Changes in Clinical Control of COPD Patients Measured by the Clinical COPD Questionnaire During Therapy With Spiolto®Respimat® in Routine Clinical Practice
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
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TITLE PAGE
Non-interventional Study Protocol
Document Number:
c20825865-01
BI Study Number:
1237-0072
BI Investigational
Product(s):
Spiolto® Respimat®
Title:
Changes in clinical control of COPD patients measured by the 
Clinical COPD Questionnaire during therapy with Spiolto® 
Respimat® in routine clinical practice
Brief lay title
A study on the control of chronic obstructive pulmonary disease 
(COPD) in patients taking the combination of tiotropium and 
olodaterol using the Respimat® inhaler
Protocol version 
identifier:
Version 1.0
Date of last version of 
protocol:
26 March 2018
PASS:
No
EU PAS register 
number:
Study not yet registered
Active substance:
R03AL06 
Tiotropium bromide + Olodaterol
Medicinal product:
Spiolto® Respimat® 2.5 microgram/2.5 microgram per puff
inhalation solution
Product reference:
NL/H/3157/001/DC
Procedure number:
n.a.
Marketing authorisation 
holder(s):
MAH:
This study is initiated, managed and sponsored by:
Joint PASS:
No

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Research question and 
objectives:
The objective of this NIS is to measure changes in clinical 
control using Clinical COPD Questionnaire (CCQ ) scores in 
COPD patients receiving treatment with Spiolto® Respimat®
after approximately 6 weeks in routine clinical practice.
Primary objective: Assess proportion of patients achieving 
“therapeutic success” (= 0.4 point decrease in the CCQ score 
between baseline and after approximately 6 weeks of treatment)
Secondary objectives are assessment of changes in the different 
CCQ domains, the Symptom domain (questions 1,2, 5, 6 of the 
CCQ) Mental state (questions 3,4 of the CCQ) and Funcional 
state domain known in literature also as CCQ-4 (questions 7, 8, 
9 and 10 of the CCQ), 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® and willingness to continue treatment with 
Spiolto® Respimat® at visit 2 as proxy for adherence.
Country(-ies) of study:
It is planned that data of approximately 4500 patients in 11
countries will be collected (Bulgaria, Czech Republic, Hungary, 
Israel, Lithuania, Poland, Romania, Russia, Slovenia, 
Switzerland and Ukraine).
Author:
Date:
26 March 2018
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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..................................................................... 10
6.
MILESTONES..................................................................................................... 11
7.
RATIONALE AND BACKGROUND................................................................ 12
7.1
MEDICAL BACKGROUND ......................................................................... 12
7.2
DRUG PROFILE ............................................................................................ 13
7.2.1
Fixed Dose Combination of Tiotropium and Olodaterol ........................ 13
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 15
8.1
STUDY OBJECTIVES................................................................................... 17
9.
RESEARCH METHODS .................................................................................... 18
9.1
STUDY DESIGN............................................................................................ 18
9.2
SETTING........................................................................................................ 18
9.2.1
Study sites ............................................................................................... 18
9.2.2
Study population ..................................................................................... 18
9.2.3
Study visits .............................................................................................. 18
9.2.4
Study discontinuation.............................................................................. 20
9.3
VARIABLES .................................................................................................. 20
9.3.1
Exposures ................................................................................................ 21
9.3.2
Outcomes................................................................................................. 21
9.3.2.1
Primary outcome .............................................................................. 21
9.3.2.2
Secondary outcomes......................................................................... 21
9.4
DATA SOURCES........................................................................................... 22
9.5
STUDY SIZE.................................................................................................. 22
9.6
DATA MANAGEMENT................................................................................ 23
9.7
DATA ANALYSIS......................................................................................... 23
9.7.1
Main analysis........................................................................................... 24
9.7.2
Secondary analyses 
............................................... 25
9.7.3
Handling of missing data......................................................................... 25
9.8
QUALITY CONTROL................................................................................... 25

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9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 25
9.10
OTHER ASPECTS ......................................................................................... 26
9.10.1
Data quality assurance............................................................................. 26
9.10.2
Study records........................................................................................... 26
9.10.2.1
Source documents ............................................................................ 26
9.10.2.2
Direct access to source data and documents .................................... 27
9.10.3
Completion of study................................................................................ 27
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 28
10.1
Study approval, patient information and informed consent............................ 28
10. 2   Statement of confidentiality............................................................................. 28
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 29
11.1   Definitions of adverse events............................................................................ 29
11.2   Adverse event and serious adverse event collection and reporting .................. 30
11.3   Reporting to health Authorities......................................................................... 32
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 33
13.
REFERENCES .................................................................................................... 34
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 39
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 40
ANNEX 3.  ADDITIONAL INFORMATION............................................................. 41
1.
Physician’s Global Evaluation (PGE)*................................................... 41
2.
Patient Satisfaction Questionnaire .......................................................... 42
3.
Clinical COPD Questionnaire................................................................. 43
4.
Modified Medical Research Council (mMRC) Questionnaire for Assessing the 
Severity of Breathlessness ...................................................................... 44

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of special interest
AUC
Area under the Curve
CI
CCQ
Confidence Interval
Clinical COPD Questionnaire
CML
Local Clinical Monitor 
COPD
Chronic Obstructive Pulmonary Disease
CRA
CRO
Clinical Research Associate
Clinical Research Organisation 
eCRF
Electronic Case Report Form
EU
European Union
FDC
Fix Dose Combination
FEV1
Forced expiratory volume in one second
GCP
GEP
GPP
Good Clinical Practice
Good Epidemiological Practice
Good Pharmacoepidemiology Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
ICH
International Conference on Harmonisation
ICS
Inhalative Corticosteroides
IEC
IPCRG
Independent Ethics Committee
International Primary Care Respiratory Group
IRB
Institutional Review Board
ISF
Investigator Site File
LABA
Long-acting beta2 adrenoceptor agonist
LAMA
MACE
MAH
MCID
Long-acting muscarinic antagonist 
Major Adverse Cardiovascular Event
Marketing Authorisation Holder
Minimum Clinically Important Difference
MedDRA
mMRC
Medical Dictionary for Drug Regulatory Activities
Modified Medical Research Council
CTCAE
Common Terminology Criteria for Adverse Events
NIS
Non-Interventional Study
PF-10
Patient questionnaire
PGE
Physician’s Global Evaluation
SABA
SADR
Short-acting beta2 adrenoceptor agonist
Suspected Adverse Drug Reaction
SAE
Serious Adverse Event
SAMA
SmPC
Short-acting muscarinic antagonist
Summary of product characteristics
TDI
Transitional dyspnoea index 
WHO
World Health Organisation

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3.
RESPONSIBLE PARTIES
Function
Name 
Scientific Coordinator
Therapeutic Area 
 
Respiratory Medicine (TA )
Team Member Medical Affairs 
(TM MA)
Scientific Advisor Medical Affairs
Team Member Epidemiology
(TM Epi)
Deputy 
 Global 
Epidemiology 
(  GEpi)
Therapeutic Area
 Risk 
Management (TA  RM), and
Pharmacovigilance Working 
Group (PVWG) chairperson
GPV CT Coordinator
Trial Clinical Monitor
Statistical Analysis
Data Management
Trial Programming

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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:
26 March 2018
1237-0072
1.0
Not applicable
Title of study:
Changes in clinical control of COPD patients measured by the 
Clinical COPD Questionnaire during therapy with Spiolto® 
Respimat® in routine clinical practice
Rationale and 
background:
Clinical studies investigating treatment with Spiriva® (tiotropium
bromide), with Striverdi® (Olodaterol) Respimat® as well as with the 
LAMA-LABA combination Spiolto® Respimat® have shown 
significant improvement in symptoms, health related quality of life and 
exercise capacity in patients with COPD. However, real world data 
with regards to the effects of a combination therapy with Spiolto®
Respimat® in COPD patients who need two long-acting 
bronchodilators are not yet available.
This NIS aims to investigate the potential changes in clinical control of 
COPD patients using the Clinical COPD Questionnaire (CCQ) and its 
three domains during treatment with Spiolto® Respimat®.
Research question 
and objectives:
The primary objective of this NIS is to assess therapeutic success, 
measured  by the a predefined decrease of the CCQ score in COPD 
patients on treatment with Spiolto® Respimat® after approximately 6 
weeks.
A secondary objective is to evaluate changes in full CCQ score and its 
symptom, mental state and functional state domains 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), the patient’s general 
condition (physician’s evaluation) at visit 1 and at visit 2, and 
patient’s willingness to continue treatment with Spiolto® Respimat®
after study end (proxy for adherence).
Study design:
Open-label observational: all included COPD patients are receiving 
treatment with Spiolto® Respimat® for approximately 6 weeks, which 
is the average time between two medical consultations.
Population:
COPD patients requiring a combination therapy of two long-acting 
bronchodilators (LAMA + LABA) according to approved SmPC and 
GOLD guidelines, COPD GOLD groups B to D (Version 2018).

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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:
26 March 2018
1237-0072
1.0
Not applicable
Variables:
-
Patient demographics (age, gender, height & weight)
-
Concomitant diseases / Comorbidities
-
Concomitant medication
-
General condition of patient based on Physician’s Global 
Evaluation PGE)
-
Smoking history
-
Exacerbation history
-
Breathlessness based on mMRC score
-
CCQ and the CCQ symptom, mental state and functional state 
domain scores
-
Patient satisfaction with Spiolto® Respimat®
-
Safety; ADR (serious and non-serious), fatal AEs, pregnancies
-
GOLD patient groups (B, C, D)
-
GOLD spirometric classification (1-4), if available
Data sources:
To be completed by the physician:
-
Patient demographics
-
Patient medical files 
-
Physician’s Global Evaluation (PGE) at visit 1 and visit 2
-
Document patient’s willingness to continue treatment
To be completed by the patient:
-
mMRC breathlessness scale at visit 1
-
Health and functional status by CCQ questionnaire at visit 1 and 2
-
Patient satisfaction survey at Visit 2

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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:
26 March 2018
1237-0072
1.0
Not applicable
Study size
It is planned that data of approximately 4500 patients in 11 countries 
will be collected (Bulgaria, Czech Republic, Hungary, Israel, 
Lithuania, Poland, Romania, Russia, Slovenia, Switzerland and 
Ukraine).
Data analysis:
Primary outcome:
For the primary outcome, the percentage of patients with therapeutic 
success will be presented together with the 95% confidence interval, 
whereupon “Therapeutic success” is defined as 0.4 - point decrease in 
the Clinical COPD Questionnaire (CCQ) score from visit 1 to visit 2. 
Secondary outcomes: 
For secondary outcomes, the Physician’s Global Evaluation (PGE) at 
visit 1 and visit 2, patient satisfaction and willingness to continue 
treatment at visit 2 with Spiolto® Respimat® at visit 2 as proxy for 
Adherence are categorical variables so they will be analysed as 
tabulations of frequencies. Change from Visit 1 to Visit 2 in the CCQ 
and CCQ symptom, mental state and functional state score is a 
continuous outcome, so it will be analysed with N / mean / SD / min / 
median / max.

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5.
AMENDMENTS AND UPDATES
None

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
Q2 2018
End of data collection
Q1 2019
Final report of study results:
Q4 2019

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7.
RATIONALE AND BACKGROUND
7.1
MEDICAL BACKGROUND
According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Chronic 
Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disease that 
is characterized by persistent respiratory symptoms and airflow limitation that is due to airway 
and/or alveolar abnormalities usually caused by significant exposure to noxious particles or 
gases [I].
COPD is currently the fourth leading cause of death in the world and projected to be the third 
by 2020. It represents therefore an important public health challenge. Globally the COPD 
burden is projected to increase in the coming decades because of continued exposure to 
COPD risk factors and aging of the population [I].
The inhalation of noxious substances such as smoke with harmful particles or gases (air 
pollution), but in the majority of cases tobacco smoking triggers an abnormal inflammatory 
response in the lung. This inflammatory response leads to increased mucus production, tissue 
remodelling and, connected with this, to a narrowing of the air passages in the lower 
respiratory tract. As a result, the pulmonary parenchyma is destroyed and pulmonary 
emphysema is caused. Over time, there are further systemic consequences, such as myopathy, 
osteoporosis, cor pulmonale and hypertension with severe restriction of physical functioning. 
Recurrent acute exacerbations (e.g. due to pulmonary infections) bring about a further 
deterioration in the condition of the lungs [II].
Inactivity is believed to be crucial to the development of the extra-pulmonary 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 [III].
Physical activity is reduced early in the disease progression, as of GOLD Stage 2 [III]. 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 [IV]. 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 [V, VI].
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) [VI]. For patients with severe breathlessness initial therapy with two bronchodilators 
might be considered [I].  The rationale for combining bronchodilators with different 
mechanisms is based on the notion of additive relaxation of airway smooth muscle by direct 

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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.
Fixed-dose combinations of a short-acting β2–agonist and a short-acting anticholinergic 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 [VII]. Olodaterol is a highly selective and nearly full β2 agonist [VIII,
IX] that provides 24-h bronchodilation in patients with COPD [X, XI, XII, XIII]. Olodaterol is 
also associated with symptomatic benefit [XIV] and enhanced exercise capacity[XV].
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
[XVI, XVII, XVIII, XIX].
In the Phase III program 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, the impact on exacerbations of 
COPD, is currently evaluated in a Phase IIIb trial. 
7.2
DRUG PROFILE
7.2.1
Fixed Dose Combination of Tiotropium and Olodaterol
Tiotropium + olodaterol FDC, Spiolto®, 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. 
The Respimat® inhaler uses mechanical energy to create a soft mist which is released over a 
period of approximately 1.5 seconds. It produces a slowly dispersing, long-lasting mist with 
very fine-particle distribution that is readily able to circulate into the lower respiratory tract in
the lungs [XX]. Thus, deep pulmonary deposition is achieved and the product is efficiently 
administered to the target site.
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 [XXI].
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 [XXI, XXII]. The observed incremental 

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bronchodilator response for the combination compared to the individual components 
translated into benefits that were meaningful to the patient, with improvements in several 
patients centered outcomes. For further information please refer to the SmPC of Spiolto®
Respimat®.

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8.
RESEARCH QUESTION AND OBJECTIVES
COPD Patients usually do not only show respiratory symptoms, but also physical incapacity 
and several comorbidities [XXIII]. These often result in impaired health status and reduced 
health-related quality of life and may lead to hospitalisations and increased mortality [XXIV]. 
Amongst others, low lung function [XXV], frequent exacerbations [XXVI], comorbidities
[XXVII] and a low level of physical activity are negative factors for health status in COPD. 
Physical exercise [XXVIII] and pharmacological interventions may improve health status, as 
e.g. shown in the UPLIFT trial with tiotropium [XXIX].
The cross-sectional BOLD study assessed the impact of COPD on health status in a general 
population-based survey including almost 12000 subjects from 17 countries [XXX]. 2269 
COPD patients (defined by a post-bronchodilator forced expiratory volume in 1 s/forced vital 
capacity <0.70) were found to show lower physical component scores (44±10 vs. 48±10 units, 
p<0.0001) and mental health component scores (51±10 vs. 52±10 units, p = 0.005) than 
subjects without COPD. The effect of reported heart disease, hypertension and diabetes on 
physical health component scores (-3 to -4 units) was considerably less than the effect of 
COPD GOLD grade 3 (-8 units) or 4 (-11 units). 
Dyspnoea was the most important determinant of low physical and mental health component 
scores. In addition, lower forced expiratory volume in 1 s, chronic cough, chronic phlegm and 
the presence of comorbidities were all associated with a lower physical health component 
score.
The authors conclude COPD to be associated with poorer health status but the effect to be 
stronger on the physical than the mental aspects of health status. Severe COPD had a greater 
negative impact on health status than self-reported cardiovascular disease and diabetes.
The contribution of physical inactivity to disability in COPD can be difficult to distinguish 
from disease progression [XXXI]. However, it is clear that physical activity is significantly 
lower in patients with COPD than in healthy controls [XXXII, XXXIII] .
COPD prevents patients from carrying out daily activities due to exercise intolerance, which 
is often attributed to limited pulmonary ventilation. 
However, a number of observations have suggested that, for many COPD patients, other 
factors are involved, including deconditioning due to physical inactivity. This may be related 
to avoidance of exertion as a result of fear of dyspnoea. Furthermore, physical inactivity has 
been associated with skeletal muscle weakness and exercise intolerance [XXXIV, XXXV].
The loss of physical activity in COPD is also associated with increased mortality [XXXVI]. 
Data from a study of 2386 patients with COPD demonstrated that, following adjustment for 
all 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)[XXXVII].

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Clinical studies [XXXVIII, XXXIX, XL] of both Spiriva® and Striverdi® Respimat® in COPD 
patients have demonstrated significant improvement in exercise capacity [XV].
The benefits of tiotropium + olodaterol FDC have been studied in controlled Phase III 
programs on health related quality of life, symptoms and exercise endurance, however, data 
when treated with Spiolto® Respimat® is not available from a real world setting.
Various questionnaires on quality of life and physical functioning are used to try assessing 
COPD patients’ health status and physical state. The Clinical COPD questionnaire (CCQ) has 
been developed and validated in the Netherlands especially for COPD patients by Jan Kocks 
et al in 2006 [XLI] to categorize patients’ impairments generally and focus patients’ treatment 
on their specific needs. 
The CCQ is easy to apply. It takes less than 2 minutes to complete. CCQ is used to monitor 
the clinical control of COPD. It consists of 10 questions, covering 3 domains: symptom 
domain (4 questions (#’s 1,2,5,6)); functional status domain (4 questions(#’s 7,8,9,10)) and 
mental status domain (2 questions (#’s 3,4)). The questionnaire is responsive to intervention 
and has been translated and validated in over 140 languages [XLII]. The CCQ thus is a well-
known and widespread questionnaire, which is included in the GOLD guidelines and is 
validated in several languages. 
In a head to head comparison of CAT and CCQ the patients preferred the latter as it reflected 
their status better than CAT by giving more details on breathing problems which was more 
important for them than sleep or energy [XLIII]. CCQ has been given maximum ranking in 
“COPD wellness tools” overview by the International Primary Care Respiratory Group 
(IPCRG) [XLVI].

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8.1
STUDY OBJECTIVES
The objective of this NIS is to measure changes in clinical control by the CCQ in COPD 
patients receiving treatment with Spiolto® Respimat® after approximately 6 weeks in routine 
clinical practice.
Each of the 10 CCQ questions is scored by the patient on a 7-point scale between 0 and 6 at 
baseline and at the end of the observation after approximately 6 weeks. The sum of the scores 
divided by 10 gives the CCQ score, which measures the health and functional status. A higher 
CCQ score is indicative of worse status.
The functional state score is a calculation of the sum of the 4 questions (#’s 7, 8, 9, 10) 
divided by 4, the symptom score is calculation of the sum of the 4 questions (#’s 1, 2, 5, 6) 
divided by 4 and the mental state score is a calculation of the sum of the 2 questions (#’s 3, 4) 
divided by 2. More details will be described in the statistical analysis plan.
A change of 0.4 points is considered to be the MCID for the total CCQ score [XLIV]. 
Primary objective: Assess the proportion of patients achieving “therapeutic success” 
(0.4 point decrease in the CCQ score between baseline and after approximately 6 weeks of 
treatment).
Secondary objectives are assessment of changes in CCQ and in the CCQ symptom, mental 
state and functional state domains 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), the patient’s general 
condition (physician’s evaluation) at visit 1 and at visit 2, as well as patient satisfaction with 
Spiolto® Respimat® and willingness to continue treatment with Spiolto® Respimat® at visit 2 
as proxy for adherence.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a self-controlled non-interventional study (NIS) enrolling consented COPD patients 
who will be treated with Spiolto® Respimat® according to the approved SmPC.
9.2
SETTING
9.2.1
Study sites
It is planned that data of approximately 4500 patients from approximately 11 countries will be 
collected. Site selection will be performed to reflect routine COPD care in order to secure 
representativeness of the COPD population. 
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.
9.2.2
Study population
Inclusion Criteria:
Patients can be included if all of the following criteria are met:
•
Written informed consent prior to participation
•
Female and male patients ≥40 years of age
•
Patients diagnosed with COPD and based upon the investigator’s decision requiring a
new prescription of Spiolto® Respimat® (combination of two long-acting 
bronchodilators) according to Spiolto® Respimat® SmPC,  GOLD COPD Strategy 
Document 2018 (GOLD COPD groups B to D) and local COPD guidelines
Exclusion Criteria:
•
Patients with contraindications according to Spiolto® Respimat® SmPC
•
Patients already on a LABA/LAMA combination (free and fixed dose) in the last 6 
weeks before study entry
•
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 
•
Pregnancy and lactation
•
Current participation in any clinical trial or any other non-interventional study of a 
drug or device.
9.2.3
Study visits
Patients will be enrolled consecutively and will be followed over an observational period of 
approximately 6 weeks. Data as listed in Table 9.2.3.1 will be collected.

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Two study visits will be performed. At Visit 1 (baseline) the patient will be included into the 
NIS. At visit 2, after approximately 6 weeks from baseline, the observation of the patient will 
end. The respective exams and data to be collected are listed in Table 9.2.3.1.
Table 9.2.3.1: 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
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
mMRC breathlessness scale, completed by the patient
X
Past COPD therapies (6 weeks before visit 1)
X
Respimat® training (yes/no)
X
COPD severity based on GOLD assessment1
X
GOLD spirometric classification, if available2
X
Smoking status/history
X
X
Concomitant diseases / Comorbidities
X
X
COPD related and other relevant concomitant medication
X
X
Health and functional status by CCQ questionnaire, completed by patient
X
X
 
X
X
General condition of patient evaluated by Physician’s Global Evaluation 
(PGE), completed by the physician
X
X
Safety: Adverse Drug Reactions (serious and non-serious), fatal AE, 
pregnancy
X
X
Patient satisfaction with Spiolto® Respimat®, completed by the patient
X
Rationale 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 ( B, C or D) will be automatically calculated within the eCRF based on available exacerbation history 
and mMRC. 
2 GOLD stage 1-4 spirometric classification of airflow limitation based on post-bronchodilator FEV1 if available.

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9.2.4
Study discontinuation
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular study site
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the study, or any other administrative reasons, i.e. lack of recruitment
3. Violation of the observational plan or the contract by a study site or investigator, 
disturbing the appropriate conduct of the study
9.3
VARIABLES
The following parameters will be collected and assessed at visit 1 and/ or visit 2:
-
Patient demographics (age, gender, height & weight)
-
Smoking status (current smokers, former smokers, and never smokers) and pack-years
-
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 concomitant medication such as beta-blockers, beta-agonists, 
corticosteroids, or proton pump inhibitors
-
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) at baseline
-
Clinical control based on CCQ and CCQ symptom, mental state and functional state 
domain scores
-
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
-
Safety Reporting; Adverse Drug Reactions (serious and non-serious), fatal AEs, and 
pregnancies at the beginning and at the end of the study
-
GOLD spirometric classifications (1, 2, 3, 4) and GOLD patient groups (B, C, D) based 
on GOLD 2018

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9.3.1
Exposures
All patients will receive LAMA/LABA combination treatment with Spiolto® Respimat®
according to the SmPC.
Spiolto® Respimat® contains 

the long-acting anticholinergic tiotropium bromide. 
The dose dispensed is 2.5 micrograms of tiotropium per puff

the selective beta2-adrenoceptor agonist olodaterol. The dose dispensed is 2.5 
micrograms of olodaterol per puff (as olodaterol hydrochloride). 
The recommended daily dose of Spiolto® Respimat® for adults is 5 micrograms of tiotropium 
plus 5 micrograms of olodaterol, equivalent to inhaling 2 puffs from the Respimat® inhaler 
once daily at the same time of day. 
The Summaries of Product Characteristics on Spiolto® Respimat® is contained in the NIS ISF 
in the “Summary of Product Characteristics” section.
Note: The recommended doses stated in the Summary of Product Characteristics should not 
be exceeded.
9.3.2
Outcomes
9.3.2.1
Primary outcome
“Therapeutic success” approximately 6 weeks at visit 2 (0.4 point decrease in the Clinical 
COPD Questionnaire - CCQ score from visit 1 to visit 2).
9.3.2.2
Secondary outcomes
-
Changes in the Clinical COPD Questionnaire (CCQ) and the CCQ symptom, mental state 
and functional state domain scores from visit 1 (baseline) to visit 2 (approximately 6 
weeks)
-
General condition of the patient, evaluated by the physician (PGE score) at 
visit 1(baseline) and visit 2 (approximately 6 weeks).
-
Patient satisfaction with Spiolto® Respimat® at visit 2 (approximately 6 weeks).
-
Willingness to continue treatment with Spiolto® Respimat® at visit 2 (approximately 6 
weeks) as proxy for adherence

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9.4
DATA SOURCES
Medical records collected through routine clinical care will be used to assess the 
inclusion/exclusion criteria of patients. Such medical records will be used for patient 
demographics, smoking history, collection of previous COPD medication, concomitant 
diseases, concomitant medication, previous exacerbation history.
All patients will be enrolled consecutively. The study physician has the ultimate responsibility 
for the collection and reporting of all clinical and patient data through the eCRFs as well as 
ensuring that they are accurate and complete.
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 will be used to automatically calculate the 
GOLD patient group (B, C, or D) in the eCRF.
The CCQ questionnaire contains 10 questions. Each question can be scored by patients on a 7-
point scale between 0 and 6. The sum of the scores divided by 10 gives the total CCQ score.
For the functional status calculation the sum of the 4 questions (# 7, 8, 9, 10) is divided by 4, 
for the symptom domain the sum of the 4 questions (# 1, 2, 5, 6) is divided by 4 and for the 
mental state domain the sum of the 2 questions (# 3, 4) is divided by 2. A change of 0.4 
points is considered to be the MCID. This questionnaire will be filled out by the patient and 
entered into the database. Patients will be asked to complete the CCQ in order to evaluate 
their clinical control before and approximately 6 weeks after treatment with Spiolto®
Respimat®.
The patients will be asked by the physician to estimate the daily average rescue medication 
(eg. SABA, like Salbutamol) use in the week before Visit 1 and in the week before Visit 2
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.
Willingness to continue treatment is assessed by a yes/no question.
9.5
STUDY SIZE
We assume that patients treated with Spiolto® Respimat® will have a CCQ therapeutic 
success rate similar to the SGRQ responder rate considering the following:
1) CCQ has the great advantage of simplicity for the patient, having a very good correlation
(rho = 0.67 to rho = 0.72) with the St George respiratory questionnaire (SGRQ) [XLV]. 
2) In TONADO studies [XXI] patients treated with Spiolto® Respimat® had a 57.5% SGRQ 
responder rates after 24 weeks.

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The TONADO had a selected trial population, so a real world population would probably 
show somewhat lower numbers due to the wide diversity of potential patients that will be 
followed up. Therefore a 50% CCQ responder rate is a reasonable assumption.
Assuming a 50% therapeutic success rate for CCQ and a sample size of 4050 patients, the 
95% confidence interval for the therapeutic success rate would be between 48.5% (lower 
limit) and 51.5% (upper limit).
To account for a 10% drop-out rate, the sample size becomes approximately 4500patients.
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 and the safety requirements of the FDA (US Food & Drug Administration) 
concerning systems for the data acquisition of clinical studies in accordance with "Title 21 
Code of Federal Regulations (21 CFR Part 11): Electronic Records; Electronic Signatures. 
Patient confidentiality will be strictly maintained.
9.7
DATA ANALYSIS
Planned analyses
More details will be described in the statistical analysis plan (SAP).
No formal hypothesis testing will be performed since this is a self-controlled study.
All patients who have received at least one dose of Spiolto® Respimat® will be included in the 
analysis; 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 CCQ score at

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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 CCQs 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. Proportion rates and 95% CI will be given when appropriate.
The analyses will relate to the following data: 

Patient demographics (gender, age, height, 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 
Reported exacerbations
Breathlessness based on mMRC score at visit 1

Therapeutic success based on CCQ score; primary outcome 

Changes from Visit1 to Visit 2 in the CCQ and CCQ symptom, mental state and 
functional state scores; secondary outcome

Patient reported daily average number of puffs of COPD rescue medication (eg. 
SABA, like Salbutamol)  at the week before Visit 1 and the week before Visit 2

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

Willingness to continue; secondary outcome

Adverse Drug Reactions (ADR & SADR), fatal AEs, pregnancies
GOLD spirometric classifications (1, 2, 3, 4) and GOLD patient groups (B, C, D)  
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 
9.7.1
Main analysis
For the primary outcome, the proportion of patients with CCQ therapeutic success will be 
presented together with the 95% confidence interval.

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9.7.2
Secondary analyses 
For secondary analyses, the Physician’s Global Evaluation (PGE) at visit 1 and visit 2, patient 
satisfaction and willingness to continue treatment at visit 2 are categorical variables so they 
will be analysed as tabulations of frequencies. Change from Visit 1 to Visit 2 in the CCQ and 
CCQ symptom, mental state and functional state 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.
9.7.3
Handling of missing data
For rules regarding the imputation of CCQ score, refer to www.ccq.nl (Section health care 
professionals, scoring, missing data rules). 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.
9.9
LIMITATIONS OF THE RESEARCH METHODS
The intention of this NIS is to collect data on the changes in health and functional status in 
patients with COPD during therapy with Spiolto® Respimat® in a real world setting.

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NIS appears 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 centres 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.
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
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.
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.

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9.10.2.2
Direct access to source data and documents
The investigator will permit study-related monitoring, audits 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 each participating EU member state needs to be notified about 
the end of the study (last patient/patient out, unless specified differently in Section 9.2) or 
early termination of the study. 

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10.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) (to the extent applicable to the NIS setting and required by local 
regulations), Good Epidemiological Practice (GEP), 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/ICH GCP.
10.1
STUDY APPROVAL, PATIENT INFORMATION AND INFORMED 
CONSENT 
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / 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 authorized 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 study 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities, i.e. the Competent Authorities 
(CA).

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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 unfavourable 
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.

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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 
and safety assessment within this study, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. 
No AESIs have been defined for this study.
11.2   ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorisation. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined.
The following must be collected by the investigator in the eCRF from signing the informed 
consent onwards until the end of the study: 
-
all (serious and non-serious) adverse drug reaction(ADRs), related to Spiolto® Respimat®, 
-
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 in addition be used and forwarded to the local 
Pharmacovigilance 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 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:

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•
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
•
No medically sound alternative etiologies that could explain the event (e.g. pre-
existing 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 a study. Once a subject has been enrolled into the 
study, after having taken 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 (S)AE form is to be completed and forwarded to the local 
Pharmacovigilance point of contact for each country within 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: 

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Type of Report
Timeline
All serious ADRs associated with Spiolto® Respimat®
immediately within 24 hours
All AEs with fatal outcome in patients exposed to 
Spiolto® Respimat®
immediately within 24 hours
All non-serious ADRs associated with Spiolto®
Respimat®
7 calendar days
All pregnancy monitoring forms 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 eCRF pages and the (S)AE NIS 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 MAH 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.
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 finalisation of the Study Report.

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13.
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Lange P, Aumann JL, Derom E, Hamilton A, Tetzlaff K, Ting N, van Noord JA. The 
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Feldman G, Bernstein JA, Hamilton A, Nivens C, LaForce C. The 24-hour FEV1 time 
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via Aerolizer in patients with COPD: results from two 6-week studies. Chest 2013, 
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XIII.
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 (P13-11345)
XIV.
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 (P13-11341)
XV.
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 (ID 688). ACCP 2013 (P13-14109)
XVI.
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. 2010; 181: A4445, Abstr 
(P10-09337)
XVII.
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 (P14-12073)
XVIII.
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. 
2010; 36 (Suppl 54): 1014S, Abstr 5557 (2010) (P10-14042)
XIX.
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. 2012; 40 
(Suppl 56): 525S - 526S, Abstr P2882 (P13-02357)

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XX.
Newman SP, Steed KP, Reader SJ, Hooper G, Zierenberg B. Efficient delivery to the 
lungs of flunisolide aerosol from a new portable hand-held multidose nebulizer.
J Pharm Sci. 1996 Sep; 85 (9): 960-964 (P96-8282)
XXI.
Buhl R, Maltais F, Abrahams R, Bjermer L, Derom E, Ferguson G et al. Tiotropium 
and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–
4). Eur Respir J. 2015; DOI: 10.1183/09031936.00136014 (P15-03349)
XXII.
Beeh KM, Westerman J, Kirsten AM, Hébert J, Grönke L, Hamilton A. The 24-h 
lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination 
in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2015 Jun; 32: 53-59
(P15-04531)
XXIII.
Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional 
burden of disease and risk factors, 2001: systematic analysis of population health 
data. Lancet 2006; 367: 1747–1757 (R07-0651)
XXIV.
Almagro P, Calbo E, Ochoa de Echagüen A, Barreiro B, Quintana S, Heredia JL, 
Garau J. Mortality after hospitalization for COPD. Chest. 2002; 121: 1441–1448 
(R04-1526)
XXV.
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Properties of the COPD assessment test in a cross-sectional European study. Eur 
Respir J. 2011; 38: 29–35 (R17-0261)
XXVI.
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of unreported COPD exacerbations on health-related quality of life at 1 year.
Eur Respir J. 2010; 35: 1022–1030 (R17-0260)
XXVII.
Esteban C, Quintana JM, Aburto M, Moraza J, Egurrola M, Pérez-Izquierdo J et al. 
Impact of changes in physical activity on health-related quality of life among patients 
with chronic obstructive pulmonary disease. Eur Respir J. 2010; 36: 292–300 (R17-
0259)
XXVIII.
Burtin C, Saey D, Saglam M, Langer D, Gosselink R, Janssens W et al. Effectiveness 
of exercise training in patients with COPD: the role of muscle fatigue. Eur Respir J.
2012; 40: 338–344 (R17-0258)
XXIX.
Troosters T, Celli B, Lystig T, Kesten S, Mehra S, Tashkin DP et al. Tiotropium as a 
first maintenance drug in COPD: secondary analysis of the UPLIFT trial. Eur Respir 
J. 2010; 36: 65–73 (P10-03336)
XXX.
Janson C, Marks G, Buist S, Gnatiuc L, Thorarinn Gislason T, McBurnie MA et al.
The impact of COPD on health status: findings from the BOLD study.
Eur Respir J. 2013; 42 (6): 1472-1483. doi: 10.1183/09031936.00153712
(P17-00943)

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XXXI.
Katz P, Chen H, Omachi TA, Gregorich SE, Julian L, Cisternas M. The role of 
physical inactivity in increasing disability among older adults with obstructive airway 
disease. 
J Cardiopulm Rehabil Prec. 2011; 31: 193-197 (R15-4559)
XXXII.
Troosters T, Sciurba F, Battaglia S, Langer D, Valluri SR, Martino L et al. Physical 
inactivity in patients with COPD, a controlled multi-center pilot-study. Respir Med. 
2010 Jul; 104 (7): 1005-1011.
doi: 10.1016/j.rmed.2010.01.012. Epub 2010 Feb 18 (R13-3633)
XXXIII.
Watz H, Waschki B, Meyer T, Magnussen H. Physical activity in patients with 
COPD. Eur Respir J. 2009 Feb; 33 (2): 262-272.
doi: 10.1183/09031936.00024608. Epub 2008 Nov 14 (R09-1615)
XXXIV.
Maltais F, LeBlanc P, Simard C, , Jobin J, Bérubé C, Bruneau J et al. Skeletal muscle 
adaptation to endurance training in patients with chronic obstructive pulmonary 
disease. 
Am J Respir Crit Care Med. 1996; 154: 442-447 (R15-4561)
XXXV.
Mador MJ, Bozkanat E. Skeletal muscle dysfunction in chronic obstructive 
pulmonary disease. Respir Res. 2001; 2: 216-224 (R15-4562)
XXXVI.
Garcia-Rio F, Rojo B, Casitas R, Lores V, Madero R, Romero D et al. Prognostic 
value of the objective measurement of daily physical activity in patients with COPD. 
Chest. 2012 Aug; 142 (2): 338-346 (R15-4563)
XXXVII.
Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Antó JM. Regular physical activity 
reduces hospital admission and mortality in chronic obstructive pulmonary disease: a 
population based cohort study. Thorax. 2006 Sep; 61 (9): 772-778. Epub 2006 May 
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XXXVIII.
Cooper C, Celli B, Jardim J, Wise RA, Legg D, Guo J, Kesten S. Treadmill 
Endurance During 2-Year Treatment With Tiotropium in Patients With COPD. A 
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(P13-04267)
XXXIX.
Maltais F, Hamilton A, Marciniuk D, Hernandez P, Sciurba FC, Richter K et al.
Improvements in symptom-limited exercise performance over 8 h with once-daily 
tiotropium in patients with COPD. Chest. 2005 Sep; 128 (3): 1168 - 1178 (P05-
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XL.
Casaburi R, Kukafka D, Cooper C et al. Improvement in Exercise Tolerance With the 
Combination of Tiotropium and Pulmonary Rehabilitation in Patients With COPD. 
Chest. 2005 Mar; 127 (3): 809-817 (P05-02413)
XLI.
Kocks JWH, van de Ven M, Uil S. M., van den Berg JW, Asijee G. M., van der 
Molen T. Functional Status measurement in COPD: The value of the functional status 
domain of the CCQ. Thorax. 2006; 61(Suppl II): ii40 (R17-0254)

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XLII.
http://ccq.nl/?page_id=85&lang=nl
XLIII.
Tsiligianni IG, van der Molen T, Moraitaki D, Lopez I, Kocks JW, Karagiannis K et 
al. BMC Pulmonary Medicine. 2012; 12: 20. http://www.biomedcentral.com/1471-
2466/12/20
XLIV.
Kocks JWH, Tuinenga MG, Uil SM, van den Berg JW, Ståhl E, vander Molen T. 
Health status measurement in COPD: the minimal clinically important difference of 
the clinical COPD questionnaire. Respir Res. 2006; 7: 62 (R17-0256)
XLV.
Van der Molen T, Willemse BWM, Schokker S, ten Haken NHT, Postma DS, Juniper 
E. Development, validity and responsiveness of the Clinical COPD Questionnaire. 
Health Qual Life Outcomes. 2003; 1: 13 (R04-2815)
XLVI.
DOI: http://www.dx.doi.org/10.2147/COPD S29868 (R17-0255) and 
http://www.theipcrg.org/display/RESCOPD/COPD+Assessment+Tool+Guides (R17-
0257)

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
The stand-alone documents for this non-interventional study are:

Informed Consent Form

CCQ Questionnaire

Physician’s Global Evaluation (PGE)*

Breathlessness Scale (mMRC)

Statistical Analysis Plan (SAP)

Data Management Plan (DMP)

Serious Adverse Event Report in Non-Interventional Studies - (S)AE NIS Form

Pregnancy Monitoring Form
All of the above documents will be archived in the Trial Master File in its original English 
master version.
* to be completed directly within the eCRF

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable

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ANNEX 3. ADDITIONAL INFORMATION
1. Physician’s Global Evaluation (PGE)*
* to be completed directly within the eCRF
General condition of the patient at the initial examination (Visit 1)
Please mark with a cross as applicable
Poor
Satisfactory
Good
Excellent 
1  2
3  4
5  6
7  8
General condition of the patient after 4 to 6 weeks of treatment (Visit 2)
Please mark with a cross as applicable
Poor
Satisfactory
Good
Excellent 
1  2
3  4
5  6
7  8

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2. Patient Satisfaction Questionnaire
Please choose 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 you with inhaling from the Respimat® device?
1
very dissatisfied
2
dissatisfied
3
rather
dissatisfied
4
neither satisfied 
nor dissatisfied
5
rather satisfied
6
satisfied
7
very satisfied
How satisfied are you 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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3. Clinical COPD Questionnaire

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4. Modified Medical Research Council (mMRC) Questionnaire for Assessing the 
Severity of Breathlessness 
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 the level or walking up a slight hill.
1
I walk slower than people of the same age on the level because of 
breathlessness, or have to stop for breath when walking at my own pace on the 
level.
2
I stop for breath after walking about 100 meters or after a few minutes on level. 3
I am too breathless to leave the house or I am breathless when dressing or 
undressing.
4

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c20825865
1.0
clinical-trial-protocol-version-01
Changes in clinical control of COPD patients measured by the Clinical COPD
Questionnaire during therapy with Spiolto® Respimat® in routine clinical practice
Author-Trial Clinical Monitor
26 Mar 2018 15:20 CEST
Author-Other
26 Mar 2018 17:47 CEST
Author-Trial Statistician
26 Mar 2018 19:02 CEST
Approval-
 Safety Evaluation
Therapeutic Area
27 Mar 2018 09:02 CEST
Approval-
 of Global
Epidemiology
28 Mar 2018 19:49 CEST
Approval-Team Member Medical
Affairs
02 Apr 2018 10:29 CEST
Author-Trial Clinical Monitor
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Approval-Team Member Medical
Affairs
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.0
Approval-
 Safety Evaluation
Therapeutic Area
03 Apr 2018 10:34 CEST
Author-Trial Statistician
03 Apr 2018 14:27 CEST
Approval-
 of Global
Epidemiology
03 Apr 2018 14:38 CEST
Author-Other
04 Apr 2018 12:14 CEST
Verification-Paper Signature
Completion
04 Apr 2018 15:29 CEST
Approval-Team Member Medical
Affairs
04 Apr 2018 15:55 CEST