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

TITLE PAGE
Non-interventional Study Protocol
Document Number:
c03809777-01
BI Study Number:
1237.42
BI Investigational
Product(s):
Spiolto® Respimat®
Title:
SPIRIT: 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:
3 December 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 per puff
inhalation solution
Product reference:
Spiolto® Respimat® 2,5 Mikrogramm/2,5 Mikrogramm pro Hub 
Lösung zur Inhalation
Procedure number:
DCP:  NL/H/3157/001 / DC
Zul.-Nr.: 92213.00.00
Marketing authorisation 
holder(s):
MAH:
Boehringer Ingelheim International GmbH
Binger Straße 173
55216 Ingelheim am Rhein
Study initiator:
Boehringer Ingelheim Pharma GmbH&Co.KG
Binger Straße 173
55216 Ingelheim am Rhein
Joint PASS:
No

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Research question and 
objectives:
The objective of this NIS is to measure changes in physical 
functioning – as a surrogate for physical activity and exercise 
capacity – in COPD patients on treatment with Spiolto®
Respimat® after approximately 6 weeks.
A 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 at the end of the 
study, approx. 6 weeks after visit 1), as well as patient 
satisfaction with Spiolto® Respimat® at visit 2.
Country(-ies) of study:
Germany
Author:
Marketing authorisation 
holder(s):
Boehringer Ingelheim International GmbH 
Binger Straße 173
55216 Ingelheim am Rhein
Date:
3 December 2015
Page 2 of 48
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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 ................................................. 17
8.1
RATIONALE FOR PERFORMING THE STUDY ....................................... 17
8.2
STUDY OBJECTIVES................................................................................... 17
9.
RESEARCH METHODS .................................................................................... 18
9.1
STUDY DESIGN............................................................................................ 18
9.1.1
Outcomes................................................................................................. 19
9.2
SETTING........................................................................................................ 19
9.2.1
Inclusion criteria...................................................................................... 19
9.2.2
Exclusion criteria..................................................................................... 20
9.3
VARIABLES .................................................................................................. 20
9.4
DATA SOURCES........................................................................................... 21
9.5
STUDY SIZE.................................................................................................. 21
9.6
DATA MANAGEMENT................................................................................ 22
9.7
DATA ANALYSIS......................................................................................... 22
9.7.1
Statistical design – Model ....................................................................... 22
9.7.2
Null and alternative hypotheses .............................................................. 22
9.7.3
Planned analyses ..................................................................................... 22
9.7.4
Handling of missing data......................................................................... 24
9.8
QUALITY CONTROL................................................................................... 24
9.8.1
Administrative requirements................................................................... 24
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 25
9.10
OTHER ASPECTS ......................................................................................... 25
9.10.1
Informed consent, data protection, study records ................................... 25
9.10.1.1
Study approval, patient information, and informed consent ....... 26

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9.10.1.2
Data quality assurance................................................................. 27
9.10.1.3
Source documents........................................................................ 27
9.10.1.3.1
Direct access to source data and documents................................ 27
9.10.1.4
Statement of confidentiality ........................................................ 28
9.10.1.5
Completion of study .................................................................... 28
9.10.1.6
Protocol violations....................................................................... 28
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 29
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE DRUG 
REACTIONS....................................................................................................... 30
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 30
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 32
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 35
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 36
13.
REFERENCES .................................................................................................... 37
13.1
PUBLISHED REFERENCES......................................................................... 37
13.2
UNPUBLISHED REFERENCES................................................................... 39
14.
APPENDICES ..................................................................................................... 40
APPENDIX 1: PGE .................................................................................................... 41
APPENDIX 2: PF-10 QUESTIONNAIRE AND MMRC.......................................... 42
APPENDIX 3: (S)AE FORM ..................................................................................... 44
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 47
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 48

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of special interest
AMG
Arzneimittelgesetz (German Drug Act)
AUC
Area under the Curve
BfArM
Bundesinstitut für Arzneimittel und Medizinprodukte (German CA)
CI
Confidence Interval
CML
Local Clinical Monitor 
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
eCRF
Electronic Case Report Form
EU
European Union
FDC
Fix Dose Combination
FEV1
Forced expiratory volume in one second
GCP
Good Clinical Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
ICH
International Conference on Harmonisation
ICS
Inhalative Corticosteroides
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File
LABA
Long-acting beta2 adrenoceptor agonist
LAMA
Long-acting muscarinic antagonist 
MedDRA
Medical Dictionary for Drug Regulatory Activities
NCI - CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NIS
Non-Interventional Study
PF-10
Patient questionnaire
PGE
Physician’s Global Evaluation
SABA
Short-acting beta2 adrenoceptor agonist
SAE
Serious Adverse Event
SAMA
Short-acting muscarinic antagonist
SPC
Summary of Product Characteristics
VFA
Verband Forschender Arzneimittelhersteller
WHO
World Health Organisation

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3.
RESPONSIBLE PARTIES
Table 3: 1
Responsible parties
Function
Name / Location
Scientific coordinator
 
Therapeutic Area 
 
Respiratory Medicine 
(TA )
Team Member Medical 
Affairs (TM MA)
Team Member 
Epidemiology (TM Epi)
 
 Global 
Epidemiology (
GEpi)
Therapeutic Area 
 
Risk Management  (TA  
RM), and
Pharmacovigilance 
Working Group  (PVWG) 
GPV Study Coordination
Trial clinical monitor
Statistical analysis
Boehringer Ingelheim Pharmaceuticals, Inc.
Global Biom. And Clin. Appl./BDM
Data management
Boehringer Ingelheim Pharmaceuticals, Inc.
Global Biom. And Clin. Appl./BDM
Trial Programming
Boehringer Ingelheim Pharmaceuticals, Inc.
Global Biom. And Clin. Appl./BDM
CRO
Alcedis GmbH 
Winchesterstr. 3 
35394 Gießen (Europaviertel) 
Germany
Project 
: 

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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:
3 December 2015
1237.42
1.0
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.
Author 
, 
Rationale and 
background:
Reduced physical activity resulting in deconditioning and restricted 
physical functioning is a common problem of patients with moderate 
to severe COPD. Clinical studies investigating treatment with Spiolto®
Respimat® and its single components have shown significant 
improvements in exercise capacity in patients with COPD. Real-world
exercise data on the effects of a fixed-dose combination therapy of 
tiotropium and olodaterol administered in a single device in COPD 
patients who need treatment with two long-acting bronchodilators are 
not yet available.
Research question 
and objectives:
The primary objective of this NIS is to measure changes in physical 
functioning – as a surrogate for physical activity and exercise capacity 
– in COPD patients on treatment with Spiolto® Respimat® after 
approximately 6 weeks. 
A 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 at the end of the study, approx. 6 weeks 
after visit 1), as well as patient satisfaction with Spiolto® Respimat® at 
visit 2.
Study design:
Open-label observational study according to §4, section 23 and §67, 
section 6 German Medicines Act: all included COPD patients are 
receiving treatment with Spiolto® Respimat® for approximately 6 
weeks, which is the average time between two medical consultations.
Population:
COPD patients requiring a 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:
3 December 2015
1237.42
1.0
Variables:
-
Patient demographics (age, gender, height & weight)
-
Concomitant diseases / Comorbidities
-
Concomitant medication
-
General condition of patient based on Physician’s Global 
Evaluation PGE)
-
Smoking history
-
Exacerbations
-
Breathlessness based on mMRC score
-
Physical Functioning based on PF-10 scores
-
Patient satisfaction with Spiolto® Respimat®
-
Safety; ADR (serious and non-serious), fatal AEs, pregnancies
-
GOLD spirometric classifications (1, 2, 3, 4)
-
GOLD patient groups (A, B, C, D)
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 and at visit 2:
-
Physical Functioning Questionnaire (PF-10)
To be completed by the patient at visit 2 only:
Patient satisfaction survey. 
Study size:
2000 patients, 650 sites

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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:
3 December 2015
1237.42
1.0
Data analysis:
Primary outcome: “therapeutic success” at visit 2.
(10-point increase in the PF-10 score between visit 1 and visit 2).
Secondary outcomes: 
Change in the PF-10 score from visit 1 to visit 2.
General condition of the patient evaluated by the physician: PGE-score
at visit 1 and visit 2
Patient satisfaction with Spiolto® Respimat® at visit 2
 
 
 
 
Milestones:
Start of data collection
January 2016
End of data collection
December 2016
Final report of study results
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
December 2016
Final report of study results:
April 2017

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7.
RATIONALE AND BACKGROUND
7.1
MEDICAL BACKGROUND
Chronic obstructive pulmonary disease (COPD) is the term used to describe the occurrence of 
chronic bronchitis with or without pulmonary emphysema. It is a common lung disease, 
characterised by gradual airway constriction. This leads to a gradual limitation of the flow of 
air to and from the lungs, causing ventilation disorders, which in the majority of cases 
manifest as shortness of breath (dyspnoea). COPD is often preceded by a long-standing 
history of initially acute and then chronic bronchitis and pulmonary infections [1]
In clinical practice, COPD is defined by its characteristically low airflow in lung function 
tests. In contrast to asthma, this limitation of airflow is poorly reversible and gets 
progressively worse over time. The consequence is respiratory failure, resulting in an 
inadequate supply of oxygen to the internal organs and peripheral tissues[1].
COPD is caused by the inhalation of noxious substances such as smoke with harmful 
particles or gases (air pollution), but in the majority of cases by tobacco smoking. The 
noxious substance triggers an abnormal inflammatory response in the lung. This
inflammatory response leads to increased mucus production, tissue remodelling and, 
connected with this, to a narrowing of the air passages in the lower respiratory tract. As a 
result, the pulmonary parenchyma is destroyed and pulmonary emphysema is caused. Over 
time, there are further systemic consequences, such as myopathy, osteoporosis, cor 
pulmonale and hypertension with severe restriction of physical functioning. Recurrent acute 
exacerbations (e.g. due to pulmonary infections) bring about a further deterioration in the 
condition of the lungs[1].
The guidelines of the Deutsche Atemwegsliga (German Respiratory Association), for 
example, contain a detailed description of COPD and its causes, diagnosis and treatment[2].
According to the Helmholtz Centre in Munich[3], COPD is one of the most common diseases 
in the world. In its recent estimates from 2007, the World Health Organization assumes that 
there are 210 million sufferers, with the trend on the increase. The disease currently ranks 
fourth in the list of the most common causes of death. According to WHO forecasts, it will 
have moved up to third place in these statistics by 2020. The Organization has named indoor 
air pollution in developing countries, such as that caused by cooking on an open fire, and the 
fact that more and more women in industrialised nations smoke, as the reasons for the global 
increase in cases of COPD. Thus, disease rates are set to rise in the future, particularly in the 
female population.
COPD is diagnosed from the clinical presentation and also from mechanical lung function 
tests, such as spirometry, body plethysmography, measurement of diffusion and blood gas 
analysis. 
It is classified into degrees of severity 1 to 4 according to the reduction in forced expiratory 
volume in one second, FEV1 (%) from the age-related predicted value in the presence of a 
reduced (<70%) FEV1/forced vital capacity ratio [1].
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) include also symptoms 
and risk of exacerbations in their staging system, ranging from A to D [4].

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.
The most important treatment strategies are cessation of tobacco abuse and/or exposure to the 
noxious trigger, vaccinations against, pneumococci and, rehabilitation activities such as 
respiratory muscle stretch gymnastics and lung training (according to exercise capacity) and 
pharmacological treatment [1]. 
In accordance with the GOLD guidelines [4], for mild COPD (stage GOLD A) monotherapy 
with short-acting bronchodilators (ß-2 sympathomimetics, SABA and/or anticholinergics, 
SAMA) is the recommended first choice. 
At stage GOLD B, long-term inhaled treatment with long-acting bronchodilators (LABA, 
LAMA) is firstly recommended. A combination of LAMA and LABA is another option.
At stage GOLD C, glucocorticosteroid + LAMA or LABA is recommended as first choice. 
Alternatives are LAMA + LABA, LAMA + phosphodiesterase-4 inhibitors or LABA + 
phosphodiesterase-4 inhibitors. 
Patients at stage GOLD D should be treated with a double or triple therapy consisting of 
inhaled corticosteroids + LABA and/or LAMA.
Pharmacological therapy for COPD is used to lessen symptoms, reduce the frequency and
severity of exacerbations, and improve health status and exercise tolerance [4]. To date,
COPD medications have not been conclusively shown to modify the long-term decline in
lung function [4], so patients should be treated with the agents most likely to result in
effective bronchodilation and prevention of exacerbations. 
The GOLD strategy states that bronchodilators are the mainstay of COPD management, long-
acting inhaled bronchodilators are convenient and more effective at producing maintained 
symptom relief than short-acting bronchodilators, and combining bronchodilators of different
classes (e.g. LAMAs and LABAs) may improve efficacy and decrease the risk of side effects
compared to increasing the dose of a single agent [4]. 
Recently, the fixed combination of tiotropium and olodaterol has been shown to increase lung 
function significantly in moderate to very severe COPD, and to a greater extent than with 
either agent alone [5]. Therefore, treatment with combination therapy is likely to be an 
effective option for the management of moderate-to severe COPD.
7.2
DRUG PROFILE
Tiotropium bromide is a long-acting (24-hour) inhaled anticholinergic bronchodilator (known 
as a LAMA), used in the treatment of COPD. The drug is authorised in many countries 
around the world, including in Germany since 2002 under the name Spiriva® [6], [7]. 
The Spiriva® Respimat® was developed from the Spiriva® pharmaceutical form, which 
optimises pulmonary deposition of the drug [8], [9], and means that the Respimat® is able to 
reduce the quantity of drug used [10]. 
It produces a slowly dispersing, long-lasting mist with very fine particle distribution that is 
readily able to circulate into the lower respiratory tract and the lungs [11]. Thus, even when 
coordination of breathing is poor, pulmonary deposition is optimal and the product is 
efficiently administered to the target site. The Respimat® does not contain any propellant gas. 
Olodaterol is a highly selective, long-acting beta2-adrenoceptor agonist (known as a LABA) 
for long-term once-daily bronchodilator treatment in COPD patients with impaired airflow 
including chronic bronchitis and/or emphysema.

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The efficacy and safety of olodaterol in the treatment of moderate to severe COPD (GOLD 2-
4) was studied in a Phase III programme in over 3000 patients and showed that the additional 
administration of olodaterol via Respimat® brought about an effective and long-lasting 
improvement in lung function (FEV1) over 24h compared to conventional standard treatment 
(e.g. long- and short-acting anticholinergics, short-acting beta-agonists, inhaled 
corticosteroids and xanthines [12], [13], [14] and also demonstrated a more rapid onset of 
effect [15].
The drug has been authorised since 2013 in 
countries worldwide and is available in 
Germany under the name Striverdi® Respimat® [16].
First treatment experiences with the free combination of tiotropium and olodaterol in COPD 
patients were reported from two replicate, double-blind, randomized, 12-week studies 
(ANHELTO 1 and ANHELTO 2) evaluating the efficacy and safety regarding the 
combination of olodaterol 5 μg once daily (via Respimat®) plus tiotropium 18 μg once daily 
(via HandiHaler®) versus tiotropium 18 μg once daily (via HandiHaler®) plus placebo (via 
Respimat®) in patients with moderate to severe COPD[17]. 
Primary efficacy endpoints were area under the curve from 0 to 3 hours of forced expiratory 
volume in 1 second (FEV1 AUC 0–3) and trough FEV1 after 12 weeks (for each trial). A key 
secondary end point was health status assessed by St George’s Respiratory Questionnaire 
(SGRQ) total score.
The free combination of olodaterol plus tiotropium resulted in significant improvement 
compared to tiotropium + placebo in FEV1 AUC 0 to 3 (treatment differences: 0.117 L 
[p = 0.001], ANHELTO 1; 0.106 L [p = 0.001], ANHELTO 2) and trough FEV1 (treatment 
differences: 0.062 L [p = 0.001], ANHELTO 1; 0.040 L [p = 0.0029], ANHELTO 2). 
These positive results were supported by secondary endpoints. 
The effects described above translated into improvement of SGRQ total scores (treatment 
difference –1.85; p = 0.0001). The safety profile of olodaterol plus tiotropium, however, was 
similar to tiotropium monotherapy.
Both studies demonstrate that the free combination of olodaterol (Respimat®) plus tiotropium 
(HandiHaler®) provide significantly higher bronchodilatory efficacy than tiotropium alone in 
COPD patients.
The new medicinal product Spiolto® Respimat® delivers the two ingredients described above 
as fixed combination in one device and is indicated as bronchodilating long-term treatment in 
adult COPD patients for symptom relieve. 
EU registration was given July, 1st, 2015, based on 2 pivotal, replicate, multinational 1-year, 
randomised double-blind, active-controlled, parallel-group Phase III studies, TOnado 1 and 2 
(Study 1237.5 and Study 1237.6), assessed the efficacy and safety of once-daily treatment 
with a fixed-dose combination (FDC) of olodaterol (a LABA), and tiotropium (a LAMA), 
delivered via the Respimat® Soft Mist™ inhaler and compared to the individual mono-
components in patients with moderate to very severe COPD (GOLD 2–4)[5]. 
Patients were randomised to one of five treatment groups and received tiotropium plus 
olodaterol FDC 2.5 / 5 μg or 5 / 5 μg, or tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg 
delivered once daily via Respimat® inhaler for 52 weeks. 
Inclusion and exclusion criteria:
Patients with moderate to very severe COPD (GOLD 2-4) were included if: 

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
Post-bronchodilator FEV1 <80% of predicted normal 

Post-bronchodilator FEV1/FVC <70% 

Age ≥40 years with a smoking history (current or former) of >10 pack-years 
Patients with moderate to very severe COPD (GOLD 2-4) were excluded if: 

Significant disease other than COPD 
The key results on efficacy are summarized below:

Across 25 countries, study 1237.5 (TOnado 1, n=2624) and study 1237.6 (TOnado 2, 
n=2539) randomised a total of 5163 patients, of whom 5162 patients were treated and 
84.6% completed the studies. 

At 24 weeks, both studies demonstrated significant improvements in lung function 
(FEV1 AUC 0–3 response [p <0.0001] and trough FEV1 response [p<0.05]) 
compared with either tiotropium or olodaterol monotherapy. 

At 24 weeks, only the higher-dose combination of olodaterol and tiotropium 
(5 μg / 5 μg) provided statistically significant improvement in SGRQ total scores 
compared with either monotherapy (FDC 5/5 μg versus olodaterol 5 μg: 95% CI -
1.693 (-2.778, -0.608), p<0.01; versus tiotropium 5 μg 95% CI - 1.233 (-2.313, -
0.153), p<0.05). 
The responder rates were also significantly greater for the higher-dose FDC compared 
with either olodaterol or tiotropium alone (nominal p<0.05).

Generally, patients who had more severe disease at baseline also had a lower response 
to treatment, although inhaled corticosteroid use did not affect the response to the 
combination treatment. 
The key results on safety are summarized below:
Overall, 74.4% of patients reported at least one adverse event (AE). The rate of serious AEs 
(16.4%) was broadly similar across all treatment groups. 
In the two studies, the overall fatality rate was 1.5%. Of the 75 deaths, 14 occurred in the 
olodaterol 5 μg group, 12 in the tiotropium 2.5 μg group, 17 in the tiotropium 5 μg group, 
14 in the FDC tiotropium / olodaterol 2.5 / 5 μg group, and 18 in the FDC tiotropium /
olodaterol 5 / 5 μg group. 
Most treatment-emergent AEs were respiratory events (incidence >3%) and predominantly 
included COPD exacerbations, which were reported most often in the monotherapy groups, 
and infections, which occurred most frequently in the FDC tiotropium plus olodaterol 
2.5 / 5μg group. 
There were no safety concerns with regard to laboratory parameters and vital signs. 
The incidence of major adverse cardiac events and cardiac disorders were similar across 
treatment groups. 
The authors concluded that these two 1-year studies, TOnado 1 and TOnado 2, demonstrated 
that once-daily treatment with a FDC of olodaterol and tiotropium may present an effective 
and well-tolerated maintenance treatment for patients with moderate to very severe COPD 

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(GOLD 2–4). In particular, the higher-dose FDC (5 μg / 5 μg) appeared to offer the optimum 
combination.
In conclusion, the phase III clinical trials conducted to date have shown tiotropium plus
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. The overall 
incidences of adverse events (AEs), serious adverse event (SAEs), fatal AEs, frequencies for 
cardiac events and Major adverse cardiovascular event (MACE) in the tiotropium plus
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.
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 centred 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 can be difficult to distinguish 
from disease progression [18]. However, it is clear that physical activity is significantly lower 
in patients with COPD than in healthy controls [19],[20]. 
COPD prevents patients from carrying out daily activities due to exercise intolerance, which 
is often attributed to limited pulmonary ventilation. 
However, a number of observations have suggested that, for many COPD patients, other 
factors are involved, including deconditioning due to physical inactivity. This may be related 
to avoidance of exertion as a result of fear of dyspnoea. Furthermore, physical inactivity has 
been associated with skeletal muscle weakness and exercise intolerance [18],[21], [22]. 
The loss of physical activity in COPD is also associated with increased mortality [23]. Data 
from a study of 2386 patients with COPD demonstrated that, following adjustment for all 
relevant confounders, subjects who reported low, moderate or high physical activity had a 
significantly lower risk of all-cause mortality than those with very low physical activity (p =
0.001) [24].
Clinical studies of both Spiriva® [25], [26], [27] and Striverdi® Respimat® in COPD patients 
have demonstrated significant improvement in exercise capacity [28].
The benefits of tiotropium + olodaterol FDC have been studied in controlled Phase III 
programs on exercise endurance, however, data regarding physical activity when treated with 
Spiolto® Respimat® is not available from a real world setting.
8.2
STUDY OBJECTIVES
The objective of this NIS is to measure changes in physical functioning – serving as a 
surrogate for physical activity and exercise capacity – in COPD patients on treatment with 
Spiolto® Respimat® after approximately 6 weeks in routine clinical practice.
The secondary objectives are to evaluate the patient’s general condition (physician’s 
evaluation) at visit 1 (baseline visit at the start of the study) and at visit 2 (final visit at the 
end of the study, approx. 6 weeks after visit 1), as well as patient satisfaction with Spiolto®
Respimat® at visit 2.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a self-controlled, non-interventional study (NIS), as referred to in §4.23 and §67.6 
AMG, 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 history
X
X
Concomitant diseases / Comorbidities
X
X
COPD related and other relevant concomitant medication
X
X
Physical functioning (PF-10) questionnaire, completed by 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®, survey completed by the 
patient
X
Rational for Spiolto® Respimat® treatment discontinuation (if applicable)
X
Continuation or discontinuation of treatment with Spiolto® Respimat® after 
the study (yes/no)
X
1 GOLD patient group (A, B, C or D) will be automatically calculated within the eCRF based on available exacerbation 
history,   mMRC, and GOLD spirometric classification of airflow limitation based on post-bronchodilator FEV1 if 
available.

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Baseline characteristics of patients being eligible and who gave Informed Consent, but were 
not treated in the study will also be collected.
9.1.1
Outcomes
Primary 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 2000 patients from approximately 650 sites in 
Germany will be collected. Site selection will be performed to reflect routine COPD care in 
Germany in order to secure representativeness of the COPD population.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
or not.
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular study site
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the study, or any other administrative reasons, i.e. lack of recruitment.
3. Violation of the observational plan or the contract by a study site or investigator, 
disturbing the appropriate conduct of the study
9.2.1
Inclusion criteria
Patients can be included if all of the following criteria are met:

Written informed consent prior to participation

Female and male patients ≥40 years of age

Patients diagnosed with COPD and requiring long-acting dual bronchodilation 
(LAMA + LABA) treatment according to approved SmPC and GOLD COPD 
guideline recommendation

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9.2.2
Exclusion criteria

Patients with contraindications according to Spiolto® Respimat® SmPC.

Patients who have been treated with a LABA/LAMA combination (free and fixed 
dose) in the previous 6 months.

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. 

Patient for whom further follow-up is not possible at enrolling site during planned 
study period of approx. 6 weeks.

Pregnancy and lactation

Patients currently listed for lung transplantation

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 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® to assess the overall satisfaction with 
Spiolto® Respimat® as well as specific inhalation from the device and device handling,
-
General condition of patient based on Physician’s Global Evaluation (PGE) to assess the 
general condition of the patient at the beginning and at the end of the study,
-
Safety Reporting; Adverse Drug Reactions (serious and non-serious), fatal AEs, and 
pregnancies at the beginning and at the end of the study,
-
GOLD spirometric classifications (1, 2, 3, 4) and GOLD patient groups (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 

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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 patient group (A, B, C, or D) in the eCRF.
The physical functioning (PF-10) questionnaire is a subscale of the validated 36-Item Short 
Form Health Survey and contains 10 questions about everyday physical activity and 
functioning. Patients will be asked to complete the PF-10, in order to evaluate their physical 
functioning before and after treatment with Spiolto® Respimat®.
A patient satisfaction survey will also be completed at visit 2, using a 7-point ordinal scale 
with divisions from very dissatisfied to very satisfied.
9.5
STUDY SIZE
In a previous study (205.426) with over 1000 patients treated with Sprivia® Respimat®
therapeutic success (= 10-point increase in the PF-10 score between baseline and week 6) was 
achieved in 61% of patients.
In this study a therapeutic lower success rate is expected as patients may be already on 
maintenance treatment at baseline.
Assuming a 50% therapeutic success rate and 1860 patients, the 95% confidence interval for 
the therapeutic success rate would be between 47.7% (lower limit) and 52.3% (upper limit). 
 
 
 
 

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To account for a 7% drop-out rate, the sample size becomes 2000 patients.
9.6
DATA MANAGEMENT
A data management plan (DMP) will be created to describe all functions, processes, and 
specifications for data collection, cleaning and validation. The electronic Case Report Forms 
(eCRFs) will include programmable edits to obtain immediate feedback if data are missing 
(also negative answers, unknown), out of range, illogical or potentially erroneous. These rules 
may encompass simple checks such as range validation or presence/absence of data. 
Concurrent manual data review may be performed based on parameters dictated by the DMP. 
Ad hoc queries to the sites may be generated and followed up for resolution. A source data 
quality audit may be initiated to ensure that the data in the database is accurate. Source data 
verification (SDV) will be performed at sites identified by a risk-based approach as needed. 
The database will be housed in a physically and logically secure computer system maintained 
in accordance with a written security policy. The system will meet the standards of the 
International Committee on Harmonization guideline E6R1 regarding electronic study data 
handling. Patient confidentiality will be strictly maintained.
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: 

Patient demographics (gender, age, height, weight) 

Comorbidities

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
COPD related and other concomitant medication 

History of smoking 
Reported exacerbations
Breathlessness based on mMRC score at visit 1

Physical Functioning based on PF-10 scores (therapeutic success at visit 2); primary 
outcome 

Changes from visit1 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 

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.
Further exploratory analyses may be done to examine the distribution of baseline and follow-
up covariates and their potential impact on the primary outcome; details will be specified in 
the analysis plan.
 
 
 
 
The safety data will be reported according to local requirements. 

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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.
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.
9.8.1
Administrative requirements 
This NIS will be performed in compliance with §4.23 and §67.6 of the Medicines Act of the 
Federal Republic of Germany (AMG) and the recommendation of the Federal Institute for 
Drugs and Medical Devices and the Paul Ehrlich Institute for the planning, performance and 
analysis of observational studies as well as applicable BI standard operating procedures 
(SOPs).
In compliance with §67.6 AMG, this NIS will be notified by Boehringer Ingelheim Pharma 
GmbH & Co. KG to the National Association of Statutory Health Insurance Physicians, the 
Central Federal Association of Health Insurance Funds, the Association of Private Health 
Insurance Funds as well as the competent federal higher authority Federal Institute for Drugs 
and Medical Devices (BfArM), or to the appropriately authorised institute. 
In addition, the National Association of Statutory Health Insurance Physicians, the Central 
Federal Association of Health Insurance Funds and the Association of Private Health 
Insurance Funds will be given the names of the participating physicians and will be told the 
nature and level of payments made to them and will be provided with a copy of the contracts 
entered into with them.

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Copies of the notifications, unless made purely electronically, will be kept in the relevant 
section of the investigator site file.
Additionally, an entry in the publicly accessible database at clinicaltrials.gov is planned, in 
accordance with the announcement of the Association of Research-Based Pharmaceutical 
Companies (VFA).
The NIS will be submitted to the competent Ethics Committee before it starts, as will any 
amendments to the observational plan. A copy of the opinion can be found in the appropriate 
section of the clinical trial master file. 
In addition, every participating physician is to be advised by his/her ethics committee in 
accordance with the rules of professional conduct.
9.9
LIMITATIONS OF THE RESEARCH METHODS
The intention of this NIS is to collect new data on the physical functioning and exercise 
capacity of COPD patients on treatment with Spiolto® Respimat® in a real world setting.
An NIS appears the most suitable instrument for obtaining information about the use of 
medicines in everyday therapeutic practice and thus for investigating prospectively questions 
in everyday therapeutic practice.
Consecutive enrolment will be employed to minimize selection bias. The entry criteria are 
non-restrictive which will permit the enrolment of a broad patient population. The choice of 
treatment is at the discretion of the investigator.
Selection bias could occur at the site level and the patient level. To minimize the site level 
selection bias, the goal is to have participating 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 only 
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), Good Pharmacoepidemiology Practice 
(GPP) and relevant BI Standard Operating Procedures (SOPs).Standard medical care 

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(prophylactic, diagnostic and therapeutic procedures) remains in the responsibility of the 
treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalization of the Study Report.
Insurance cover is not necessary for a NIS in Germany.
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 Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
This NIS will be performed in compliance with §4.23 and §67.6 of the Medicines Act of the 
Federal Republic of Germany (AMG) and the recommendation of the Federal Institute for 
Drugs and Medical Devices and the Paul Ehrlich Institute for the planning, performance and 
analysis of observational studies as well as applicable BI standard operating procedures 
(SOPs).
The NIS will be reviewed by the submitted to the competent Ethics Committee before it 
starts, as will any amendments to the observational plan. A copy of the opinion can be found 
in the appropriate section of the clinical trial master file. 
In addition, every participating physician is to be advised by his/her ethics committee in 
accordance with the rules of professional conduct.
The physician will explain the nature of the study to the patient and obtain written informed 
consent prior to patient participation in the study be obtained from each patient (or the 
patient’s legally accepted representative) according to ICH GCP and to the regulatory and 
legal requirements of the participating country. Each signature must be personally dated by 
each signatory and the informed consent and any additional patient-information form retained 
by the investigator as part of the trial records. A signed copy of the informed consent and any 
additional patient information must be given to each patient or the patient’s legally accepted 
representative.
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.
The written informed consent has to be obtained before the patient is enrolled in the NIS and 
the observations are entered in the eCRF. 

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It must be documented in the eCRF that the informed consent of the patient was obtained 
before the start of the observation.
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 IRBs/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.
To provide further quality assurance of the documented patient observations, a random 
source data validation will take place at approx. 10% of sites and involve an on-site review of 
the documented data for completeness and consistency. An additional check/review of the 
quality assurance of this NIS can be performed.
9.10.1.3
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, also current medical records must be 
available.
For eCRFs all data must be derived from source documents:
-
Patient demographics (age, gender, height, and weight);
-
History of smoking 
-
Reported exacerbations
-
Past COPD therapies (6 months before visit 1)
-
Respimat® training (Yes/No)
-
GOLD spirometric classification (1,2, 3, 4)
-
GOLD patient groups (A, B, C, D)  
-
Concomitant diseases / Comorbidities
-
Concomitant COPD and other relevant medication
-
Breathlessness based on mMRC score 
-
Physical Functioning (PF-10) Questionnaire
-
Patient Satisfaction Questionnaire
-
Adverse Drug Reactions (ADR & SADR), fatal AEs, pregnancies
-
Rational for Spiolto® Respimat® treatment discontinuation (if applicable)
-
Details of treatment continuation / discontinuation .
9.10.1.3.1 Direct access to source data and documents
The investigator / institution will permit study-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 

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medical test results must be available at all times for review by the sponsor’s clinical study 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents 
described in Section 9.10.1.4
9.10.1.4
Statement of confidentiality
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the 
study need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IRB / IEC and the regulatory authorities, i.e. the CA.
9.10.1.5
Completion of study
The EC/competent authority in Germany will be notified about the end of the trial (last 
patient out) or early termination of the trial. 
9.10.1.6
Protocol violations
There are no protocol waivers. All protocol violations must be reported to the sponsor 
immediately.

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10.
PROTECTION OF HUMAN SUBJECTS
Please refer to section 9.10.1.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE DRUG REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event (AE)
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 AE 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 drug reaction (ADR)
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 AE is at least a reasonable possibility. ADRs 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 (SAE)
A serious adverse event (SAE) 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 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.

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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 
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.

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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 authorization. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined.
The following must be collected by the investigator in the eCRF from signing the informed 
consent onwards until the end of the study: 
-
all ADRs (serious and non-serious), 
all AEs with fatal outcome (serious adverse events),
Note*: For all patients on these data must be recorded on the AE pages in the eCRF. 
They will automatically be reported to the Pharmacovigilance department of Boehringer 
Ingelheim within 24 hours after data entry in the form of a PDF file via a secure email 
connection. The Boehringer Ingelheim SAE/AE form will be generated from the eCRF
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 AEs
The definition of an adverse drug reaction (ADR) implies at least a reasonable possibility of a 
causal relationship between a suspected medicinal product and an adverse event (AE). An 
ADR, in contrast to an AE, 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
•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).

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•
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 AEs
The intensity of AEs should be classified and recorded according to the NCI-CTCAE criteria 
in the eCRF.
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a female subject has been enrolled into 
the study, after having taken , the investigator must report any drug exposure during 
pregnancy 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. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B).
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 

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Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS AE form from signing the 
informed consent onwards until the end of the study (V2): 
Type of Report
Timeline
All serious ADRs related to 
immediately within 24 hours
All AEs with fatal outcome
immediately within 24 hours
All non-serious ADRs related to 
7 calendar days
All pregnancy monitoring forms
7 calendar days
All ADRs (serious and non-serious) and all fatal AEs will automatically be reported to the 
Pharmacovigilance department of Boehringer Ingelheim within 24 hours after data entry in 
the form of a PDF file via a secure email connection. The Boehringer Ingelheim SAE/AE 
form will be generated from the eCRF. 
Therefore, data entry for all ADRs and all fatal AEs within the timelines given above is 
mandatory.
If there is no Internet access at the time of the report, the SAE form must alternatively be sent 
to the following address by fax or e-mail within 24 hours after becoming known:
Boehringer Ingelheim Pharma GmbH & Co. KG
Pharmacovigilance Germany (PV Germany)
Binger Straße 173
55216 Ingelheim
Fax: +49 (6132) 72 – 141522
PV_local_Germany@boehringer-ingelheim.com
In this case, these data must be entered into the eCRF later as soon as possible.
The same timelines apply if follow-up information becomes available for the respective 
events. All additional information has to be entered into the eCRF and will be transmitted 
automatically within 24 hours.
In specific occasions the Investigator could inform the Sponsor upfront via telephone. 
Information required
For each reportable AE, the investigator should provide the information requested on the 
appropriate eCRF pages.
Reporting of related AEs associated with any other BI drug
The investigator is encouraged to report all AEs 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 

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occurred or not, any abuse, off-label use, misuse, medication error, occupational exposure, 
lack of effect, and unexpected benefit.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local
and international regulatory requirements.

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

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
[1]
from: Herold G et al.: Innere Medizin 2012S. 343ff (R15-5282)
[2]
Vogelmeier C, Buhl R, Criee C et al.: Leitlinie der Deutschen 
Atemwegsliga und der Deutschen Gesellschaft für Pneumologie und 
Beatmungsmedizin zur Diagnostik und Therapie von Patienten mit 
chronisch obstruktiver Lungenerkrankung (COPD). DOI 10.1055/s 2007 
959200. Online Publication: 13.4.2007. Pneumologie 2007;61;e1-e40. 
www.atemwegsliga.de/copd.html (P13-10686)
[3]
http://www.lungeninformationsdienst.de/krankheiten/copd/verbreitung/
index.html (R15-5292)
[4]
Global initiative for Chronic Obstructive Lung Disease, Inc: Global strategy 
for the diagnosis, management, and prevention of chronic obstructive 
pulmonary disease; updated 2015. www.goldcopd.org (P15-01740)
[5]
Buhl R, Maltais F, Abrahams R, Bjermer L, Derom E, Ferguson G, Flezar 
M, Hébert J, McGarvey L, Pizzichini E, Reid J, Veale A, Grönke L, 
Hamilton A, Korducki L, Tetzlaff K, Waitere-Wijker S, Watz H, Bateman 
E. Tiotropium and olodaterol fixed-dose combination versus mono-
components in COPD (GOLD 2–4) Eur Respir J 2015; DOI: 
10.1183/09031936.00136014 (P15-03349)
[6]
Spiriva® Respimat® Summary of Product Characteristics, date December
2014 (R15-5251)
[7]
Spiriva® 18 Mikrogramm, Summary of Product Characteristics, date 
January 2015 (R15-5252)
[8]
Hochrainer D, Hölz H, Kreher C, Scaffidi L, Spallek M, Wachtel H: 
Comparison of the aerosol velocity and spray duration of Respimat Soft 
Mist inhaler and pressurized metered dose inhalers. J Aerosol Med. 2005 
Fall; 18(3):273-82. (P05-10481)
[9]
Pitcairn G, Reader S, Pavia D, Newman S: Deposition of corticosteroid 
aerosol in the human lung by Respimat Soft Mist inhaler compared to 
deposition by metered dose inhaler or by Turbohaler dry powder inhaler. J 
Aerosol Med. 2005 Fall; 18(3):264-72 (P05-10480)
[10]
Kilfeather SA, Ponitz HH, Beck E, Schmidt P, Lee A, Bowen I, Hesse Ch:
Improved delivery of ipratropium bromide/fenoterol from Respimat Soft 
Mist Inhaler in patients with COPD. Respir Med. 2004 May; 98(5):387-97.
(P04-05651)
[11]
Newman SP, Steed KP, Reader SJ, Hooper G, Zierenberg B: Efficient 
delivery to the lungs of flunisolide aerosol from a new portable hand-held 
multidose nebulizer. J Pharm Sci. 1996 Sep; 85(9):960-4. (P96-8282)
[12]
Ferguson GT, Feldman GJ, Hofbauer P et al. Lung function efficacy of 
olodaterol QD delivered via Respimat® in COPD patients: Results from two 
48-week studies. ERS 2013 abstract 187. (P13-11346)
[13]
Koch A, Pizzichini E, Hamilton A et al. Lung function efficacy of 
olodaterol QD delivered via Respimat® vs. Placebo and formoterol BID in 
patients with COPD: two 48-week studies. ERS 2013 poster P764
(P13-11345

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[14]
Lange P, Aumann J-L, Derom E et al. The 24-h FEV1 time profile of 
olodaterol QD delivered via Respimat® in COPD: results from two 6-week 
studies. ERS 2013 poster P3633 (P13-11469)
[15]
Koch A, Paggiaro P, Hamilton A et al. Lung function efficacy and 
symptomatic benefit of olodaterol once daily delivered via Respimat®
versus placebo and formoterol twice daily in patients with GOLD 2–4 
COPD: results from two replicate 48-week studies. . Int J of COPD 2014 
July;9(1):697-714 (P14-09975)
[16]
Striverdi® Respimat® Summary of Product Characteristics, dated November 
2013 (R14-50351)
[17]
ZuWallack R, Allen L, Hernandez G, Ting N, Abrahams R. Efficacy and 
safety of combining olodaterol Respimat® and tiotropium HandiHaler® in 
patients with COPD: results of two randomized, double-blind, active-
controlled studies. Int J of COPD Vol.2014:9(1) 1133-1144. DOI 
http://dx.doi.org/10.2147/COPD.S72482 (P14-14958)
[18]
Katz P, Chen H, Gregorich SE et al. The role of physical inactivity . in 
increasing disability among older adults with obstructive airway disease. J 
Cardiopulm Rehabil Prec 2011; 31: 193-197 (R15-4559)
[19]
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-centre pilot study. Respir Med. 2010 Jul: 
104(7): 1005-11. Doi: 10.1016/j.rmed.2010.01.012. Epub 2010 Feb 18 
(R13-3633)
[20]
Watz H1, Waschki B, Meyer T, Magnussen H. Physical activity in patients 
with COPD. Eur Respir J. 2009 Feb;33(2):262-72. doi: 
10.1183/09031936.00024608. Epub 2008 Nov 14 (R09-1615)
[21]
F. Maltais, P. LeBlanc, C. Simard et al. Skeletal muscle adaptation to 
endurance training in patients with chronic obstructive pulmonary disease. 
Am J Respir Crit Care Med 1996;154:442-447 (R15-4561)
[22]
Mador MJ, Bozkanat E. Skeletal muscle dysfunction in chronic obstructive 
pulmonary disease. Respir Res 2001;2:216-224 (R15-4562)
[23]
Garcia-Rio F1, Rojo B, Casitas R, Lores V, Madero R, Romero D, Galera 
R, Villasante C. Prognostic value of the objective measurement of daily 
physical activity in patients with COPD. Chest. 2012 Aug;142(2):338-46
(R15-4563)
[24]
Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Antó JM. Regular 
physical activity reduces hospital admission and mortality in chronic 
obstructive pulmonary disease: a population based cohort study. Thorax.
2006 Sep;61(9):772-8. Epub 2006 May 31 (R15-4564)
[25]
Cooper C, Celli B, Jardim J et al. Treadmill Endurance During 2-Year 
Treatment With Tiotropium in Patients With COPD. A Randomized Trial. 
Chest 144,2,August 2013 (P13-04267)

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[26]
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) (P05-09483)
[27]
Casaburi R, Kukafka D, Cooper C et al. Improvement in Exercise 
Tolerance With the Combination of Tiotropium and Pulmonary 
Rehabilitation in Patients With COPD. Chest 127, 3, March 2005
(P05-02413)
[28]
Maltais F et al. Evaluation of the Effects of Olodaterol on Exercise 
Endurance in Patients With COPD: Results From Two 6-Week Studies (ID 
688). ACCP 2013 (P13-14109)
13.2
UNPUBLISHED REFERENCES
Not applicable

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14.
APPENDICES
Appendix 1: Physicians’ Global Evaluation (PGE)
Appendix 2: PF-10 Questionnaire
Appendix 3: SAE Form

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APPENDIX 1: PGE
General condition of the patient at the initial examination (Visit 1)
Please mark with a cross as applicable
Poor
Satisfactory
Good
Excellent 
1  2
3  4
5  6
7  8
General condition of the patient after 4 to 6 weeks of treatment (Visit 2)
Please mark with a cross as applicable
Poor
Satisfactory
Good
Excellent 
1  2
3  4
5  6
7  8

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APPENDIX 2: PF-10 QUESTIONNAIRE AND MMRC
Patient No.:
Gender:
Year of birth:
PF-10 Questionnaire
The following questions are about activities you might do during a typical day. Does your 
present state of health limit you in these activities? If so, how much?
Yes, 
limited a 
lot
Yes, 
limited a 
little
No, not 
limited at all
Not 
answered
a) Vigorous activities, e.g. 
running, lifting heavy 
objects, participating in 
strenuous sports*
b) Moderate activities, e.g. 
moving a table, vacuuming, 
bowling, playing golf*
c) Lifting or carrying 
shopping bags*
d) Climbing several flights of 
stairs*
e) Climbing one flight of 
stairs*
f) Bending, kneeling, stooping
g) Walking more than a 
kilometre*
h) Walking several hundred 
metres*
i)
Walking one hundred 
metres*
j)
Bathing or dressing 
yourself*

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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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APPENDIX 3: (S)AE FORM

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Please send immediately to Boehringer Ingelheim Pharma GmbH & Co. KG at fax No. 06132-72-141522 or PV Germany.de@boehringer-ingelheim.com. Do not complete shaded areas.
Report of Serious/Non-Serious Adverse Events
In Non-Interventional Study (NIS)
NIS Title: 1237.42
Spiolto® Respimat®
OPI Case ID Number:
Reporter’s Name / Telephone and Fax Number
BI CTMS Number: 1237.42
Site Number:
|__|__|__|__|
Pat. initials
|__|__|__|
Pat. No.
|__|__|
Gender
1 male
2 female
Year of birth
|__|__|__|
Age
|__|__|
Height (cm)
|__|__|__|
Weight (kg)
|__|__|__| . |__|
Race
1 white
2 black
3 Asian
Pregnant0 no
1 yes Week: |__|__|
Initial report
Follow-up report:
Date of Event
(Enter date for each event)
Intensity of 
event
(CTCAE 
grade)
Event treated
0 = no
1 = yes
if yes, please 
explain under 
Description.
Because of the event, 
administration of 
Spiolto® Respimat®
was:
1= continued
2= reduced
3= discontinued
4= increased
5= finished as per the 
observational plan
6= discontinued and 
resumed
7= not applicable
Outcome of event
1= recovered 
2= not yet recovered 
3= permanent damage
4= fatal
5= unknown
Was the event 
serious?
0 = no
1 = yes
If yes, state relevant code 
number 
1= fatal**
2= immediately life-
threatening
3= persistent or significant 
disability / incapacity
4= requires hospitalisation 
5= requires prolongation of 
hospitalisation
6= congenital anomaly
7= other/further comparable 
med. criteria
(drug dependence, abuse, 
cancer, etc.)
**If fatal, please attach a copy 
of the death certificate
Causal
Relationship.
Is there a justified suspicion of a 
causal relationship between the event 
and the use of
Event
Describe all observed events and 
symptoms as well as all non-serious 
events related to the serious event
If continuing please enter “Cont” in the “End date” column
Spiolto® Respimat®
Onset
date
Day/Mth/
Year
Time in 
hh:mm 
(24)
End
date
Day/Mth/
Year
Time in 
hh:mm 
(24)
Repor-ter
0= no
1= yes
PV Ger
0= no
1= yes
1.
2.
3.
4.
Description of the above-mentioned events (if necessary, please give number as per the above table, Event column):
Please send immediately to Boehringer Ingelheim Pharma GmbH & Co. KG at fax No. 06132-72-141522 or PV Germany.de@boehringer-ingelheim.com. Do not complete shaded areas.

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Report of Serious/Non-Serious Adverse Events
In Non-Interventional Study (NIS)
NIS Title: 1237.42
Spiolto® Respimat®
OPU Case ID Number:
BI CTMS Number:
1237.42
Site Number:
|__|__|__|__|
Pat. initials
|__|__|__|
Pat. No.
|__|__|
Medication / Treatment
If a drug, give brand name and generic name
Pharm. form
Total daily dose at 
start (dose, unit)
Method of 
administration
Start (date
Day / Month / Year
End (date)
Day / Month / Year
Given for which 
indication?
Other suspected drug: Is there a causal relationship
between the event and concomitant therapy?
Boehringer Ingelheim drug
Spiolto® Respimat®
Reporter:
0= no
If yes,
Enter event number
PV Ger:
0= no
If yes,
Enter event number
Concomitant treatment (relevant)
1.
2.
3.
4.
Concurrent diagnoses (relevant):
1.
2.
Comments (attendant circumstances, alternative explanation for event, any re-exposure, etc.)
Name of reporter
Signature
Date Day/Month/Year

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
The stand-alone documents for this non-interventional study are:
Informed Consent Form
Statistical and Epidemiological Analysis Plan (SEAP)
The above documents will be archived in the Trial Master File in their original English master 
version.

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ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS
Not applicable

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number:  
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03809777
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clinical-trial-protocol-version-1-1237-42-observational-plan
SPIRIT: 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-Trial Clinical Monitor
03 Dec 2015 10:46 CET
Approval-Therapeutic Area 
03 Dec 2015 11:25 CET
Author-Trial Statistician
03 Dec 2015 15:27 CET
Approval-
 Safety Evaluation
Therapeutic Area
03 Dec 2015 16:29 CET
Approval-Other
04 Dec 2015 11:39 CET
Approval-Team Member Medicine
07 Dec 2015 10:09 CET
Approval-On behalf of 
 or 
or 
07 Dec 2015 13:58 CET

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03809777
1.0