Assessment of Physical Functioning and Handling of Spiolto® Respimat® in Patients With Chronic Obstructive Pulmonary Disease (COPD) Requiring Long-acting Dual Bronchodilation in Routine Clinical Practice
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
TITLE PAGE
Document Number:
c06524595-04
BI Study Number:
1237.45
BI Investigational
Product(s):
Spiolto® Respimat®
Title:
Assessment of physical functioning and handling of Spiolto® 
Respimat® in patients with chronic obstructive pulmonary 
disease (COPD) requiring long-acting dual bronchodilation in 
routine clinical practice
Protocol version identifier:
3.0
Date of last version of 
protocol:
21 April 2017
PASS:
No
EU PAS register number:
EUPAS12750
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:
n.a.
Marketing authorisation 
holder(s):
Market Authorisation Holder:
Boehringer Ingelheim International GmbH
Binger Straße 173
55216 Ingelheim am Rhein
Study initiator:
Joint PASS:
No
Research question and 
objectives:
The objective of this NIS is to measure changes in physical 
functioning – a surrogate for physical activity and exercise 
capacity – in COPD patients on treatment with Spiolto®
Respimat® in routine daily treatment after approximately 6 

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weeks.
A secondary objective is to evaluate the patient’s general 
condition (physician’s evaluation) from Visit 1 (baseline visit 
at the start of the study) to Visit 2 (final visit at the end of the 
study, approx. 6 weeks after Visit 1), as well as patient 
satisfaction with Spiolto® Respimat® at Visit 2.
Country(-ies) of study:
6 countries: Belgium, Denmark, Sweden, The Netherlands, 
Luxembourg, Portugal
Author:
(Medical Team 
Respiratory MIDI)
  Mobile:
  
  
 (Trial Clinical Monitor)
Mobile: 
EU PAS Register Number
EUPAS12750
Date:
21 April 2017
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1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 6
4.
ABSTRACT........................................................................................................... 7
5.
AMENDMENTS AND UPDATES..................................................................... 10
6.
MILESTONES..................................................................................................... 12
7.
RATIONALE AND BACKGROUND................................................................ 13
7.1
MEDICAL BACKGROUND ......................................................................... 13
7.2
DRUG PROFILE ............................................................................................ 14
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 15
8.1
RATIONALE FOR PERFORMING THE STUDY ....................................... 15
8.2
STUDY OBJECTIVES................................................................................... 15
9.
RESEARCH METHODS .................................................................................... 16
9.1
STUDY DESIGN............................................................................................ 16
9.1.1
Outcomes................................................................................................. 17
9.2
SETTING........................................................................................................ 17
9.2.1
Selection of Patient Population ............................................................... 18
9.2.2
Inclusion criteria...................................................................................... 18
9.2.3
Exclusion criteria..................................................................................... 18
9.3
VARIABLES .................................................................................................. 19
9.4
DATA SOURCES........................................................................................... 19
9.5
STUDY SIZE.................................................................................................. 20
9.6
DATA MANAGEMENT................................................................................ 20
9.7
DATA ANALYSIS......................................................................................... 21
9.7.1
Statistical design – Model ....................................................................... 21
9.7.2
Null and alternative hypotheses .............................................................. 21
9.7.3
Planned analyses ..................................................................................... 21
9.7.4
Handling of missing data......................................................................... 22
9.8
QUALITY CONTROL................................................................................... 22
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 23
9.10
OTHER ASPECTS ......................................................................................... 23
9.10.1
Informed Consent, Data Protection, Study Records ............................... 23

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9.10.1.1
Study Approval, Patient Information, and Informed Consent.................24
9.10.1.2
Data Quality Assurance ...........................................................................24
9.10.1.3
Records ....................................................................................................24
9.10.1.3.1
Source Documents ...................................................................................25
9.10.1.3.2
Direct Access to Source Data and Documents ........................................25
9.10.1.4
Statement of Confidentiality....................................................................25
9.10.1.5
Completion of Study................................................................................26
9.10.1.6
Protocol Violations ..................................................................................26
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 27
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................................................................... 35
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 36
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 37
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 38

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
BI
Boehringer Ingelheim
CA
Competent Authority
CI
Confidence Interval
CML
Local Clinical Monitor 
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
eCRF
Electronic Case Report Form
DMP
Data Management Plan
EU
European Union
FDC
Fix Dose Combination
FEV1
Forced expiratory volume in one second
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
ICH
International Conference on Harmonisation
ICS
Inhalative Corticosteroides
IEC
Independent Ethics Committee
ISF
Investigator Site File
LABA
Long-acting beta2 adrenoceptor agonist
LAMA
Long-acting muscarinic antagonist 
MedDRA
Medical Dictionary for Drug Regulatory Activities
mMRC
Modified Medical Research Council
NIS
Non-Interventional Study
PF-10
Patient questionnaire
PGE
Physician’s Global Evaluation
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SF-36
36-Item Short Form Health Survey
SGRQ
St George’s Respiratory Questionnaire
SmPC
Summary of Product Characteristics
WHO
World Health Organisation

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3.
RESPONSIBLE PARTIES
Therapeutic Area 
 Respiratory Medicine (TA )
Team Member Medical Affairs (TM MA)
Team Member Epidemiology (TM Epi)
 Global Epidemiology (  GEpi)
Therapeutic Area
 Risk Management  (TA  RM), and
Pharmacovigilance Working Group  (PVWG) 
GPV Study Coordination
Trial Statistician (TSTAT)
Trial Data Manager (TDM)
Trial Programming
Medical Team 
Respiratory
Trial Clinical Monitor (TCM)
Coordinating Investigator (CI)
not applicable
CRO --

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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 + Olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
02 Mar 2016
1237.45
3.0
21 Apr 2017
Title of study:
Assessment of physical functioning and handling of Spiolto®
Respimat® in patients with chronic obstructive pulmonary disease 
(COPD) requiring long-acting dual bronchodilation in routine clinical 
practice.
Rationale and 
background:
Reduced physical activity resulting in deconditioning and restricted 
physical functioning is a common problem of patients with moderate 
to severe COPD. Clinical studies investigating treatment with Spiolto®
Respimat® and its single components have shown significant 
improvements in exercise capacity in patients with COPD. Real-world
data on the effects of a fixed-dose combination (LABA+LAMA) 
therapy with tiotropium and olodaterol administered in a single device, 
in COPD patients who need treatment with two long-acting 
bronchodilators, is not available.
Research question 
and objectives:
The primary objective of this NIS is to measure changes in physical 
functioning – a surrogate for physical activity and exercise capacity –
in COPD patients on treatment with Spiolto® Respimat® in routine 
daily treatment after approximately 6 weeks.
A secondary objective is to evaluate the patient’s general condition
(physician’s evaluation) from Visit 1 (baseline visit at the start of the 
study) to Visit 2 (final visit at the end of the study, approx. 6 weeks 
after Visit 1), as well as patient satisfaction with Spiolto® Respimat® at 
Visit 2.
Study design:
Open-label observational study: 6 countries, including COPD patients 
receiving treatment with Spiolto® Respimat® for approximately 6 
weeks, which is the average time between two medical consultations.
Population:
COPD patients requiring a fixed combination therapy of two long-
acting bronchodilators (LAMA + LABA) according to approved 
SmPC and GOLD guidelines.
Variables:
-
Patient demographics (age, gender, height & weight)
-
Concomitant diseases / Comorbidities
-
Concomitant medication
-
General condition of patient based on Physician’s Global 

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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:
02 Mar 2016
1237.45
3.0
21 Apr 2017
Evaluation (PGE)
-
Smoking history
-
Exacerbations
-
Breathlessness based on mMRC score
-
Physical Functioning based on PF-10 scores
-
Patient satisfaction with Spiolto® Respimat®
-
Safety; ADR (serious and non-serious), fatal AEs, pregnancies
-
GOLD spirometric classifications (1, 2, 3, 4)
-
GOLD patient groups (A, B, C, D)

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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:
02 Mar 2016
1237.45
3.0
21 Apr 2017
Data sources:
To be completed by the physician:
-
Patient demographics
-
Patient medical files 
-
Physician’s Global Evaluation (PGE) at Visit 1 and Visit 2
To be completed by the patient at Visit 1:
-
mMRC breathlessness scale
To be completed by the patient at Visit 1 and at Visit 2:
-
Physical Functioning Questionnaire (PF-10)
To be completed by the patient at Visit 2 only:
-
Patient satisfaction survey
Study size:
1200 patients, 225 sites; 6 countries: Belgium, Denmark, Sweden, The 
Netherlands, Luxembourg, Portugal
Data analysis:
Primary outcome: “therapeutic success” at Visit 2
(= 10-point increase in the PF-10 score between Visit 1 and Visit 2). 
Secondary outcomes: 
-
Changes in the PF-10 score from Visit 1 to Visit 2
-
General condition of the patient, evaluated by the physician (PGE 
score) at Visit 1 and Visit 2.
-
Patient satisfaction with Spiolto® Respimat® at Visit 2.
 
 
 
 
 
Milestones:
Start of data collection
September 2016
End of data collection
March 2018
Final report of study results
                June 2018

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5.
AMENDMENTS AND UPDATES
Protocol v3.0, Amendment 2
Number
Date
Section of 
study protocol
Amendment or 
update
Reason
1
21 Apr 2017
Front Page, p. 2
Changing 
countries of the 
study
Deleting Norway, 
Adding Portugal
2
21 Apr 2017
Front Page, p. 2
Adding protocol 
author
New Medical Team 
Leader Respiratory 
MIDI
3
21 Apr 2017
Front Page, p. 2
Adding protocol 
author
New TCM
4
21 Apr 2017
Paragraph 3 
Responsible 
parties, p. 6
Changing 
Therapeutic Area 
Head Risk 
Management  
(TAH RM), and
Pharmacovigilan
ce Working 
Group  (PVWG) 
chairperson 
New Therapeutic 
Area Head Risk 
Management  (TAH 
RM), and
Pharmacovigilance 
Working Group  
(PVWG) 
chairperson
5
21 Apr 2017
Paragraph 3 
Responsible 
parties, p. 6
Changing Trial 
Data Manager
New Trial Data 
Manager
6
21 Apr 2017
Paragraph 3 
Responsible 
parties, p. 6
Changing Trial 
Programming
New Trial 
Programmer
7
21 Apr 2017
Paragraph 3 
Responsible 
parties, p. 6
Changing 
Medical Team 
Leader 
Respiratory
New Medical Team 
Leader Respiratory
8
21 Apr 2017
Paragraph 3 
Responsible 
parties, p. 6
Changing TCM    
name
New TCM
9
21 Apr 2017
Paragraph 4 
Abstract, p. 9
Changing study 
size
Changing number 
of sites from 250 to 
225
10
21 Apr 2017
Paragraph 4 
Changing study 
Deleting Norway, 

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Abstract, p. 9
size
Adding Portugal
11
21 Apr 2017
Paragraph 4 
Abstract, p. 9
Changing 
Milestones
Updated date of 
start of data 
collection
12
21 Apr 2017
Paragraph 4 
Abstract, p. 9
Changing 
Milestones
Updated date of end
of data collection
13
21 Apr 2017
Paragraph 4 
Abstract, p. 9
Changing 
Milestones
Updated date of 
Final report of study 
results
14
21 Apr 2017
Paragraph 6, p. 
12
Changing 
Milestones
Updated date of end
of data collection
15
21 Apr 2017
Paragraph 6, p. 
12
Changing 
Milestones
Updated date of 
Final report of study 
results
16
21 Apr 2017
Paragraph 9 
Research 
Methods, p. 17 
and p. 18
Changing setting 
(9.2) and 
Selection of 
Patient 
Population 
(9.2.1.)
Changing number 
of sites from 250 to 
225
17
21 Apr 2017
Paragraph 9 
Research 
Methods, p. 17 
and p. 18
Changing setting 
(9.2) and 
Selection of 
Patient 
Population 
(9.2.1.)
Deleting Norway, 
Adding Portugal
18
21 Apr 2017
Paragraph 9 
Research 
Methods, p. 18
Change in 
exclusion criteria 
(9.2.3.)
Change in 
exclusion criterion 
n°2: “previous 6 
weeks” instead of 
“previous 6 
months”
19
21 Apr 2017
Paragraph 9 
Research 
Methods, p. 18
Adding note in 
exclusion criteria 
(9.2.3.)
Adding note to 
clarify exclusion 
criterion n° 2

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
September 2016
End of data collection
March 2018
Final report of study results:
June 2018

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7.
RATIONALE AND BACKGROUND
7.1
MEDICAL BACKGROUND
COPD is defined as a preventable and treatable disease of the airways, with significant 
systemic consequences. Inactivity is believed to be crucial to the development of the 
extrapulmonary effects of the disease like skeletal muscle weakness, osteoporosis and 
cardiovascular disease. Recent data suggest that patients suffering from COPD with low 
levels of physical activity have increased risk for hospital admission and have significantly 
enhanced mortality. Epidemiological data suggest that this may directly or indirectly lead to 
more rapid decline in lung function [R13-3633]. 
Physical activity is reduced early in the disease progression, as of GOLD Stage 2 [R13-3633]. 
More recent evidence from large placebo controlled clinical trials indicates that COPD 
patients are experiencing a steeper absolute decline in lung function with GOLD 2 airflow 
limitation than with GOLD 3 and 4 [R15-5015]. All these observations suggest the 
importance of early optimal treatment of the disease.
Long-acting bronchodilators, such as long-acting muscarinic antagonists (LAMAs), are the 
cornerstone of maintenance therapy for patients with moderate to very severe chronic 
obstructive pulmonary disease (COPD) whose symptoms are not adequately controlled by 
short-acting bronchodilators alone [P13-05794, P14-01052].
An option recommended by GOLD guideline for patients not adequately controlled on a 
single long-acting bronchodilator is to combine a LAMA with a long-acting β2-agonist 
(LABA) [P14-01052].This has prompted the development of combining LAMA+LABA as 
fixed-dose combinations [P13-05794]. The rationale for combining bronchodilators with 
different mechanisms is based on the notion of additive relaxation of airway smooth muscle 
by direct inhibition of cholinergic activity and functional antagonism of bronchoconstriction 
through β2-adrenergic pathways, with the expectation of an increase in the degree of 
bronchodilation for equivalent or lesser side effects. Several recent studies have provided 
evidence in support of this increased bronchodilatory effect when LABAs are added to 
LAMAs.
When long acting beta-agonists (LABA) and long acting muscarinic antagonists (LAMA) 
with similar or equivalent posologies are combined, the opportunity exists for offering a 
simpler and more convenient administration regimen with the development of fixed 
combinations within the same inhaler device. Fixed-dose combinations of a short-acting β2–
agonist (SABA) and a short-acting anticholinergic (SAMA) have been developed and have 
been shown to be safe, efficacious and convenient for the patient (e.g., Berodual®: 
Fenoterolhydrobromid + Ipratropiumbromid, Combivent®: salbutamol + ipratropium 
bromide; [P94-1346]). Olodaterol is a highly selective and nearly full β2 agonist [P10-07776, 
P11-07720] that provides 24-h bronchodilation in patients with COPD [P13-11467,           
P13-14112, P13-11346, P13-11345]. Olodaterol is also associated with symptomatic benefit 
[P13-11341] and enhanced exercise capacity [P13-14109].
The complementary modes of action of tiotropium and olodaterol have previously been 
demonstrated in animal models, phase II clinical trials and during the Phase IIIa programs
[P10-09337, P14-12073, P13-02357]. 

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In the Phase III programs the additional benefits of the tiotropium + olodaterol fixed-dose 
combination (FDC) over its mono-components has been assessed on lung function, quality of 
life (St. George's Respiratory Questionnaire -SGRQ), dyspnea (Transition Dyspnea Index-
TDI) and exercise endurance time. Another clinically important potential benefit of the 
tiotropium + olodaterol FDC over the mono components is the impact on exacerbations of 
COPD. 
7.2
DRUG PROFILE
Tiotropium + olodaterol FDC is an aqueous solution of tiotropium and olodaterol contained 
in a cartridge. It is administered by using the Respimat® inhaler. One cartridge is used per 
inhaler, which is inserted into the device prior to first use. In pivotal clinical trials and for the 
intended marketed product, the clinical dose consists of two puffs once daily. The Respimat®
inhaler uses mechanical energy to create a soft mist which is released over a period of 
approximately 1.5 seconds.
Tiotropium + olodaterol FDC was 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 event in the tiotropium + olodaterol FDC treatment group were similar to the 
mono-components. 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 [P15-03349].
In conclusion, the clinical trials conducted to date have shown tiotropium + 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 [P15-04531, P15-03349].  
The observed incremental bronchodilator response for the combination compared to the 
individual components translated into 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 contribution of physical inactivity to disability in COPD is difficult to distinguish from 
disease progression; however, it is clear that physical activity is significantly lower in patients 
with COPD than in healthy controls [R13-3633].
COPD prevents patients from carrying out daily activities due to exercise intolerance, which 
is often attributed to limited pulmonary ventilation. Physical inactivity may be related to 
avoidance of exertion as a result of fear of dyspnea. Furthermore, physical inactivity has been 
associated with skeletal muscle weakness and exercise intolerance [R15-4559, R15-4561].
The loss of physical activity in COPD is also associated with increased mortality. Data from a 
study of 2386 patients with COPD demonstrated that, following adjustment for relevant 
confounders, subjects who reported low, moderate or high physical activity had a 
significantly lower risk of all-cause mortality than those with very low physical activity (p = 
0.001) [R15-4564]. Clinical studies of both Spiriva® [P13-04267, P05-09483, P13-14109] 
and Striverdi® Respimat® in COPD patients have demonstrated significant improvement in 
exercise capacity [P13-14109]. 
The benefits of tiotropium + olodaterol FDC have been studied in controlled Phase III 
programs on exercise endurance, however, data regarding physical activity when treated with 
Spiolto® Respimat® is not available from a real world setting.
8.2
STUDY OBJECTIVES
The primary objective of the study is to measure changes in physical functioning - serving as 
a surrogate for physical activity and exercise capacity - in COPD patients being treated with 
Spiolto® Respimat® after approximately 6 weeks in routine clinical practice.
The secondary objectives are to evaluate the patient’s general condition (physician’s 
evaluation) at Visit 1 (baseline visit at the start of the study) and at Visit 2 (final visit at the 
end of the study, approx. 6 weeks after Visit 1), as well as patient satisfaction with Spiolto®
Respimat® at Visit 2.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a self-controlled study design enrolling consented COPD patients who will be treated 
with Spiolto® Respimat® according to the approved SmPC.
Patients will be enrolled consecutively and will be followed over an observational period of 
approx. 6 weeks. Data as listed in Table 9.1:1 will be collected.
Table 9.1:1:  Visit flow chart and data collection parameters
Parameter
Visit 1;
baseline 
visit
Visit 2;
approx. 6 
weeks after 
baseline visit
Informed Consent
X
Inclusion / Exclusion Criteria
X
Patient demographics (age, gender, height, and weight)
X
Smoking history
X
X
Start of COPD
X
Number of exacerbations in the last 12 months
X
Number of exacerbations leading to hospitalization in the last 12 months
X
Past COPD therapies (6 months before Visit 1)
X
COPD related and other relevant concomitant medication
X
X
Concomitant diseases / Comorbidities
X
X
Respimat® training (yes/no)
X
COPD severity based on GOLD assessment1
X
mMRC breathlessness scale, completed by the patient
X
Physical functioning (PF-10) questionnaire, completed by patient
X
X
General condition of patient evaluated by Physician’s Global Evaluation 
(PGE) 
X
X
Adverse Drug Reactions (serious and non-serious), fatal AE, pregnancy
X
X
Patient satisfaction with Spiolto® Respimat®, survey completed by the 
patient
X
Rational for Spiolto® Respimat® treatment discontinuation (if applicable)
X
Continuation or discontinuation of treatment with Spiolto® Respimat® after 
the study (yes/no)
X
1 GOLD patient group (A, B, C or D) will be automatically calculated within the eCRF based on available exacerbation 
history,   mMRC, and GOLD spirometric classification of airflow limitation based on post-bronchodilator FEV1 if 
available.

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Baseline characteristics of patients being eligible and who gave Informed Consent, but were 
not treated in the study will also be collected.
9.1.1
Outcomes
Primary outcome:
The primary outcome is to measure “Therapeutic success” (as a 10-point increase of PF-10) 
between Visit 1 and Visit 2 using a physical functioning questionnaire, which is a sub-
domain of the SF-36 patient questionnaire. The PF-10 sub-domain consists of 10 questions 
evaluating the extent of experienced restrictions while conducting usual activities. Each 
question of the PF-10 can be answered with “yes, limited a lot”, “yes, limited a little”, or 
“No, not limited at all”, with a score of 1, 2, or 3. The scores over the 10 questions will be 
summed, resulting in a value between 10 (a patient answering all questions with “yes, limited 
a lot”) and 30 (a patient answering all questions with “No, not limited at all”). The final sum 
of the individual scores will be standardized to a range of 0 to 100 using the following 
formula: 100*(sum-10)/20.
Secondary outcomes:
-
Changes in the PF-10 score from Visit 1 to Visit 2
-
General condition of the patient, evaluated by the physician (PGE score) at Visit 1 and 
Visit 2.
-
Patient satisfaction with Spiolto® Respimat® at Visit 2.
9.2
SETTING
It is planned that data of approximately 1200 patients from approximately 225 sites in 6
countries will be collected. Site selection will be performed to reflect routine COPD care in 
the participating countries to secure representativeness of the COPD population. The 
following countries will participate in this non-interventional study: Belgium, Denmark, 
Sweden, The Netherlands, Luxembourg and Portugal.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
or not.
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
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason).

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9.2.1
Selection of Patient Population
1200 patients with chronic obstructive pulmonary disease (COPD) in whom combination 
treatment with long-acting bronchodilators is indicated in accordance with the guidelines are 
to be observed in approx. 225 sites (hospital and non-hospital pulmonary medicine physicians 
and general practitioners) as part of this NIS. In the six participating countries (Belgium, 
Denmark, Sweden, The Netherlands, Luxembourg and Portugal), sites in urban as well as 
rural areas will be included. The nationwide distribution of the participating sites in the six
countries and the number of patients enrolled are intended to ensure that the data collected 
are representative.
Possible contraindications are to be checked prior to treatment with Spiolto® Respimat®. See 
also the latest Summaries of Product Characteristics on Spiolto® Respimat®.
Every physician is to enrol the first consecutive patients he/she chooses to treat with Spiolto®
Respimat®. The inclusion of four to six patients is planned per site.
The decision to treat will be taken independently of participation in this NIS and will be made 
before participation is considered.
9.2.2
Inclusion criteria
Patients can be included if all of the following criteria are met:
1. Written informed consent prior to participation
2. Female and male patients ≥ 40 years of age
3. Patients diagnosed with COPD and requiring long-acting dual bronchodilation 
(LAMA + LABA) treatment according to approved Spiolto® Respimat® SmPC and 
COPD GOLD guideline recommendation
9.2.3
Exclusion criteria
1. Patients with contraindications according to Spiolto® Respimat® SmPC
2. Patients who have been treated with a LABA/LAMA combination (free and fixed 
dose) in the previous 6 weeks
Note: 
-
Patients previously treated with LABA or LAMA (with or without ICS) are 
eligible to be included in the study.
-
Patients previously treated with LABA+LAMA or LABA+LAMA+ICS cannot 
be included in the study, if they received this treatment in the last 6 weeks.
3. Patients continuing LABA-iCS treatment should not be additionally treated with
Spiolto® Respimat® in order to avoid a double dosing of long-acting beta-agonists
4. Patients for whom further follow-up is not possible at the enrolling site during the 
planned study period of approx. 6 weeks
5. Pregnancy and lactation
6. Patients currently listed for lung transplantation
7. Current participation in any clinical trial or any other non-interventional study of a 
drug or device

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9.3
VARIABLES
During the observational period, the following data will be collected in an eCRF:
-
Patient demographics (age, gender, height & weight)
-
Concomitant diseases / Comorbidities such as cardiovascular disease, diabetes mellitus, 
musculoskeletal impairment, renal diseases, liver diseases, osteoporosis, 
gastroesophageal reflux (GERD), or lung cancer
-
COPD related and other relevant concomitant medication such as beta-blockers, beta-
agonists, corticosteroids, or proton pump inhibitors
-
General condition of patient based on Physician’s Global Evaluation (PGE) to assess the 
general condition of the patient at the beginning and at the end of the study
-
Smoking status (current smoker, former smoker, and never smoker) and pack-years
-
Reported exacerbations based on medical history in the last 12 months and 
exacerbations leading to hospitalization in the last 12 months
-
Assessment of the severity of breathlessness based on the Modified Medical Research 
Council Questionnaire (mMRC score)
-
Physical Functioning based on PF-10 scores
-
Patient satisfaction with Spiolto® Respimat® to assess the overall satisfaction with 
Spiolto® Respimat® as well as specific inhalation from the device and device handling
-
Safety Reporting; Adverse Drug Reactions (serious and non-serious), fatal AEs, 
pregnancies at the beginning and at the end of the study
-
GOLD spirometric classifications (1, 2, 3, 4), based on GOLD guidelines
-
GOLD patient groups (A, B, C, D), based on GOLD guidelines
*The PF-10 is a sub-domain of the SF-36 and consists of 10 questions evaluating the extent 
of experienced restrictions while conducting usual activities. Each question of the PF-10 can 
be answered with “yes, limited a lot”, “yes, limited a little”, or “No, not limited at all”, with 
a score of 1, 2, or 3. The scores over the 10 questions will be summed, resulting in a value 
between 10 (a patient answering all questions with “yes, limited a lot”) and 30 (a patient 
answering all questions with “No, not limited at all”). The final sum of the individual scores 
will be standardized to a range of 0 to 100 using the following formula: 100*(sum-10)/20.
9.4
DATA SOURCES
Patient files (paper and/or electronically) of 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 original documents. 
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 analysed only using the 
patient number. 
As the physical exercise capacity of the COPD patients cannot be measured directly as part of 
an NIS, the evaluation of general condition by the physician and an extract from the SF-36 
quality-of-life questionnaire relating to physical functioning (PF-10) will be documented as 
surrogate parameters.

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The treating physician will use the Physician’s Global Evaluation (PGE) to evaluate the 
general condition of the patient on an 8-point ordinal scale from 1 (very poor) to 8 
(excellent). PGE will be completed before and approx. 6 weeks after treatment initiation.
The modified Medical Research Council (mMRC) scale will be used to assess the 
breathlessness state of the patient before the treatment. The mMRC stage (0 to 4) collected 
from the patient, as well as the exacerbation history and the post-bronchodilator FEV1, will 
be used to automatically calculate the GOLD patient group (A, B, C, or D) in the eCRF.
The physical functioning (PF-10) questionnaire is a subscale of the validated 36-Item Short 
Form Health Survey and contains 10 questions about everyday physical activity and 
functioning. Patients will be asked to complete the PF-10, in order to evaluate their physical 
functioning before and after treatment with Spiolto® Respimat®.
A patient satisfaction survey will also be completed at Visit 2, using a 7-point ordinal scale 
with divisions from very dissatisfied to very satisfied.
9.5
STUDY SIZE
In a previous study, 205.426 with over 1000 patients treated with Spiriva® Respimat®, 
therapeutic success (i.e., 10-point increase in the PF-10 score between Visit 1 and Visit 2) 
was achieved in 61% of the patients. 
However, in the present study a lower therapeutic success rate is expected as patients may be 
already on maintenance treatment at baseline. Assuming a 50% therapeutic success rate and a 
sample size of 1116 patients, the 95% confidence interval for the therapeutic success rate 
would be between 47.1% (lower limit) and 52.9% (upper limit).
To account for a 7% drop-out rate, the sample size becomes 1200 patients.
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 the standards of the 
International Committee on Harmonization guideline E6R1 regarding electronic study data 
handling. Patient confidentiality will be strictly maintained.

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9.7
DATA ANALYSIS
9.7.1
Statistical design – Model
Details will be described in the statistical epidemiological analysis plan (SEAP).
9.7.2
Null and alternative hypotheses
No formal hypothesis testing will be performed since this is a self-controlled study.
9.7.3
Planned analyses 
All patients who have received at least one dose of Spiolto® Respimat® will be included in 
the analyses; this is the treated set. All analyses will be performed on the treated set (as-
treated analysis). If patients have missing values for an outcome, those patients will be 
excluded for that outcome’s analysis. For example, if a patient is missing the PF-10 score at 
Visit 1 and/or Visit 2, that patient will be excluded from the analyses for the primary 
endpoint of therapeutic success and the secondary endpoint of change in PF-10 from Visit 1 
to Visit 2.
The assessment will be carried out using SAS® software. The statistical characteristics 
presented in the end-of-text tables will be N / mean / SD / min / median / max for continuous 
variables. Tabulations of relative and absolute frequencies will be presented for categorical 
variables. Incidence rates and 95% CI will be given when appropriate.
The analyses will relate to the following data: 
Patient demographics (age, gender, height, and weight);
Comorbidities (main diagnosis and concurrent diagnosis according to MedDRA, 
version valid as at the time of database closure); 
COPD related and other concomitant medication (according to the WHO 
classification, version valid at the time of database closure) 
History of smoking 
Exacerbations
Breathlessness based on mMRC score at Visit 1
Physical Functioning based on PF-10 scores (therapeutic success at Visit 2); primary 
outcome
Changes from Visit 1 to Visit 2 in the PF-10 score; secondary outcome
Patient satisfaction with Spiolto® Respimat® at Visit 2 only; secondary outcome
General condition of the patient: evaluated by the physician (Physician´s Global 
Evaluation (PGE)); secondary outcome
Adverse Drug Reactions (ADR & SADR), fatal AEs, pregnancies
GOLD spirometric classification (1,2, 3, 4)
GOLD patient groups (A, B, C, D)  

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Details of treatment with inhaled respiratory agents before the study 
Details of treatment with respiratory agents during the study 
Reasons for ending treatment during the observation period 
Details of treatment continuation / discontinuation 
Main analysis
For the primary outcome, the proportion of patients with therapeutic success will be 
presented together with the 95% confidence interval. 
Further analyses
The patient’s general condition (PGE) at Visit 1 and Visit 2, patient satisfaction at Visit 2 are 
categorical variables so they will be analysed as tabulations of frequencies. Change from 
Visit 1 to Visit 2 in the PF-10 score is a continuous outcome so it will be analysed with N / 
mean / SD / min / median / max.
 
 
 
 
 
 
The safety data will be reported according to local requirements. As similar studies will also 
be performed in other European countries, data pooling might be considered at the end.
9.7.4
Handling of missing data 
If less than half of the PF-10 questions are missing for a patient, the missing values will be 
replaced with the mean of the other values, then the PF-10 score will be calculated. If half or 
more than half of the PF-10 questions are missing, no score will be calculated and the PF-10 
score will be marked as missing. No other missing data will be imputed. Every effort will be 
made to collect complete data at the specified time points.
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.

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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.
9.9
LIMITATIONS OF THE RESEARCH METHODS
The intention of this NIS is to collect new data on the physical functioning and exercise 
capacity of COPD patients on treatment with Spiolto® Respimat® in a real world setting.
A NIS is the most suitable instrument for obtaining information about the use of medicines in 
everyday therapeutic practice and thus for investigating prospectively questions in everyday 
therapeutic practice.
Consecutive enrolment will be employed to minimize 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.
Selection bias could occur at the site level and the patient level. To minimize the site level 
selection bias, the goal is to have participating centers that have access to all available 
treatment options which are approved for use in that country for the targeted COPD patients. 
To minimize selection bias at the patient level, consecutive enrolment is performed.
Information bias will be minimized by the use of standard eCRF, questionnaire and 
physicians’ training on the study protocol.
An additional limitation is that the physical functioning questionnaire (PF-10) is assessing 10 
items of the full 36-Item Short Form Health Survey (SF-36).
The 7-item satisfaction scale, which is to be completed by the patient in order to measure 
satisfaction with Spiolto® Respimat® use, is a self-designed Boehringer-Ingelheim scale, 
without a public source or validation status.
9.10
OTHER ASPECTS
9.10.1
Informed Consent, Data Protection, Study Records
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, and as close as possible to the standards of the International 
Conference of Harmonisation (ICH) Tripartite Guideline for Good Clinical Practice (GCP), 
Guidelines 
for 
Good 
Epidemiological 
Practice 
(GEP) 
[R10-4560], 
Good 
Pharmacoepidemiology Practice (GPP) [R09-0182] 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.
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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Insurance Cover: The requirements for insurance depend on local law and legislations in the 
participating country. If required, the terms and conditions of the insurance cover are made 
available to the investigator and the patients, and the documentation must be archived in the 
Investigator Site File (ISF).
9.10.1.1
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.
The NIS will be reviewed by the submitted to the competent Ethics Committee before it 
starts, as will any amendments to the observational plan. A copy of the opinion can be found 
in the appropriate section of the clinical trial master file. 
In addition, every participating physician is to be advised by his/her ethics committee in 
accordance with the rules of professional conduct.
Prior to patient participation in the study, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative). 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 Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IEC members, and by inspectors from regulatory authorities.
The observing physician will keep the original documents in accordance with the legal 
storage period. 
9.10.1.2
Data Quality Assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by 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.
9.10.1.3
Records
Case Report Forms (eCRFs) for individual patients will be provided by the sponsor via 
remote data capture. All of the clinical data and site/investigator characteristics will be 
captured via a web-based Electronic Data Capturing system. The site staff will enter and edit 
the data via a secure network, with secure access features (username, password and secure 
identification – an electronic password system).  A complete electronic audit trail will be 
maintained.

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Patients must not be identified on the eCRF by name.  Appropriately coded identification (i.e. 
Patient numbers) must be used.
All patient questionnaires will be paper-based and will be left at the site upon completion by 
the patient.
9.10.1.3.1 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; also current medical records must be 
available.
For the eCRF, the following data must be derived from source documents:
-
Patient demographics (age, gender, height, and weight);
-
History of smoking 
-
Reported exacerbations
-
Past COPD therapies (6 months before visit 1)
-
Respimat® training (Yes/No)
-
GOLD spirometric classification (1,2, 3, 4)
-
GOLD patient groups (A, B, C, D)  
-
Concomitant diseases / Comorbidities
-
Concomitant COPD and other relevant medication
-
Breathlessness based on mMRC score 
-
Physical Functioning (PF-10) Questionnaire
-
Patient Satisfaction Questionnaire
-
Adverse Drug Reactions (ADR & SADR), fatal AEs, pregnancies
-
Rational for Spiolto® Respimat® treatment discontinuation (if applicable)
-
Details of treatment continuation / discontinuation
9.10.1.3.2 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. 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. The Clinical Research Associate (CRA) / on site 
monitor 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 9.10.1.3.1.
9.10.1.4
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.

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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, i.e. the competent authority (CA).
9.10.1.5
Completion of Study
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last patient/patient out, unless specified differently in section 6 of the 
observational plan) or early termination of the trial. 
9.10.1.6
Protocol Violations
There are no protocol waivers. All protocol violations must be reported to the sponsor 
immediately.

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10.
PROTECTION OF HUMAN SUBJECTS
Please refer to section 9.10.1

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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 drug 
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 judgment 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 AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this 

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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 signing the informed 
consent onwards until the end of the study: 
-
all ADRs (serious and non-serious),
-
all AEs with fatal outcome (serious adverse events),
Note*: For all patients on these data must be recorded on the AE pages in the eCRF. The 
separate NIS (S)AE form must be used only when eCRF system is unavailable and must 
be forwarded to the local Pharmacovigilance fax as indicated in the form.
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 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 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

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•
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.
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
Pregnancy:
In rare cases, pregnancy might occur in this study. Once a subject has been enrolled into the 
study with 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 (by fax) to the local 
Pharmacovigilance point of contact for each country within respective timelines.
Expedited Reporting of ADRs / Fatal AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS (S)AE Form from signing the 
informed consent onwards until the end of the study: 

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Table 11.2:1 Reporting types and timelines
Type of Report*
Timeline
All SADRs 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 associated with 
Spiolto® Respimat®
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/email the NIS (S)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 (S)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 
the Spiolto® Respimat® 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 Sponsor according to local 
and international regulatory requirements. 

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
Results of this non-interventional study will be disclosed on encepp.eu and clinicaltrials.gov 
and a study specific publication plan will be developed to describe planned publications.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P05-09483
Maltais F, Hamilton A, Marciniuk D, Hernandez P, Sciurba FC, Richter K, 
Kesten S, O'Donnell D Improvements in symptom-limited exercise 
performance over 8 h with once-daily tiotropium in patients with COPD. 
Chest 128 (3), 1168 - 1178 (2005)
R09-0182
Guidelines for Good Pharmacoepidemiology Practices (GPP). 
Pharmacoepidemiology and Drug Safety 17, 200 - 208 (2008).
R10-4560
Good Epidemiological Practice (GEP). IEA Guidelines for Proper Conduct of 
Epidemiological Reseach (2007).
R13-3633
Troosters T1, Sciurba F, Battaglia S, Langer D, Valluri SR, Martino L, Benzo 
R, Andre D, Weisman I, Decramer M. Physical inactivity in patients with 
COPD, a controlled multi-center pilot-study. Respir Med. 2010 
Jul;104(7):1005-11. doi: 10.1016/j.rmed.2010.01.012. Epub 2010 Feb 18
R15-5015
Claudio Tantucci, Denise Modina. Lung function decline in COPD. 
International Journal of COPD. 2012:7, 95-99.
R15-4559
Katz P, Chen H, Omachi TA, Gregorich SE, Julian L, Cisternas M, Balmes J, 
Blanc PD Therole of physical inactivity in increasing disability among older 
adults with obstructive airway disease. J Cardiopulm Rehabil Prev 31 (3), 193 
- 197 (2011)
R15-4561
Maltais F, LeBlanc P, Simard C, Jobin J, Berube C, Bruneau J, Carrier L, 
Belleau R Skeletalmuscle adaptation to endurance training in patients with 
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 154, 442 -
447 (1996)
R15-4564
Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Anto JM Regularphysical 
activity reduces hospital admission and mortality in chronic obstructive 
pulmonary disease: a population based cohort study. Thorax 61, 772 - 778 
(2006)
P10-07776
Bouyssou T, Casarosa P, Naline E, Pestel S, Konetzki I, Devillier P, Schnapp 
A. Pharmacological characterization of olodaterol, a novel inhaled beta2-
adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical 
models. J Pharmacol Exp Ther 334 (1), 53 - 62 (2010)
P10-09337
Bouyssou T, Schnapp A, Casarosa P, Pieper MP. Addition of the new once-
daily LABA BI 1744 to tiotropium results in superior bronchoprotection in 
pre-clinical models. ATS 2010, 106th Int Conf of the American Thoracic 
Society (ATS), New Orleans, 14 - 19 May 2010. Am J Respir Crit Care Med 
181, A4445, Abstr (2010)

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P10-14042
Maltais F, Beck E, Webster D, Maleki-Yazdi MR, Seibt JV, Arnoux A, 
Hamilton A. Four weeks once daily treatment with tiotropium + olodaterol (BI 
1744) fixed dose combination compared with tiotropium in COPD patients. 
20th Ann Cong of the European Respiratory Society (ERS), Barcelona, 18 - 22 
Sep 2010. Eur Respir J 36 (Suppl 54), 1014S, Abstr 5557 (2010)
P11-07720
Casarosa P, Kollak I, Kiechle T, Ostermann A, Schnapp A, Kiesling R, Pieper 
M, Sieger P, Gantner F. Functional and biochemical rationales for the 24-
hour-long duration of action of olodaterol. J Pharmacol Exp Ther 337 (3), 600 
- 609 (2011)
P13-02357
Aalbers R, Maleki-Yazdi MR, Hamilton A, Waitere-Wijker S, Pivovarova A, 
Schmidt O, Bjermer L. Dose-finding study for tiotropium and olodaterol when 
administered in combination via the Respimat inhaler in patients with COPD. 
22nd Ann Cong of the European Respiratory Society (ERS), Vienna, 1 - 5 Sep 
2012. Eur Respir J 40 (Suppl 56), 525S - 526S, Abstr P2882 (2012)
P13-04267
Cooper CB, Celli BR, Jardim JR, Wise RA, Legg D, Guo J, Kesten S. 
Treadmill endurance during 2-year treatment with tiotropium in patients with 
COPD: a randomized trial. Chest 144 (2), 490 - 497 (2013)
P13-05794
Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the 
management of chronic obstructive pulmonary disease. Respir Res (Lond) 14, 
49 (2013)
P13-11341
Koch A, Paggiaro P, Hamilton A, Hart L, Korducki L, Salvo MC de, 
Pizzichini E. Symptomatic benefit of olodaterol QD delivered via Respimat vs 
placebo and formoterol BID in patients with COPD: combined analysis from 
two 48-week studies. 23rd Ann Cong of the European Respiratory Society 
(ERS), Barcelona, 7 - 11 Sep 2013
P13-11345
Koch A, Pizzichini E, Hamilton A, Hart L, Korducki L, Salvo MC de, 
Paggiaro P. Lung function efficacy of olodaterol QD delivered via Respimat 
vs placebo and formoterol BID in patients with COPD: two 48-week studies. 
23rd Ann Cong of the European Respiratory Society (ERS), Barcelona, 7 - 11 
Sep 2013
P13-11346
Ferguson G, Feldman G, Hofbauer P, Hamilton A, Allen L, Korducki L, Sachs 
P. Lung function efficacy of olodaterol QD delivered via Respimat in COPD 
patients: results from two 48-week studies. 23rd Ann Cong of the European 
Respiratory Society (ERS), Barcelona, 7 - 11 Sep 2013
P13-11467
Lange P, Aumann JL, Derom E, Hamilton A, Tetzlaff K, Ting N, Noord JA 
van. The 24-h FEV1 time profile of olodaterol QD delivered via Respimat in 
COPD: results from two 6-week studies. 23rd Ann Cong of the European 
Respiratory Society (ERS), Barcelona, 7 - 11 Sep 2013
P13-14109
Maltais F, Kirsten AM, Hamilton A, Sousa D de, Wang F, Decramer M. 
Evaluation of the effects of olodaterol on exercise endurance in patients with 

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COPD: results from two 6-week studies. Chest 2013, 79th Ann Mtg of the 
American College of Chest Physicians, Chicago, 26 - 31 Oct 2013. Chest 144 
(4) (Suppl), 748A, Abstr (2013)
P13-14112
Feldman G, Bernstein JA, Hamilton A, Nivens C, LaForce C. The 24-hour 
FEV1 time profile of olodaterol once daily (QD) via Respimat and formoterol 
twice daily (BID) via Aerolizer in patients with COPD: results from two 6-
week studies. Chest 2013, 79th Ann Mtg of the American College of Chest 
Physicians, Chicago, 26 - 31 Oct 2013. Chest 144 (4) (Suppl), 749A, Abstr 
(2013)
P14-01052
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global 
strategy for the diagnosis, management, and prevention of chronic obstructive 
pulmonary disease (updated 2014). 
http://www.goldcopd.org/uploads/users/files/GOLD_Report_2014.pdf (access 
date: 22 January 2014) ; Global Initiative for Chronic Obstructive Lung 
Disease (GOLD) (2014)
P14-12073
Bouyssou T, Casarosa P, Pieper M, Schnapp A, Gantner F. Synergistic 
bronchoprotective activity of the long-acting beta 2-agonist olodaterol with 
tiotropium (long-acting M3 antagonist) and ciclesonide (inhaled steroid) on 
the ovalbumin-induced bronchoconstriction in anaesthetized guinea pigs. ERJ 
September 1, 2011 vol. 38 no. Suppl 55 3451
P13-14109
Maltais F, Kirsten AM, Hamilton A, Sousa D de, Wang F, Decramer M 
Evaluation of the effects of olodaterol on exercise endurance in patients with 
COPD: results from two 6-week studies. Chest 2013, 79th Ann Mtg of the 
American College of Chest Physicians, Chicago, 26 - 31 Oct 2013 Chest 144 
(4) (Suppl), 748A, Abstr (2013)
P15-03349
Buhl R, Maltais F, Abrahams R, Bjermer L, Derom E, Ferguson G, Flezar M, 
Hébert J, McGarvey L, Pizzichini E, Reid J, Veale A, Grönke L, Hamilton A, 
Korducki L, Tetzlaff K, Waitere-Wijker S, Watz H, Bateman E. Tiotropium 
and olodaterol fixed-dose combination versus mono-components in COPD 
(GOLD 2–4) Eur Respir J 2015; DOI: 10.1183/09031936.00136014
P15-04531
Kai-Bichael Beeh, et al. The 24-h lung-function profile of once-daily 
tiotropium and olodaterol fixed-dose combination in chronic obstructive 
pulmonary disease. Elsevier Ltd, 2015. 1094-5539
P94-1346
Bone R, et al. In chronic obstructive pulmonary disease, a combination of 
ipratropium and albuterol is more effective than either agent alone: an 85-day 
multicenter trial. Chest 105 (5), 1411 - 1419 (1994)
13.2
UNPUBLISHED REFERENCES
n.a.

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
The stand-alone documents for this non-interventional study are:
Informed Consent Form
Physicians’ Global Evaluation (PGE)
PF-10 Questionnaire based on SF-36
Breathlessness Scale (mMRC)
Patient Satisfaction Survey
Statistical Epidemiological Analysis Plan (SEAP)
Data Management Plan (DMP)
Pregnancy Monitoring Form
Serious Adverse Event Report in Non-Interventional Studies (NIS (S)AE Form)
Publication Plan
All of the above documents will be archived in the Trial Master File in its original English 
master version.

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable.

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ANNEX 3. ADDITIONAL INFORMATION
Physical Functioning Questionnaire (PF-10) based on the 36-Item Short Form Survey.
Please circle one number on each line.
Yes, 
Limited a 
Lot
Yes, 
Limited a 
Little
No, Not 
limited at 
All
1.
Vigorous activities, such as running, lifting 
heavy objects, participating in strenuous 
sports
[1]
[2]
[3]
2.
Moderate activities, such as moving a 
table, pushing a vacuum cleaner, bowling, 
or playing golf
[1]
[2]
[3]
3.
Lifting or carrying groceries
[1]
[2]
[3]
4.
Climbing several flights of stairs
[1]
[2]
[3]
5.
Climbing one flight of stairs
[1]
[2]
[3]
6.
Bending, kneeling, or stooping
[1]
[2]
[3]
7.
Walking more than a mile
[1]
[2]
[3]
8.
Walking several blocks
[1]
[2]
[3]
9.
Walking one block
[1]
[2]
[3]
10.
Bathing or dressing yourself
[1]
[2]
[3]

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Modified Medical Research Council (mMRC) dyspnea (breathlessness) scale
Please circle the number which best describes your grade of breathlessness.
I only get breathless with strenuous 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, or have 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 breathless when 
dressing.
4

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Patient Satisfaction Questionnaire
Please circle the number which best describes your satisfaction with Spiolto®
Respimat®.
What is your overall satisfaction with the Spiolto® Respimat® treatment?
1
very dissatisfied
2
dissatisfied
3
rather dissatisfied
4
neither satisfied 
nor dissatisfied
5
rather satisfied
6
satisfied
7
very satisfied
How satisfied are your with inhaling from the Respimat® device (e.g. feeling of 
inhalation, ease of inhalation, speed of inhalation)?
1
very dissatisfied
2
dissatisfied
3
rather dissatisfied
4
neither satisfied 
nor dissatisfied
5
rather satisfied
6
satisfied
7
very satisfied
How satisfied are your with the handling of the Respimat® inhalation device?
1
very dissatisfied
2
dissatisfied
3
rather dissatisfied
4
neither satisfied 
nor dissatisfied
5
rather satisfied
6
satisfied
7
very satisfied

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Physicians’ Global Evaluation (PGE) to be used directly within the eCRF
General condition of the patient at the initial examination (Visit 1)
Please mark with a cross as applicable
Poor
1  2
Satisfactory
3  4
Good
5  6
Excellent
7  8
General condition of the patient after approximately 6 weeks of treatment (Visit 2)
Please mark with a cross as applicable
Poor
1  2
Satisfactory
3  4
Good
5  6
Excellent
7  8