Effectiveness and Handling of Spiolto® Respimat ® in COPD Patients - Italy
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
TITLE PAGE
Non-interventional Study Protocol
Document Number:
c10166821
BI Study Number:
1237.43
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.
Brief lay title
OTIVACTO
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
13 July 2016
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:
Joint PASS:
No

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Research question and 
objectives:
The primary objective of this NIS 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.
Country(-ies) of study:
Italy
Author:
 
Tel: 
Fax: 
Mobile:
Marketing authorisation 
holder(s):
Boehringer Ingelheim International GmbH
Binger Str. 173
D-55216 Ingelheim am Rhein
Germany
In case of PASS, add:
MAH contact person:
Not applicable
In case of PASS, add:
<EU-QPPV:>
Not applicable
In case of PASS, add:
<Signature of EU-
QPPV:>
Not applicable
Date:
13 July 2016
Page 1 of 41
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© 2016 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
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 14
9.
RESEARCH METHODS .................................................................................... 15
9.1
STUDY DESIGN............................................................................................ 15
9.2
SETTING........................................................................................................ 16
9.2.1
Study sites ............................................................................................... 16
9.2.2
Study population ..................................................................................... 16
9.3
VARIABLES .................................................................................................. 17
9.4
DATA SOURCES........................................................................................... 18
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
Further analysis ....................................................................................... 19
9.7.3
Planned analyses ..................................................................................... 19
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
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

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9.10.1.6 Protocol Violations ............................................................................... 24
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 25
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
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................................................................... 34
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 35
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 36
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 37
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 38

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
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
LAMALong-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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Trial Data Manager (TDM)
Trial Programming
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30( %&&7)*%=7#

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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:
13 July 2016
1237.43
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, 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.

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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:
13 July 2016
1237.43
1.0
n.a.
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 -
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
-
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:
13 July 2016
1237.43
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 400 patients in 40  Italian 
centres will be collected
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-2017
Planned end of data collection: January-2018
Planned final study report: April-2018

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5.
AMENDMENTS AND UPDATES
None.

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6.
MILESTONES
Milestone
Planned Date
IRB/IEC approval
15 Jan 2017
Start of data collection
31 January 2017
End of data collection
31 January 2018
Final report of study 
results:
30 April 2018

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7.
RATIONALE AND BACKGROUND
7.1
MEDICAL BACKGROUND
COPD is defined as a preventable and treatable disease of the airways, with significant 
systemic consequences. Inactivity is believed to be crucial to the development of the 
extrapulmonary effects of the disease like skeletal muscle weakness, osteoporosis and 
cardiovascular disease. Recent data suggest that patients suffering from COPD with 
low levels of physical activity have increased risk for hospital admission and have 
significantly enhanced mortality. Epidemiological data suggest that this may directly 
or indirectly lead to more rapid decline in lung function [R13-3633]. 
Physical activity is reduced early in the disease progression, as of GOLD Stage 2 
[R13-3633]. More recent evidence from large placebo controlled clinical trials 
indicates that COPD patients are experiencing a steeper absolute decline in lung 
function with GOLD 2 airflow limitation than with GOLD 3 and 4 [R15-5015]. All 
these observations suggest the importance of early optimal treatment of the disease.
Long-acting bronchodilators, such as long-acting muscarinic antagonists (LAMAs), 
are the cornerstone of maintenance therapy for patients with moderate to very severe 
chronic obstructive pulmonary disease (COPD) whose symptoms are not adequately 
controlled by short-acting bronchodilators alone [P13-05794, P14-01052].
An option recommended by GOLD guideline for patients not adequately controlled on 
a single long-acting bronchodilator is to combine a LAMA with a long-acting β2-
agonist (LABA) [P14-01052]. This has prompted the development of combining 
LAMA+LABA as fixed-dose combinations [P13-05794]. The rationale for combining 
bronchodilators with different mechanisms is based on the notion of additive 
relaxation of airway smooth muscle by direct inhibition of cholinergic activity and 
functional antagonism of bronchoconstriction through β2-adrenergic pathways, with 
the expectation of an increase in the degree of bronchodilation for equivalent or lesser 
side effects. Several recent studies have provided evidence in support of this increased 
bronchodilatory effect when LABAs are added to LAMAs.
When long acting beta-agonists (LABA) and long acting muscarinic antagonists 
(LAMA) with similar or equivalent posologies are combined, the opportunity exists 
for offering a simpler and more convenient administration regimen with the 
development of fixed combinations within the same inhaler device. Fixed-dose 
combinations of a short-acting β2–agonist 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]. 
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 

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(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 date 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

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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.
Baseline characteristics of eligible patients 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 400 patients from approximately 40 sites in 
Italy 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 in the study (i.e. who have 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
Study sites
It is planned that data of approximately 400 patients from approximately 40 sites in 
Italy will be collected. Site selection will be performed to reflect routine COPD care in 
order to secure representativeness of the COPD population.
9.2.2
Study population

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

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3.
Patients diagnosed with COPD and requiring long-acting dual 
bronchodilation (LAMA + LABA) treatment according to approved 
Spiolto® Respimat® SmPC.

Exclusion Criteria:
1. Patients with contraindications according to Spiolto® Respimat® SmPC
2. Patients who have been treated with a LABA/LAMA combination (free and 
fixed dose) in the previous 6 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 

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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 
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 
372 patients, the 95% confidence interval for the therapeutic success rate would be 
between 44.9% (lower limit) and 55.1% (upper limit). 
To account for a 7% drop-out rate, the sample size becomes 400 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 

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validation or presence/absence of data. Concurrent manual data review may be 
performed based on parameters dictated by the DMP. Ad hoc queries to the sites may 
be generated and followed up for resolution. A source data quality audit may be 
initiated to ensure that the data in the database is accurate. Source data verification 
(SDV) will be performed at sites identified by a risk-based approach as needed.
The database will be housed in a physically and logically secure computer system 
maintained in accordance with a written security policy. The system will meet the 
standards of the International Committee on Harmonization guideline E6R1 regarding 
electronic study data handling. Patient confidentiality will be strictly maintained.
9.7
DATA ANALYSIS
9.7.1
Statistical design – Model
Details will be described in the statistical epidemiological analysis plan (SEAP).
9.7.2
Further analysis
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

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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 
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. 

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Based on this, checks on completeness and plausibility will be performed upon data 
entry in the eCRF.
Validity of data entry thus is ensured by integrated validation checks performed by the 
system, indicating missing or implausible entries to the document list or investigator. 
All corrections will be visible from the systems audit trail.
No regular source data verification is planned in this study. However, in case of 
decreasing compliance (i.e. of missing data, data discrepancies, protocol violations, 
etc.) a for-cause audit or risk-based monitoring visit will be performed.
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.

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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.
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.
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.
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.

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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 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.
Adverse Event of Special Interest (AESI)

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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 (e)CRF from signing the 
informed consent onwards until the end of the study: 
-
all adverse drug reaction (ADRs) (serious and non-serious), 
-
all AEs with fatal outcome, 
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. 

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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
•
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.
Expedited Reporting of AEs and Drug Exposure During Pregnancy

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The following must be reported by the investigator on the NIS AE form from signing 
the informed consent onwards until the end of the study: 
Table 11.2:1 Reporting types and timelines
Type of Report
Timeline
All serious ADRs associated with 
Spiolto® Respimat®
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to
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 the 
NIS AE form.
Information required
For each reportable adverse event, the investigator should provide the information 
requested on the appropriate (e)CRF pages and the NIS AE form.
Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other 
than the associated with 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. Also the investigator is encouraged to 
report all adverse event related to any drug to LHA according to local 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
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13.2
UNPUBLISHED REFERENCES
n.a.

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS

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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 CHECKLIST 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
3Patient 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

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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
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

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