AERIAL®: Changes in Health and Functional Status in Patients With COPD During Therapy With Spiolto® Respimat®
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
TITLE PAGE
Document Number:
c15737297-03
BI Study Number:
1237-0065
BI Investigational
Product(s):
Spiolto® Respimat®
Title:
AERIAL®: Changes in health and functional status in patients 
with COPD during therapy with Spiolto® Respimat®
Brief lay title
Not applicable
Protocol version 
identifier:
Version 2.0
Date of last version of 
protocol:
24 April 2017
PASS:
No
EU PAS register 
number:
Study not yet registered
Active substance:
R03AL06 
Tiotropium bromide + Olodaterol
Medicinal product:
Spiolto® Respimat® 2.5 microgram/2.5 microgram per puff
inhalation solution
Product reference:
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

Boehringer Ingelheim
Page 2 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Research question and 
objectives:
The objective of this NIS is to measure changes in health status 
including functional status using CCQ scores in COPD patients 
receiving treatment with Spiolto® Respimat® after approximately 
6 weeks in routine clinical practice.
Primary objective: Assess proportion of patients achieving 
“therapeutic success” (= 0.4 point decrease in the CCQ score 
between baseline and approximately week 6)
Secondary objectives are assessment of changes in CCQ and 
CCQ-4, the patient’s general condition (physician’s evaluation) 
at visit 1 (baseline visit at the start of the study) and at visit 2 
(final visit at the end of the study, approx. 6 weeks after visit 1), 
as well as patient satisfaction with Spiolto® Respimat® and 
willingness to continue treatment with Spiolto® Respimat® at
visit 2 as proxy for adherence.
Country(-ies) of study:
Germany
Author:
Marketing authorisation 
holder(s):
Boehringer Ingelheim International GmbH 
Binger Straße 173
55216 Ingelheim am Rhein
Date:
24 April 2017
Page 1 of 58
Proprietary confidential information
© 2017 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

Boehringer Ingelheim
Page 3 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 11
6.
MILESTONES..................................................................................................... 12
7.
RATIONALE AND BACKGROUND................................................................ 13
7.1
MEDICAL BACKGROUND ......................................................................... 13
7.2
DRUG PROFILE ............................................................................................ 15
7.2.1
Tiotropium and Olodaterol...................................................................... 15
7.2.2
Spiolto® Respimat®............................................................................... 16
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 21
8.1
STUDY OBJECTIVES................................................................................... 23
9.
RESEARCH METHODS .................................................................................... 24
9.1
STUDY DESIGN............................................................................................ 24
9.2
SETTING........................................................................................................ 24
9.2.1
Study sites ............................................................................................... 24
9.2.2
Study population ..................................................................................... 24
9.2.3
Study visits .............................................................................................. 24
9.2.4
Study discontinuation.............................................................................. 26
9.3
VARIABLES .................................................................................................. 26
9.3.1
Exposures ................................................................................................ 27
9.3.2
Outcomes................................................................................................. 27
9.3.2.1
Primary outcomes............................................................................. 27
9.3.2.2
Secondary outcomes......................................................................... 27
9.4
DATA SOURCES........................................................................................... 28
9.5
STUDY SIZE.................................................................................................. 28
9.6
DATA MANAGEMENT................................................................................ 29
9.6.1
Data Entry / EDC .................................................................................... 29
9.6.2
Source Documents................................................................................... 30
9.6.3
File Retention and Archiving.................................................................. 30

Boehringer Ingelheim
Page 4 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.7
DATA ANALYSIS......................................................................................... 30
9.7.1
Main analysis........................................................................................... 31
9.7.3
Handling of missing data......................................................................... 32
9.8
QUALITY CONTROL................................................................................... 32
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 32
9.10
OTHER ASPECTS ......................................................................................... 33
9.10.1
Data quality assurance............................................................................. 33
9.10.2
Study records........................................................................................... 33
9.10.2.1
Source documents ............................................................................ 33
9.10.2.2
Direct access to source data and documents .................................... 33
9.10.3
Completion of study................................................................................ 34
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 35
10.1
Study approval, patient information, AND informed consent ........................ 35
10.2
Statement of confidentiality............................................................................ 36
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 37
11.1
Definitions of adverse events.......................................................................... 37
11.2
Adverse event and serious adverse event collection and reporting................. 38
11.3
Reporting to health Authorities....................................................................... 41
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 42
13.
REFERENCES .................................................................................................... 43
13.1
PUBLISHED REFERENCES......................................................................... 43
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 48
Appendix 1: Physicians’ Global Evaluation (PGE).................................................... 49
Appendix 2: Clinical COPD Questionnaire (CCQ) and mMRC ................................ 50
Appendix 3: (S)AE form............................................................................................. 52
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 57
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 58

Boehringer Ingelheim
Page 5 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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
CCQ
Confidence Interval
Clinical COPD Questionnaire
CML
Local Clinical Monitor 
COPD
Chronic Obstructive Pulmonary Disease
CRA
CRO
Clinical Research Associate
Clinical Research Organisation 
eCRF
Electronic Case Report Form
EU
European Union
FDC
Fix Dose Combination
FEV1
Forced expiratory volume in one second
GCP
GEP
GPP
Good Clinical Practice
Good Epidemiological Practice
Good Pharmacoepidemiology Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
ICH
International Conference on Harmonisation
ICS
Inhalative Corticosteroides
IEC
IPCRG
Independent Ethics Committee
International Primary Care Respiratory Group
IRB
Institutional Review Board
ISF
Investigator Site File
LABA
Long-acting beta2 adrenoceptor agonist
LAMA
MACE
MAH
MCID
Long-acting muscarinic antagonist 
Major Adverse Cardiovascular Event
Marketing Authorisation Holder
Minimum Clinically Important Difference
MedDRA
mMRC
Medical Dictionary for Drug Regulatory Activities
Modified Medical Research Council
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
SADR
Short-acting beta2 adrenoceptor agonist
Suspected Adverse Drug Reaction
SAE
Serious Adverse Event
SAMA
SGRC
Short-acting muscarinic antagonist
St. George's Respiratory Questionnaire
SPC
TDI
Summary of Product Characteristics
Transitional dyspnoea index 

Boehringer Ingelheim
Page 6 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
VFA
Verband Forschender Arzneimittelhersteller
WHO
World Health Organisation

Boehringer Ingelheim
Page 7 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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 CT Coordinator
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
 
 
Project 
 

Boehringer Ingelheim
Page 8 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide + Olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
24 April 2017
1237-0065
2.0
Not applicable
Title of study:
AERIAL®: Changes in health and functional status in patients with 
COPD during therapy with Spiolto® Respimat®
Author: 
Rationale and 
background:
Clinical studies investigating treatment with Spiriva®, with Striverdi®
Respimat® as well as with the LAMA-LABA combination Spiolto®
Respimat® have shown significant improvement in exercise capacity in 
patients with COPD. However, real world exercise data with regards to 
the effects of a combination therapy with Spiolto® Respimat® in COPD 
patients who need two long-acting bronchodilators are still ongoing 
and thus not yet available.
This NIS aims to investigate health and functional status of COPD 
patients treated with Spiolto® Respimat® by means of the CCQ 
questionnaire (CCQ and CCQ-4).
Research question 
and objectives:
The primary objective of this NIS is to measure changes in health and 
functional status using the CCQ score, in COPD patients on treatment 
with Spiolto® Respimat® after approximately 6 weeks.
A secondary objective is to evaluate changes in CCQ and CCQ-4 
scores from visit 1 (baseline visit at the start of the study)  to visit 2 
(final visit at the end of the study, approx. 6 weeks after visit 1), the 
patient’s general condition (physician’s evaluation) at visit 1 and at 
visit 2, as well as patient satisfaction with Spiolto® Respimat® at visit 2 
and patient’s willingness to continue treatment with Spiolto®
Respimat® after study end (proxy for adherence).
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 combination therapy of two long-acting 
bronchodilators (LAMA + LABA) according to approved SmPC and 
GOLD guidelines, COPD GOLD groups B to D (Version 2017).

Boehringer Ingelheim
Page 9 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide + Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
24 April 2017
1237-0065
2.0
Not applicable
Variables:
-
Patient demographics (age, gender, height & weight)
-
Concomitant diseases / Comorbidities
-
Concomitant medication
-
General condition of patient based on Physician’s Global 
Evaluation PGE)
-
Smoking history
-
Exacerbations
-
Breathlessness based on mMRC score
-
CCQ and CCQ-4 scores
-
Patient satisfaction with Spiolto® Respimat®
-
Safety; ADR (serious and non-serious), fatal AEs, pregnancies
-
GOLD patient groups (B, C, D)
-
GOLD spirometric classification (1-4), if available
Data sources:
To be completed by the physician:
-
Patient demographics
-
Patient medical files 
-
Physician’s Global Evaluation (PGE) at visit 1 and visit 2
-
Patient satisfaction
-
Patient’s willingness to continue treatment
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:
-
Health and functional status by CCQ questionnaire
Study size:
1300 patients, 400 sites

Boehringer Ingelheim
Page 10 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide + Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
24 April 2017
1237-0065
2.0
Not applicable
Data analysis:
Primary outcome:
“Therapeutic success” at visit 2 (0.4 - point decrease in the CCQ score 
from visit 1 to visit 2). 
Secondary outcomes: 
Change in the CCQ and CCQ-4 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
Patient’s willingness to continue treatment
Subgroup analysis for maintenance naïve patients and the ones already 
treated at baseline with long acting bronchodilators or LABA + ICS
will be performed for the primary outcome. 
Subgroup analyses will be performed by GOLD spirometric 
classifications (2 vs. 3 vs. 4) and GOLD patient groups (B vs. C/D and 
B vs. C vs. D) for the primary outcome and changes in CCQ score for 
the secondary outcome
Milestones:
Start of data collection                          Q2 2017
End of data collection                            Q2 2018
Final report of study results                    Q3 2018

Boehringer Ingelheim
Page 11 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
5.
AMENDMENTS AND UPDATES
None

Boehringer Ingelheim
Page 12 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
6.
MILESTONES
Milestone
Planned Date
Start of data collection
Q2 2017
End of data collection
Q2 2018
Final report of study results:
Q3 2018

Boehringer Ingelheim
Page 13 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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 I.
According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Chronic 
Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disease that 
is characterized by persistent respiratory symptoms and airflow limitation that is due to 
airway and/or alveolar abnormalities usually caused by significant exposure to noxious 
particles or gases I.
The inhalation of noxious substances such as smoke with harmful particles or gases (air 
pollution), but in the majority of cases tobacco smokingtriggers an abnormal inflammatory 
response in the lung. This inflammatory response leads to increased mucus production, tissue 
remodelling and, connected with this, to a narrowing of the air passages in the lower 
respiratory tract. As a result, the pulmonary parenchyma is destroyed and pulmonary 
emphysema is caused. Over time, there are further systemic consequences, such as myopathy, 
osteoporosis, cor pulmonale and hypertension with severe restriction of physical functioning. 
Recurrent acute exacerbations (e.g. due to pulmonary infections) bring about a further 
deterioration in the condition of the lungs II.
According to the Helmholtz Centre in Munich III, 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 or stages from 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 (standard for COPD 
diagnosis) I.

Boehringer Ingelheim
Page 14 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
GOLD reassessed their classification and separated the spirometric assessment from 
symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient 
symptoms and their history of exacerbations IV.
The most important treatment strategies include inhalative pharmacological treatment, beside
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) I.
In accordance with the GOLD guidelines IV, for mild COPD (group GOLD A) monotherapy 
with short-or long acting bronchodilators is the recommended first choice. 
For group GOLD B, long-term inhaled treatment with long-acting bronchodilators (LABA, 
LAMA) is the primary recommendation. In case of persisting symptoms, therapy should be 
escalated to a LAMA/LABA combination.
For group GOLD C, an escalation from LAMA monotherapy to preferably LAMA plus 
LABA or, alternatively, to glucocorticosteroid plus LABA is recommended in case of further 
exacerbations. 
For patients in group GOLD D a double or triple therapy consisting of LAMA plus LABA or 
inhaled corticosteroids plus LABA and/or LAMA, respectively, is recommended. In case 
LABA/LAMA/ICS is not sufficient, for some patients adding roflumilast or a macrolide may 
be an option, but also de-escalation from triple therapy with ICS to dual bronchodilation is 
considered as an option for some patients. 
Pharmacological therapy for COPD is used to lessen symptoms, reduce the frequency and 
severity of exacerbations, and improve health status and exercise tolerance. To date, COPD 
medications have not been conclusively shown to modify the long-term decline in lung 
function, 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 IV.
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 V. Therefore, treatment with combination therapy is likely to be an effective
option for the management of moderate-to severe COPD.

Boehringer Ingelheim
Page 15 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
7.2
DRUG PROFILE
7.2.1
Tiotropium and Olodaterol
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® VI, VII.
The Spiriva® Respimat® was developed from the Spiriva® pharmaceutical form. This device
optimises the pulmonary deposition of the drug VIII, VIX and thus reduces the quantity of drug 
used X.
The Respimat® 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 XI. 
Thus, deep pulmonary deposition is achieved 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.
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 XII, XIII, XIV and also demonstrated a more rapid onset of effect
XV.
The drug has been authorised since 2013 in 43 countries worldwide and is available in 
Germany under the name Striverdi® Respimat® XVI.
NIS AKTIV! (1222.56)
A prospective, open-label, non-interventional study was performed in Germany in 2014-2015 
to evaluate the effectiveness of a free combination of Tiotropium plus Olodaterol on physical 
function in a broad range of COPD patients treated in primary care XVII.
In this real-world clinical setting study enrolling 1858 patients in 800 sites, Tiotropium plus 
Olodaterol rapidly improved physical functioning in patients with moderate to very severe
COPD within the first 4-6 weeks of treatment in general practice. Patients with less severe 
COPD (B and C) and no prior maintenance treatment demonstrated the greatest benefit. The 
majority of patients were 
“satisfied” or “very satisfied” with the Respimat® inhaler.
Within a short time frame, the combination of Tiotropium plus Olodaterol improved physical 
functioning, translating into overall improved general condition in patients presenting with a 
broad COPD severity range.
The findings of significant better results in maintenance-naïve COPD patients and less severe 
COPD disease are in line with results of the post hoc subgroup analysis of two replicate 
randomised controlled studies (OTEMTO).

Boehringer Ingelheim
Page 16 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
These results support the assumption of the benefit of using the combination of Tiotropium 
plus Olodaterol in early stages of COPD disease.
7.2.2
Spiolto® Respimat®
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) V.
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.

Boehringer Ingelheim
Page 17 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Inclusion and exclusion criteria:
Patients with moderate to very severe COPD (GOLD 2-4) were included if: 
!
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, 

Boehringer Ingelheim
Page 18 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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 
(GOLD 2–4) V. 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®.
Several studies investigated the impact of tiotropium/olodaterol on patient-related outcopmes 
as e.g. quality of life and exercice capacity.
The OTEMTO® studies XVIII are two replicate, randomised, double-blind, placebo-controlled 
Phase III studies investigating the effects of tiotropium/olodaterol on lung function and 
quality of life over 12 weeks in patients with moderate to severe chronic obstructive 
pulmonary disease (COPD). Post hoc analyses investigated the benefits of combination 
therapy over tiotropium monotherapy according to GOLD categories (GOLD 2-3 and GOLD 
A-D as well) or previous treatment.
Patients were randomised to receive one of four treatments delivered via Respimat® inhaler: 
Tiotropium/olodaterol 2.5/5 μg, Tiotropium/olodaterol 5/5 μg, Tiotropium 5 μg or placebo.
Only results of the subgroup analyses for the licensed doses (tiotropium/olodaterol 5/5 μg, 
tiotropium 5 μg) and placebo were presented in this publication. 
Results 
Trial Population 
Both studies (OTEMTO® 1 and 2) randomised a total of 1,623 patients, with 1,621 receiving 
treatment and 1,525 completing the study. Baseline characteristics were similar across the 

Boehringer Ingelheim
Page 19 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
subgroups except mean FEV1 values and baseline pulmonary medications, which differed 
between subgroups. Patients already on maintenance therapy tended to be ex-smokers and to 
have worse lung function compared to those who were treatment naïve.
Efficacy 
Overall, tiotropium/olodaterol therapy produced better responses than monotherapy or 
placebo.
GOLD 2 and 3 subgroups showed similar improvements in trough FEV1 responses and 
FEV1 AUC0-3 with tiotropium/olodaterol and the same applied for TDI focal score. 
SGRQ total score improved with tiotropium/olodaterol 5/5 μg in the GOLD 2 subgroup 
(compared to tiotropium and placebo) and in the GOLD 3 subgroup (compared to placebo). 
Tiotropium/olodaterol showed significant treatment effects for all endpoints as compared to 
placebo. When compared to tiotropium monotherapy, significant treatment effects between 
treatments could also be noted for most endpoints, except FEV1 in both subgroups and 
SGRQ in GOLD 3 patients. 
In GOLD A-D subgroups tiotropium/olodaterol showed better improvements in FEV1 
AUC0-3 than monotherapy and placebo across all subgroups. 
Trough FEV1 showed improved responses as compared to placebo in all subgroups.  
SGRQ total score as well as TDI focal score showed greater improvements with 
tiotropium/olodaterol as compared to placebo across all subgroups.
When compared to tiotropium monotherapy the combination treatment effects differed and 
showed best effects in the GOLD B subgroup with statistically significant difference vs 
tiotropium. 
Subgroup analyses of the OTEMTO® studies demonstrated an improvement in lung function, 
and quality of life for tiotropium/olodaterol in patients with moderate (GOLD 2) as well as 
severe COPD (GOLD 3).
Following the GOLD classification A-D, tiotropium/olodaterol had a similar treatment effect 
on lung function in all patient groups whereas in regard to QoL, the improvement was most 
apparent in GOLD B patients.
The superior effect of tiotropium/olodaterol over monotherapy with each component has also 
been shown in post hoc analyses of the TONADO® studies.
Although the treatment effect of tiotropium/olodaterol on lung function was similar in all 
subgroups, the benefit of tiotropium/olodaterol for SGRQ was most pronounced in GOLD B 
patients.
Considering the finding that the fastest decline of lung function is seen in the early stages of 
the disease, initiation of an appropriate maintenance treatment could be of particular 
importance. 
The authors conclude that the results of this post hoc analysis of the OTEMTO® studies 
clearly demonstrated that in all subgroups the improvement with tiotropium/olodaterol in 

Boehringer Ingelheim
Page 20 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
comparison to monotherapy and placebo was superior in lung function and patient related 
outcomes such as quality of life and dyspnoea.
Tiotropium/olodaterol can be considered for maintenance treatment of patients in a moderate 
and a more severe stage of the disease.
Tiotropium/olodaterol is a suitable option for initiating treatment already in patients with 
moderate COPD associated with the treatment goal of maintaining patients’ functionality and 
slowing down disease progression.
The PHYSACTO trial XIX investigated the effect of 8 and 12 weeks’ once-daily 
tiotropium/olodaterol, alone and combined with exercise training, on exercise endurance 
during walking in 303 patients with COPD. It could be shown that the treatment with 
tiotropium/olodaterol 5/5 μg, alone and combined with exercise training, improved walking 
exercise capacity compared to placebo in patients with moderate to severe chronic obstructive 
pulmonary disease who participated in a 12-week self-management behaviour- modification 
programme.
Further analysis of this data set XX has explored the impact of behaviour modification, 
combined with tiotropium/olodaterol treatment and exercise capacity, on physical activity 
and patient-reported outcomes in patients with moderate to severe chronic obstructive 
pulmonary disease. Self-management behaviour-modification was the most effective 
component in obtaining short-term increases in physical activity. Significant differences 
between treatment arms in amount of physical activity were not obtained with the given 
sample size. While physical activity did not increase with tiotropium/olodaterol 5/5 μg alone 
or in combination with exercise training compared to placebo, a reduction in symptom burden 
(perceived difficulty associated with physical activity) was observed. 
Also the MORACTOTM XXI and the TORRACTO XXII studies give first hints on the 
improvement of exercise capacity and exercise endurance with tiotropium/olodaterol
compared to placebo.

Boehringer Ingelheim
Page 21 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
8.
RESEARCH QUESTION AND OBJECTIVES
COPD Patients usually do not only show respiratory symptoms, but also physical incapacity 
and several comorbidities XXIII. These often result in impaired health status and reduced 
health-related quality of life and may lead to hospitalisations and increased mortality XXIV. 
Amongst others, low lung function XXV, frequent exacerbations XXVI comorbidities XXVII and a 
low level of physical activity are negative factors for health status in COPD. Physical 
exercise XXVIII and pharmacological interventions may improving health status, as e.g. shown 
in the UPLIFT trial with tiotropium XXIX.
The cross-sectional BOLD study assessed the impact of COPD on health status in a general 
population-based survey including almost 12000 subjects from 17 countries XXX. 2269 COPD
patients (defined by a post-bronchodilator forced expiratory volume in 1 s/forced vital
capacity <0.70) were found to show lower physical component scores (44±10 vs. 48±10 
units, p<0.0001) and mental health component scores (51±10 vs. 52±10 units, p = 0.005) than 
subjects without COPD. The effect of reported heart disease, hypertension and diabetes on 
physical health component scores (-3 to -4 units) was considerably less than the effect of 
COPD GOLD grade 3 (-8 units) or 4 (-11 units). 
Dyspnoea was the most important determinant of low physical and mental health component 
scores. In addition, lower forced expiratory volume in 1 s, chronic cough, chronic phlegm and 
the presence of comorbidities were all associated with a lower physical health component 
score.
The authors conclude COPD to be associated with poorer health status but the effect to be 
stronger on the physical than the mental aspects of health status. Severe COPD had a greater 
negative impact on health status than self-reported cardiovascular disease and diabetes.
The contribution of physical inactivity to disability in COPD can be difficult to distinguish 
from disease progression XXXI. However, it is clear that physical activity is significantly lower 
in patients with COPD than in healthy controls XXXII, XXXIII.
COPD prevents patients from carrying out daily activities due to exercise intolerance, which 
is often attributed to limited pulmonary ventilation. 
However, a number of observations have suggested that, for many COPD patients, other 
factors are involved, including deconditioning due to physical inactivity. This may be related 
to avoidance of exertion as a result of fear of dyspnoea. Furthermore, physical inactivity has 
been associated with skeletal muscle weakness and exercise intolerance XXXIV, XXXV.
The loss of physical activity in COPD is also associated with increased mortality XXXVI. Data 
from a study of 2386 patients with COPD demonstrated that, following adjustment for all 
relevant confounders, subjects who reported low, moderate or high physical activity had a 
significantly lower risk of all-cause mortality than those with very low physical activity (p = 
0.001) XXXVII.
Clinical studies XXXVIII, XXXIX, XL of both Spiriva® and Striverdi® Respimat® in COPD patients 
have demonstrated significant improvement in exercise capacity XLI.
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.

Boehringer Ingelheim
Page 22 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
In the AKTIV! observational study the combination of Tiotropium plus Olodaterol showed 
improved physical functioning, translating into overall improved general condition in patients 
presenting with a broad COPD severity range within a short time frame XLII. Thus, it is the 
first study to give a hint that the tiotropium + olodaterol combination may improve physical 
functioning and health condition.
Various questionnaires on quality of life and physical functioning are used to try assessing 
COPD patients’ health status and physical state. The Clinical COPD questionnaire (CCQ) has 
been developed and validated in the Netherlands especially for COPD patients by Jan Kocks 
et al in 2006 XLIII to categorize patients’ impairments generally and focus patients’ treatment 
on their specific needs. 
The CCQ is easy to apply. It takes less than 2 minutes to complete, is widely used to monitor 
COPD health status and control and consists of 10 questions, covering 3 domains: symptom 
domain (4 questions (#’s 1,2,5,6)); functional status domain (4 questions(#’s 7,8,9,10)) and 
mental status domain (2 questions (#’s 3,4)). The questionnaire is responsive to intervention 
and has been translated and validated in over 140 languages XLIV. The CCQ thus is a very 
well-known and widespread questionnaire, which is also included in the GOLD guidelines 
and is validated also in German language. It has been given maximum ranking in “COPD 
wellness tools” overview by the International Primary Care Respiratory Group (IPCRG) XLV.

Boehringer Ingelheim
Page 23 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
8.1
STUDY OBJECTIVES
The objective of this NIS is to measure changes in health and functional status by the CCQ, 
in COPD patients receiving treatment with Spiolto® Respimat® after approximately 6 weeks
in routine clinical practice.
Each of the 10 CCQ questions is scored by the patient on a 7-point scale between 0 and 6 at 
baseline and end of the observation after approximately 6 weeks. The sum of the scores 
divided by 10 gives the CCQ score, which measures the health and functional status. A 
higher CCQ score is indicative of worse status.
The functional status (CCQ-4) is calculation as the sum of the 4 questions (#’s 7, 8, 9, 10) 
divided by 4. A change of 0.4 points is considered to be the MCID for both CCQ score and 
CCQ-4.
Primary objective: Assess the proportion of patients achieving “therapeutic success” 
(= 0.4 point decrease in the CCQ score between baseline and approximately week 6).
Secondary objectives are assessment of changes in CCQ and CCQ-4 from visit 1 (baseline 
visit at the start of the study) to visit 2 (final visit at the end of the study, approx. 6 weeks 
after visit 1), the patient’s general condition (physician’s evaluation) at visit 1 and at visit 2, 
as well as patient satisfaction with Spiolto® Respimat® and willingness to continue treatment 
with Spiolto® Respimat® at visit 2 as proxy for adherence.

Boehringer Ingelheim
Page 24 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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.
9.2
SETTING
9.2.1
Study sites
It is planned that data of approximately 1300 patients from approximately 400 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.
9.2.2
Study population
Inclusion Criteria:
Patients can be included if all of the following criteria are met:
•
Written informed consent prior to participation
•
Female and male patients ≥40 years of age
•
Patients diagnosed with COPD and requiring a combination of two long-acting 
bronchodilators (LAMA + LABA) according to approved SmPC and GOLD COPD 
guideline recommendation 2017 (GOLD COPD groups B to D)
•
Treatment with Spiolto® Respimat® acc. to SmPC at the discretion of the physician.
Exclusion Criteria:
•
Patients with contraindications according to Spiolto® Respimat® SmPC
•
Patients already on a LABA/LAMA combination (free and fixed dose) in the last 6 
weeks before study entry
•
Patients continuing LABA-ICS treatment should not be additionally treated with 
Spiolto® Respimat® in order to avoid a double dosing of long-acting beta-agonists 
•
Pregnancy and lactation
•
Current participation in any clinical trial or any other non-interventional study of a 
drug or device.
9.2.3
Study visits
Patients will be enrolled consecutively and will be followed over an observational period of 
approximately 6 weeks. Data as listed in Table 9.2.3.1 will be collected.

Boehringer Ingelheim
Page 25 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Two study visits will be performed. At Visit 1 (baseline) the patient will be included into the 
NIS. At visit 2, after approximately 6 weeks from baseline, the observation of the patient will 
end. The respective exams and data to be collected are listed in Table 9.2.3.1.
Table 9.2.3.1: Visit flow chart and data collection parameters
Parameter
Visit 1;
baseline 
visit
Visit 2;
approx. 6 
weeks after 
baseline visit
Informed Consent
X
Inclusion / Exclusion Criteria
X
Patient demographics (age, gender, height, and weight)
X
Start of COPD
X
Number of exacerbations in the last 12 months
X
Number of exacerbations leading to hospitalization in the last 12 months
X
mMRC breathlessness scale, completed by the patient
X
Past COPD therapies (6 weeks before visit 1)
X
Respimat® training (yes/no)
X
COPD severity based on GOLD assessment1
X
GOLD spirometric classification, if available2
X
Smoking history
X
X
Concomitant diseases / Comorbidities
X
X
COPD related and other relevant concomitant medication
X
X
Health and functional status by CCQ questionnaire, completed by patient
X
X
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®
X
Rationale for Spiolto® Respimat® treatment discontinuation (if applicable)
X
Continuation or discontinuation of treatment with Spiolto® Respimat® after 
the study (yes/no)
X
1 GOLD patient group ( B, C or D) will be automatically calculated within the eCRF based on available exacerbation 
history and mMRC. 
2 GOLD stage 1-4 spirometric classification of airflow limitation based on post-bronchodilator FEV1 if available.

Boehringer Ingelheim
Page 26 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.2.4
Study discontinuation
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular study site
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the study, or any other administrative reasons, i.e. lack of recruitment
3. Violation of the observational plan or the contract by a study site or investigator, 
disturbing the appropriate conduct of the study
9.3
VARIABLES
The following parameters will be collected and assessed at visit 1 and/ or visit 2:
-
Patient demographics (age, gender, height & weight)
-
Smoking status (current smokers, former smokers, and never smokers) and pack-years
-
Concomitant diseases / Comorbidities such as cardiovascular disease, diabetes mellitus, 
musculoskeletal 
impairment, 
renal 
diseases, 
liver 
diseases, 
osteoporosis, 
gastroesophageal reflux (GERD), or lung cancer
-
COPD-related and other concomitant medication such as beta-blockers, beta-agonists, 
corticosteroids, or proton pump inhibitors
-
Reported exacerbations based on medical history in the last 12 months and 
exacerbations leading to hospitalization in the last 12 months
-
Assessment of the severity of breathlessness based on the Modified Medical Research 
Council Questionnaire (mMRC)
-
Health and functional status based on CCQ 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 (B, C, D) based 
on GOLD guidelines 2017

Boehringer Ingelheim
Page 27 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.3.1
Exposures
All patients will receive LAMA/LABA combination treatment with Spiolto® Respimat®
according to the German SmPC.
Spiolto® Respimat® contains 
!
the long-acting anticholinergic tiotropium bromide. 
The dose dispensed is 2.5 micrograms of tiotropium per puff, equivalent to 3.124 
micrograms tiotropium bromide 1 H2O. The dose dispensed is the quantity available 
to patients after crossing the mouthpiece.
!
the selective beta2-adrenoceptor agonist olodaterol. The dose dispensed is 2.5 
micrograms of olodaterol per puff (as olodaterol hydrochloride). The dose dispensed 
is the quantity available to patients after crossing the mouthpiece.
The recommended daily dose of Spiolto® Respimat® for adults is 5 micrograms of tiotropium 
ion (tiotropium) plus 5 micrograms of olodaterol, equivalent to inhaling 2 puffs from the 
Respimat® inhaler once daily at the same time of day. 
The Summaries of Product Characteristics on Spiolto® Respimat® is contained in the NIS ISF 
in the “Summary of Product Characteristics” section.
Note: The recommended doses stated in the Summary of Product Characteristics should not 
be exceeded.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
“Therapeutic success” at visit 2 (0.4 -point decrease in the CCQ score from visit 1 to visit 2).
The primary outcome is not a safety outcome.
9.3.2.2
Secondary outcomes
-
Changes in the CCQ and CCQ-4 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.
-
Willingness to continue treatment with Spiolto® Respimat® at visit 2 as proxy for 
adherence
The secondary outcomes are not safety outcomes.

Boehringer Ingelheim
Page 28 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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 will be used to automatically calculate the 
GOLD patient group (B, C, or D) in the eCRF.
The CCQ questionnaire contains 10 questions about everyday physical activity and 
functioning. Each question can be scored by patients on a 7-point scale between 0 and 6. The 
sum of the scores divided by 10 gives the CCQ score, which measures the health and 
functional status. For the functional status calculation the sum of the 4 questions (# 7, 8, 9, 
10) is divided by 4. A change of 0.4 points is considered to be the MCID. This questionnaire 
will be filled out by the patient and entered into the database. Patients will be asked to 
complete the CCQ in order to evaluate their health and functional status 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.
Willingness to continue treatment is assessed by a yes/no question.
9.5
STUDY SIZE
We assume that patients treated with Spiolto® Respimat® will have a CCQ therapeutic 
success rate similar to the SGRQ responder rate. In the TONADO studiesV patients treated 
with Spiolto® Respimat® had a 57.5% SGRQ responder rates after 24 weeks.
The TONADO was a selected trial population, so a real world population would probably 
show somewhat lower numbers due to the wide diversity of potential patients that will be 
followed up. Therefore a 50% CCQ therapeutic success rate is a reasonable assumption.
Assuming a 50% therapeutic success rate for CCQ and a sample size of 1170 patients, the 
95% confidence interval for the therapeutic success rate would be between 47.1% (lower 
limit) and 52.9% (upper limit).
Subgroups with long acting bronchodilators at baseline (i.e., LABA only, LAMA only, 
LABA and ICS) will be analyzed only if they include more than 20% of all patients. In the 
smallest subgroup (with at least 234 patients), assuming a 50% therapeutic success rate, the 
95% confidence interval would be between 43.6% and 56.4%. 
To account for a 10% drop-out rate, the sample size becomes 1300 patients.

Boehringer Ingelheim
Page 29 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.6
DATA MANAGEMENT
A data management plan (DMP) will be created to describe all functions, processes, and 
specifications for data collection, cleaning and validation. The electronic Case Report Forms 
(eCRFs) will include programmable edits to obtain immediate feedback if data are missing 
(also negative answers, unknown), out of range, illogical or potentially erroneous. These rules 
may encompass simple checks such as range validation or presence/absence of data. 
Concurrent manual data review may be performed based on parameters dictated by the DMP. 
Ad hoc queries to the sites may be generated and followed up for resolution. A source data 
quality audit may be initiated to ensure that the data in the database is accurate. Source data 
verification (SDV) will be performed at sites identified by a risk-based approach as needed.
The database will be housed in a physically and logically secure computer system maintained 
in accordance with a written security policy. The system will meet the standards of the 
International Committee on Harmonization guideline E6R1 regarding electronic study data 
handling and the safety requirements of the FDA (US Food & Drug Administration) 
concerning systems for the data acquisition of clinical studies in accordance with "Title 21 
Code of Federal Regulations (21 CFR Part 11): Electronic Records; Electronic Signatures. 
Patient confidentiality will be strictly maintained.
9.6.1
Data Entry / EDC
Data entry into the eCRF follows the instructions in the EDC system user manual and is 
further supported by help and hint texts. Support documents will also be provided within the 
online system documents which give explanations to basic functions and field types in the 
eCRF.
With data entry into the EDC system, all changes and user information will be saved in an 
audit trail.
The data review and validation steps for a project are defined in the data validation plan 
(DVP).
The DVP includes all definitions of electronic checks and the defined manual checks, which 
will be performed directly in the EDC system or can be based on listings.
Electronic edit checks (eChecks) are performed automatically and directly when entering data 
into the eCRF. Missing data entries or implausibilities are indicated to the user immediately.
Manual Checks are applied to verify the entered data validity and plausibility.
Queries can result from various sources:
!
Manual Checks by data management
!
Manual Checks by pharmacovigilance 
!
Source data verification during on-site monitoring 

Boehringer Ingelheim
Page 30 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.6.2
Source Documents
The source documents are contained in the patient’s medical record. Data collected on the 
eCRFs must be traceable to these source documents in the patient’s medical records as far as 
this is routine documentation. All original source documentation is expected to be stored at 
the site for the longest possible time required by local applicable regulations. The site will be 
instructed to notify the Sponsor before any destruction of medical records of study 
participants.
9.6.3
File Retention and Archiving
The study database and all study-specific documents received by 
 will be transferred 
to BI regularly during and after the study period. Archiving will be performed by BI Pharma 
in accordance with BI SOPs.
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the 
investigator agrees to keep records, including the identity of participating patients, copies of 
all CRFs, SAE forms, source documents and adequate documentation of relevant 
correspondence (e.g., letters, meeting minutes, telephone calls reports). The records should be 
retained by the investigator according to local regulations, or as specified in the study 
contract, whichever is longer.
Each site will receive a study site file at study initiation which contains all documents 
necessary for the conduct of the study and is updated throughout the study. This file must be 
available for review in the event the site is selected for monitoring, audits, or inspections and 
must be safely archived for at least ten years after the completing participation in the study. 
In the event that archiving of the file is no longer possible at the site, the site will be 
instructed to notify the Sponsor.
9.7
DATA ANALYSIS
Planned analyses
More details will be described in the statistical analysis plan (SAP).
No formal hypothesis testing will be performed since this is a self-controlled study.
All patients who have received at least one dose of Spiolto® Respimat® will be included in 
the analysis; this is the treated set. All analyses will be performed on the treated set (as-
treated analysis). If patients have missing values for an outcome, those patients will be 
excluded for that outcome’s analysis. For example, if a patient is missing the CCQ score at
Visit 1 and/ or Visit 2, that patient will be excluded from the analyses for the primary
endpoint of therapeutic success and the secondary endpoint of change in CCQs from Visit 1
to Visit 2.
The assessment will be carried out using SAS® software. The statistical characteristics 
presented in the end-of-text tables will be N / mean / SD / min / median / max for continuous 

Boehringer Ingelheim
Page 31 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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 (main diagnosis and concurrent diagnosis according to MedDRA,
version valid as at the time of database closure)
!
COPD related and other concomitant medication (according to the 
WHO classification, version valid at the time of database closure)
!
History of smoking 
! Reported exacerbations
! Breathlessness based on mMRC score at visit 1
!
Therapeutic success based on CCQ score; primary outcome 
!
Changes from Visit1 to Visit 2 in the CCQ and CCQ-4 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
!
Willingness to continue; secondary outcome
!
Adverse Drug Reactions (ADR & SADR), fatal AEs, pregnancies
! GOLD spirometric classifications (1, 2, 3, 4) and GOLD patient groups (B, C, D)  
! Details of treatment with inhaled respiratory agents before the study 
!
Details of treatment with respiratory agents during the study 
!
Reasons for ending treatment during the observation period 
!
Details of treatment continuation / discontinuation
9.7.1
Main analysis
For the primary outcome, the proportion of patients with CCQ therapeutic success will be 
presented together with the 95% confidence interval.

Boehringer Ingelheim
Page 32 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.7.3
Handling of missing data
For rules regarding the imputation of CCQ score, refer to www.ccq.nl (Section health care 
professionals, Scoring, missing data rules). No other missing data will be imputed.  Every 
effort will be made to collect complete data at the specified time points. Any removal from 
the analysis will be documented, stating the site and patient number as well as the reason for 
removal.
9.8
QUALITY CONTROL
To improve and secure data quality, automatic data checks upon data entry will be done 
within the eCRF. In the eCRF, plausible ranges of values for numeric data entries as well as 
logical data entries and listings will be provided for each entry field. Based on this, checks on 
completeness and plausibility will be performed upon data entry in the eCRF.
Validity of data entry thus is ensured by integrated validation checks performed by the
system, indicating missing or implausible entries to the document list or investigator. All 
corrections will be visible from the systems audit trail.
Source data verification is planned to be performed in about 10% of the planned sites in this 
study. However, in case of decreasing compliance (i.e. of missing data, data discrepancies, 
protocol violations, etc.) a for-cause audit or risk-based monitoring visit will be performed.
9.9
LIMITATIONS OF THE RESEARCH METHODS
The intention of this NIS is to collect new data on the physical functioning and exercise 
capacity of COPD patients on treatment with Spiolto® Respimat® in a real world setting.
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.

Boehringer Ingelheim
Page 33 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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.
The 7-item satisfaction scale, which is to be completed by the patient in order to measure 
satisfaction with Spiolto® Respimat® use, is a self-designed Boehringer-Ingelheim scale, 
without a public source or validation status.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Board (IRBs)/ Independent Ethics Committee 
(IECs) or by regulatory authorities. The quality assurance auditor will have access to all 
medical records, the investigator’s study-related files and correspondence, and the informed 
consent documentation of this study.
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.
9.10.2
Study records
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on 
paper or via remote data capture. 
9.10.2.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the study; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
9.10.2.2
Direct access to source data and documents
The investigator will permit study-related monitoring, audits and regulatory inspection, 
providing direct access to all related source data / documents. CRFs/eCRFs and all source 

Boehringer Ingelheim
Page 34 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
documents, including progress notes and copies of laboratory and medical test results must be 
available at all times for review by the sponsor’s clinical study monitor, auditor and 
inspection by health authorities (e.g. US Food and Drug Administration (FDA)). The Clinical 
Research Associate (CRA) / Clinical Monitor Local (CML) and auditor may review all 
CRFs/eCRFs, and written informed consents. The accuracy of the data will be verified by 
reviewing the documents described in Section 9.10.2.1.
9.10.3
Completion of study
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the study (last patient/patient out, unless specified differently in Section 9.2) or 
early termination of the study. 

Boehringer Ingelheim
Page 35 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
10.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) (to the extent applicable to the NIS setting and required by 
local regulations), Good Epidemiological Practice (GEP), Guidelines for Good 
Pharmacoepidemiology Practice (GPP), and relevant BI Standard Operating Procedures 
(SOPs). Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 
in the responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
10.1
STUDY 
APPROVAL, 
PATIENT 
INFORMATION, 
AND 
INFORMED 
CONSENT
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and Competent Authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
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 NIS master file and the investigator site file. 
In addition, every participating physician is to be advised by his/her ethics committee in 
accordance with the rules of professional conduct.
Prior to patient participation in the study, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the study records. A signed copy of 
the informed consent and any additional patient information must be given to each patient or 
the patient’s legally accepted representative.
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.

Boehringer Ingelheim
Page 36 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
10.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the 
study need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IRB / IEC and the regulatory authorities, i.e. the CA.

Boehringer Ingelheim
Page 37 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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.

Boehringer Ingelheim
Page 38 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Adverse Event of Special Interest (AESI)
The term Adverse Event of Special Interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this study, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. 
No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorisation. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined.
The following must be collected by the investigator in the (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
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. 

Boehringer Ingelheim
Page 39 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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 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 subject has been enrolled into the 
study, after having taken Spiolto® Respimat®, the investigator must report any drug exposure 
during pregnancy, which occurred in a female subject or in a partner to a male subject to the 
Sponsor by means of Part A of the Pregnancy Monitoring Form. The outcome of the 
pregnancy associated with the drug exposure during pregnancy must be followed up and 
reported by means of Part B of the Pregnancy Monitoring Form. 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 

Boehringer Ingelheim
Page 40 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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 associated with Spiolto®
Respimat®
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to Spiolto® Respimat®
immediately within 24 hours
All non-serious ADRs associated with 
Spiolto® Respimat®
7 calendar days
All pregnancy monitoring forms
associated with Spiolto® Respimat®
7 calendar days
All serious ADRs  and all fatal AEs must be documented in the eCRF and reported to the 
Pharmacovigilance department of Boehringer Ingelheim within 24 hours after getting 
knowledge of the event. The Boehringer Ingelheim NIS AE form must be printed from the 
eCRF and sent per fax. 
Non-serious ADRs and pregnancies must be documented in the eCRF and reported to the 
Pharmacovigilance department of Boehringer Ingelheim within 7 calendar days after getting 
knowledge of the event. The Boehringer Ingelheim NIS AE form must be printed from the 
eCRF and sent per fax.
If there is no eCRF access at the time of the report, the NIS AE form must alternatively be 
filled out by hand and sent to the following address by fax within 24 hours / 7 days after 
becoming known:
Boehringer Ingelheim Pharma GmbH & Co. KG
Pharmacovigilance Germany (PV Germany)
Binger Straße 173
55216 Ingelheim
Phone: +49 (6132) 72 - 2604
Fax: +49 (6132) 72 – 141522
In this case, these data must be entered into the eCRF as soon as possible when electronically 
available.
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.

Boehringer Ingelheim
Page 41 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Information required
For each reportable adverse event, the investigator should provide the information requested
on the appropriate eCRF pages.
Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other than 
the Spiolto® Respimat® according to the local regulatory requirements for spontaneous AE 
reporting at the investigator’s discretion by using the locally established routes and AE report 
forms. The term AE includes drug exposure during pregnancy, and, regardless of whether an 
AE occurred or not, any abuse, off-label use, misuse, medication error, occupational 
exposure, lack of effect, and unexpected benefit.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local
and international regulatory requirements.

Boehringer Ingelheim
Page 42 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
Results of this non-interventional study will be disclosed on encepp.eu and clinicaltrials.gov
and a study specific publication plan will be developed to describe planned publications.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalisation of the Study Report.

Boehringer Ingelheim
Page 43 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
13.
REFERENCES
13.1
PUBLISHED REFERENCES
I.
Global initiative for Chronic Obstructive Lung Disease, Inc: Global strategy for the 
diagnosis, management, and prevention of chronic obstructive pulmonary disease; 
updated 2017. http://goldcopd.org (P15-01740)
II.
from: Herold G et al.: Innere Medizin 2012; S. 343ff (R15-5282)
III.
https://www.lungeninformationsdienst.de/krankheiten/copd/verbreitung/index.html
(R15-5292)
IV.
Global initiative for Chronic Obstructive Lung Disease, Inc: Global strategy for the 
diagnosis, management, and prevention of chronic obstructive pulmonary disease; 
updated 2017. http://goldcopd.org (P15-01740)
V.
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)
VI.
Spiriva® Respimat® Summary of Product Characteristics, date November 2014
(R14-5036)
VII.
Spiriva® 18 Mikrogramm, Summary of Product Characteristics, dated November 
2014 (R17-0263)
VIII.
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)
IX.
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 Turbuhaler dry powder inhaler. J Aerosol Med. 2005 Fall; 18(3):264-72 
(P05-10480)
X.
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)
XI.
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)

Boehringer Ingelheim
Page 44 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
XII.
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)
XIII.
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)
XIV.
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)
XV.
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)
XVI.
Striverdi® Respimat® Summary of Product Characteristics, dated November 2013
(R17-0262)
XVII.
Sauer R, Hänsel M, Buhl R, Rubin RA, Frey M, Glaab T. Impact of tiotropium + 
olodaterol on physical functioning in COPD: results of an open-label observational 
study. Int J COPD 2016;11:891-898 (P16-04987)
XVIII.
Singh D, Gaga M, Schmidt O, Bjermer L, Grönke L, Voß F, Ferguson GT. Effects of 
tiotropium/olodaterol versus tiotropium or placebo by COPD disease severity and 
previous treatment history in the OTEMTO® studies Respiratory Research 2016. 
DOI 10.1186/s12931-016-0387-7 (P16-07071)
XIX.
Troosters T, Bourbeau J, Maltais F et al. Effect of 8 and 12 weeks’ once-daily 
tiotropium/olodaterol, alone and combined with exercise training, on exercise 
endurance during walking in patients with COPD. Poster presented at the European 
Respiratory Society International Congress, London, UK, 3–7 September 2016
(P16-11500)
XX.
Troosters T, Lavoie K, Leidy N, Maltais F, Sedeno M, Janssens W, et al. Effects of 
bronchodilator therapy and exercise training, added to a self-management behaviour-
modification programme, on physical activity in COPD.
Poster presented at the European Respiratory Society International Congress, 
London, UK, 3–7 September 2016 (P16-12344)
XXI.
O'Donnell D, Casaburi R, Sousa D de, Xue W, Frith P, Hamilton A, Kirsten A, 
Maltais F. Effects of 6 weeks’ treatment with once-daily tiotropium and olodaterol on 
inspiratory capacity and exercise capacity in patients with COPD: the MORACTO™ 
studies. P609 ATS 2015 (P15-05652)

Boehringer Ingelheim
Page 45 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
XXII.
Maltais F; Galdiz Iturri JB; Kirsten A; Singh D; Hamilton A; Tetzlaff K; Zhao Y; 
Casaburi R. Effects of 12 weeks of once-daily tiotropium and olodaterol fixed-dose 
combination on exercise endurance in patients with COPD. ERS 2014 (P14-13656)
XXIII.
Lopez AD, Mathers CD, Ezzati M, et al. Global and regional burden of disease and 
risk factors, 2001: systematic analysis of population health 
data. Lancet 2006; 367: 1747–1757 (R07-0651)
XXIV.
Almagro P, Calbo E, Ochoa de Echagüen A, et al. Mortality after hospitalization for 
COPD. Chest 2002;121: 1441–1448 (R04-1526)
XXV.
Jones PW, Brusselle G, Dal Negro RW, et al. Properties of the COPD assessment test 
in a cross-sectional European study. Eur Respir J 2011; 38: 29–35 (R17-0261)
XXVI.
Xu W, Collet JP, Shapiro S, et al. Negative impacts of unreported COPD 
exacerbations on health-related quality of life at 1 year.
Eur Respir J 2010; 35: 1022–1030 (R17-0260)
XXVII.
Esteban C, Quintana JM, Aburto M, et al. Impact of changes in physical activity on 
health-related quality of life among patients with chronic obstructive pulmonary 
disease. Eur Respir J 2010; 36: 292–300 (R17-0259)
XXVIII.
Burtin C, Saey D, Saglam M, et al. Effectiveness of exercise training in patients with 
COPD: the role of muscle fatigue. Eur Respir J 2012; 40: 338–344
(R17-0258)
XXIX.
Troosters T, Celli B, Lystig T, et al. . Tiotropium as a first maintenance drug in 
COPD: secondary analysis of the UPLIFT trial. Eur Respir J 2010; 36: 65–73
(P10-03336)
XXX.
Janson C, Marks G, Buist S, Gnatiuc L, Thorarinn Gislason T, McBurnie MA, 
Nielsen R, Studnicka M, Toelle B, Benediktsdottir B, Burney P. The impact of 
COPD on health status: findings from the BOLD study.
Eur Respir J 2013 42(6): 14721483; DOI: 10.1183/09031936.00153712
(P17-00943)
XXXI.
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)
XXXII.
Troosters T, Sciurba F, Battaglia S, Langer D, Valluri SR, Martino L, Benzo R,
Andre D, Weisman I, Decramer M. Physical inactivity in patients with COPD, a 
controlled multi-center pilot-study. Respir Med. 2010 Jul;104(7):1005-11.
doi: 10.1016/j.rmed.2010.01.012. Epub 2010 Feb 18 (R13-3633)

Boehringer Ingelheim
Page 46 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
XXXIII.
Watz H, 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)
XXXIV.
Maltais F, LeBlanc P, Simard C et al. Skeletal muscle adaptation to endurance 
training in patients with chronic obstructive pulmonary disease. 
Am J Respir Crit Care Med 1996;154:442-447 (R15-4561)
XXXV.
Mador MJ, Bozkanat E. Skeletal muscle dysfunction in chronic obstructive 
pulmonary disease. Respir Res 2001;2:216-224 (R15-4562)
XXXVI.
Garcia-Rio 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)
XXXVII.
Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Antó JM. Regular physical 
activity reduces hospital admission and mortality in chronic obstructive pulmonary 
disease: a population based cohort study. Thorax. 2006 Sep;61(9):772-8. Epub 2006 
May 31 (R15-4564)
XXXVIII.
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)
XXXIX.
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)
XL.
Casaburi R, Kukafka D, Cooper C et al. Improvement in Exercise Tolerance With the 
Combination of Tiotropium and Pulmonary Rehabilitation in Patients With COPD. 
Chest 127, 3, March 2005 (P05-02413)
XLI.
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)
XLII.
Kocks JWH, Tuinenga MG, Uil SM, van den Berg JW, Ståhl E, vander Molen T. 
Health status measurement in COPD: the minimal clinically important difference of 
the clinical COPD questionnaire. Respir Res. 2006;7:62 (R17-0256)
XLIII.
Kocks JWH, van de Ven M, Uil S. M., van den Berg JW, Asijee G. M., van der 
Molen T. Functional Status measurement in COPD: The value of the functional 
status domain of the CCQ. THORAX 2006;61(Suppl II):ii40 (R17-0254)
XLIV.
http://ccq.nl/?page_id=85&lang=nl

Boehringer Ingelheim
Page 47 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
XLV.
DOI: http://www.dx.doi.org/10.2147/COPD S29868 (R17-0255) and
http://www.theipcrg.org/display/RESCOPD/COPD+Assessment+Tool+Guides
(R17-0257)

Boehringer Ingelheim
Page 48 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference Number
Date
Title
1
Appendix 1
20 January 2017
Physicians’ Global 
Evaluation (PGE)
2
Appendix 2
20 January 2017
CCQ Questionnaire 
and mMRC
3
Appendix 3
20 January 2017
SAE Form

Boehringer Ingelheim
Page 49 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
APPENDIX 1: PHYSICIANS’ GLOBAL EVALUATION (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

Boehringer Ingelheim
Page 50 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
APPENDIX 2: CLINICAL COPD QUESTIONNAIRE (CCQ) AND MMRC
Clinical COPD Questionnaire

Boehringer Ingelheim
Page 51 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
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

Boehringer Ingelheim
Page 52 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
APPENDIX 3: (S)AE FORM

Boehringer Ingelheim
Page 53 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015

Boehringer Ingelheim
Page 54 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015

Boehringer Ingelheim
Page 55 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015

Boehringer Ingelheim
Page 56 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015

Boehringer Ingelheim
Page 57 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable

Boehringer Ingelheim
Page 58 of 58
Non-interventional Study Protocol
BI Study Number 1237-0065
c15737297-03
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 3. ADDITIONAL INFORMATION
Will be completed after study approval by ethic’s committee.

 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F

FOLQLFDOWULDOSURWRFROQLV
$(5,$/&KDQJHVLQKHDOWKDQGIXQFWLRQDOVWDWXVLQSDWLHQWVZLWK&23'GXULQJ
WKHUDS\ZLWK6SLROWR5HVSLPDW
$SSURYDO±&OLQLFDO0RQLWRU
$SU&(67
$SSURYDO
6DIHW\(YDOXDWLRQ
7KHUDSHXWLF$UHD
$SU&(67
$SSURYDO
0HGLFDO$IIDLUV
$SU&(67

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F
