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
Non-interventional Study Protocol
Document Number:
c03680587-01
BI Study Number:
1237.44
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:
1.0
Date of last version of 
protocol:
16 November 2015
PASS:
No
EU PAS register 
number:
Not yet available  
(study will be registered in EU PAS Register (ENCePP) and 
clinicaltrials.gov)
Active substance:
R03AL06
Tiotropium bromide + Olodaterol
Medicinal product:
Spiolto® Respimat® 2.5 microgram/2.5 microgram, inhalation 
solution; tiotropium/olodaterol 
Product reference:
NL/H/3157/001/DC
Procedure number:
n.a.
Marketing authorisation 
holder(s):
MAH:
Boehringer Ingelheim International GmbH
Binger Straße 173
55216 Ingelheim am Rhein
This study is initiated, managed and sponsored by:
Boehringer Ingelheim RCV GmbH & Co KG
Division Medicine/Medical Affairs
Dr. Boehringer-Gasse 5-11
A-1121 Wien
Joint PASS:
No
Research question and 
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.
The secondary objective is to evaluate the patient’s general 

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condition (physician’s evaluation) at visit 1 (= baseline visit at 
the start of the study) and at visit 2 (= final visit approx. 6 weeks 
after visit 1), as well as patient satisfaction with Spiolto® 
Respimat® at visit 2.
Country(-ies) of study:
11 countries incl. Russia, Romania, Hungary, Austria, Czech 
Republic, Bulgaria, Slovenia, Croatia, Israel, Slovakia, and 
Switzerland
Author:
 (Trial Clinical Monitor)
Tel: 
Fax: 
Mobile: 
 (Team Member Medicine)
Tel: 
Fax: 
Mobile: 
Marketing authorisation 
holder(s):
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
MAH contact person in 
case of PASS:
Not applicable
EU-QPPV in case of 
PASS:
Not applicable
Signature of EU-QPPV 
in case of PASS:
Not applicable
Date:
16 November 2015
Page 1 of 39
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© 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
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
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 14
8.1
Rationale for performing the study................................................................. 14
8.2
Study objectives .............................................................................................. 14
9.
RESEARCH METHODS .................................................................................... 15
9.1
STUDY DESIGN............................................................................................ 15
9.1.1
Outcomes................................................................................................. 16
9.2
SETTING........................................................................................................ 16
9.2.1
Inclusion criteria...................................................................................... 16
9.2.2
Exclusion criteria..................................................................................... 16
9.3
VARIABLES .................................................................................................. 17
9.4
DATA SOURCES........................................................................................... 17
9.5
STUDY SIZE.................................................................................................. 18
9.6
DATA MANAGEMENT................................................................................ 18
9.7
DATA ANALYSIS......................................................................................... 19
9.7.1
Statistical design – Model ....................................................................... 19
9.7.2
Null and alternative hypotheses .............................................................. 19
9.7.3
Planned analyses ..................................................................................... 19
9.7.4
Handling of missing data......................................................................... 20
9.8
QUALITY CONTROL................................................................................... 20
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 21
9.10
OTHER ASPECTS ......................................................................................... 21
9.10.1
Informed Consent, Data Protection, Study Records ............................... 21
9.10.1.1 Study Approval, Patient Information, and Informed Consent .......................22
9.10.1.2 Data Quality Assurance .................................................................................22

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9.10.1.3 Records ..........................................................................................................22
9.10.1.3.1
Source documents....................................................................................22
9.10.1.3.2
Details of treatment continuation / discontinuation Direct access to source 
data and documents......................................................................................................23
9.10.1.4 Statement of Confidentiality..........................................................................23
9.10.1.5 Completion of Study......................................................................................23
9.10.1.6 Protocol Violations ........................................................................................24
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 25
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS & ADVERSE 
DRUG REACTIONS .......................................................................................... 26
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 26
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 27
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 29
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 30
13.
REFERENCES .................................................................................................... 31
13.1
PUBLISHED REFERENCES......................................................................... 31
13.2
UNPUBLISHED REFERENCES................................................................... 33
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 34
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 35
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 36

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
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 Corticosteroids
IEC
Independent Ethics Committee
ISF
Investigator Site File
LABA
Long-acting beta2 adrenoceptor agonist
LAMA
Long-acting muscarinic antagonist 
mMRC
Modified Medical Research Council Scale
NIS
Non-Interventional Study
PF-10
Physical Functioning patient questionnaire
PGE
Physician’s Global Evaluation
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SF-36
36-Item Short Form Health Survey
SGRQ
St George’s Respiratory Questionnaire
SmPC
Summary of Product Characteristics

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3.
RESPONSIBLE PARTIES
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 Risk Management  (TA  RM), and
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Trial Data Manager (TDM)
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:
16 Nov. 2015
1237.44
1.0
n.a.
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 constraint of patients with moderate to 
very 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 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.
The secondary objective is 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 approx. 6 weeks after visit 1), as well 
as patient satisfaction with Spiolto® Respimat® at visit 2.
Study design:
Open-label observational study in 11 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)
-
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

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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:
16 Nov. 2015
1237.44
1.0
n.a.
-
COPD related and other relevant 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)
-
Physical Functioning based on PF-10 scores (sub-domain of SF-36)
-
Patient satisfaction with Spiolto® Respimat® assessing the overall 
satisfaction with Spiolto® Respimat®, the satisfaction of inhalation,
as well as the device handling satisfaction
-
General condition of patient based on Physician’s Global Evaluation 
(PGE) assessing the general condition of the patient at visit 1 and at 
visit 2
-
Safety Reporting; Adverse Drug Reactions (serious and non-
serious), fatal AEs, and pregnancies at visit 1 and visit 2
-
GOLD spirometric classifications (1, 2, 3, 4) and GOLD patient 
groups (A, B, C, D) based on GOLD guidelines at visit 1

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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:
16 Nov. 2015
1237.44
1.0
n.a.
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:
It is planned that data of approximately 7000 patients in 11 countries will 
be collected (Russia, Romania, Hungary, Austria, Czech Republic, 
Bulgaria, Slovenia, Croatia, Israel, Slovakia, and Switzerland).
Data analysis:
Primary outcomes:
“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:
Planned start of data collection: January-2016
Planned end of data collection: January-2017
Planned final study report: April-2017

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5.
AMENDMENTS AND UPDATES
None

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
January 2016
End of data collection
January 2017
Final report of study results:
April 2017

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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 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; [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, P10-14042, P13-02357]. 

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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
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 life 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 and at visit 2, 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
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 months before visit 1)
X
Respimat® training (yes/no)
X
COPD severity based on GOLD assessment1
X
Smoking status/history
X
X
Concomitant diseases / Comorbidities
X
X
COPD related and other relevant concomitant medication
X
X
Physical functioning (PF-10) questionnaire, completed by the patient
X
X
General condition of patient evaluated by Physician’s Global Evaluation 
(PGE) 
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
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 outcomes:
“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.
9.2
SETTING
It is planned that data of approximately 7000 patients from approximately 750 sites in 11 
countries will be collected. Site selection will be performed to reflect routine COPD care in 
the participating countries in order to secure representativeness of the COPD population. The 
following countries will participate in this non-interventional study: Russia, Romania, 
Hungary, Austria, Czech Republic, Bulgaria, Slovenia, Croatia, Israel, Slovakia, and 
Switzerland.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
or not.
Boehringer Ingelheim reserves the right to discontinue the study or to remove a patient at a
particular study site 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.
9.2.1
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
9.2.2
Exclusion criteria
1. Patients with contraindications according to Spiolto® Respimat® SmPC

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2. Patients who have been treated with a LABA/LAMA combination (free and fixed 
dose) in the previous 6 months
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
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 relevant 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)
-
Physical Functioning based on PF-10 scores
-
Patient satisfaction with Spiolto® Respimat® assessing the overall satisfaction with 
Spiolto® Respimat®, the inhalation satisfaction as well as the device handling
-
General condition of patient based on Physician’s Global Evaluation (PGE) assessing 
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 (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
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 

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demographics, smoking history, collection of previous COPD medication, concomitant 
diseases, and concomitant medication.
All patients will be enrolled consecutively.
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 stage and patient group 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 the end of the study, using a 7-point 
ordinal scale with divisions from very dissatisfied to very satisfy.
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. 
In this 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 6510 
patients, the 95% confidence interval for the therapeutic success rate would be between 
48.8% (lower limit) and 51.2% (upper limit). 
 
 
 
 
To account for a 7% drop-out rate, the sample size becomes 7000 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 

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International Committee on Harmonization guideline E6R1 regarding electronic study data 
handling. Patient confidentiality will be strictly maintained.
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 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.
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 as recorded in the eCRF:
Patient demographics (age, gender, height, and weight)
Comorbidities
COPD related and other concomitant medication 
History of smoking 
Reported exacerbations
Breathlessness based on mMRC score
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)  
Details of treatment with inhaled respiratory agents before the study 
Details of treatment with respiratory agents during the study 

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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, mMRC at visit 1 and patient 
satisfaction at visit 2 are categorical variables so they will be analyzed as tabulations of 
frequencies. Change from visit 1 to visit 2 in the PF-10 score is a continuous outcome, so it 
will be analyzed 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 and 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 life 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.
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.
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.
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.
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 (CRFs) 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.
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.

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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);
-
Smoking status / history
-
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 Details of treatment continuation / discontinuation 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. Patient confidentiality will be 
ensured by using patient identification code numbers.
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 study (last patient out) or early termination of the study.

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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 DRUG 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), 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 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 to the local Pharmacovigilance 
point of contact for each country within respective timelines.

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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: 
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 (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 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 T, 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 104, 1005 – 1011 
(2010)
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
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models. J Pharmacol Exp Ther 334 (1), 53 - 62 (2010)
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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 
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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)
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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 
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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)
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management of chronic obstructive pulmonary disease. Respir Res (Lond) 14, 
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Pizzichini E. Symptomatic benefit of olodaterol QD delivered via Respimat vs 
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(ERS), Barcelona, 7 - 11 Sep 2013
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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
PF-10 Questionnaire based on SF-36
Breathlessness Scale (mMRC)
Patient Satisfaction Survey
Statistical Epidemiological Analysis Plan (SEAP)
Data Management Plan (DMP)
Serious Adverse Event Report in Non-Interventional Studies - (S)AE NIS Form
Pregnancy Monitoring 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 CECKLIST FOR STUDY PROTOCOLS
Not applicable.

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ANNEX 3. ADDITIONAL INFORMATION
1. Physical Functioning Questionnaire (PF-10) based on the 36-Item Short Form 
Survey.

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2. 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

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3. 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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4. 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

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
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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.
Approval-Pharmacovigilance
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16 Nov 2015 16:32 CET
Author-Clinical Project 
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