Changes in Health and Functional Status in Patients With Chronic Obstructive Pulmonary Disease (COPD) During Therapy With Spiolto® Respimat® [ELLACTO]
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015 
 
 
 
Non-interventional Study Protocol 
Document Number: 
c20892554-01 
BI Study Number: 
1237-0073 
BI Investigational 
Product(s): 
Spiolto® Respimat® 
Title: 
Changes in health and functional status in patients with Chronic 
Obstructive Pulmonary Disease (COPD) during therapy with 
Spiolto® Respimat® [ELLACTO] 
Brief lay title 
Not applicable 
Protocol version 
identifier: 
2.0 
Date of last version of 
protocol: 
28 Aug 18 
PASS: 
No 
EU PAS register number: 
EUPAS21422 
Active substance: 
R03AL06 Tiotropium bromide + Olodaterol 
Medicinal product: 
Spiolto® Respimat® 2.5 microgram/2.5 microgram, inhalation 
solution; tiotropium/olodaterol 
Product reference: 
NL/H/3157/001/DC 
Procedure number: 
n.a. 
Marketing authorization 
holder(s): 
Market Authorization Holder: 
Boehringer Ingelheim International GmbH 
Binger Straße 173 
55216 Ingelheim am Rhein 
Study Initiator: 
Boehringer Ingelheim Ellas  
Leoforos Andrea Sygrou 
340,17673, 
Kallithea,Athens 
Greece 
Joint PASS: 
No 

Boehringer Ingelheim 
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BI Study Number 1237-0073 
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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® at Visit 2. 
Country(-ies) of study: 
Greece 
Author: 
Tel: 
 
Fax: 
 
Mobile: 
 
E-mail 
 
Tel: 
 Fax: 
 
Mob: 
 
Email: 
 
Date: 
28/08/2018 
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1. 
TABLE OF CONTENTS 
Non-interventional Study Protocol ................................................................................................. 1 
1. 
TABLE OF CONTENTS .................................................................................................. 3 
2. 
LIST OF ABBREVIATIONS ........................................................................................... 5 
3. 
RESPONSIBLE PARTIES ............................................................................................... 6 
4. 
ABSTRACT ...................................................................................................................... 7 
5. 
AMENDMENTS AND UPDATES ................................................................................ 10 
6. 
MILESTONES ................................................................................................................ 11 
7. 
RATIONALE AND BACKGROUND ........................................................................... 12 
7.1 
MEDICAL BACKGROUND ......................................................................................... 12 
7.2 
DRUG PROFILE ............................................................................................................ 12 
8. 
RESEARCH QUESTION AND OBJECTIVES ............................................................. 13 
8.1 
RATIONALE FOR PERFORMING THE STUDY ....................................................... 13 
8.2 
STUDY OBJECTIVES ................................................................................................... 13 
9. 
RESEARCH METHODS ............................................................................................... 14 
9.1 
STUDY DESIGN ............................................................................................................ 14 
9.2 
SETTING ........................................................................................................................ 15 
9.2.1 
Study sites .................................................................................................................. 15 
9.2.2 
Study population ........................................................................................................ 15 
9.2.3 
Study visits ................................................................................................................. 16 
9.2.4 
Study discontinuation ................................................................................................. 16 
9.3 VARIABLES………………………………………………………………………….. 16 
9.3.1 
Exposures ................................................................................................................... 17 
9.3.2 
Outcomes.................................................................................................................... 17 
9.3.2.1 Primary outcome:…. ........................................................................................... …….17 
9.3.2.2 Secondary outcomes: ........................................................................................... …….18 
9.4 DATA SOURCES........................................................................................................... 19 
9.5 STUDY SIZE .................................................................................................................. 19 
9.6 DATA MANAGEMENT ................................................................................................ 20 
9.7 DATA ANALYSIS ......................................................................................................... 20 
9.7.1 
Main analysis.............................................................................................................. 21 
........................................................................................................ 21 
9.7.3 
Handling of missing data……………………………………………………………21 
9.8 QUALITY CONTROL ................................................................................................... 22 
9.9 LIMITATIONS OF THE RESEARCH METHODS ...................................................... 22 

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9.10 OTHER ASPECTS ......................................................................................................... 22 
9.10.1 Data quality assurance ................................................................................................ 22 
9.10.2 Study records .............................................................................................................. 22 
9.10.2.1 
Source documents.......................................................................................................... 22 
9.10.2.2 
Direct access to source data and documents .................................................................. 23 
9.10.3 Completion of study ................................................................................................... 23 
9.10.4 Protocol violations ..................................................................................................... 23 
10. 
PROTECTION OF HUMAN SUBJECTS ..................................................................... 23 
10.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED CONSENT..24 
10.2  STATEMENT OF CONFIDENTIALITY ...................................................................... 24 
11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ............................................................................................................................... 25 
11.1 DEFINITIONS OF ADVERSE EVENTS ...................................................................... 25 
11.2 ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................................. 26 
11.3 REPORTING TO HEALTH AUTHORITIES ................................................................ 28 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .... 28 
13. 
REFERENCES ............................................................................................................... 29 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................................. 33 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ................................................ 34 
ANNEX 3. ADDITIONAL INFORMATION ............................................................................. 35 

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2. 
LIST OF ABBREVIATIONS 
 
ADR 
AE 
BI 
CA 
CCQ 
CI 
CML 
COPD 
CRA 
eCRF 
DMP 
EU 
FDC 
FEV1 
GCP 
GEP 
GPP 
GOLD 
HCPs 
HH 
ICH 
ICS 
IEC 
ISF 
LABA 
LAMA 
MedDRA 
mMRC 
NIS 
RMT 
PGE 
SAE 
SAP 
SD 
SF-36 
SGRQ 
SmPC 
WHO 
 
Adverse Drug Reaction 
Adverse Event 
Boehringer Ingelheim 
Competent Authority 
Clinical COPD Questionnaire 
Confidence Interval 
Local Clinical Monitor 
Chronic Obstructive Pulmonary Disease 
Clinical Research Associate 
Electronic Case Report Form 
Data Management Plan 
European Union 
Fix Dose Combination 
Forced expiratory volume in one second 
Good Clinical Practice 
Good Epidemiological Practice 
Good Pharmacoepidemiology Practice 
Global Initiative for Chronic Obstructive Lung Disease 
Health Care Professionals 
HandiHaler Inhaler Device 
International Conference on Harmonisation 
Inhalative Corticosteroides 
Independent Ethics Committee 
Investigator Site File 
Long-acting beta2 adrenoceptor agonist 
Long-acting muscarinic antagonist 
Medical Dictionary for Drug Regulatory Activities 
Modified Medical Research Council 
Non-Interventional Study 
Respimat Inhaler Device 
Physician’s Global Evaluation 
Serious Adverse Event 
Statistical Analysis Plan 
Standard Deviation 
36-Item Short Form Health Survey 
St George’s Respiratory Questionnaire 
Summary of Product Characteristics 
World Health Organisation 

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3. 
RESPONSIBLE PARTIES 
 
 
 
Therapeutic Area 
Respiratory Medicine (TA ) 
Team Member Medical Affairs (TM MA) 
Team Member Epidemiology (TM Epi) 
Global Epidemiology (  GEpi) 
Therapeutic Area 
 Risk Management (TA  RM), and 
Pharmacovigilance Working Group (PVWG) 
 
GPV Study Coordination 
Trial Statistician (TSTAT) 
Trial Data Manager (TDM) 
Trial Programming 
Trial Clinical Monitor (TCM) 
Coordinating Investigator (CI) 
Not applicable 
CRO -- 
 
 

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4. 
ABSTRACT 
 
Name of company: 
Boehringer Ingelheim 
Name of finished medicinal product: 
Spiolto® Respimat® 
Name of active ingredient: 
R03AL06 
Tiotropium bromide +Olodaterol 
Protocol date: 
18 December 2017 
Study number: 
1237-0073 
Version/Revision: 
2.0 
Version/Revision date: 
Not applicable 
Title of study: 
Changes in functional status in patients with COPD during therapy with 
Spiolto® Respimat® 
Rationale and 
background: 
Reduced physical activity resulting in deconditioning and restricted physical 
functioning is a key problem of COPD patients, which even in early disease 
stages is of concern. 
Clinical studies investigating treatment with Spiriva® or with Striverdi® 
Respimat® and as well as with the combination Spiolto® Respimat ®, have 
shown significant improvement in exercise capacity in patients with COPD 
[PO5-09483, R13-2524, P17-04769, P17-06396]. However, real life data with 
regards to the effects of a combination therapy with the approved brand Spiolto® 
Respimat® in COPD patients who need two long-acting bronchodilators are not 
yet available. This study aims to investigate functional status of COPD patients 
treated with Spiolto ® Respimat® by means of the CCQ questionnaire, more 
specifically by its ‘functional status’ subdomain (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. 
The secondary objectives are to evaluate the absolute change in the CCQ and 
CCQ-4 between Visit 1 (baseline visit at the start of the study) and 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 (and in a subset, preference) with Spiolto® Respimat® at Visit 2 
and treatment continuation of Spiolto® Respimat® after the study. 
 
Study design: 
Open-label observational study: including COPD patients receiving treatment 
with Spiolto® Respimat® for approximately 6 weeks, which is the average time 
between two medical consultations. 
Population: 
COPD patients requiring a fixed combination therapy of two long-acting 
bronchodilators (LAMA + LABA) according to approved SmPC and the updated 
COPD GOLD 2017 guidelines regarding groups B to D [P17-01597]. 

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Name of company: 
Boehringer Ingelheim 
Name of finished medicinal product: 
Spiolto® Respimat® 
Name of active ingredient: 
R03AL06 
Tiotropium bromide +Olodaterol 
Protocol date: 
18 December 2017 
Study number: 
1237-0073 
Version/Revision: 
2.0 
Version/Revision date: 
Not applicable 
Title of study: 
Changes in functional status in patients with COPD during therapy with 
Spiolto® Respimat® 
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 
Health Status based on CCQ scores 
Functional Status based on the CCQ subdomain 4 (CCQ-4) 
Patient satisfaction with Spiolto® Respimat® and preference (abbreviated 
PASAPQ Part 1 + Part 2) 
Safety; ADR (serious and non-serious), fatal AEs, pregnancies 
GOLD spirometric classifications (1, 2, 3, 4) (when available). 
GOLD patient groups (B, C, D) 
Data sources: 
To be completed by the physician: 
- 
Patient demographics 
- 
Patient medical files 
- 
Physician’s Global Evaluation (PGE) at Visit 1 and Visit 2 
To be completed by the patient at Visit 1: 
- 
mMRC breathlessness scale 
To be completed by the patient at Visit 1 and at Visit 2: 
- 
Physical Functioning Questionnaire (CCQ) 
To be completed by the patient at Visit 2 only: 
- 
Patient satisfaction and preference survey (abbreviated PASAPQ Part 1 +
Part 2) 
Study size: 
1300 COPD patients will be recruited by 100 pulmonologists in private practice 
and 2 hospital centers throughout Greece. Each investigator will include 10-15 
consecutive patients for whom he/she decided for a treatment with Spiolto ® 
Respimat®. 

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Name of company: 
Boehringer Ingelheim 
Name of finished medicinal product: 
Spiolto® Respimat® 
Name of active ingredient: 
R03AL06 
Tiotropium bromide +Olodaterol 
Protocol date: 
18 December 2017 
Study number: 
1237-0073 
Version/Revision: 
2.0 
Version/Revision date: 
Not applicable 
Title of study: 
Changes in functional status in patients with COPD during therapy with 
Spiolto® Respimat® 
Data analysis: 
Primary endpoint: proportion of patients achieving “therapeutic success” (= 0.4 
point decrease in the CCQ score between baseline and week 6) [R17-0254]. 
0.4 points is the well accepted MCID [R17-0256] 
Secondary endpoints: 
Absolute change in the CCQ 
Absolute change in CCQ-4. 
Patient´s general condition: Physician´s Global Evaluation (PGE) score at 
baseline and end of study. 
Patient satisfaction with (tiotropium and olodaterol) Respimat® at end of study 
using a seven-point ordinal scale (ranging from very dissatisfied to very satisfied) 
(abbreviated PASAPQ Part 1). 
Patient preference HH (HandiHaler) vs RMT (Respimat) Inhaler devices – only 
for those patients that used Spiriva HH previous to the study (PASAPQ Part 2). 
Treatment continuation of Spiolto® Respimat® after the study. 
Milestones: 
Start of data collection: FPI: Jan 2018 
End of data collection: LPO: June 2018 
Final report of study results: Mar 2019 

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5. 
AMENDMENTS AND UPDATES 
 
Number 
Date 
Section of 
study protocol 
Amendment or 
update 
Reason 
02 
28 Aug 2018 
1,4,7,8,9 
clarification of primary 
endpoint, addition of a 
secondary endpoint 
and correction in 
Section 9.7.3 

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6. 
MILESTONES 
 
Milestone 
Planned Date 
IRB/IEC approval 
14 Mar 2018 
Start of data collection 
19 Mar 2018 
End of data collection 
30 Nov 2018 
Final report of study results: 
30 April 2019 

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7. 
RATIONALE AND BACKGROUND 
 
7.1 
MEDICAL BACKGROUND 
 
COPD is defined as a quite preventable and treatable disease of the airways, with significant systemic 
consequences especially in cardiology. Inactivity is believed to be crucial to the further development of 
extrapulmonary effects of the disease like skeletal muscle weakness, osteoporosis and cardiovascular 
disease. Recent data suggest that patients suffering from COPD combined with low levels of physical 
activity have increased risk for hospital admissions and have significantly enhanced mortality. 
Epidemiological data suggest that this may directly or indirectly lead to more rapid decline in lung 
function [R13-3633]. 
Physical activity is reduced early in concomitance with the disease progression, as of GOLD Stage 2 
[R13-3633]. More recent evidence from large placebo-controlled clinical trials indicates that COPD 
patients experience a steeper absolute decline in lung function with GOLD 2 airflow limitation than with 
GOLD 3 and 4 [R15-5015]. All these observations suggest the importance of early and optimal treatment 
of the disease. 
Long-acting bronchodilators, such as long-acting muscarinic antagonists (LAMAs), are the cornerstone 
of maintenance therapy for patients with moderate to very severe chronic obstructive pulmonary disease 
(COPD) whose symptoms are not adequately controlled by short-acting bronchodilators alone [P13- 
05794, P14-01052]. 
An option recommended by GOLD guideline for patients not adequately controlled on a single long- 
acting bronchodilator is to combine a LAMA with a long-acting β2-agonist (LABA) [P14-01052]. This 
has prompted the development of combining LAMA+LABA as fixed-dose combinations [P13-05794]. 
The rationale for combining bronchodilators with different mechanisms is based on the notion of 
additive, synergic relaxation of airway smooth muscle by direct inhibition of cholinergic activity and 
functional antagonism of bronchoconstriction through β2-adrenergic pathways, with the expectation of 
an increased degree of bronchodilation for equivalent or even lesser side effects. Several recent studies 
have provided evidence in support of this increased bronchodilatory effect when LABAs are combined 
to LAMAs. 
When long acting beta-agonists (LABA) and long acting muscarinic antagonists (LAMA) with similar or 
equivalent posologies are combined, the opportunity exists for offering a simpler and more convenient 
administration regimen with the development of fixed combinations within the same inhaler device. 
Fixed-dose combinations of a short-acting β2– agonist and a short-acting anticholinergic have been 
developed and have been shown to be safe, efficacious and convenient for the patient (e.g., Berodual®: 
Fenoterolhydrobromid + Ipratropiumbromid, Combivent®: salbutamol + ipratropium bromide; [P94- 
1346]). Olodaterol is a highly selective and nearly full β2 agonist [P10-07776, P11-07720] that provides 
24-h bronchodilation in patients with COPD [P13-11467, P13-14112, P13-11346, P13-11345]. 
Olodaterol is also associated with symptomatic relief [P13-11341] and enhanced exercise capacity [P13- 
14109]. 
The complementary modes of action of tiotropium and olodaterol have previously been demonstrated in 
animal models, phase II clinical trials and during Phase IIIa programs [P10-09337, P14-12073, P13- 
02357]. In Phase III programs, additional benefits of the tiotropium + olodaterol fixed-dose combination 
(FDC) has been assessed on lung function over its mono-components, as well as quality of life (St. 
George's Respiratory Questionnaire-SGRQ), dyspnea (Transition Dyspnea Index-TDI) and exercise 
endurance time. Another clinically important potential benefit of the tiotropium + olodaterol FDC over 
the mono components is the impact on exacerbations of COPD. 
 
7.2 
DRUG PROFILE 
 
Tiotropium + olodaterol FDC is an aqueous solution of tiotropium and olodaterol contained in a 
cartridge. It is administered by using the Respimat® inhaler. One cartridge is used per inhaler, which is 

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inserted into the device prior to first use. In pivotal clinical trials and for the intended marketed product, 
the clinical dose consists of two puffs once daily. The Respimat® inhaler uses mechanical energy to 
create a soft mist which is released over a period of approximately 1.5 seconds. 
Tiotropium + olodaterol FDC was shown to be safe and well tolerated over 1 year in a moderate to very 
severe COPD population. The overall incidences of adverse events (AEs), serious adverse event (SAEs), 
fatal AEs, frequencies for cardiac events and major adverse cardiovascular event in the tiotropium + 
olodaterol FDC treatment group were similar to the components alone. The nature and frequency of AEs 
in general was consistent with the disease under study. There were no results in the clinical development 
program suggesting the need for absolute contraindications for the combination product [P15-03349]. 
In conclusion, the clinical trials conducted to date have shown tiotropium + olodaterol FDC to be a safe, 
well tolerated and efficacious combination therapy according to treatment guidelines in a moderate to 
very severe COPD patient population [P15-04531, P15-03349]. The observed incremental 
bronchodilator response due to the combination compared to the components alone, was translated into 
clinical benefits that were meaningful to the patient, with improvements in several patient centered 
outcomes. For further information please refer to the SmPC of Spiolto® Respimat®. 
 
 
8. 
RESEARCH QUESTION AND OBJECTIVES 
8.1 
RATIONALE FOR PERFORMING THE STUDY 
 
The contribution of physical inactivity to disability in COPD is difficult to distinguish from disease 
progression; however, it is clear that physical activity is significantly lower in patients with COPD than 
in healthy controls [R13-3633] 
COPD prevents patients from carrying out daily activities due to exercise intolerance, which is often 
attributed to limited pulmonary ventilation. Physical inactivity may be related to avoidance of exertion as 
a result of fear of dyspnea. Furthermore, physical inactivity has been associated with skeletal muscle 
weakness and exercise intolerance [R15-4459, R15-4561]. 
The loss of physical activity in COPD is associated with increased mortality. Data from a study of 2386 
patients with COPD demonstrated that, following adjustment for relevant confounders, subjects who 
reported low, moderate or high physical activity had a significantly lower risk of all-cause mortality than 
those with very low physical activity (p = 0.001) [R15-4564]. Clinical studies of both Spiriva® [P13- 
04267, P05-09483, P13-14109] and Striverdi® Respimat® in COPD patients have demonstrated 
significant improvement in exercise capacity [P13-14109]. 
The benefits of tiotropium + olodaterol FDC have been studied in controlled Phase III programs on 
exercise endurance, however, data regarding physical activity when treated with Spiolto® Respimat® in a 
real world setting is not available. 
 
 
8.2 
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. [R17-0256] 
Primary objective: Assess the proportion of patients achieving “therapeutic success” (= 0.4 point 
decrease in the CCQ score between baseline and approximately week 6). 

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The secondary objectives are to evaluate the absolute change in the CCQ and CCQ-4 between Visit 1 
(baseline visit at the start of the study) and 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 (and in a subset, preference) with Spiolto® Respimat® at Visit 2. 
 
9. 
RESEARCH METHODS 
 
9.1 
STUDY DESIGN 
 
This is a self-controlled non interventional study enrolling consented COPD patients who will be treated 
with Spiolto® Respimat® according to approved SmPC. The Patients will be enrolled consecutively and 
will be followed over an observational period of approx. 6 weeks. Data as listed in Table 9.1.1 will be 
collected. 
Baseline characteristics of eligible patients and provided Informed Consent but were not treated in the 
study will also be collected. 
The intended Health Care Professionals (HCPs) are private practice physicians who are treating 
symptomatic and COPD patients every day, being aware that most of their patients suffer from the 
physical restrictions induced by the disease per se. 
Study results will be used to document the effectiveness of Spiolto® Respimat® in improving the 
functional status of COPD patients impaired in activity of daily living (ADL). It will complement the 
results of a previous trial using the PF-10 (1222.56). The biggest advantage of the current proposal is 
that the CCQ is a very well-known and widespread questionnaire, which is also included in the GOLD 
guidelines [R17-3684] and is validated in Greek [R17-3682, R17-3681]. 
 
Table 9.1.1: Visit flow chart and data collection parameters 
 
Parameter 
Visit 1 
baseline 
visit 
Visit 2 
approx. 6 
weeks 
after 
baseline 
visit 
Telephone 
contact 2 
weeks after 
baseline 
visit 
Informed Consent 
X 
Inclusion / Exclusion Criteria 
X 
Patient demographics (age, gender, height, and weight) 
X 
Smoking history 
X 
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 
Past COPD therapies (6 months before Visit 1) 
X 
COPD related and other relevant concomitant medication 
X 
X 
Concomitant diseases / Comorbidities 
X 
X 
Respimat® training (yes/no) 
X 
COPD severity based on GOLD assessment1 
X 

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Table 9.1.1: Visit flow chart and data collection parameters (cont’d) 
mMRC breathlessness scale, completed by the patient 
X 
CCQ completed by the patient 
X 
X 
General condition of patient evaluated by Physician’s Global Evaluation 
(PGE) 
X 
X 
Adverse Drug Reactions (serious and non-serious), fatal AE, pregnancy 
X 
X 
X 
Patient satisfaction with Spiolto® Respimat®, survey completed by the 
Patient (abbreviated PASAPQ part 1). Patient preference for who used 
HH in precedence (PASAPQ part 2). 
X 
Rational for Spiolto® Respimat® treatment discontinuation (if 
applicable) 
X 
X 
Continuation or discontinuation of treatment with Spiolto® Respimat® 
after the study (yes/no) 
X 
X 
GOLD patient group (B, C or D) will be automatically calculated within the eCRF based on available exacerbation history, 
mMRC and GOLD spirometric classification of airflow limitation based on post-bronchodilator FEV1 if available. 
 
 
 
 
9.2 
SETTING 
It is planned that data of approximately 1300 patients from approximately 102 sites (around 100 
pulmonologists in private practice and 2 hospital sites) throughout Greece will be collected. Each 
investigator (site) will include 10-15 consecutive patients for whom he/she decided for a treatment with 
Spiolto ® Respimat® 
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. 
 
 
9.2.1 
Study sites 
 
Patients will undergo visits 1 and 2 in private practice services disposed by pulmonologists who will 
participate in the study. In the case of hospital setting this will be guaranteed by outpatient clinics in 
agreement with the investigator pulmonologist. 
 
9.2.2 
Study population 
 
1300 patients with chronic obstructive pulmonary disease (COPD) in whom combination treatment with 
long-acting bronchodilators is indicated in accordance with the guidelines are to be observed by approx. 
100 pulmonologists in the setting of private practice. The NIS will take place in Greece and sites in 
urban as well as rural areas will be included. The nationwide distribution of the participating 
pulmonologists as well as the number of patients enrolled are intended to ensure that the data collected 
are representative. 
Possible contraindications are to be checked prior to treatment with Spiolto® Respimat®. See also the 
latest Summaries of Product Characteristics on Spiolto® Respimat®. 
Every physician should enroll the first consecutive patients he/she chooses to treat with Spiolto® 
Respimat®. The inclusion of ten to fifteen patients is planned per pulmonologist. 
The decision to treat will be taken independently of participation in this NIS and will be made before 
participation is considered. 

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Inclusion criteria 
 
Therapeutic indication before entering the enrollment phase is patients diagnosed with COPD 
requiring a combination therapy of two long-acting bronchodilators (LAMA + LABA) according 
to approved SmPC and guidelines, COPD GOLD 2017 groups B to D. 
 
Female and male patients ≥40 years of age 
 
Treatment with Spiolto ® Respimat® acc. to SmPC and at the discretion of the physician. 
 
Written informed consent prior to participation 
 
Exclusion criteria 
 
Patients with contraindications according to Spiolto® Respimat® SmPC 
 
Patients who have been treated with a LABA/LAMA combination (free and fixed dose) in the 
previous 6 weeks or patients already on a combination of LAMA and LABA therapy; either as a 
fixed combination product or as separate components 
Note: Patients previously treated with LABA or LAMA (with or without ICS) are eligible to be included 
in the study 
 
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 
 
Patients for whom further follow-up is not possible at the enrolling site during the planned study 
period of approx. 6 weeks 
 
Pregnancy and lactation 
 
Patients currently listed for lung transplantation 
 
Current participation in any clinical trial or any other non-interventional study of a drug or 
device. 
 
 
 
9.2.3 
Study visits 
 
Enrolled patients will undergo 2 study visits. Visit 1 (baseline visit) during screening and enrollment, 
visit 2 (follow up visit) at the end of 6 weeks therapy with the product. A telephone contact will take 
place 2 weeks after first day of therapy to check for compliance and safety issues. 
 
 
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 protocol, the contract, or applicable laws and regulations for non-interventional 
studies, which could disturb the appropriate conduct of the NIS. 
 
The investigator / the study site will be reimbursed for reasonable expenses incurred in case of study 
termination (except in case of the third reason). 
 
9.3 
VARIABLES 
 
In this NIS the following information about the effect of a dual long-acting bronchodilation with 
Spiolto® Respimat® on functional status in 1300 COPD patients treated in private practice will be 
collected in an e-CRF. 
 
Baseline: documentation of patient demographics, COPD and other relevant medical history, 

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comorbidities, reported exacerbations based on medical history in the last 12 months and 
exacerbations leading to hospitalization in the last 12 months, GOLD patient groups (B, C, D), 
based on GOLD guidelines, GOLD spirometric classifications (1, 2, 3, 4) (when available), 
 
mMRC, smoking history, previous and concomitant pulmonary medication, self-administered (patient) 
Clinical COPD Questionnaire (CCQ (total as well as functional status subdomain CCQ-4)), patient´s 
general condition (Physician´s Global Evaluation (PGE) score). Pregnancies at the beginning of the 
study. 
 
Next medical consultation (at 6 weeks): self-administered (patient) 4-item Clinical COPD 
Questionnaire (Total CCQ and CCQ-4, subdomain of CCQ), patient´s general condition 
(Physician´s Global Evaluation (PGE) score), Patient satisfaction (and in a subset also 
preference) with Spiolto® Respimat®, adverse events and safety Reporting; Adverse Drug 
Reactions (serious and non-serious), fatal AEs, pregnancies at the end of the study, withdrawal 
from treatment since baseline. 
 
Safety Reporting: Adverse Drug Reactions (serious and non-serious), fatal AEs, pregnancies at 
the beginning and at the end of the study 
 
The PGE (Physician´s Global Evaluation) assesses the patient´s general condition using an 
eight-point scale (ranging from poor to excellent). 
 
Patient satisfaction with Respimat® will be measured with the abbreviated PASAPQ (part 1) 
and patient preference Spiriva HH vs RMT for those that used Spiriva HH previous to the study 
will be measured using PASAPQ (part 2), a practical, valid, reliable and responsive instrument 
for measuring respiratory device satisfaction [P05-02607]. 
 
Treatment continuation of Spiolto® Respimat® after the study. 
 
The CCQ questionnaire contains 10 questions; each question can be scored by patients on a 7- 
point scale between 0 and 6. The sum of the scores divided by 10 gives the CCQ score. For the 
functional status calculation the sum of the 4 questions 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. 
 
9.3.1 
Exposures 
 
All patients will receive LAMA/LABA combination treatment with Spiolto® Respimat® according to the 
Greek 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 outcome: 
The primary outcome is to measure the proportion of patients achieving the “therapeutic success” defined 
as a ≥ 0.4 point of decrease in the Clinical COPD Questionnaire (CCQ) score between baseline and week 
6. [R17-02546] .  

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As already known 0.4 points is the well accepted minimal clinically important difference (MCID) of the 
clinical COPD questionnaire [R17-0256]. 
The CCQ is a very short 10 question survey through which patients are requested to recall their experiences 
during the previous week with regards to their symptoms, functional and mental state. It is self-
administered and takes patients approximately 2 minutes to complete. It is subdivided into three domains: 
symptom related (items 1-2-5-6), functional state related (items 7-8-9-10) and mental state related (items 
3-4). Subjects respond to each question on a 7 point scale (ranging between 0=asymptomatic/no-limitation, 
to 6=extremely symptomatic/totally limited). The overall clinical COPD control score and the score of the 
three domains is calculated by adding all the scores together and dividing the sum by the number of 
questions. 
9.3.2.2 
Secondary outcomes: 
 
- 
Absolute change in the CCQ 
- 
Absolute change in CCQ-4. 
- 
Patient´s general condition: Physician´s Global Evaluation (PGE) score at baseline and end of 
study. 
- 
Patient satisfaction with (tiotropium and olodaterol) Respimat® at end of study using a seven- 
point ordinal scale (ranging from very dissatisfied to very satisfied) of the abbreviated PASAPQ 
(Part 1). 
- 
Patient preference HH vs RMT (PASAPQ Part 2) – only for those patients that used Spiriva HH 
previous to the study. 
- 
Treatment continuation of Spiolto® Respimat® after the study.

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9.4 
DATA SOURCES 
 
Patient files (paper and/or electronically) of COPD patients as documented by the treating physician in 
his/her daily practice will be used as data source. 
All participating physicians will be obliged to make a note of the patient’s participation in the NIS in the 
patient‘s original documents. 
In the event of possible queries, the participating physician must be able to identify the patient observed. 
Medical information on the patient must be communicated and analyzed only using the patient number. 
During this trial the following has to be completed: 
To be completed by the physician: 
- 
Patient demographics 
- 
Patient medical files 
- 
Physician’s Global Evaluation (PGE) at Visit 1 and Visit 2 
To be completed by the patient at Visit 1: 
- 
mMRC              breathlessness              scale 
To be completed by the patient at Visit 1 and at Visit 2: 
- 
Physical Functioning Questionnaire (CCQ) 
To be completed by the patient at Visit 2 only: 
- 
Patient satisfaction survey (abbreviated PASAPQ Part 1) and Patient Preference only for those 
patients that used Spiriva HH previous to the study (PASAPQ Part 2) 
 
 
 
 
9.5 
STUDY SIZE 
We assume that patients treated with Spiolto® Respimat® will have a CCQ therapeutic success rate 
similar to SGRQ responder rate considering the following:  
1) CCQ has the great advantage of simplicity for the patient, having a very good correlation (rho = 
0.67 to rho = 0.72) with the St George respiratory questionnaire (SGRQ) [R04-2815]. 
 
2) In TONADO studies [P15-03349] patients treated with Spiolto® Respimat® had a 57.5% SGRQ 
responder rate 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. Therefor a 50% 
CCQ responder rate is a reasonable assumption. 
Assuming a 50% therapeutic success rate and a sample size of about 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. 

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9.6 
DATA MANAGEMENT 
A data management plan (DMP) will be created to describe all functions, processes, and specifications 
for data collection, cleaning and validation. The electronic Case Report Forms (eCRFs) will include 
programmable edits to obtain immediate feedback if data are missing (also negative answers, unknown), 
out of range, illogical or potentially erroneous. These rules may encompass simple checks such as range 
validation or presence/absence of data. Concurrent manual data review may be performed based on 
parameters dictated by the DMP. Ad hoc queries to the sites may be generated and followed up for 
resolution. A source data quality audit may be initiated to ensure that the data in the database is accurate. 
Source data verification (SDV) will be performed at sites identified by a risk-based approach as needed. 
The database will be housed in a physically and logically secure computer system maintained in 
accordance with a written security policy. The system will meet the standards of the International 
Committee on Harmonization guideline E6R1 regarding electronic study data handling. Patient 
confidentiality will be strictly maintained. 
 
9.7 
DATA ANALYSIS 
 
All patients who have received at least one dose of Spiolto® Respimat® will be included in the analyses; 
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 CCQ from Visit 1 to Visit 2. 
The statistical characteristics presented in the end-of-text tables will be N / mean / SD / min / median / 
max for continuous variables. Tabulations of relative and absolute frequencies will be presented for 
categorical variables. Proportion and 95% CI will be given when appropriate. 
The analyses will relate to the following data: 
 
 
Patient demographics (age, gender, height, and 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. 
 
Exacerbations. 
 
Breathlessness based on mMRC score at Visit 1. 
 
Physical Functioning based on CCQ scores (therapeutic success at Visit 2); primary outcome. 
 
Changes from Visit 1 to Visit 2 in the CCQ score; secondary outcome. 
 
Changes from Visit 1 to Visit 2 in the CCQ-4 score (subdomain of the CCQ); secondary 
outcome. 
 
Patient satisfaction with Spiolto® Respimat® and device preference for those patients that used Spiriva HH 
previous to the study, at Visit 2 only; secondary outcome. 
 
Treatment continuation of Spiolto® Respimat® after the study; secondary outcome 
 
General condition of the patient: evaluated by the physician (Physician´s Global Evaluation 
(PGE)); secondary outcome. 
 
Adverse Drug Reactions (ADR & SADR), fatal AEs, pregnancies. 
 
GOLD spirometric classification (1,2, 3, 4), if available. 
 
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 

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9.7.1 
Main analysis 
 
For the primary outcome, the proportion of patients with therapeutic success will be presented together 
with the 95% confidence interval. 
 
 
9.7.3 
Handling of missing data 
CCQ missing values: as already mentioned, the questions in the Clinical COPD Questionnaire (CCQ) are   
divided into three areas, or domains: 
Symptoms: items 1, 2, 5, 6 
Functional state: items 7, 8, 9, 10 
Mental state: items 3, 4 
In case of missing data or ambiguous answers (e.g. double answers) the following rules have to be applied 
to calculate the CCQ scores: 
 
Domain 
No. items in domain 
No. items required   % required items 
Symptoms 
4 
3 
75 
Functional state 
4 
3 
75 
Mental state 
2 
2 
100 
 
The total CCQ score can still be calculated when the individual domains can be calculated even if data 
is missing. For both, symptoms and functional state domains, 75% of answered items is required. The 
mental domain can be calculated only if all items are answered. Also, when a patient fills in two 
answers on one question the data should be considered as missing.  
When the three domain scores can be calculated, the total score is calculated by multiplying the domain 
score with the original amount of questions and adding these numbers and dividing by 10. 
For example, when question 5 is not completed, or there are two answers, the scores will be calculating 
as follows: 
For the symptom domain add the score from questions 1,2, and 6 and divide by 3. Calculate the other 
domain scores as usual. 
To calculate the total score use the following algorithm: ((symptom domain score)*4+(functional state 
domain score)*4+(mental state domain score)*2)/10 = CCQ total score (www.ccq.nl section: healthcare 
professionals/missing data rules). 
 
 

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Any removal from the analysis will be documented, stating the site and patient number as well as the 
reason for removal. 
 
9.8 
QUALITY CONTROL 
To improve and secure data quality, automatic data checks upon data entry will be done within the 
eCRF. In the eCRF, plausible ranges of values for numeric data entries as well as logical data entries and 
listings will be provided for each entry field. Based on this, checks on completeness and plausibility will 
be performed upon data entry in the eCRF. 
Validity of data entry thus is ensured by integrated validation checks performed by the system, 
indicating missing or implausible entries to the document list or investigator. All corrections will be 
visible from the systems audit trail. 
No regular source data verification is planned in this study. However, in case of decreasing compliance 
(i.e. of missing data, data discrepancies, protocol violations, etc.) a for-cause audit or risk-based 
monitoring visit will be performed. 
 
9.9 
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. 
 
Per definition, non-interventional studies do not allow randomization or any other procedure outside 
clinical routine that would reduce the risk of biases. No interventions for improving follow-up, 
compliance, event reporting etc. are allowed. Thus, real life setting studies can only deliver data and 
results that have to be regarded and interpreted in the limits of this context. 
Consecutive enrolment is expected to reduce selection bias. The entry criteria are non-restrictive which 
will permit the enrolment of a broad patient population. The choice of treatment is at the discretion of 
the investigator. 
Selection bias could occur at the site level and the patient level. Therefore, to reduce the site level 
selection bias, the goal is to have participating pulmonologists/centers that have access to all available 
treatment options which are approved for use in Greece for the targeted COPD patients. Information 
bias will be minimized by the use of standard eCRF, questionnaire and physicians’ training on the 
study protocol. 
 
9.10 
OTHER ASPECTS 
9.10.1 
Data quality assurance 
 
A quality assurance audit/inspection of this study may be conducted by the sponsor or sponsor’s 
designees or by Institutional Review Board (IRBs) / Independent Ethics Committee (IECs) or by 
regulatory authorities. The quality assurance auditor will have access to all medical records, the 
investigator’s study-related files and correspondence, and the informed consent documentation of this 
study. 
 
9.10.2 
Study records 
 
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via remote data 
capture. 
 
9.10.2.1 
Source documents 
 
Source documents provide evidence for the existence of the patient and substantiate the integrity  
 

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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 the eCRF, the following data must be derived from source documents: 
- 
Patient demographics (age, gender, height, and weight); 
- 
History of smoking 
- 
Reported exacerbations 
- 
Past COPD therapies (6 months before visit 1) 
- 
Respimat® training (Yes/No) 
- 
GOLD patient groups (B, C, D) 
- 
GOLD spirometric classifications (1, 2, 3, 4) (if available). 
- 
Concomitant diseases / Comorbidities 
- 
Concomitant COPD and other relevant medication 
- 
Breathlessness based on mMRC score 
- 
Physical Functioning (CCQ) 
- 
Patient Satisfaction and Preference Questionnaire (abbreviated PASAPQ Part 1 + Part 2) 
- 
Adverse Drug Reactions (ADR & SADR), fatal AEs, pregnancies 
- 
Rational for Spiolto® Respimat® treatment discontinuation (if applicable) 
- 
Details of treatment continuation / discontinuation 
 
9.10.2.2 
Direct access to source data and documents 
 
The investigator / institution will permit study-related monitoring, audits, IRB / IEC review and 
regulatory inspection, providing direct access to all related source data / documents. 
E-CRFs and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the sponsor’s clinical study monitor, auditor and 
inspection by health authorities. The Clinical Research Associate (CRA) / Clinical Monitor Local (CML) 
and auditor may review all CRFs/eCRFs, and written informed consents. 
 
9.10.3 
Completion of study 
 
The IRB/IEC in hospital sites in Greece need to be notified about the end of the study (last 
patient/patient out, unless specified differently in Section 6 of the observational plan) or early 
termination of the trial. 
 
 
9.10.4 
Protocol violations 
 
All protocol violations must be reported to the sponsor immediately. 
 
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) [R10-4560], Guidelines for Good Pharmacoepidemiology Practice 
(GPP) [R09-0182], and relevant BI Standard Operating Procedures (SOPs). Standard medical care 
(prophylactic, diagnostic and therapeutic procedures) remains in the responsibility of the treating  
 

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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. 
Insurance Cover: The requirements for insurance depend on local law and legislations in Greece. If 
required, the terms and conditions of the insurance cover are made available to the investigator and the 
patients, and the documentation must be archived in the Investigator Site File (ISF). 
 
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) according to 
national and international regulations. The same applies for the implementation of changes introduced by 
amendments. 
Prior to patient participation in the study, written informed consent must be obtained from each patient 
(or the patient’s legally accepted representative) according to ICH GCP and to the regulatory and legal 
requirements of Greece. Each signature must be personally dated by each signatory and the informed 
consent and any additional patient- information form retained by the investigator as part of the study 
records. A signed copy of the informed consent and any additional patient information must be given to 
each patient or the patient’s legally accepted representative. 
The patient must be informed that his/her personal study-related data will be used by Boehringer 
Ingelheim in accordance with the local data protection law. The level of disclosure must also be 
explained to the patient. 
The patient must be informed that his / her medical records may be examined by authorized monitors 
(CML/CRA) or Quality Medicine auditors appointed by Boehringer Ingelheim, by appropriate IRB / IEC 
members, and by inspectors from regulatory authorities. 
 
 
10.2 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient confidentiality will be 
ensured by using patient identification code numbers. 
Treatment data may be given to the patient’s personal physician or to other appropriate medical 
personnel responsible for the patient’s welfare. Data generated as a result of the study need to be 
available for inspection on request by the participating physicians, the sponsor’s representatives, by the 
IRB / IEC and the regulatory authorities. 

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11. 
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 
 
11.1 
DEFINITIONS OF ADVERSE EVENTS 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign 
(e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
 
Adverse 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 authorization or from occupational exposure. Conditions of use 
outside the marketing authorization include off- label use, overdose, misuse, abuse and medication 
errors. 
 
Serious adverse event 
- 
A serious adverse event is defined as any AE which 
- 
results in death, 
- 
is life-threatening, 
- 
requires in-patient hospitalization, or 
- 
prolongation of existing hospitalization, 
- 
results in persistent or significant disability or incapacity, or 
- 
is a congenital anomaly/birth defect.  
 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at the time of 
the reaction; it does not refer to a reaction that hypothetically might have caused death if more severe. 
 
Medical and scientific 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 hospitalization but might jeopardize the patient or might require 
intervention to prevent one of the other outcomes listed above. 
 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or development of 
dependency or abuse. Any suspected transmission via a medicinal product of an infectious agent is also 
considered a serious adverse reaction. 
 
 
Adverse Event of Special Interest (AESI) 
The term 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. 

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11.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING 
 
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
 
Collection of AEs 
The study design is of non-interventional nature and the study is conducted within the conditions of the 
approved marketing authorization. Sufficient data from controlled interventional trials are available to 
support the evidence on the safety and efficacy of the studied BI drug. For this reason, the following AE 
collection and reporting requirements have been defined. 
 
The following must be collected by the investigator in the (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 characterized by the fact that a causal relationship between a medicinal product and 
an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors 
such as concomitant medication, concomitant diseases and relevant history. 
 
Arguments that may suggest a reasonable causal relationship could be: 
• 
The event is consistent with the known pharmacology of the drug 
• 
The event is known to be caused by or attributed to the drug class. 
• 
A plausible time to onset of the event relative to the time of drug exposure. 
• 
Evidence that the event is reproducible when the drug is re-introduced 
• 
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications). 
• 
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 

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concerned) 
• 
Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives). 
Of note, this criterion may not be applicable to events whose time course is prolonged despite 
removing the original trigger. 
• 
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned). 
• 
Disappearance of the event even though the study drug treatment continues or remains 
unchanged. 
 
Intensity of adverse event 
The intensity of the AE should be judged based on the following: 
Mild: 
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe: 
Incapacitating or causing inability to work or to perform usual activities 
 
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) criteria in the (e)CRF. 
 
Pregnancy: 
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the study, after 
having taken, 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. 
 
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: 
 
Type of Report 
Timeline 
All serious ADRs associated with Spiolto® 
Respimat® 
immediately within 24 hours 
All AEs with fatal outcome in patients exposed to 
Spiolto® Respimat® 
immediately within 24 hours 
All non-serious ADRs associated with Spiolto® 
Respimat® 
7 calendar days 
All pregnancy monitoring forms associated with 
Spiolto® Respimat® 
7 calendar days 
The same timelines apply if follow-up information becomes available for the respective events. In 
specific occasions the Investigator could inform the Sponsor upfront via telephone. This does not replace 
the requirement to complete and fax the NIS AE form. 
 
 
 

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Information required 
 
For each reportable adverse event, the investigator should provide the information requested on the 
appropriate (e)CRF pages and the NIS AE form. 
 
Reporting of related Adverse Events associated with any other BI drug 
The investigator is encouraged to report all adverse events related to any BI drug other than the 
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. 
 
 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
 
The rights of the investigator and of the sponsor with regard to publication of the results of this study are 
described in the investigator contract. As a general rule, no study results should be published prior to 
finalization of the Study Report. 

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13. 
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formoterol BID in patients with COPD: two 48-week studies. 23rd Ann Cong of the 
European Respiratory Society (ERS), Barcelona, 7 - 11 Sep 2013 
 
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Koch A, Paggiaro P, Hamilton A, Hart L, Korducki L, Salvo MC de, Pizzichini E. 
Symptomatic benefit of olodaterol QD delivered via Respimat vs placebo and formoterol 
BID in patients with COPD: combined analysis from two 48-week studies. 23rd Ann 
Cong of the European Respiratory Society (ERS), Barcelona, 7 - 11 Sep 2013 
 
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effects of olodaterol on exercise endurance in patients with COPD: results from two 6-
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Chicago, 26 - 31 Oct 2013 Chest 144 (4) (Suppl), 748A, Abstr (2013) 
 
P10-09337  
Bouyssou T, Schnapp A, Casarosa P,  Pieper  MP.  Addition  of  the  new  once-daily 
LABA BI 1744 to tiotropium results in superior bronchoprotection in pre -clinical 
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bronchoprotective activity of the long-acting beta 2-agonist olodaterol with tiotropium 
(long-acting M3 antagonist) and ciclesonide (inhaled steroid) on the ovalbumin- induced 
bronchoconstriction in anaesthetized guinea pigs. ERJ September 1, 2011 vol. 38 no. 
Suppl 55 3451 
 
P13-02357      Aalbers R, Maleki-Yazdi MR, Hamilton A, Waitere-Wijker S, Pivovarova A, Schmidt O, 
Bjermer L. Dose-finding study for tiotropium and olodaterol when administered in 
combination via the Respimat inhaler in patients with COPD. 22nd Ann Cong of the 
European Respiratory Society (ERS), Vienna, 1 - 5 Sep 2012. Eur Respir J 40 (Suppl 
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P15-03349  
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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 
 
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Kai-Bichael Beeh et al.The 24-h lung-function profile of once-daily tiotropium and 
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Katz P, Chen H, Omachi TA, Gregorich SE, Julian L, Cisternas M, Balmes J, Blanc PD 
The role of physical inactivity in increasing disability among older adults with 
obstructive airway disease. J Cardiopulm Rehabil Prev 31 (3), 193 - 197 (2011) 
 
R15-4561   
Maltais F, LeBlanc P, Simard C, Jobin J, Berube C, Bruneau J, Carrier L, Belleau R  
Skeletal muscle adaptation to endurance training in patients with chronic obstructive 
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R15-4564  
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The impact Of GOLD 1 and 2 COPD on self -reported functional limitations, activity, 
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Maltais F. Effects of combined tiotropium/olodaterol on inspiratory capaci ty and 
exercise endurance in COPD Eur Respir J. (2017) 
 
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measurement properties of constant work-rate cycling and endurance shuttle  walking  in  
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NH, Achterberg WP Health status measured by the Clinical COPD Questionnaire (CCQ) 
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Kocks, M. van de Ven, S.M. Uil, J.W.K. van den Berg, G.M. Asijee, T. van der Molen 
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Kocks JW1,  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 
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EF: Development, validity and responsiveness of the Clinical COPD Questionnaire. 
Health Qual Life Outcomes 2003, 1:13 
 
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a patient satisfaction and preference questionnaire for inhalation de vices. Treat Respir 
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Miravitlles M, García-Sidro P, Fernández-Nistal A, Buendía MJ, Espinosa de los 
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  Buhl R, Maltais F, Abrahams R, Bjermer L, Derom E, Ferguson G et al. Tiotropium 
and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2– 
4). Eur Respir J. 2015; DOI: 10.1183/09031936.00136014 .

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
 
The stand-alone documents for this non-interventional study are: 
 Informed Consent Form
 Physicians’ Global Evaluation (PGE)
 CCQ Questionnaire
 Breathlessness Scale (mMRC)
 Patient Satisfaction and Patient Preference Questionnaire (abbreviated PASAPQ Part 1 + 
Part 2)
 Statistical Epidemiological Analysis Plan (SEAP)
 Data Management Plan (DMP)
 Pregnancy Monitoring Form
 
Serious Adverse Event Report in Non-Interventional Studies (NIS (S)AE Form)
 Publication Plan
All of the above documents will be archived in the Trial Master File in its original English 
master version. 

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Not applicable 

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ANNEX 3. ADDITIONAL INFORMATION 
 
CCQ Questionnaire 
 

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

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Patient Satisfaction Questionnaire (PASAPQ) 
PART 1 (abbreviated): RATING OF SATISFACTION WITH INHALER ATTRIBUTES 
Instructions: For the following questions, please check the response that best describes how satisfied 
you are with each of the following items. Please take as much time as you need to 
answer each question. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Patient Satisfaction Questionnaire (PASAPQ) 
 
PART II: RATING OF PREFERENCE AND WILLINGNESS TO CONTINUE WITH 
INHALER 
 
 
1. 
Comparing the two inhalers that you have used during the study, overall, would you prefer to 
use Inhaler 1 or Inhaler 2? 
 
Please check one box 
I prefer Inhaler 1 
                                         
I prefer Inhaler 2 
 
No preference 
 
 
2. 
Comparing the two inhalers that you have used during the study, overall, how would you feel 
about continuing to use Inhaler 1 or Inhaler 2? 
 
Please indicate your willingness to continue using each of the inhalers that you used during the 
study by providing a value between 0 and 100. 
 
0 indicates that you would not be willing to continue using this inhaler and 100 indicates that 
you would definitely be willing to continue. 
 
Please write in a number in each box that is between 0 and 100. 
 
Inhaler 1 
 
 
Inhaler 2 
 
 
Both boxes should contain a number between 0 and 100. 

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Physicians’ Global Evaluation (PGE) to be used directly within the eCRF 
 
General condition of the patient at the initial examination (Visit 1) 
Please mark with a cross as applicable 
Poor 
1 2 
Satisfactory 
3 4 
Good 
5 6 
Excellent 
7 8 
 
General condition of the patient after approximately 6 weeks of treatment (Visit 2) 
Please mark with a cross as applicable 
 
Poor 
1 2 
Satisfactory 
3 4 
Good 
5 6 
Excellent 
7 8