient profile for patients not treated with ICS 
at the time of study visit
b) To assess the proportion and the number (count) of patients 
with COPD treated with ICS at the time of study visit with or 
without moderate-to-severe exacerbations, both in the previous 
1 year and previous 2 years before the study visit.
c)
To assess the proportion and the number (count) of patients 
with COPD not treated with ICS at the time of study visit with 
or without moderate-to-severe exacerbations, both in the 
previous 1 year and previous 2 years before the study visit.
d) Use of rescue medication.
e)
Adherence to treatment recommendations according GesEPOC 
guidelines.
f)
To describe ICS-related adverse events.
Study design:
Non-Interventional, descriptive, cross-sectional cohort and multicentre 
study with COPD patients attended at Spanish Primary Care offices.
Population:
Approximately 1,000 patients with COPD are planned to be included 
in the study. To minimize selection bias at the patient level, the first 5 
consecutive patients from each site who met all inclusion criteria and 
none of the exclusion criteria will be enrolled.
Inclusion criteria:
1.
Written informed consent prior to participation.

Boehringer Ingelheim
Page 9 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide + Olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
19 September 2017
1237- 0070
Version 1.0
2.
Female and male patient ≥ 40 years of age.
3.
COPD diagnosis more than two years before the study visit.
4.
Previously confirmed COPD diagnosis (post-bronchodilator 
FEV1/FVC ratio <70%)
5.
Clinical data available 2 years before the study visit.
6.
Ability to complete CAT – COPD Assessment Test.
Exclusion criteria: 
1.
Current participation in any clinical trial involving a drug or 
device.
2.
A
moderate 
or 
severe 
exacerbation 
(requiring 
oral 
corticosteroid, antibiotics or hospitalization) during the study 
visit or within 4 weeks before the study visit.
Variables:
-
Age, gender, ethnicity.
-
Height & weight (BMI auto calculated).
-
Smoking history.
-
Pulmonary Function Test – Spirometry.
-
Bronchodilator test.
-
History and details of Exacerbations (last 2 years).
-
Episodes of wheezing in exacerbations.
-
COPD diagnosis (year).
-
History of asthma (yes/no) and year of diagnosis.
-
History of atopy (yes/no).
-
Blood Eosinophilia (number of eosinophils and %).
-
Inmunoglobulin E (Ig E).
-
Current COPD treatment (including ICS).
-
History of antibiotics and oral corticosteroids for COPD.
-
Rescue medication.
-
Comorbidities (COTE index).
-
Concomitant medication.
-
Occurrence of pneumonias, candidiasis and other AEs related 

Boehringer Ingelheim
Page 10 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide + Olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
19 September 2017
1237- 0070
Version 1.0
with ICS treatment.
-
COPD GesEPOC 2017 phenotypes.
-
GOLD 2017 spirometric classifications (1, 2, 3, 4).
-
GOLD 2017 patient groups (A, B, C, D).
-
BODEx. (BMI / % FEV1 / mMRC / severe Exacerbations)
-
Breathlessness based on mMRC score.
-
QoL: CAT – COPD Assessment Test.
Data sources:
Data will be obtained from patient medical records and during the 
study visit. Most of data will be available in the charts but as a routine 
clinical practice, some data could be missing. Data will be collected 
through an eCRF which will include all the study variables. 
CAT – COPD Assessment Test will be filled in by the patient 
following the user guide during the study visit and data will be entered 
electronically into the CRF system by the Investigator.
Study size:
It is planned that a total of approximately 1000 patients will be 
recruited in 200 sites for the study. Additional details regarding sample 
size considerations are provided in Section 9.5
Data analysis:
The primary outcome is to describe the proportion of patients 
currently on ICS who did not have moderate/severe exacerbation in the 
year prior to the study visit.
Secondary outcomes are provided in Section 9.3.2.2
 
 
Since the study is descriptive, the variables included in the study 
objectives will be summarized overall and by factors of interest. All 
results will be summarized with measures of central tendency (mean 
and 
median), 
variability/dispersion 
(standard 
deviation 
and 
interquartile ranges), absolute and relative frequencies, and ranges. 
The analysis population will consist of all eligible patients (i.e. all 
patients fulfilling all inclusion criteria and no exclusion criteria). If 
patients have missing values for an outcome, those patients will be 

Boehringer Ingelheim
Page 11 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide + Olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
19 September 2017
1237- 0070
Version 1.0
excluded for that outcome’s analysis. Missing data will not be 
imputed.
Milestones:
Note that the times described below may be modified by the 
administrative processing periods for study initiation:
-
Final Protocol: September 2017
-
Start of data collection: April 2018
-
End of data collection: April 2019
-
Final study report: November 2019

Boehringer Ingelheim
Page 12 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
5.
AMENDMENTS AND UPDATES
None

Boehringer Ingelheim
Page 13 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
6.
MILESTONES
Milestone
Planned Date
IRB/IEC approval
December 2017
Start of data collection
April 2018
End of data collection
April 2019
Registration in the EU PAS 
register
November 2017
Final report of study results:
November 2019

Boehringer Ingelheim
Page 14 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
7.
RATIONALE AND BACKGROUND
Chronic obstructive pulmonary disease (COPD) is essentially characterized by chronic 
airflow limitation that is irreversible and mainly associated with tobacco smoke. It is an 
underdiagnosed disease with high morbidity and mortality and is a very significant public 
health problem. 
COPD is a complex disease with a very heterogeneous clinical presentation. Within what we 
know as COPD, different phenotypes can be defined that have clinical, prognostic and 
therapeutic repercussions. 
GesEPOC guidelines identify four clinical phenotypes with differential treatment: non-
exacerbator, mixed COPD-asthma (ACOS), exacerbator with emphysema and exacerbator 
with chronic bronchitis. Exacerbation is defined as an acute episode of clinical instability that 
occurs in the natural course of the disease and is characterized by a sustained deterioration of 
respiratory symptoms that goes beyond their daily variations. The main symptoms referred to 
are worsening of the dyspnoea, cough, increased volume and / or changes in the colour of the 
sputum (1).
Different clinical practice guidelines (2) recognize the usefulness of using inhaled 
corticosteroid (ICS) in patients who present frequent exacerbations despite optimal 
bronchodilator treatment, and their use associated with long-acting bronchodilators (LABD) 
produces a significant decrease in the number of exacerbations and an improved quality of 
life, even though they have not been shown to have a beneficial effect on mortality (3). 
However, clinical evidence has showed a higher prevalence and incidence of side effects 
when ICS is long-term used (such as pneumonias) (2).
According to the new GOLD 2017 report (2) for patients with 0-1 exacerbations (not leading 
to hospital admission – group A/B) treatment with ICS is not recommended and for patients 
with ≥ 2 exacerbations or ≥ 1 exacerbation leading to hospital admission (group C/D) the 
preferred option is Long acting bronchodilation. It is known that almost 2/3 of the COPD 
patients are non-exacerbators; in these patients, an inhaled corticosteroids (ICS) therapy is 
not recommended and despite of this, 61% of these patients are being treated with ICS (4). 
Additionally, a Spanish consensus in the use of ICS in COPD patients recommends that the 
ICS therapy should be withdrawn in those patients without evidence of exacerbations in the 
previous two years (5). However there are discrepancies between guidelines and real-life 
practice, as ICS are still being overused.

Boehringer Ingelheim
Page 15 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
8.
RESEARCH QUESTION AND OBJECTIVES
This study has been designed in order to describe the COPD patient profile of patients treated 
with or without ICS in primary care, in Spain.
Primary objective:
To describe the patient profile for patients treated with ICS at the time of study visit.
Secondary objectives: 
a) To describe the patient profile for patients not treated with ICS at the time of study 
visit.
b) To assess the proportion and the number (count) of patients with COPD treated with 
ICS at the time of study visit with or without moderate-to-severe exacerbations, both in 
the previous 1 year and previous 2 years before the study visit.
c) To assess the proportion and the number (count) of patients with COPD not treated 
with ICS at the time of study visit with or without moderate-to-severe exacerbations, 
both in the previous 1 year and previous 2 years before the study visit.
d) Use of rescue medication.
e) Adherence to treatment recommendations according GesEPOC guidelines.
f)
To describe ICS-related adverse events.

Boehringer Ingelheim
Page 16 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.
RESEARCH METHODS
9.1
STUDY DESIGN
This non-Interventional, descriptive, cross-sectional cohort and multicentre study will be 
conducted with COPD patients attended at Spanish Primary Care offices.
The design of the study impose an only visit to be performed that will coincide with one of 
those performed by the patients as part of routine follow-up of their disease, without 
interfering with usual clinical practice of the investigator.
A specific therapeutic strategy has already been assigned to each included patient, based on 
routine practice and without interference with the physician’s prescription habits. The 
observational nature of the study is ensured as no diagnostic or therapeutic intervention 
outside of routine clinical practice will be applied.
9.2
SETTING
Approximately 1,000 patients with COPD are planned to be included in the study. To 
minimize selection bias at the patient level, the first 5 consecutive patients from each site who 
met all inclusion criteria and none of the exclusion criteria will be enrolled from 
approximately April 2018 and during one year. 
It is necessary to ensure that study population is representative of the entire national territory. 
Therefore, patients will be recruited from primary care centers in different geographical areas 
according to the distribution of the overall population in this area. Site selection will be 
performed in order to secure representativeness of the COPD population.
9.2.1
Study sites
Approximately 200 primary care centers, who regularly attend COPD patients, will be 
selected to participate. It is necessary to ensure that study population is representative of the 
entire national territory, including sites of all 17 autonomous communities. Number of 
sites/patients in each Autonomous Communities will be approached according COPD 
population distribution extracted from Spanish Statistic National Institute (data available for 
2014). Site feasibility assessments will be performed by the CRO during the site selection 
process.
9.2.2
Study population
To be eligible to participate in the study, patients must meet the following selection criteria. 
The patient will be considered included when he/she agrees to participate in the study by 
signing the informed consent.
Patients will be included in the study if all of the following criteria are met:
1) Written informed consent prior to participation.
2) Female and male patient ≥ 40 years of age.

Boehringer Ingelheim
Page 17 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
3) COPD diagnosis more than 2 years before the study visit.
4) Previously confirmed COPD diagnosis (post-bronchodilator FEV1/FVC ratio <70%)
5) Clinical data available 2 years before the study visit.
6) Ability to complete CAT – COPD Assessment Test.
Patients will be excluded from participating in this study if the following criterion is met:
1) Current participation in any clinical trial involving a drug or device.
2) A moderate or severe exacerbation (requiring oral corticosteroid, antibiotics or 
hospitalisation) during the study visit or within 4 weeks before the study visit.
In addition, a log of all patients included into the study (i.e. having given informed consent) 
will be maintained in the study file (ISF) at the study site.
9.2.3
Study visits
The design of the study impose an only one visit to be performed that will coincide with one 
of those performed by the patients as part of routine follow-up of their disease, without 
interfering with usual clinical practice of the investigator. 
After signing the informed consent (if patient agreed to participate in the study) patients will 
be asked to answer the breathlessness scale (mMRC) and the CAT – COPD Assessment Test
at the unique study visit. Other variables needed to answer study objectives will be obtained 
directly from patient medical records. The end of the study visit is the end of the study for 
each patient.  
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
3. Violation of the study protocol, or the contract by a study site or investigator, disturbing 
the appropriate conduct of the study
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason).
9.3
VARIABLES
9.3.1
Exposures
Patients in this study will have been prescribed a treatment for their COPD. They could have 
been prescribed ICS or not. Prescription of the treatments will have been done under the sole 
responsibility of the healthcare professional and before the study initiation visit.

Boehringer Ingelheim
Page 18 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
In addition, no intervention, either diagnostic or therapeutic, will be applied to patients other 
than that used for routine clinical practice.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
The primary outcome is to describe the proportion of patients currently on ICS who did not 
have moderate/severe exacerbation in the year prior to the study visit.
Table 9.3.2.1:1 Variable related to primary outcome
Data from Medical Charts
Data Measured at Study Visit
History and details of Exacerbations (last 1
year).
X
9.3.2.2
Secondary outcomes
The secondary outcomes are:
a) To describe the proportion of patients currently on ICS who have had 
moderate/severe exacerbation in the year prior to the study visit.
b) Proportion of patients with COPD treated with ICS at the time of study visit with 
or without moderate-to-severe exacerbations, in the previous 2 years before the 
study visit.
c) Proportion of patients with COPD not treated with ICS at the time of study visit 
with or without moderate-to-severe exacerbations, both in the previous 1 year 
and previous 2 years before the study visit.
d) Number (count) of moderate-to-severe exacerbations in COPD patients treated 
with ICS at the time of study visit, both in the previous 1 year and previous 2 
years before the study visit.
e) Number (count) of moderate-to-severe exacerbations in COPD patients not 
treated with ICS at the time of study visit, both in the previous 1 year and 
previous 2 years before the study visit.
f)
General patient profile for patients treated with ICS and patients not treated with 
ICS. These data will be obtained from medical charts.
g) Description of Rescue medication used in patients treated with ICS and without 
ICS (active substance, dose, start date, end date). These data will be obtained from 
medical charts.
h) Adherence to treatment recommendations according GesEPOC 2017 guidelines. 
For this analysis, patients will be stratified between patients with 0-1 
exacerbations (not leading to hospital admission) and for patients with ≥ 2 
exacerbations or ≥ 1 exacerbation leading to hospital admission in the last 1 year 
prior to index date. Taking into account the algorithm of treatment 
recommendations included in GesEPOC (phenotype) guidelines, we will define:

Boehringer Ingelheim
Page 19 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015

Adherence:
-
Those patients (%) treated with ICS that according to GesEPOC 
guidelines should have been treated with ICS. 
-
Those patients (%) not treated with ICS that according to 
GesEPOC guidelines should not have been treated with ICS. 

Non-Adherence: 
-
Those patients (%) treated with ICS but according to GesEPOC
guidelines should not have been treated with ICS.
-
Those patients (%) not treated with ICS but according to 
GesEPOC guidelines should have been treated with ICS.
i)
To describe ICS-related adverse events (Pneumonia, Fracture, Skin thinning/easy 
bruising, Cataract, Diabetes, Oropharyngeal candidiasis). These data will be 
obtained from medical charts.
An exacerbation is defined as an acute worsening of respiratory symptoms that result in 
additional therapy (6):
-
Moderate exacerbation: increase in, or new onset of, ≥ 2 respiratory symptoms 
(cough, sputum, dyspnea, wheezing, chest tightness) with ≥ 1 symptom lasting ≥ 3 
days and leading the patient’s attending physician to initiate treatment with systemic 
corticosteroids and/or antibiotics.
-
Severe exacerbation: increase in or new onset of ≥ 2 respiratory symptoms (cough, 
sputum, dyspnoea, wheezing, chest tightness) with ≥ 1 symptom lasting ≥ 3 days and 
leading to patient’s hospitalization.
9.3.3
Covariates
Table 9.3.3:1 Covariates related to patient profile
Data from Medical Charts
Data Measured at Study Visit
Age, gender, ethnicity.
X
Height & weight (BMI auto-calculated) *
X
Smoking history.
X
Pulmonary function test - Spirometry # *
X
Bronchodilator test # *
(FEV1
increase, 
absolute values).
X
Episodes of wheezing in exacerbations.
X
COPD diagnosis (year)
X

Boehringer Ingelheim
Page 20 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
History of
asthma (yes/no)
and year of 
diagnose
X
History of atopy (yes/no).
X
Blood Eosinophilia (number of eosinophils 
and %) *
X
Inmunoglobulin E (Ig E) *
X
Current COPD treatment (including ICS: start 
and stop dates, dose, reason) §  
X
History and details of Exacerbations (last 2
years).
X
History of antibiotics and oral corticosteriods 
for COPD
X
Comorbidities (COTE index)
X
Concomitant medication.
X
COPD GesEPOC 2017 phenotypes
X
GOLD 2017 spirometric classifications (1, 2, 
3, 4).
Auto-calculated
GOLD 2017 patient groups (A, B, C, D).
Auto-calculated
BODEx (BMI / % FEV1 / mMRC / severe 
Exacerbations)
Auto-calculated
Breathlessness based on mMRC score.
X
QoL: CAT - COPD Assessment Test
X
* Last measure available
# available in medical charts <12 months
§ Not including possible changes or new prescriptions 
done at study visit 
The covariates will also be included as independent variables for multivariable analysis: 
COPD phenotypes, GOLD group, BODEx index, mMRC score and CAT – COPD 
Assessment Test.
9.4
DATA SOURCES
Data collection will be limited to those variables available in the medical records and data 
obtained / measured during the study visit (see Table 9.3.2.1:1 and Table 9:3:3: 1) of selected 
patients.
CAT – COPD Assessment Test will be filled in by the patient following the user guide during 
the study visit and data will be entered electronically into the CRF system.
9.5
STUDY SIZE
Due to the descriptive design of the proposed non interventional study, a formal sample size 
calculation has not been performed based on statistical power and protection for type I error. 

Boehringer Ingelheim
Page 21 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
In previously published studies in usual clinical practice in primary care in Spain (4), 66% of 
patients are non-exacerbators and of these, 61% are treated with ICS, therefore 
approximately 40% of all patients are currently treated with ICS without having 
exacerbations in the prior year. 
Assuming a sample size of 900 patients and 40% of the patients are treated with ICS at the 
study visit and did not have a moderate or severe COPD exacerbation in the prior year, the 
95% confidence interval for this proportion would be between 36.8% (lower limit) and 
43.2% (upper limit). To account for a 10% drop-out rate (patients with inconsistent, 
incomplete or missing data), the sample size becomes 1,000 patients.
Table 9.5:1 Scenario for estimated proportions by 95% CI
9.6
DATA MANAGEMENT
The data will be entered by the investigators themselves and/or authorized personnel directly 
in the electronic case report form (eCRF). A data management plan (DMP) will be created to 
describe all functions, processes, and specifications for data collection, cleaning and 
validation. The eCRFs will include programmable edits to obtain immediate feedback if data 
are missing, out of range, illogical or potentially erroneous. 
AE reconciliation will be performed by the CRO, quarterly after study initiation.
When data management is outsourced, the designated contract organization will be 
responsible for the development and implementation of the data management plan and 
preparation of the data handling report according to the sponsor´s standards.
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 the standards of the 
International Committee on Harmonization guideline E6R1 regarding electronic study data 
handling. Patient confidentiality will be strictly maintained.
9.7
DATA ANALYSIS
Analyses will be performed by Boehringer Ingelheim’s designees. The analysis population 
will consist of all eligible patients (i.e. all patients fulfilling all inclusion criteria and no 
exclusion criteria).
In this non-interventional study, retrospective data from medical charts and data at the study 
visit will be collected for COPD patients. Once the study has been completed and all data 
Scenario for estimated proportions by 95%
confidence intervals (95% CI)
1
2
3
4
5
6
Expected proportion
0.4
0.5
Lower and Upper limit of 95% CI
(0.37;0.43) (0.368;0.432) (0.365;0.435)
(0.47;0.53) (0.468;0.532) (0.465;0.535)
Precission of estimation
0.03
0.032
0.035
0.03
0.032
0.035
N (at final analysis)
1000
900
753
1042
938
784
Dropout
10%
1112
1000
838
1159
1043
872

Boehringer Ingelheim
Page 22 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
from the last patient have been recorded, the database will be closed and statistical analysis 
will be performed.
The proposed methods for statistical analysis presented below are a summary of the methods 
that will be applied in the study to analyze the data collected and to answer the study 
objectives. 
Since the study is essentially descriptive the variables included in the study objectives will be 
summarized by factors of interest and globally. All results will be analysed with measures of 
central tendency (mean and median), variability/dispersion (standard deviation and 
interquartile ranges), absolute and relative frequencies, and ranges. 95% confidence intervals 
will be provided as appropriate. The level of significance will be established at the 0.05 level 
(two-sided).
A Statistical Analysis Plan (SAP),
will 
be prepared to describe all processes, treatment and specifications for data collection, 
cleaning, validation and analysis.
9.7.1
Main analysis
All patients who have signed the informed consent and fulfil all selection criteria will be 
included in the analysis. If patients have missing values for an outcome, those patients will 
be excluded for that outcome’s analysis. Missing data will not be imputed. Number of 
missing values will be presented for each outcome.
Descriptive statistics will be used for describing the patient profile. All results will be 
analyzed with measures of central tendency (mean and median), variability/dispersion 
(standard deviation and interquartile ranges), distributions of absolute and relative 
frequencies, and ranges. 95% confidence intervals will be provided as appropriate. The level 
of significance will be established at the 0.05 level (two-sided).
9.7.2
Further analysis
For the secondary objectives:
Categorical variables will be analysed using Fisher’s Exact test and quantitative variables by 
means t-test for independent groups. In case of more than two groups, One-Way ANOVA 
will be used and an appropriated post-hoc analysis will be done. For quantitative variables 
that do not meet parametric applicability criteria, adequate statistical analysis will be used, as 
Mann-Whitney U test or Kruskal Wallis test.
Logistic regression will be used to assess the independent contribution of clinical and 
demographic factors to the estimation of proportions of interest-dependent variables, such as 
inadequate use of ICS in patients with COPD. Additionally, multivariate logistic regression 
models will be used to propose estimation of proportion of these patients of interest.

Boehringer Ingelheim
Page 23 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Descriptive statistics will be used for describing the use of rescue medication and adverse 
events ICS-related.
Any update of GesEPOC /GOLD guidelines and treatment recommendations during the study 
will be taken into account for analysis.
9.8
QUALITY CONTROL
The eCRF will include programmable edit checks to obtain feedback if data is missing, out of 
range, illogical or potentially erroneous. These checks will be performed once data is entered 
into the eCRF. Thus the data entered in to the eCRF will be validated within the system and 
the physician will receive alerts for missing or inconsistent data. In case any changes of 
already entered data will be required, an audit trail will be available. 
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 could be performed.
Strict and continuous quality control will be maintained to ensure the accuracy and scientific 
rigor of the data obtained, maintaining uniform conditions for collecting the information. 
Quality control will be carried out by qualified personnel designated for this purpose.
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 document of this study.

Boehringer Ingelheim
Page 24 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.9
LIMITATIONS OF THE RESEARCH METHODS
A NIS is the most suitable design to obtain information about the use of medicines in 
everyday therapeutic practice and thus for investigating questions in everyday therapeutic 
practice. However, there are some limitations inherent to this design.
Consecutive enrolment will be employed to minimize selection bias. The entry criteria are 
less restrictive than the ones of a randomised clinical trial, which will permit the enrolment of 
a broader patient population. Additionally, as the setting is limited to the primary care setting, 
patients treated in other clinical settings may not be part of this study.
Another limitation is that data in medical records may have missing values and could reduce 
the validity of conclusions. However, the data included as variables in this study are those 
most frequent for COPD in world real practice.
Finally, recruitment period will include winter season. Due to seasonality of exacerbations in 
COPD, with higher incidence of exacerbations in winter season, this may account for the 
over-representation of exacerbator patients. To avoid this limitation, a full year for 
recruitment has been stablished.
Due to the cross-sectional study design no conclusion on any causal association can be 
drawn.
9.10
OTHER ASPECTS
Not applicable
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 Institutional Review Board (IRBs) / 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, either on 
paper or 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.

Boehringer Ingelheim
Page 25 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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.
For eCRFs all data must be derived from source documents.
9.10.2.2
Direct access to source data and documents
The investigator / institution will permit study-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/eCRFs 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 (e.g. US Food and Drug Administration
(FDA)). The Clinical Research Associate (CRA) / Clinical Monitor Local (CML) and auditor 
may review all CRFs/eCRFs, and written informed consents. The accuracy of the data will be 
verified by reviewing the documents described in Section 9.10.2.1.
9.10.3
Completion of study
The EC/competent authority in Spain needs to be notified about the end of the study (last 
patient out), or early termination of the study. 

Boehringer Ingelheim
Page 26 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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), Guidelines for Good 
Pharmacoepidemiology Practice (GPP), 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.
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) and Competent Authority 
(CA) according to national and international 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 the participating country. 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 authorised 
monitors (CML/CRA) or Quality Medicine auditors appointed by Boehringer Ingelheim, by 
appropriate IRB / 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 

Boehringer Ingelheim
Page 27 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
study need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IEC and the competent authority.

Boehringer Ingelheim
Page 28 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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 reaction
An adverse reaction 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 authorisation 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 hospitalisation, 
-
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 hospitalisation but might jeopardise 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 hospitalisation 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 

Boehringer Ingelheim
Page 29 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
and safety assessment within this study, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. 
The following are considered as AESIs:
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 (e)CRF from signing the informed 
consent onwards until the end of the study: 
-
All adverse drug reaction (ADRs) (serious and non-serious).
-
All AEs with fatal outcome.
All ADRs , 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 characterised 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 drug class.
•
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

Boehringer Ingelheim
Page 30 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
•
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 
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.
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
study, after having taken SPIOLTO®, STRIVERDI®, SPIRIVA® or ATROVENT®,
, 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 signing the 
informed consent onwards until the end of the study: 
Table 11.2:1 Type of reports and timelines
Type of Report
Timeline
All serious ADRs associated with 
SPIOLTO®, STRIVERDI®, SPIRIVA® or 
ATROVENT®
immediately within 24 hours
All AEs with fatal outcome in patients 
immediately within 24 hours

Boehringer Ingelheim
Page 31 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
exposed to SPIOLTO®, STRIVERDI®, 
SPIRIVA® or ATROVENT®
All non-serious ADRs associated with 
SPIOLTO®, STRIVERDI®, SPIRIVA® or 
ATROVENT®
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 (e)CRF 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®, STRIVERDI®, SPIRIVA® or ATROVENT® 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.

Boehringer Ingelheim
Page 32 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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.
Final study report will be distributed to national health authority and ethics committees. 
The results of this study may be published in a national journal and presented in regional or
national congresses.

Boehringer Ingelheim
Page 33 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
13.
REFERENCES
13.1
PUBLISHED REFERENCES
[1]
Miravitlles et al. Clinical Practice Guideline for the Diagnosis and Treatment of 
Patients with Chronic Obstructive Pulmonary Disease (COPD) – the Spanish COPD 
Guideline (GesEPOC). 2017 version. Arch Bronconeumol 2017;53 (Supl 1):2-64.
[2]
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global 
Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Available from:
goldcopd.org [accessed 15 November 2016]
[3]
Nannini et al. Combined corticosteroid and long-acting beta-agonist in one inhaler 
versus long-acting beta-agonists for chronic obstructive pulmonary disease. 
Cochrane Database Syst Rev, 4 (2007), pp. CD006829
[4]
Miravitlles et al. Frequency and characteristics of different clinical phenotypes of 
chronic obstructive pulmonary disease. Int J Tuberc Lung Dis. 2015 Aug; 19(8): 
992-8.
[5]
Alcázar Navarrete et al. Correct use of inhaled corticosteroids in chronic obstructive 
pulmonary disease: a consensus document. Working Group “Consensus document 
on the appropriate use of inhaled corticosteroids in COPD”. Arch Bronconeumol. 
2015 Apr; 51(4):193-8.
[6]
Beeh et al. Characterisation of exacerbation risk and exacerbator phenotypes in the 
POET-COPD trial. Respiratory Research 2013, 14:116
13.2
UNPUBLISHED REFERENCES
Not applicable

Boehringer Ingelheim
Page 34 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Title
<1>
Patient information and Informed Consent Form
<2>
Investigator  List
<3>
Statistical Analysis Plan (SAP)
<4>
Data Management Plan (DMP)
<5>
Serious Adverse Event Report in Non-Interventional Studies (NIS (S)AE Form)
<6>
Pregnancy Monitoring Form

Boehringer Ingelheim
Page 35 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
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).
Study title:
Non-interventional, cross-sectional, multicenter study to describe the exacerbations profile of 
COPD patients Treated with ICS in a real-life primary care population in Spain. OPTI Study.
Study reference number:
1237- 0070
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
                                                
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.

Boehringer Ingelheim
Page 36 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Comments:
Study progress reports for EC and authorities will be done annually.
Section 2: Research question
Yes
No
N/
A
Section
Number
2.1
Does the formulation of the research question 
and objectives clearly explain: 
8
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)
7
2.1.2 The objective(s) of the study?
8
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
7
2.1.4 Which hypothesis(-es) is (are) to be 
tested?
2.1.5 If applicable, that there is no a priori
hypothesis?
Comments:
Descriptive study and measures of association
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?
9.4
3.3
Does the protocol specify measures of 
occurrence? (e.g. incidence rate, absolute risk)
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 to harm 
(NNH) per year)
9.3
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:
Descriptive study and measures of association (logistic regression / negative binomial).
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
9.2
4.2
Is the planned study population defined in terms 
of:
4.2.1 Study time period?
9.2

Boehringer Ingelheim
Page 37 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.2.2 Age and sex?
9.2.2
4.2.3 Country of origin?
4.2.4 Disease/indication?
9.2.2
4.2.5 Duration of follow-up?
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
Comments:
Cross-sectional study. No follow-up is carried out
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
5.2
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, use 
of validation sub-study)
5.3
Is exposure classified according to time 
windows? (e.g. current user, former user, non-use)
9.3
5.4
Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
Comments:
Observational study. Patients treated as per routine clinical practice.
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
6.2
Does the protocol describe how the outcomes
are defined and measured? 
9.3
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)
9.3
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)
9.3

Boehringer Ingelheim
Page 38 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Comments:
Descriptive outcomes. For QoL: CAT – COPD Assessment Test.
Section 7: Bias
Yes
No
N/
A
Section
Number
7.1
Does the protocol describe how confounding will 
be addressed in the study?
9.7.1
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)
9.2
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
Comments:
Descriptive study and measures of association (logistic regression / negative binomial)
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)
9.4
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics)
9.4
9.1.3 Covariates?
9.4
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
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event)
9.3
9.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, lifestyle)
9.3

Boehringer Ingelheim
Page 39 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Section 9: Data sources
Yes
No
N/A
Section 
Number
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 Outcomes? (e.g. International Classification of 
Diseases (ICD)-10, Medical Dictionary for Regulatory 
Activities (MedDRA))
9.3.3 Covariates?
9.4
Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)
10.2
Comments:
Unique patient identification code numbers will be used.
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
10.4 Does the plan describe methods for adjusting for 
confounding?
9.7
10.5 Does the plan describe methods for handling 
missing data?
9.7
10.6 Is sample size and/or statistical power 
estimated?
9.5
Comments:
Descriptive study and measures of association.
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)
9.6
11.2 Are methods of quality assurance described?
9.8
11.3 Is there a system in place for independent 
review of study results? 
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?
9.2

Boehringer Ingelheim
Page 40 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Section 12: Limitations
Yes
No
N/
A
Section
Number
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)
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?
10.1
13.2 Has any outcome of an ethical review procedure 
been addressed?
13.3 Have data protection requirements been 
described?
10.1
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:

Boehringer Ingelheim
Page 41 of 41
Non-interventional Study Protocol
BI Study Number 1237- 0070
c19714253-01
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 3. ADDITIONAL INFORMATION
CAT – COPD Assessment Test

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c19714253
1.0
non-interventional-study-protocol-version-1.0
Non-interventional, cross-sectional, multicenter study to describe the exacerbations
profile of COPD patients Treated with ICS in a real-life primary care population in
Spain. OPTI Study.
Approval-
 Safety Evaluation
Therapeutic Area
21 Sep 2017 12:29 CEST
Approval-Medical 
21 Sep 2017 14:09 CEST
Author-Trial Statistician
21 Sep 2017 16:00 CEST
Approval-Therapeutic Area 
22 Sep 2017 11:45 CEST
Approval-Team Member Medical
Affairs
02 Oct 2017 11:19 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c19714253
1.0