EVELUT®: Assessment of Dyspnea and Other Symptoms as Patient Reported Outcomes (PRO) in Patients With Chronic Obstructive Pulmonary Disease (COPD), Symptomatic on LABA/ICS Maintenance Therapy (Now) Treated With Spiolto® Respimat® (Tiotropium/Olodaterol) in Comparison to Open or Fixed Triple Combination Treatment in Routine Clinical Practice
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
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TITLE PAGE
Non-interventional Study Protocol
TITLE PAGE
Document Number:
c26538106-02
BI Study Number:
1237-0087
BI Investigational
Product(s):
Spiolto® Respimat®
Title:
EVELUT®: Assessment of dyspnea and other symptoms as 
patient reported outcomes (PRO) in patients with chronic 
obstructive pulmonary disease (COPD), symptomatic on 
LABA/ICS maintenance therapy (now) treated with Spiolto®
Respimat® (tiotropium/olodaterol) in comparison to open or 
fixed triple combination treatment in routine clinical practice.
Brief lay title
Spiolto® Respimat® (tiotropium/olodaterol) versus triple 
combination therapy in everyday clinical treatment practice for 
chronic obstructive pulmonary disease (EVELUT®)
Protocol version 
identifier:
Version 2.0
Date of last version of 
protocol:
27 May 2019
PASS:
No
EU PAS register 
number:
EUPAS29784
Active substance:
R03AL06 
tiotropium bromide and 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:

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Study Initiator:
Joint PASS:
No
Research question and 
objectives:
The primary objective of this prospective NIS is to investigate 
the comparative effectiveness of Spiolto® Respimat® in the new 
reusable inhaler vs any free or fixed-dosed triple therapy 
(LAMA + LABA + ICS) in reducing dyspnea (as measured via 
mMRC questionnaire) and symptom burden (as measured via 
CATTM) in COPD patients who are dyspneic despite LABA/ICS 
maintenance treatment when switched to either Spiolto®
Respimat® or to any triple therapy, both in a real-word setting.
This study aims to analyze the comparative effectiveness of 
Spiolto® Respimat® in the new reusable inhaler vs any triple 
therapy in reducing dyspnea and symptom burden from each 
individual patient’s score difference between baseline and after 
approximately 12 weeks of treatment. Two descriptive primary 
endpoints will be assessed:
(1) Difference in mMRC (modified Medical Research 
Council) score at baseline and after end of observation 
(ca. 12 weeks of treatment, Visit 2)
(2) Difference in CATTM (COPD assessment test) score at 
baseline and after end of observation (ca. 12 weeks of 
treatment, Visit 2)
Secondary endpoints to be determined and compared in an 
exploratory manner include:

Patients’ general condition according to the Physician’s 
Global Evaluation (PGE) score at baseline and end of the 
observation period,

Patient satisfaction with inhaler and therapy at end of 
observation period according to a seven-point ordinal 
scale (ranging from very dissatisfied to very satisfied as 
documented in non-interventional BI studies (BI 1237-
0042, 1237-0043, 1237-0044, 1237-0045, 1237-0065, 
1237-0072),

proportion of responders with mMRC ≥1 and proportion of 
responders with CAT ≥2.
Descriptive analyses of handling of the new reusable Respimat®
inhaler and user experiences will be performed.

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Additional groupwise descriptive statistics will be calculated 
with respect to 

exacerbations (overall and stratified by levels of 
eosinophils (where available)),

hospitalizations due to COPD exacerbations,

adherence,

levels of eosinophils (where available in patient 
documentation),

improvement in dyspnea and responder rates (overall and 
according to levels of eosinophils (where available)), and

improvement in lung function (overall and stratified by 
levels of eosinophils; where available in patient 
documentation)
Country(-ies) of study:
Germany
Author:
Marketing authorisation 
holder(s):
Date:
7 June 2019
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1. TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 4
2.
LIST OF ABBREVIATIONS................................................................................ 7
3.
RESPONSIBLE PARTIES.................................................................................... 9
4.
ABSTRACT......................................................................................................... 10
5.
AMENDMENTS AND UPDATES..................................................................... 19
6.
MILESTONES..................................................................................................... 20
7.
RATIONALE AND BACKGROUND................................................................ 21
7.1
MEDICAL BACKGROUND............................................................... 21
7.1.1
COPD ...................................................................................................... 21
7.1.2
Assessment and Classification of COPD ................................................ 21
7.1.3
Pharmacotherapy of COPD..................................................................... 23
7.1.4
Tiotropium/Olodaterol in COPD treatment............................................. 25
7.1.5
Dyspnea................................................................................................... 26
7.1.6
Intention of the study............................................................................... 26
7.2
DRUG PROFILE.................................................................................. 27
7.2.1
Tiotropium and Olodaterol...................................................................... 27
7.2.2
Spiolto® Respimat® ................................................................................. 27
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 30
8.1
STUDY OBJECTIVES......................................................................... 30
9.
RESEARCH METHODS .................................................................................... 31
9.1
STUDY DESIGN.................................................................................. 31
9.2
SETTING.............................................................................................. 31
9.2.1
Study sites ............................................................................................... 31
9.2.2
Study population ..................................................................................... 32
9.2.3
Study visits .............................................................................................. 33
9.2.4
Study discontinuation.............................................................................. 34
9.3
VARIABLES ........................................................................................ 34
9.3.1
Exposures ................................................................................................ 35
9.3.2
Outcomes................................................................................................. 36
9.3.2.1
Primary outcomes............................................................................. 36
9.3.2.2
Secondary outcomes......................................................................... 36
9.4
DATA SOURCES ................................................................................ 36

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9.4.1
PGE ......................................................................................................... 37
9.4.2
Symptomatic Burden: mMRC and CATTM............................................. 37
9.4.3
Patient Satisfaction.................................................................................. 37
9.5
STUDY SIZE........................................................................................ 38
9.5.1
Sample size justification.......................................................................... 38
9.6
DATA MANAGEMENT...................................................................... 39
9.6.1
Data Entry / EDC .................................................................................... 39
9.6.2
Source Documents................................................................................... 40
9.6.3
File Retention and Archiving.................................................................. 40
9.7
DATA ANALYSIS............................................................................... 40
9.7.1
Main analysis........................................................................................... 41
9.7.3
Handling of missing data......................................................................... 43
9.8
QUALITY CONTROL......................................................................... 43
9.9
LIMITATIONS OF THE RESEARCH METHODS............................ 43
9.10
OTHER ASPECTS............................................................................... 44
9.10.1
Data quality assurance............................................................................. 44
9.10.2
Study records........................................................................................... 44
9.10.2.1
Source documents ............................................................................ 44
9.10.2.2
Direct access to source data and documents .................................... 44
9.10.3
Completion of study................................................................................ 44
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 45
10.1
STUDY APPROVAL, PATIENT INFORMATION AND INFORMED 
CONSENT............................................................................................ 45
10.2
STATEMENT OF CONFIDENTIALITY............................................ 46
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 46
11.1
DEFINITIONS OF ADVERSE EVENTS............................................ 46
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING .............................................................................. 47
11.3
REPORTING TO HEALTH AUTHORITIES ..................................... 50
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 51
13.
REFERENCES .................................................................................................... 52
13.1
PUBLISHED REFERENCES .............................................................. 52

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 56
APPENDIX 1: PHYSICIANS’ GLOBAL EVALUATION (PGE) ........................... 57
APPENDIX 2: COPD ASSESSMENT TEST (CATTM) ............................................ 58
APPENDIX 3:
MODIFIED MEDICAL RESEARCH COUNCIL (MMRC) 
QUESTIONNAIRE FOR ASSESSING THE SEVERITY OF 
BREATHLESSNESS ........................................................................... 59
APPENDIX 4: NIS AE FORM................................................................................... 60
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 65
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 65

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2. LIST OF ABBREVIATIONS
  ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of special interest
AMG
Arzneimittelgesetz (German Drug Act)
AUC
Area under the Curve
BfArM
BI
CATTM
Bundesinstitut für Arzneimittel und Medizinprodukte (German CA)
Boehringer Ingelheim
COPD Assessment Test
CI
Confidence Interval
CML
Clinical Monitor Local
COPD
Chronic Obstructive Pulmonary Disease
CRA
CRO
CTCAE
DVP
Clinical Research Associate
Clinical Research Organisation 
Common Terminology Criteria for Adverse Events
Data Validation Plan
eCRF
EDC
Electronic Case Report Form
Electronic Data Capture
EU
European Union
FDC
Fixed Dose Combination
FEV1
Forced expiratory volume in one second
GCP
GEP
GP
GPP
Good Clinical Practice
Good Epidemiological Practice
General Practitioner
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
National Cancer Institute 
NIS
Non-Interventional Study

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  PGE
PRO
Physician’s Global Evaluation
Patient-reported outcome
SABA
SADR
Short-acting beta2 adrenoceptor agonist
Suspected Adverse Drug Reaction
SAE
Serious Adverse Event
SAMA
SGRQ
Short-acting muscarinic antagonist
St. George's Respiratory Questionnaire
SmPC
TDI
Summary of Product Characteristics
Transitional dyspnea index 
VFA
WHO
Verband Forschender Arzneimittelhersteller
World Health Organization

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3.
RESPONSIBLE PARTIES
Table 3.1
Responsible parties
Function
Name / Location
Scientific Coordinator
Therapeutic Area 
 
Respiratory Medicine (TA )
Team Member Medical Affairs 
(TM MA)
Team Member Epidemiology
(TM Epi)
 Global Epidemiology 
(  GEpi)
G0(",K(/52> J"(,
 Risk 
Management (TA  RM), and
Pharmacovigilance Working 
Group (PVWG) 
9!R Q5/)E O##")2-,5#"
NIS 
Statistical Analysis
Data Management
Trial Programming
CRO

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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 and Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
27 May 2019
1237-0087
2.0
7 June 2019
Title of study:
EVELUT®: Assessment of dyspnea and other symptom burden as 
patient reported outcomes (PRO) in patients with chronic obstructive 
pulmonary disease (COPD), symptomatic on LABA/ICS maintenance 
therapy (now) treated with Spiolto® Respimat® (tiotropium/olodaterol)
in comparison to open or fixed triple combination treatment (LAMA + 
LABA + ICS) in routine clinical practice
Author: 
Rationale and 
background:
Dyspnea is the most relevant symptom burden that leads to diagnosis, 
initiation or change of maintenance COPD therapy. Clinical studies 
have demonstrated that the LAMA-LABA combination Spiolto®
Respimat® significantly improves dyspnea in COPD patients1. 
However, real world data with regard to the effects of dual 
bronchodilation with Spiolto® Respimat® vs triple therapy (LAMA + 
LABA + ICS) in COPD patients that are dyspneic and symptomatic 
despite being on a LABA/ICS maintenance therapy are not yet 
available. 
This non-interventional study (NIS) aims to investigate alleviation of 
dyspnea and other symptom burden in COPD patients who are 
symptomatic (dyspneic) despite LABA/ICS maintenance therapy and 
who are switched to Spiolto® Respimat® in the new reusable inhaler or 
triple therapy at the discretion of their attending physician. If a patient 
has symptoms other than dyspnea that led to a change from 
LABA/ICS, these patients will also be included into the study; except 
for those classified as acute exacerbations by the treating physician. 
Dyspnea will be assessed with the mMRC questionnaire; symptom 
burden will be evaluated by the CATTM questionnaire.

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Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide and Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
27 May 2019
1237-0087
2.0
7 June 2019
The mMRC and CATTM are widely used simple measures of 
breathlessness and symptoms and are easy to complete; they relate 
well to other measures of health status and can therefore be used to 
monitor dyspnea and symptoms in COPD patients2. Furthermore, the 
questionnaires are responsive to intervention, predict future mortality 
risk, and, finally, have been translated and validated in Germany3, 4, 5, 6.
Treatment guidelines recommend effective bronchodilation as the basis 
of COPD therapy in most patients. In contrast, ICS is seen as an 
obligatory part of pharmacological treatments only in patients with 
concomitant asthma or as a therapeutic option for patients that further 
exacerbate despite dual bronchodilation therapy or that have a high 
risk for exacerbation and high levels of eosinophils7, 8, 9.
However, LABA/ICS-fixed dose combinations (FDC) remain the most 
widely prescribed therapy in COPD. Dyspnea is one of the most 
relevant patient-reported symptoms in COPD. In order to achieve 
better symptom control, therapy can be adjusted by the attending
physician from LABA/ICS to either dual bronchodilation or any triple 
therapy (free or fixed-dose: dual bronchodilation plus inhaled 
corticosteroid, ICS). 
BI developed a novel reusable Respimat® inhaler to simplify assembly 
and daily use, optimize the dose indicator and make it reusable with up 
to 6 cartridges. The updated design is intended to improve the usability 
and environmental impact of the Respimat® inhaler, while preserving 
the pharmaceutical features and basic functions of the disposable 
Respimat® inhaler. 
According to GOLD 2019, it is a clinical core question whether 
inhalative COPD therapy of patients, who suffer from dyspnea and 
other symptoms despite LABA/ICS treatment, should be switched to 
either LAMA/LABA or triple therapy (LAMA + LABA + ICS; free or 
fixed-dose).

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Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide and Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
27 May 2019
1237-0087
2.0
7 June 2019
The recent GOLD update supports the design of this study. GOLD 
2019 suggests that patients who do not suffer from frequent 
exacerbations and who present with persistent breathlessness or 
exercise limitation on LABA/ICS treatment, should either be escalated
to triple therapy or switched to LAMA/LABA. A switch from 
LABA/ICS to LAMA/LABA is suggested in case the initial indication 
of ICS was inappropriate or if there has been a lack of response to ICS 
treatment, or if ICS side effects warrant discontinuation. 
Currently, no prospective clinical evidence is available that supports a 
direct switch from LABA/ICS to LAMA/LABA instead of moving to 
triple therapy if an initial indication for ICS use is lacking. Therefore, 
this study aims to investigate if patients who are symptomatic under 
LABA/ICS treatment and are switched to LAMA/LABA do not suffer 
more from dyspnea and symptoms compared to triple therapy.
Research question 
and objectives:
The primary objective of this NIS is to investigate the changes in 
dyspnea (as measured via mMRC (Modified Medical Research 
Council) questionnaire) and symptom burden (as measured via CATTM
(COPD Assessment Test)) in COPD patients who are dyspneic despite
LABA/ICS maintenance treatment when switched to either Spiolto®
Respimat® in the new reusable inhaler or to any triple therapy (free or 
fixed-dosed). 
More precisely, this study aims to assess analyze the comparative 
effectiveness of Spiolto® Respimat® in the new reusable inhaler vs any 
triple therapy in changes in dyspnea and symptom burden from each 
individual patient’s difference between baseline and after 
approximately 12 weeks of treatment.
Two primary endpoints will be assessed:

Difference in mMRC (modified Medical Research Council)
score at baseline and after end of observation (approx. 12 
weeks of treatment, Visit 2)

Difference in CATTM (COPD assessment test) score at baseline 
and after end of observation (approx.. 12 weeks of treatment, 
Visit 2)

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  Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide and Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
27 May 2019
1237-0087
2.0
7 June 2019
MMRC and CATTM are both of interest as primary endpoints. The 
comparative effectiveness on the primary endpoints will be determined 
based on model coefficients (along with 95% confidence intervals) and 
statistical testing of these coefficients. Since the study is exploratory in 
nature, no multiplicity adjustment is planned.
Secondary endpoints to be determined and compared in an exploratory 
manner include

patients’ general condition according to the Physician’s Global 
Evaluation (PGE) score at baseline and end of the observation 
period of approximately 12 weeks,

patient satisfaction with inhaler and therapy at end of 
observation period according to a seven-point ordinal scale 
(ranging from very dissatisfied to very satisfied as documented 
in non-interventional trial (BI 1237-0042, 1237-0043, 1237-
0044, 1237-0045, 1237-0065, 1237-0072),

proportion of responders with mMRC ≥1 and proportion of 
responders with CAT ≥2
Study design:
Open-label comparative multicentric cohort study according to §4, 
section 23 and §67, section 6 German Medicines Act. 
All included COPD patients receive a LABA/ICS maintenance
treatment until visit 1 and are switched at visit 1 at the discretion of the 
attending physician to either tiotropium/olodaterol in the new reusable 
Respimat® inhaler or any triple therapy (LAMA + LABA + ICS) 
according to clinical routine. Observational period will be
approximately 12 weeks after switch, which is the average time 
between two medical consultations. 
NIS based on newly collected data.
Population:
COPD patients on LABA/ICS maintenance therapy with dyspnea 
(mMRC ≥1) and other symptoms (CATTM ≥ 10), who are  switched to 
either Spiolto® Respimat® in the new reusable inhaler or any triple 
therapy (LAMA + LABA + ICS) as an open or fixed combination 
according to approved SmPCs at baseline at the discretion of their 
attending physician.

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Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide and Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
27 May 2019
1237-0087
2.0
7 June 2019
Inclusion Criteria:

Diagnosis of COPD

Symptomatic (with regard to dyspnea (mMRC Dyspnea score 
≥1) AND with regard to symptoms (CATTM Score ≥10) at the 
same time)

Patients on LABA/ICS maintenance therapy who are switched 
to Spiolto® Respimat® in the new reusable inhaler or a 
free/fixed triple combination of LAMA + LABA + ICS at Visit 
1 at the discretion of the treating physician.

Adults who are contractually capable and mentally able to 
understand and follow the instructions of the study personnel

Male or female

Patients aged ≥40 years of age

Written informed consent prior to study participation

The patient is willing and able to follow the procedures outlined 
in the protocol
Exclusion Criteria:

Patients with contraindications acc. to SmPC 

Patients not on LABA/ICS maintenance treatment at visit 1, eg, 
mono or dual bronchodilation only, ICS only, or a triple 
combination of LAMA + LABA + ICS (either as a fixed 
combination product or as separate components)

Lack of informed consent 

Pregnant and/or lactating females

Acute exacerbation of COPD (within 4 weeks prior to Visit 1)

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Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide and Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
27 May 2019
1237-0087
2.0
7 June 2019

Frequently exacerbating patients, i. e. patients with ≥2 moderate 
exacerbations within the last 12 months or ≥1 exacerbation 
leading to hospitalization within the last 12 months

Acute respiratory failure (pH <7,35 and / or respiratory rate 
>30/min within 3 months prior to Visit 1)

History or current diagnosis of asthma

History or current diagnosis of asthma-COPD overlap

History or current diagnosis of allergic rhinitis within the last 5
years

History or current diagnosis of lung cancer within the last 5 
years

Participation in a parallel interventional clinical trial
Variables:
The following parameters will be collected and assessed at visit 1 and/ 
or visit 2:

Specialization of attending physician (GP, pulmonologist, 
internal specialist) 

Patient demographics (age, gender, height, weight)

History of COPD

Rationale for changing COPD maintenance therapy

Reported number and severity of exacerbations in the last 12 
months 

Number of exacerbations leading to hospitalization in the last 
12 months according to medical files

Device training yes/no, reason for no training

GOLD patient groups (A, B, C, D, calculatedi) based on GOLD 
guidelines 2019
                                                
i GOLD patient group (A, B, C or D) will be automatically calculated within the eCRF based on available exacerbation history, mMRC and 
CAT

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Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide and Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
27 May 2019
1237-0087
2.0
7 June 2019

GOLD spirometric classifications (1, 2, 3, 4 and date of 
exam, where availableii)

Eosinophils in peripheral blood and date of exam, where
available

Smoking history, current 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)

Current (within the last 6 months) COPD related and other 
relevant concomitant medication such as beta-blockers, beta-
agonists, corticosteroids, or proton pump inhibitors at date of 
Visit 1

Assessment of the severity of dyspnea based on the Modified 
Medical Research Council Questionnaire (mMRC), completed 
by the patient

Health and functional status by CATTM questionnaire, 
completed by the patient

General condition of patient based on Physician’s Global 
Evaluation (PGE) at the beginning and at the end of the study

Patient satisfaction with inhaler, inhalation, treatment and 
handling, according to a seven-point ordinal scale (ranging 
from very dissatisfied to very satisfied) 

Safety: ADRs (serious and non-serious), fatal AEs, 
pregnancies during the study

Patient’s willingness to continue or discontinue treatment with 
either triple therapy or Spiolto® Respimat® after the study 
(yes/no)

Rationale for treatment discontinuation (if applicable)
                                                
ii GOLD stage 1-4 spirometric classification of airflow limitation based on post-bronchodilator FEV1

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Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide and Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
27 May 2019
1237-0087
2.0
7 June 2019
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 with inhaler, inhalation, treatment and handling

Patient’s willingness to continue or discontinue treatment
To be completed by the patient at visit 1 and at visit 2:

Health and functional status by CATTM questionnaire

mMRC breathlessness scale
Study size:
Ca. 900 patients, approx. 150 recruiting sites
Data analysis:
Main analysis:
The estimation of the relative treatment effect concerning the primary 
outcomes is subject to potential confounding; therefore adjusted 
analyses are required and will be performed. Multiple analytical 
approaches will be applied to allow an assessment of the sensitivity of 
the results to these approaches:

Propensity score matching (primary analysis; requires data to be 
discarded from the analysis)

Propensity score weighting (uses the complete data set)

Multivariable regression modeling (uses the complete data set)
The relative treatment effect will be determined based on model 
coefficients (along with 95% confidence intervals) and statistical 
testing of these coefficients. Since the study is exploratory, no 
multiplicity adjustment is planned.

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Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
Spiolto® Respimat®
Name of active ingredient:
R03AL06
Tiotropium bromide and Olodaterol
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
27 May 2019
1237-0087
2.0
7 June 2019
Handling of missing data:
Multiple imputation will be applied to estimate the propensity score 
model and the multivariable regression models. In descriptive 
analyses, the fraction of missing observations will be reported.
Safety:
Adverse drug reactions (ADRs; serious and non-serious), fatal adverse 
events (AEs), pregnancies during the study
Milestones:
Start of data collection
Q2 2019
End of data collection
Q2 2020
Final report of study results
Q4 2020

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5.
AMENDMENTS AND UPDATES
V 1.0 dated 9 April 2019
V 2.0 dated 13 May 2019

Changes as recommended by the ethics committee in chapter 9.2.3.: Enhanced 
clearance on the order of subject information – informed consent (including time for 
consideration, if necessary) – start of study medication 

Clarifications and corrections in verbal expressions and spelling errors

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
Q2 2019
End of data collection
Q2 2020
Final report of study results:
Q4 2020

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7.
RATIONALE AND BACKGROUND
7.1
MEDICAL BACKGROUND
7.1.1
COPD
Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable 
disease that is characterized by persistent respiratory symptoms and airflow limitation due 
to airway and/or alveolar abnormalities usually caused by significant exposure to noxious 
particles or gases9.
The inhalation of noxious substances such as smoke with harmful particles or gases (air 
pollution), but in the majority of cases tobacco smoking, triggers an abnormal inflammatory 
response in the lung. This inflammatory response leads to increased mucus production, tissue 
remodelling and, connected with this, to a narrowing of the air passages in the lower 
respiratory tract. As a result, the pulmonary parenchyma is destroyed and pulmonary 
emphysema may emerge. 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) result in further 
deterioration of lung function and health status of COPD patients10.
According to the Helmholtz Centre in Munich11, 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 COPD patients, with an increasing trend. The disease currently ranks 
fourth in the list of the most common causes of death. According to WHO forecasts, COPD 
will be the third leading cause of death worldwide 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.
7.1.2
Assessment and Classification of COPD
COPD is characterized by persistent airflow limitation. The degree of airflow limitation is 
associated with many disease outcomes, but was poorly predictive of dyspnea or 
symptomatic burden.
COPD is classified into severity stages from I to IV 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 (FVC) ratio9 .
However, lung function alone does not explain the heterogeneous features of COPD. 
Therefore, GOLD proposed a new classification system for COPD, combining symptom 
assessment and exacerbation risk including spirometry to identify disease severity.
For assessing symptoms, GOLD 2011 primarily recommends the use of the Modified British 
Medical Research Council (mMRC) questionnaire4 or the COPD Assessment Test (CATTM)12. 
The mMRC scale is a 5-point (0–4) scale based on the severity of dyspnea. 

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The CATTM comprises eight items relating to the severity of cough, sputum, dyspnea, chest 
tightness, capacity for exercise and activities, confidence, sleep quality and energy levels 
while mMRC scale is a quantitative assessment tool only for breathlessness. These 
questionnaires are used to distinguish patients with less severe symptoms from patients with 
more severe symptoms. 
Together with the exacerbation risk, the symptomatic burden allows to differentiate COPD 
patients into four groups.
In addition to the spirometric evaluation, the ABCD assessment tool was proposed by 
GOLD to highlight the importance of patient symptoms and exacerbation risk. Thus, ABCD 
groups and their associated implications for pharmacotherapy recommendations are derived 
exclusively from patient symptoms and their history of exacerbations.
ABCD assessment tool
Figure 1

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7.1.3
Pharmacotherapy of COPD 
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 activities9.
Pharmacotherapy for COPD aims at reducing symptoms, reducing the frequency and 
severity of exacerbations, and improving health status and exercise tolerance. To date, 
COPD treatments are not able to modify the long-term decline in lung function, so 
patients should be treated with effective bronchodilation in order to improve quality of 
life and to reduce the risk of exacerbations9, 13.
In accordance with GOLD 20199 , bronchodilators are considered as initial treatment of 
choice for most of the patients (GOLD A: monotherapy with short or long acting 
bronchodilator; GOLD B: long-acting bronchodilator (LABA or LAMA); GOLD C: LAMA). 
In GOLD D-patients, therapy should be initiated with a LAMA, except for patients with 
severe symptoms (LAMA + LABA) or patients with high levels of eosinophils (LABA + 
ICS).
Treatment of stable COPD
Figure 2

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After initiation of therapy, patients should be reassessed to evaluate the success of treatment 
and to identify any potential barriers for successful treatment. Following review of the 
patient response to treatment initiation, adjustments in pharmacological treatment may be 
necessary.
According to GOLD 2019, the reassessment focuses on two distinct patient groups
i)
Patients that mainly suffer from dyspnea
ii)
Patients that mainly experience exacerbations
Bronchodilators are the mainstay of COPD management. Long-acting inhaled 
bronchodilators are convenient and more effective at achieving symptom relief than short-
acting bronchodilators, and combining bronchodilators of different classes (e.g. LAMAs and 
LABAs) may improve efficacy compared to increasing the dose of a single agent9.
LABA/ICS-fixed dose combinations (FDC) remain the most widely prescribed therapy in 
COPD. Dyspnea is one of the most relevant patient-reported symptoms in COPD. In order 
to achieve better symptom control, therapy can be changed by the attending physician from 
LABA/ICS to either dual bronchodilation or any triple therapy (free or fixed-dose: dual 
bronchodilation plus inhaled corticosteroid, ICS). Both symptomatic patients and patients at 
high risk of exacerbations, who are symptomatic on LABA/ICS therapy, should receive 
either LAMA/LABA or triple therapy. Therefore, it is considered highly relevant to generate 
real world data on patient-reported outcomes, esp. on dyspnea, for patients, who are
symptomatic on LABA/ICS therapy and are switched to either LAMA/LABA or triple 
therapy.

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Follow-up pharmacological treatment
Figure 3
7.1.4
Tiotropium/Olodaterol in COPD treatment
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 alone13. Therefore, treatment with combination therapy is likely to be an 
effective option for the management of moderate-to very severe COPD1.
The TOviTO program has investigated the benefits of treatment with a combination of 
tiotropium and olodaterol administered via a single inhaler in > 16.000 COPD patients in all 
disease stages and severities. Tiotropium/olodaterol 5/5 µg significantly improved forced 
expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours, trough FEV1
health status and breathlessness versus the mono-components and placebo. 
Tiotropium/olodaterol 5/5 µg also increased endurance time and reduced dynamic 
hyperinflation during constant work rate cycle ergometry.
Tiotropium/olodaterol is inhaled by the patient via a soft-mist inhaler, Respimat®.
BI developed a novel reusable Respimat® inhaler to simplify assembly and daily use, 
optimize the dose indicator and make it reusable with up to six cartridges. The updated 
design is intended to improve the usability and environmental impact of the Respimat®
inhaler, while preserving the pharmaceutical performance and basic functions of the 
disposable Respimat® inhaler. 

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7.1.5
Dyspnea
Dyspnea is the most relevant symptom that leads to diagnosis, initiation or change of 
maintenance COPD therapy. Clinical studies have demonstrated that the LAMA-LABA 
combination Spiolto® Respimat® significantly improves dyspnea in COPD patients2. 
However, real world data with regard to the effects of dual bronchodilation with Spiolto®
Respimat® vs triple therapy in COPD patients that are dyspneic and symptomatic despite 
being on a LABA/ICS maintenance therapy are not yet available. 
The mMRC and CATTM questionnaires are widely used simple measures of breathlessness 
and symptoms and are easy to complete. They relate well to other measures of health status 
and can be used to monitor dyspnea and symptoms in COPD patients. Furthermore, the 
questionnaires are responsive to intervention, predict future mortality risk, and, finally, have 
been translated and validated in Germany3, 4, 5, 6. 
7.1.6
Intention of the study
This non-interventional study (NIS) aims to investigate alleviation of dyspnea and symptom 
burden in COPD patients who are symptomatic (dyspneic) despite LABA/ICS maintenance 
therapy and who are switched to Spiolto® Respimat® in the new reusable inhaler or to triple 
therapy at the discretion of their attending physician. If a patient has symptoms other than 
dyspnea that led to a change from LABA/ICS, these patients will also be included into the 
study - except for those classified as acute exacerbations by the treating physician. Dyspnea 
will be assessed with the mMRC questionnaire; symptom burden will be evaluated with the 
CATTM questionnaire.
The recent GOLD update supports the design of this study by suggesting that patients with 
persistent breathlessness or exercise limitation on LABA/ICS treatment and not suffering 
frequently from exacerbations receive

either addition of a LAMA to escalate to triple therapy or 

a switch from LABA/ICS to LAMA/LABA 
if the original indication of ICS was 

inappropriate, or 

if there has been a lack of response to ICS treatment, or 

if ICS side effects warrant discontinuation.
The current study aims at strengthening the database on this key therapeutic decision in 
everyday practice. Currently, no prospective clinical evidence is available supporting a direct 
switch from LABA/ICS to LAMA/LABA instead of moving to triple therapy if there is no 
indication for an ICS. Therefore this proposal aims at investigating if patients that are 
symptomatic under LABA/ICS treatment can be switched to LAMA/LABA and do not do 
worse compared to a triple therapy.

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7.2
DRUG PROFILE
7.2.1
Tiotropium and Olodaterol
Tiotropium is a long-acting (24-hour) inhaled anticholinergic bronchodilator (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®14, 15.
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 emphysema16. The drug has been authorized since 2013 
in 43 countries worldwide and is available in Germany under the name Striverdi®
Respimat®17.
The Respimat® is a hand-held propellant-free soft mist inhaler18, 19, 20. It produces a slowly 
dispersing, long-lasting mist with very fine-particle distribution that is readily able to 
circulate into the lower respiratory tract and the lungs21. Thus, deep pulmonary deposition 
is achieved and the product is efficiently administered to the target site. The Respimat® does 
not contain any propellant gas. 
Recently, the Respimat® was development further to generate an improved second-generation 
Respimat® inhaler (new reusable Respimat® inhaler) Human factor studies assessing the 
usability of the new inhaler and in vitro assessment of aerosol performance demonstrated the
functionality of the updated inhaler22.
7.2.2
Spiolto® Respimat®
The 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 relieve23.
EU registration was given 1 July2015. This was based on 2 pivotal replicate, multinational 
1-year, randomized double blind, active-controlled, parallel-group Phase III studies, TOnado 
1 and 2 (Study 1237.5 and Study 1237.6). These 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)12.
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.

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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, 
and infections, which occurred most frequently in the FDC tiotropium plus olodaterol 
2.5 / 5μg group. 

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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)12. In particular, the higher-dose FDC (5 μg / 5 μg) 
appeared to offer the optimum combination.
In conclusion, the phase III clinical trials conducted within the TOviTO trial program in 
more than 16.000 patients in all stages and severities of COPD have shown tiotropium plus
olodaterol (5 / 5 µg) FDC to be a safe, well tolerated and efficacious combination therapy 
according to treatment guidelines in a moderate to very severe COPD patient population. 
Tiotropium/olodaterol significantly improved forced expiratory volume in 1 second (FEV1) 
area under the curve from 0 to 3 hours, trough FEV1, health status, and breathlessness versus 
the mono-components and placebo. Tiotropium/olodaterol also increased endurance time and 
reduced dynamic hyperinflation during constant work rate cycle ergometry. 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 product1. For further information, please refer to the 
SmPC of Spiolto® Respimat®23.
Overview TOviTO trial program
Figure 4
> 16.000 Patients
304
78

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8.
RESEARCH QUESTION AND OBJECTIVES
Clinical studies24, 25, 26 have demonstrated that Spiolto® Respimat® provides significant 
improvement in dyspnea as compared to the single active substances and placebo in COPD 
patients. Tiotropium/olodaterol improved transitional dyspnea index (TDI) and St. George’s 
Respiratory Questionnaire (SGRQ) compared with mono-components, with patients more 
likely to achieve clinically important improvements in TDI (risk ratio [RR]: 1.17, 95% 
confidence interval [CI]: [1.07, 1.28] versus tiotropium and RR: 1.14, 95%CI: [1.01, 1.28] 
versus OLO) and in SGRQ (RR: 1.21, 95%CI: [1.12, 1.30] versus tiotropium and RR: 1.28, 
95%CI: [1.18, 1.40] versus olodaterol)27, 28, 3, 29, 30.
The benefits of tiotropium/olodaterol FDC on dyspnea have been studied in 
a controlled Phase III program, however, data regarding dyspnea for COPD patients 
symptomatic despite a long-term treatment with LABA/ICS and being switched 
to either Spiolto® Respimat® in the new reusable inhaler or a triple combination of LABA, 
LAMA and ICS is not available from a real world setting.
For the identification and quantification of dyspnea in COPD patients, the Modified British 
Medical Council (mMRC) questionnaire has been developed31. It relates very well to other 
measures of health status and predicts future mortality risk32, 9.
Though dyspnea seems to be the most challenging symptom for many patients and often 
leads to therapy initiation or change, it is now recognized that COPD affects patients beyond 
dyspnea. Therefore, in today’s GOLD guidelines a comprehensive assessment of symptoms 
is required. The COPD Assessment Test, CATTM, is a suitable, concise, 8-item measure of 
health-impairment in COPD patients. It correlates closely with the SGRQ and has been 
extensively studied and documented33, 34, 9. 
8.1
STUDY OBJECTIVES
The primary objective of this prospective NIS is to investigate the comparative effectiveness 
of Spiolto® Respimat® in the new reusable inhaler vs any free or fixed-dosed triple therapy 
in reducing dyspnea (as measured via mMRC) questionnaire) and symptom burden (as 
measured via CATTM) in COPD patients who are dyspneic despite LABA/ICS maintenance 
treatment when switched to either Spiolto® Respimat® inhaler or to any triple therapy 
(LAMA + LABA + ICS) by their attending physician in an real-world setting.
Primary objective:
This study aims to analyze the comparative effectiveness of Spiolto® Respimat® in the 
new reusable inhaler vs any triple therapy in reducing dyspnea and symptom burden from 
each individual patient’s score difference between baseline and after 12 weeks of treatment.
Two primary endpoints will be assessed:

Difference between mMRC (modified Medical Research Council) score at baseline 
and after end of observation (ca. 12 weeks of treatment, Visit 2)

Difference between CATTM (COPD assessment test) score at baseline and after end 
of observation (ca. 12 weeks of treatment, Visit 2)

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To address potential confounding due to differences in observed patient demographics (age, 
sex) and severity of disease, the primary analysis will be adjusted using a propensity score 
approach. Further details will be provided in a statistical analysis plan.
Secondary endpoints to be determined and compared in an exploratory manner include

Patients’ general condition according to the Physician’s Global Evaluation (PGE) 
score at baseline and end of the observation period,

Patient satisfaction with inhaler and therapy at end of observation period according
to a seven-point ordinal scale (ranging from very dissatisfied to very satisfied as 
documented in non-interventional BI studies (BI 1237-0042, 1237-0043, 1237-0044, 
1237-0045, 1237-0065, 1237-0072),

Proportion of responders with mMRC ≥1 and proportion of responders with CAT ≥2.
Descriptive analyses of handling of the new reusable Respimat® inhaler and user experiences 
will be performed.
Additional groupwise descriptive statistics will be calculated with respect to 

exacerbations (overall and stratified by levels of eosinophils, where available),

hospitalizations due to COPD exacerbations,

adherence,

levels of eosinophils (if available in patient documentation, where available),

improvement in dyspnea and responder rates (overall and according to levels of 
eosinophils), and

improvement in lung function (overall and stratified by levels of eosinophils)
9.
RESEARCH METHODS
9.1
STUDY DESIGN
Open-label comparative multicentre cohort study according to §4, section 23 and §67, 
section 6 German Medicines Act (NIS), based on newly collected data.
9.2
SETTING
9.2.1
Study sites
Data collection of approximately 900 patients from approximately 150 recruiting sites in 
Germany is planned. Site selection will be performed to reflect routine COPD care in 
Germany in order to secure representativeness of the COPD population. 

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9.2.2
Study population
Inclusion Criteria:
Patients can be included if all of the following criteria are met:

Diagnosis of COPD

Symptomatic (with regard to dyspnea (mMRC Dyspnea score ≥1) AND with regard 
to symptoms (CAT Score ≥10) at the same time)

Patients on LABA/ICS maintenance therapy who are switched to Spiolto® Respimat®
in the new reusable inhaler or a free/fixed triple combination of LABA + LAMA +
ICS at Visit 1 at the discretion of the treating physician.

Adults who are contractually capable and mentally able to understand and follow the 
instructions of the study personnel

Male or female

Patients aged ≥40 years of age

Written informed consent prior to study participation

The patient is willing and able to follow the procedures outlined in the protocol
Exclusion Criteria:

Patients with contraindications acc. to SmPC 

Patients not on LABA/ICS maintenance treatment at visit 1, e.g., mono or dual 
bronchodilation only, ICS only, or a triple combination of LAMA + LABA + ICS 
(either as a fixed combination product or as separate components)

Lack of informed consent 

Pregnant and/or lactating females

Acute exacerbation of COPD (within 4 weeks prior to Visit 1)

Frequently exacerbating COPD patients, i. e. patients with ≥2 moderate 
exacerbations within the last 12 months or ≥1 exacerbation leading to 
hospitalization within the last 12 monthsiii

Acute respiratory failure (pH <7,35 and/ or respiratory rate >30/min within 
3 months prior to Visit 1)

History or current diagnosis of asthma

History or current diagnosis of asthma-COPD overlap

History or current diagnosis of allergic rhinitis within the last 5 years
                                                
iii Definitions of exacerbation severity according to German Pulmonary Society Guideline 
(DGP-Leitlinie 2019)8

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
History or current diagnosis of lung cancer within the last 5 years

Participation in a parallel interventional clinical trial

mild exacerbation: additional use of short-acting bronchodilators and treated 
by the patient without consulting a physician

moderate exacerbation: treatment includes medical prescription of a systemic 
corticosteroid and/or antibiotic

severe exacerbation: exacerbation leading to hospitalization
9.2.3
Study visits
Patients will be enrolled consecutively and will be followed over an observational period 
of approximately 12 weeks. Two study visits will be performed.
Patients will be attributed to either group (triple therapy or Spiolto® Respimat®) on 
the investigator’s discretion and patient’s consent before study start at visit 1 (Baseline). 
If possible and manageable and in compliance with the investigator’s decision, a 1:1 group 
distribution of the patients included per site should be aimed at. However, a strict distribution 
scheme is not given.
At Visit 1 (baseline), after information and signature of the Informed Consent Form, the 
patient will be included into the NIS. The patient will of course have enough time for 
considering study participation.
At Visit 2, after approximately 12 weeks of treatment, 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. 12
weeks after 
baseline visit
Informed Consent
X
Specialization of attending physician (GP, pulmonologist, internal 
specialist) 
X
Inclusion / Exclusion Criteria
X
Patient demographics (age, gender, height, and weight)
X
History of COPD
X
Rationale for changing COPD maintenance therapy
X
Number and severity of exacerbations in the last 12 months
X
Number of exacerbations leading to hospitalization in the last 12 
months
X
Device training (yes/no), reason for no training
X

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Table 9.2.3.1 (cont´d): Visit flow chart and data collection parameters
Parameter
Visit 1;
baseline 
visit
Visit 2;
approx. 12
weeks after 
baseline visit
COPD severity based on GOLD assessmentiv (GOLD patient groups)
X
GOLD spirometric classification, if availablev, incl. date of 
examination
X
Eosinophils in peripheral blood, if available
X
Smoking history, current status, pack-years
X
Concomitant diseases / Comorbidities
X
X
Current COPD related and other relevant concomitant medication
X
X
mMRC breathlessness scale, completed by the patient
X
X
Health and functional status by CATTM 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 AEs, 
pregnancy
X
X
Patient satisfaction with inhaler, inhalation and treatment and 
handling
X
X
Patient’s willingness to continue or discontinue treatment with either 
triple therapy or Spiolto® Respimat® after the study (yes/no)
X
Rationale for treatment discontinuation (if applicable)
X
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
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:
                                                
iv GOLD patient group (A, B, C or D) will be automatically calculated within the eCRF based on available exacerbation 
history, mMRC and CAT
v GOLD stage 1-4 spirometric classification of airflow limitation based on post-bronchodilator FEV1

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
Specialization of attending physician (GP, pulmonologist, internal specialist) 

Patient demographics (age, gender, height, weight)

History of COPD

Rationale for changing COPD maintenance therapy

Reported number and severity of exacerbations in the last 12 months 

Number of exacerbations leading to hospitalization in the last 12 months according
to medical files

Device training yes/no, reason for no training

GOLD patient groups (A, B, C, D, calculated1) based on GOLD guidelines 2019

GOLD spirometric classifications (1, 2, 3, 4 and date of exam, if available 2) 

Eosinophils in peripheral blood and date of exam, if available

Smoking history, current 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)

Current (within the last 6 months) COPD related and other relevant concomitant 
medication such as beta-blockers, beta-agonists, corticosteroids, or proton pump 
inhibitors at date of Visit 1

Assessment of the severity of dyspnea based on the Modified Medical Research Council 
Questionnaire (mMRC), completed by the patient

Health and functional status by CATTM questionnaire, completed by the patient

General condition of patient based on Physician’s Global Evaluation (PGE) at the 
beginning and at the end of the study

Safety: ADRs (serious and non-serious), fatal AEs, pregnancies during the study

Patient satisfaction with inhaler, inhalation, treatment and handling

Patient’s willingness to continue or discontinue treatment with either triple therapy or 
Spiolto® Respimat® after the study (yes/no) 

Rationale for treatment discontinuation (if applicable)
9.3.1
Exposures
Patients will be treated with Spiolto® Respimat® or triple therapy and be observed for 
approximately 12 weeks.
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.

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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.
Other LAMA, LABA and/or ICS therapy will be performed according to label as described
in the respective SmPCs.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
1. Difference between mMRC score at baseline (visit 1) and mMRC score after end of 
observation (ca. 12 weeks of treatment, Visit 2)
2. Difference between CATTM score at baseline (visit 1) and CATTM score 
after end of observation (ca. 12 weeks of treatment, Visit 2)
The primary outcomes are reported in a descriptive manner, will be compared in an 
explorative manner and are not safety outcomes.
9.3.2.2
Secondary outcomes
Secondary endpoints to be determined and compared in an exploratory manner include

patients’ general condition according to the Physician’s Global Evaluation 
(PGE) score at baseline and end of the observation period,

patient satisfaction with inhaler and therapy at end of observation period 
according to a seven-point ordinal scale (ranging from very dissatisfied to very 
satisfied as documented in non-interventional BI studies (BI 1237-0042, 1237-0043, 
1237-0044, 1237-0045, 1237-0065, 1237-0072),

proportion of responders with mMRC ≥1 and the proportion of responders with 
CAT ≥2.
The secondary outcomes are not safety outcomes.
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.

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9.4.1
PGE
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. 12 weeks after treatment initiation.
9.4.2
Symptomatic Burden: mMRC and CATTM
The modified Medical Research Council (mMRC) scale is a 5-point (0–4) scale based on the 
severity of dyspnoea. The mMRC will be used to assess the breathlessness state of the patient
with just one question: “When do you experience dyspnoea?”, covering five everyday 
activities, potentially leading to dyspnoea and giving an according rate of 0 to 4 points. 
The MCID is a change of 1.0 point. It will be applied before the treatment and after 
approximately 12 weeks of treatment
The COPD Assessment Test (CATTM) was developed as a simple instrument to assess health 
status in patients with COPD12. The CATTM consists of eight items, each formatted as a
semantic six-point differential scale, making the tool easy to administer and easy for patients 
to complete35. These eight items cover cough, phlegm, chest tightness, breathlessness when 
going up hills/stairs, activity limitations at home, confidence leaving home, sleep and energy.
Each item is scored from 0 to 5 giving a total score range from 0 to 40, corresponding to the 
best and worst health status in patients with COPD, respectively34. The MCID is a change of 
2.0 points36. 
The questionnaire will be filled out by the patient and entered into the database. Patients will 
be asked to complete the CATTM in order to evaluate their health and functional status before 
treatment with Spiolto® Respimat® or triple therapy, respectively, and after approximately 12 
weeks.
Additionally, the mMRC stage and CATTM scores collected from the patient as well as the 
exacerbation history will be used to automatically calculate the GOLD patient group (A, B, 
C, or D) in the eCRF.
9.4.3
Patient Satisfaction
The 7-item satisfaction scale with divisions from very dissatisfied to very satisfied to be 
completed at Visit 1 and Visit 2 to measure patient satisfaction with inhaler use, is a Likert-
scale without validation status for the intended use. However, the application of Likert-Scales 
has been well established in a range of comparable situations37, 38, 39.
Patient’s willingness to continue treatment is assessed by a yes/no question plus reasons for 
non-willingness.

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9.5
STUDY SIZE
9.5.1
Sample size justification
It should be noted that the study is generally to be considered exploratory in design.
It is further recognized that the multivariable, observational setting complicates a realistic 
and reliable sample size calculation, e.g. due to the influence of potential confounding 
variables and dropout (both during study conduct and matched analyses). The sample size 
calculation/justification given below can therefore only provide a rough estimate of 
statistical power in an exploratory real-world setting. The sample size is based on the 
assumption that Spiolto® Respimat® is at least non-inferior compared to any triple therapy 
using two-sample t-tests (one-sided alpha-level 2.5% and 90% power). The respective 
MCIDs are treated as non-inferiority margins (to the authors knowledge, established non-
inferiority margins are lacking with respect to both endpoints).
The MCID regarding mMRC is 1 point. Based on the real world evidence study by 
Buhl et al. and BI data, a standard deviation (SD) of 1 point is assumed for the mMRC40. 
The MCID regarding CATTM is 2 points. Based on the real world evidence study by 
Buhl et al., a SD of 7 points is assumed for the CATTM40.
44 patients overall (22 per group) are required to assess non-inferiority between Spiolto®
Respimat® and triple treatment regarding the mMRC. We expect that data of about 40% of 
patients will not be available for evaluation at the end of the study: a drop out of 10% is 
based on experiences with German NIS such as BI 1237-0042. An additional drop out of 
30% appears likely due to the need to discard patients which cannot be matched (this is 
based on similar experiences by Buhl et al.41). Thus, when taking into account this dropout, 
a total number of 74 patients (37 patients per group) is required to evaluate non-inferiority 
with respect to the mMRC score.
518 patients overall (259 per group) are required to assess non-inferiority between Spiolto®
Respimat® and triple treatment regarding the CATTM. For reasons as outlined above, we 
expect that data of about 40% of patients will not be available for evaluation at the end of the 
study. Thus, when taking into account this dropout, a total number of 864 patients (432 
patients per group) is required to evaluate non-inferiority with respect to the CATTM score.
Because mMRC and CATTM are both of interest as primary endpoints here, the required 
sample size for the NIS equals the higher of the two respective estimates, i.e. 864 patients in 
total (432 patients per group).
Patients will be attributed to either group (triple therapy or Spiolto ® Respimat®) on 
the investigator’s discretion and patient’s consent at visit 1. If possible and manageable and
in compliance with the investigator’s decision, a 1:1 group distribution of the patients 
included per site should be aimed at. However, a strict distribution scheme is not given.
Measures to be considered in case of substantially unequal recruitment include the early 
closing one of the treatment arms earlier (i.e., when its target size is reached) and the analysis 
of unequal group sizes (1:2, 1:3 or 1:4).

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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 each recruiting site and further 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 or implausible data entries or 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 

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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 that 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 thirty 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
Details on the statistical analyses will be given in a statistical analysis plan (SAP).
In brief, the planned analyses will be conducted as follows:
All patients who have received at least one dose of Spiolto® Respimat® or triple combination 
(free or fixed LAMA + LABA+ ICS) will be included in the analysis; this is the treated set. 
All analyses will be performed on the treated set (as-treated analysis). 
The analyses will relate to the following data: 

primary outcome: Therapeutic success based on mMRC score difference; 

primary outcome: Therapeutic success based on CATTM score difference; 

secondary outcome: Changes from Visit1 to Visit 2 in the mMRC and CATTM scores;

Specialization of attending physician (GP, pulmonologist, internal specialist) 

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
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 / current smoking and pack years

Reported number and severity of exacerbations in the last 12 months

Dyspnea based on mMRC score at visit 1 and visit 2

Symptom burden based on CATTM score at visit 1 and visit 2

Patient satisfaction with inhaler and therapy at visit 2 only; secondary outcome

General condition of the patient: evaluated by the physician (Physician´s Global
Evaluation (PGE)), secondary outcome

Patient’s willingness to continue, reason for unwillingness; secondary outcome

Adverse Drug Reactions (ADR and SADR), fatal AEs, pregnancies

GOLD spirometric classifications (1, 2, 3, 4) and GOLD patient groups (A, B, C, D)

Details of current treatment with inhaled respiratory agents at Visit 1

Details of treatment with respiratory agents during the study

Reasons for ending treatment during the observation period

Details of treatment continuation / discontinuation
Descriptive statistics for comparison of baseline characteristics and crude outcome analyses 
comprise N / mean / SD / min / median / max for continuous variables, while for categorical 
variables tabulations of relative and absolute frequencies will be presented. Incidence rates 
and 95% CI will be given where appropriate.
All analyses will be carried out using SAS® statistical software, version 9.4 or higher 
(
).
9.7.1
Main analysis
For the two primary outcomes, as specified in section 9.3.2.1, the comparative treatment 
effect will be estimated along with 95% confidence intervals.
The estimation of the treatment effect is subject to potential confounding. Therefore,
adjusted analyses are required. Multiple analytical approaches will be applied to allow an 
assessment of the sensitivity of the results to these approaches:

Propensity score matching (primary analysis; requires data to be discarded from the
analysis)

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
Propensity score weighting (uses the complete data set)

Multivariable regression modeling (uses the complete data set)
Multiple imputation will be applied to estimate the propensity score model and the 
multivariable regression models. 
Covariates for adjustment include patient demographics (age, sex), disease characteristics 
(baseline CATTM / mMRC, exacerbation history, pack-years of smoking, FEV1, eosinophil 
levels) and health care provider (GP / pulmonologist). Baseline comparability before and 
after matching will be assessed using standardized differences.
The comparative effectiveness on the primary endpoints will be determined based on model 
coefficients (along with 95% confidence intervals) and statistical testing of these coefficients. 
Since the study is exploratory in nature, no multiplicity adjustment is planned.

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9.7.3
Handling of missing data
Multiple imputation will be used in the estimation of propensity scores and in multivariable 
regression analyses. In descriptive analyses, the fraction of missing observations will be 
reported. 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 every recruiting site of this study.
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
This prospective NIS aims to investigate the comparative effectiveness of Spiolto®
Respimat® in the new reusable inhaler vs any free or fixed-dosed triple therapy 
(LAMA + LABA + ICS) in reducing dyspnoea (as measured via mMRC questionnaire) 
and symptom burden (as measured via CATTM) in COPD patients who are dyspnoeic 
despite LABA/ICS maintenance treatment when switched to either Spiolto® Respimat®
or to any triple therapy, both in a real-word setting.
A NIS appears the most suitable instrument for obtaining information about the use of 
medicines in everyday therapeutic practice and thus for investigating prospectively questions 
in everyday therapeutic practice.
Consecutive enrolment will be employed to minimize selection bias. The entry criteria are 
non-restrictive which will permit the enrolment of a broad patient population. The choice 
of treatment is at the discretion of the investigator.
Selection bias could occur at the site level and the patient level. To minimize the site level 
selection bias, the goal is to have participating centers with access to all available and 
approved treatment options 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.

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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 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, source data 
validation will take place at each recruiting site 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 
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. 

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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 and 
 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.
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 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 
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.

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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.
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 that 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.

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Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization
or development of dependency or abuse. Any suspected transmission via a medicinal product 
of an infectious agent is also considered a serious adverse reaction.
Adverse Event of Special Interest (AESI)
The term 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 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. 

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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 
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 (most recent 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. 
The report forms are part of the investigator site file.

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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 (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 or pregnancy. The Boehringer Ingelheim NIS AE form must be 
printed from the eCRF and sent per fax. For pregnancy reports the pregnancy monitoring 
forms A and B must be completed 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. The respective forms are part of the investigator site file. In this case, these 
data must be entered into the eCRF as soon as possible when electronically available.
All of the above 1-4 to be sent to: Fax: 
Phone: 

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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 updated NIS AE 
form.
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.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS
Results of this non-interventional study will be disclosed on encepp.eu and clinicaltrials.gov
and a study specific publication plan will be developed to describe planned publications.
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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13.1
PUBLISHED REFERENCES
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[22] Dhand R, Eicher J, Haensel M, Jost I, Meisenheimer M, Wachtel H. Improving usability 
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[34] Karloh M et al. The COPD Assessment Test: What Do We Know So Far?:
A Systematic Review and Meta-Analysis About Clinical Outcomes Prediction and 
Classification of Patients Into GOLD Stages. Chest. 2016 Feb;149(2):413-425. 
[35] JonesPW, Harding G, Berry P, Wiklund I, Chen WH, Leidy NK. Development and
first validation of the COPD Assessment Test. Eur Respir J 2009;34 (3):648 - 654 
(R12-1915)
[36] Kon SS et al. Minimum clinically important difference for the COPD Assessment Test:
a prospective  lysis. Lancet Respir Med. 2014;2(3):195-203 (R19-1227)
[37] Norman, G. Likert scales, levels of measurement, and the “laws” of statistics. 
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Investigating sensitivity, specificity, and area under the curve of the Clinical COPD 
Questionnaire, COPD Assessment Test, and modified Medical Research Council scale 
according to GOLD using St George's Respiratory Questionnaire cutoff 25 (and 20) as 
reference. Int J Chronic Obstruct Pulm Dis 2016;11, 1045 - 1052 (R19-0525)
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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
4 June 2019
PGE
2
Appendix 2
4 June 2019
CATTM
Questionnaire 
3
Appendix 3
4 June 2019
mMRC
Questionnaire
4
Appendix 4
4 June 2019
NIS AE Form

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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 approximately 12 weeks of treatment (Visit 2)
Please mark with a cross as applicable
Poor
Satisfactory
Good
Excellent 
1  2
3  4
5  6
7  8

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BI Study Number 1237-0087
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APPENDIX 2: COPD ASSESSMENT TEST (CATTM)
COPD Assessment Test (CAT TM)vi
                                                
vi derived from: http://www.catestonline.org/english/indexEN.htm

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APPENDIX 3:
MODIFIED MEDICAL RESEARCH COUNCIL (MMRC)
QUESTIONNAIRE FOR ASSESSING THE SEVERITY OF 
BREATHLESSNESS
Please circle the number which best describes your grade of breathlessness.
I only get breathless with strenuous exercise.
0
I get short of breath when hurrying on the level or walking up a slight hill.
1
I walk slower than people of the same age on the level because of 
breathlessness, or have to stop for breath when walking at my own pace on 
the level.
2
I stop for breath after walking about 100 meters or after a few minutes on 
level.
3
I am too breathless to leave the house or I am breathless when dressing or 
undressing.
4

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BI Study Number 1237-0087
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APPENDIX 4: NIS AE FORM

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BI Study Number 1237-0087
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Boehringer Ingelheim
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Non-interventional Study Protocol
BI Study Number 1237-0087
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001-MCS-90-118_RD-01 (7.0)  Saved on: 09 Nov 2015

Boehringer Ingelheim
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Non-interventional Study Protocol
BI Study Number 1237-0087
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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable
ANNEX 3. ADDITIONAL INFORMATION
Not applicable

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26538106
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clinical-trial-protocol-nis-1237-0087
EVELUT: Assessment of dyspnea and other symptoms as patient reported outcomes
(PRO) in patients with chronic obstructive pulmonary disease (COPD), symptomatic
on LABA/ICS maintenance therapy (now) treated with Spiolto Respimat
(tiotropium/olodaterol) in comparison to open or fixed triple combination treatment
in routine clinical practice.
Approval-Clinical Trial Leader
11 Jun 2019 09:56 CEST
Approval-Biostatistics
11 Jun 2019 13:16 CEST
Approval-
 Medical Affairs
11 Jun 2019 17:07 CEST
Approval-
Safety Evaluation
Therapeutic Area
13 Jun 2019 12:48 CEST
Approval-
of Global
Epidemiology
17 Jun 2019 20:51 CEST
Approval-Team Member Medicine
18 Jun 2019 15:58 CEST
Approval-Pharmacovigilance
25 Jun 2019 09:19 CEST

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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26538106
2.0