Switching COPD Patients From Spiriva® HandiHaler® Maintenance Therapy to Spiriva® Respimat®: a Non-Interventional Real-world clinicAl ouTcome assEssment: NIS PIRATE
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
 
Non-Interventional Study (NIS) Protocol 
 
 
Document Number:
c38251083-01
BI Study Number:
0205-0549
BI Investigational
Product(s):
Spiriva® HandiHaler® and Spiriva® Respimat®
Title:
Switching COPD Patients from Spiriva® HandiHaler® maintenance 
therapy to Spiriva® Respimat®: a non-Interventional Real-world 
clinicAl ouTcome assEssment: NIS PIRATE
Brief lay title:
Assessment of health-related quality of life after switching COPD 
patients from a dry powder inhaler to a soft mist inhaler remaining on 
the same inhalative drug
Protocol version 
identifier:
V1.0
Date of last version of 
protocol:
03 Mar 2022
PASS:
No
EU PAS reg. number:
Not applicable
Active substance:
Tiotropium bromide
Medicinal product:
Spiriva® HandiHaler® 18 microgram capsules with powder for 
inhalation
Spiriva® Respimat® 2.5 microgram per puff inhalation solution
Product reference:
0205-P03 (Spiriva® Respimat®)
Procedure number:
Not applicable
Marketing 
authorization holder(s):
MAH:
This study is initiated, managed, and sponsored by:
Joint PASS:
No
Research question and 
objectives:
The objective of this NIS is to test whether changing COPD patients 
from a dry powder inhaler (HandiHaler®) to a soft mist inhaler 
(Respimat®), without changing the pharmacological compound, will 

Boehringer Ingelheim
Page 2 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
lead to an improvement in Clinical COPD Questionnaire (CCQ) 
overall score and the three subdomains: symptoms (4 items), 
functional state (4 items) and mental state (2 items) during a study 
period of approximately 8 weeks.
Primary objective:
•
To assess proportion of patients achieving 0.2 points decrease in the 
CCQ score* between baseline (visit 1 = visit at the start of the study)
and after approximately 8 weeks of treatment (visit 2) in patients 
with high CCQ baseline score (≥2)
*CCQ score means the CCQ overall score, unless otherwise stated
Secondary objectives: 
•
To assess proportion of patients achieving 0.2 points decrease in the 
CCQ score between baseline (visit 1) and after approximately 8 
weeks of treatment (visit 2) in patients independently from CCQ 
baseline score
•
To assess the mean change in CCQ score and in the scores of the 3 
CCQ subdomains, symptom, mental state, and functional state 
domain in all patients independently from CCQ baseline score
between baseline (visit 1) and after approximately 8 weeks of 
treatment (visit 2)
•
To assess the mean change in CCQ score and in the scores of the 
CCQ subdomains symptom, mental state, and functional state 
domain in patients with high CCQ baseline score (≥2) between 
baseline (visit 1) and after approximately 8 weeks of treatment (visit 
2)
•
To assess patients´ breathlessness based on modified Medical 
Research Council (mMRC) score at baseline (visit 1) and after 
approximately 8 weeks of treatment (visit 2)
•
To assess the change in mMRC score between baseline (visit 1) and 
after approximately 8 weeks of treatment (visit 2
Country(-ies) of study:
Approximately 225 COPD patients from Switzerland
Author:
Date:
03 Mar 2022
Page 1 of 51
Proprietary confidential information
© 2022 Boehringer Ingelheim Group of companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

Boehringer Ingelheim
Page 3 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
LIST OF ABBREVIATIONS......................................................................................... 5
2.
RESPONSIBLE PARTIES.................................................................................... 7
3.
ABSTRACT........................................................................................................... 8
4.
AMENDMENTS AND UPDATES..................................................................... 13
5.
MILESTONES..................................................................................................... 14
6.
RATIONALE AND BACKGROUND................................................................ 14
6.1
MEDICAL BACKGROUND ......................................................................... 14
6.2
DRUG PROFILE ............................................................................................ 15
6.3
ASSESSMENT OF QUALITY OF LIFE....................................................... 15
6.4
SITUATION IN SWITZERLAND................................................................. 16
6.5
RATIONALE.................................................................................................. 17
7.
RESEARCH QUESTION AND OBJECTIVES ................................................. 18
8.
RESEARCH METHODS .................................................................................... 19
8.1
STUDY DESIGN............................................................................................ 19
8.2
SETTING........................................................................................................ 20
8.2.1
Study sites ............................................................................................... 20
8.2.2
Study population ..................................................................................... 20
8.2.3
Study visits .............................................................................................. 21
8.2.4
Study discontinuation.............................................................................. 24
8.3
VARIABLES .................................................................................................. 25
8.3.1
Exposures ................................................................................................ 26
8.3.2
Outcomes................................................................................................. 26
8.3.3
Covariates................................................................................................ 29
8.4
DATA SOURCES........................................................................................... 29
8.5
STUDY SIZE.................................................................................................. 30
8.6
DATA MANAGEMENT................................................................................ 31
8.7
DATA ANALYSIS......................................................................................... 31
8.7.1
Main analysis........................................................................................... 34

Boehringer Ingelheim
Page 5 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
LIST OF ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of special interest
AICD
Additional Inhalative COPD Drugs
CA
Competent Authority
CAT
COPD Assessment Test
CI
Confidence Interval
CCQ
Clinical COPD Questionnaire
CML
Local Clinical Monitor 
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CRF
Electronic Case Report Form
CRO
Clinical Research Organization
D
Diverse
DMP
Data Management Plan
DPI
Dry Powder Inhaler
EDC
Electronic Data Capture
e. g.
Exempli Gratia
EoT
End of Treatment
F
Female
FDA
US Food and Drug Administration
FEV1
Forced Expiratory Volume in One Second
FU
Follow Up
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HH
HandiHaler
HRQoL
Health Related Quality of Life
ICH
International Conference on Harmonization

Boehringer Ingelheim
Page 6 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
i. e.
Id Est
IEC
Independent Ethics Committee
IPCRG
International Primary Care Respiratory Group
IRB
Institutional Review Board
ISF
Investigator Site File
LABA
Long acting beta2 adrenoceptor agonist
LAMA
Long-acting muscarinic antagonist 
m
Male
MAH
Marketing Authorization Holder
Max
Maximum
MedDRA
Medical Dictionary for Drug Regulatory Activities
Min
Minimum
mMRC
Modified Medical Research Council
n
Number (quantity)
NIS
Non-Interventional Study
NIS-DMRP
NIS-Data Management and Review Plan
PFIR
Peak Inspiratory Flow Rate
SADR
Suspected Adverse Drug Reaction
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SDV
Source Data Verification
SMI
Soft Mist Inhaler
SmPC
Summary of product characteristics
SOP
Standard Operating Procedure
w
week
WHO
World Health Organization

Boehringer Ingelheim
Page 7 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
2.
RESPONSIBLE PARTIES
Function
Name 
Scientific Coordinator
Therapeutic Area 
 Respiratory Medicine (TA
Team Member Medical Affairs (TM MA)
Scientific Advisor Medical Affairs
na
Team Member Epidemiology (TM Epi)
Deputy 
 Global Epidemiology (
GEpi)
Therapeutic Area
 Risk Management (TA
RM), and Pharmacovigilance Working Group 
(PVWG) 
Trial Clinical Monitor
TSTAT
Statistical Analysis
Vendor/CRO
Data Management
Vendor/CRO
Trial Programming
Vendor/CRO

Boehringer Ingelheim
Page 8 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
3.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Spiriva® HandiHaler® and Spiriva® Respimat®
Name of active ingredient:
Tiotropium bromide
Protocol date:
Study number:
Version/Revision:    Version/Revision date:
03 Mar 2022 
1.0
Title of study:
Switching COPD Patients from Spiriva® HandiHaler® maintenance therapy 
to Spiriva® Respimat®: a non-Interventional Real-world clinicAl ouTcome 
assEssment: NIS PIRATE
Rationale and 
background:
Chronic obstructive pulmonary disease (COPD) is a common and serious 
condition, characterized by persistent respiratory symptoms and airflow 
limitation. Giving to the GOLD 2021 strategy report, long-acting 
bronchodilators such as long-acting muscarinic antagonists and long-acting 
β2-agonists are the basis of maintenance therapy for patients with moderate-
to-very severe COPD.
Beside the pharmacological compound, matching each patient with the most 
appropriate inhaler is important for an optimal inhaler technique and drug 
delivery. Previous studies suggested that COPD patients with suboptimal 
peak inspiratory flow rate (PIFR) may not achieve the greatest possible drug 
deposition and efficacy when using a dry powder inhaler (DPI) for delivery 
of inhalative COPD medication.
The Respimat®, an active soft-mist inhalation device, allows COPD patients 
to inhale without effort and can be used irrespective of the PIFR a patient 
can generate.
This NIS aims to evaluate whether patients will benefit from the switch from 
the DPI Spiriva® HandiHaler® to the Spiriva® Respimat® device, which the 
physician decides based on the needs of the patient prior to study inclusion 
using the Clinical COPD Questionnaire (CCQ) and its three domains, 
changes in clinical control will be assessed.
Note: Patients will be included into the study independently of their CCQ* 
score at baseline.
*CCQ score means the CCQ overall score, unless otherwise stated
Research question 
and objectives:
The objective of this NIS is to test whether changing COPD patients from a 
dry powder inhaler (HandiHaler®) to a soft mist inhaler (Respimat®), 
without changing the pharmacological compound, will lead to an 
improvement in Clinical COPD Questionnaire (CCQ) score (covering last 7 
days prior to visit) and in the scores of the three subdomains: symptoms (4 
items), functional state (4 items) and mental state (2 items) during a study 
period of approximately 8 weeks. 

Boehringer Ingelheim
Page 9 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
The primary objective of the NIS is to assess proportion of patients 
achieving 0.2 points decrease in the CCQ score between baseline and after 
approximately 8 weeks of treatment) in patients with high CCQ baseline 
score (≥2).
Secondary objectives of the NIS are the assessment of the proportion of 
patients achieving 0.2 points decrease in the CCQ score between baseline 
and after approximately 8 weeks of treatment independently from CCQ 
baseline score, the mean change in CCQ score and in the three CCQ 
domains symptom, mental state, and functional state domain in all patients 
and in patients with high CCQ baseline score (≥ 2) between baseline and 
visit 2 (approximately at week 8 after visit 1), breathlessness based on 
modified Medical Research Council (mMRC) score at baseline, visit 2 
(approximately at week 8 after visit 1), change in mMRC score between 
baseline and visit 2 (approximately at week 8 after visit 1). 
 
 
 
 
 
 
Safety data on COPD patients switching from Spiriva® HandiHaler® to 
Spiriva® Respimat® are collected descriptively and do not represent an 
objective of the NIS.
Following subgroup analyses will be performed for the primary objective: 
•
Patients with mMRC score ≥ 2 vs patients with mMRC score <2 at 
baseline visit
•
Patients < 65 years vs patients ≥ 65 years at baseline visit
•
Patients with 0-1 exacerbations vs patients with ≥ 2 exacerbations 
requiring hospitalizations during the 12 months prior study inclusion
•
Patients using Spiriva® HandiHaler® ≥ 1 year(s) vs patients on Spiriva®
HandiHaler® < 1 year
•
Patients with at least one concomitant disease that was classified as 
mental and/or cognitive disorder vs patients without any concomitant 
disease that was classified as mental and/or cognitive disorder
•
Patients with GOLD spirometric classification 1/2 vs patients with GOLD 
spirometric classification 3/4 at baseline visit

Boehringer Ingelheim
Page 10 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Study design:
Open label, observational, non-interventional, national, multicenter study 
including COPD patients ≥ 40 years switching from Spiriva® HandiHaler® to 
Spiriva® Respimat® with an observational period of approximately 8 weeks 
(which is the average time between medical consultations). Patients will be 
followed-up to either discontinuation of Spiriva® Respimat® or up to week 
52, whatever occurs first.
Population:
COPD patients ≥ 40 years who are planned to be switched from Spiriva®
HandiHaler® to Spiriva® Respimat®.
The decision to switch is made by the treating physician and patient 
according to patient´s need and to the standard of best medical practice. This 
decision is made independently and prior to inclusion in this NIS. 
Patients who will undergo a switch from Spiriva® HandiHaler® to Spiriva®
Respimat® will be informed about the scope of the study and asked whether 
they would like to participate.
Inclusion criteria:
!
Participants ≥ 40 years of age at baseline visit
!
Patients with confirmed diagnosis of COPD* 
!
Patients who have been on Spiriva® HandiHaler® for ≥ 6 weeks at 
baseline visit
!
Patients for whom a switch from Spiriva® HandiHaler® to Spiriva®
Respimat® was planned prior to study inclusion. If additional inhalative 
COPD drugs (AICDs) are used: AICD treatment must have been stable 
for at least 6 weeks before study inclusion
!
Signed written informed consent form to participation
*Confirmed by spirometry: FEV1/FVC <0.7, (last available FEV1 and FVC including % 
predicted)
Exclusion criteria:
!
Patients who have contraindications to Spiriva® Respimat® according to 
the current prescribing information label/ summary of product 
characteristics (SmPCs)
!
Patients who have signs of a current, acute respiratory tract infection 2 
weeks prior visit 1
!
Patients for whom further follow-up will not be possible at the enrolling 
site during the planned observational period (of approximately 8 weeks)
!
Patients with confirmed diagnosis of only asthma
!
Patients who had > 1 moderate to severe exacerbation(s) within the last 
6 weeks prior to study inclusion
!
Patients who are pregnant or breastfeeding
!
Patients participating in an ongoing interventional study

Boehringer Ingelheim
Page 11 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Variables:
Eligible patients who signed the informed consent form will undergo the 
baseline visit (= visit 1).
Visits are to be scheduled as per standard-of-care. Documentation at the sites 
is planned at baseline (month 0, visit 1) and after approximately 8 weeks 
after treatment start (visit 2). Patients will be requested to have an End-of 
Treatment (EoT) visit (Follow-up visit) if they discontinue Spiriva®
Respimat® treatment or if they switch to another inhalative medication. 
Patients who are still on Spiriva® Respimat® will have a follow-up visit (visit 
3) approximately 52 weeks after baseline visit. It is planned that each patient 
will have 3 visits during the 1-year observational period. Additional visits 
may be performed as needed, such as when COPD treatment requires 
adjustment, or whenever otherwise deemed necessary by the study physician 
based on usual care.
Main data collected:
At baseline (visit 1):
!
Patient demographics (age, gender, height, weight)
!
Concomitant diseases / comorbidities (relevant comorbidities such as 
cardiovascular diseases, diabetes mellitus type 2, depression, and 
diseases affecting the preparing and handling of the device)
!
Date of confirmed COPD diagnosis 
!
Start with inhalative bronchodilators for COPD treatment [year]
!
Concomitant COPD medication including additional inhalative COPD 
drugs (AICDs, dosage, date of onset)
!
Breathlessness based on mMRC score
!
Last available FEV1 and FVC including % predicted (value and date 
measured, closest to the date of baseline visit) 
!
Exacerbation history (number of moderate-to-severe exacerbations in 
the last 12 months before study inclusion, hospitalizations required)
!
Smoking history (number of pack years) and status (never, former, 
current)
 
 
At visit 2:
!
Breathlessness based on mMRC score

Boehringer Ingelheim
Page 12 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
!
CCQ score and the CCQ symptom, mental state, and functional state 
domain scores
 
 
 
!
Safety; ADR (serious and non-serious), fatal AEs, pregnancies
At visit 3: 
!
Changes in COPD treatment scheme (yes/no, date, reason(s), kind of 
new treatment)
!
Discontinuation of Spiriva® Respimat® treatment (date, reason(s))
!
Safety; ADR (serious and non-serious), fatal AEs, pregnancies 
(including exacerbations)
Data sources:
To be completed by the physician:
!
Patient demographics
!
Patient medical files 
 
To be completed by the patient:
!
mMRC breathlessness scale at baseline (visit 1) and visit 2 
!
Health and functional status by CCQ at baseline (visit 1) and visit 2 
 
Study size:
Primary endpoint: 
Assuming 40% of high CCQ score patients have a 0.2 improvement in CCQ 
score from baseline at 8 weeks on treatment, then with a sample size of 100, 
the 95% CI for the response rate will be (0.304, 0.49)6.
Secondary endpoint: 
Assuming 30% of all patients have a 0.2 improvement in CCQ score from 
baseline at 8 weeks on treatment, then with a total sample size of 200, the 
95% CI for the response rate will be (0.236, 0,364).   
With a dropout rate of 10% we would need a total of about 225 patients.

Boehringer Ingelheim
Page 13 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Sample size assumes that Respimat® is better compared to HandiHaler®. 
The sample size calculation/justification can only provide a rough estimate 
of the statistical power in such an exploratory real-world setting. 
Recruitment will continue until the minimum sample size is achieved. 
Data analysis:
Primary outcome:
For the primary outcome, the percentage of patients with improvement will 
be presented together with the 95% confidence interval, whereupon 
improvement is defined as 0.2 points decrease in the CCQ score from 
baseline (visit 1) to visit 2. 
Secondary outcomes: 
For secondary 
 
, the mMRC breathlessness scale at visit 1 and visit 2, 
 
Changes from visit 1 to visit 2 in the CCQ score and CCQ 
symptom, mental and functional state score as well as in the 
 
 
 
 
 
Subgroup analyses on the primary objective will be performed for several 
stratifications as described before (see section Research question and 
objectives). If less than 20 patients are in one subgroup class, classes will be 
combined in a meaningful way, or the subgroup analysis will be omitted 
with reason.
Milestones:
Estimated enrolment duration: 1 year
First patient In (FPI): Q2/2022
Estimated individual observational period: at least 8 weeks, up to 52 weeks
Last patient In (LPI): Q2/2023
Last patient Last visit (LPLV): Q2/2024
Final study report: July 2024
4.
AMENDMENTS AND UPDATES
None.

Boehringer Ingelheim
Page 14 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
5.
MILESTONES
Milestone
Planned Date
IRB/IEC approval
APR 2022
Start of data collection
APR 2022
End of data collection
APR2024
Study progress report 1
Not applicable
Topline analysis
After visit 2 of the LPI
Reg. in the EU PAS register
Not applicable
Final report of study results:
JUL 2024
6.
RATIONALE AND BACKGROUND
6.1
MEDICAL BACKGROUND
According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), Chronic 
Obstructive Pulmonary Disease (COPD) is a common, preventable, and treatable disease with 
an estimated global prevalence of almost 300 million in 2017 [I, II]. By 2030, it is predicted 
that COPD will be the fourth-leading cause of death worldwide [III]. COPD is particularly 
prevalent in smokers and ex-smokers, people aged ≥40 years, and men [IV]. Disease 
characteristics comprise persistent respiratory symptoms and airflow limitation, usually 
resulting from significant exposure to noxious particles or gases, like tobacco smoke, air 
pollution or other environmental exposures [II]. The inhalation of such noxious substances 
triggers an abnormal inflammatory response in the lung leading to increased mucus production, 
tissue remodeling, and connected with this, to a narrowing of the air passages in the lower 
respiratory tract. As a result, the pulmonary parenchyma is destroyed, and pulmonary 
emphysema is caused. Over time, there are further systemic consequences, such as myopathy, 
osteoporosis, cor pulmonale, and hypertension with severe restriction of physical functioning. 
Recurrent acute exacerbations (e.g., due to pulmonary infections) bring about a further 
deterioration in the condition of the lungs [V]. In COPD patients, physical activity is reduced 
early in disease progression, as of GOLD Stage 2 [VI]. More recent evidence from large 
placebo controlled clinical trials indicates that COPD patients are experiencing a steeper 
absolute decline in lung function with GOLD 2 airflow limitation than with GOLD 3 and 4 
[VII]. Those observations suggest the importance of early optimal treatment of the disease.
The main goal in COPD treatment is achievement of disease control and consequently, an 
improvement of health-related quality of life (HRQoL). Giving to the GOLD 2021 strategy 

Boehringer Ingelheim
Page 15 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
report, long-acting bronchodilators such as long-acting muscarinic antagonists and long-acting 
β2-agonists are the basis of maintenance therapy for patients with moderate-to-very severe 
COPD [II].
Beside the pharmacological compound, matching each patient with the most appropriate 
inhaler is important for an optimal inhaler technique and drug delivery [VIII-XIII]. These days,
numerous inhaler devices for maintenance treatment in COPD patients are available on the 
market, but each class of device has a different approach to inhalation and therefore, requires 
distinct handling techniques. However, the correct usage of the respective inhaler is a 
prerequisite for achievement of maximal clinical benefit. Unfortunately, inhalers are often not 
considered as an important part of the treatment [X]. Discordance especially with prescribed 
dry powder inhalers (DPIs) was seen in 40% of COPD patients, suggesting that many COPD 
patients do not generate adequate inspiratory force to overcome prescribed DPIs resistance 
during normal use [XIII]. Therefore, when using a DPI, COPD patients with suboptimal peak 
inspiratory flow rate (PIFR) may not achieve the greatest possible drug deposition and efficacy
[XIII]. Consequently, maximal clinic benefit might be unattainable for those patients. 
The Respimat®, an active soft-mist inhalation device, allows COPD patients to inhale without 
effort and can be used irrespective of the PIFR a patient can generate [XIV, XV]. It is well 
accepted by patients due to its easy inhalation and handling characteristics which is an 
important factor for treatment compliance [XVI, XVII, XVIII]. Additionally, Soft Mist™ 
Inhaler (SMIs) have a lower intrinsic resistance and do not require a high inspiratory flow rate 
for optimal drug delivery in comparison to DPIs [XIX]. 
6.2
DRUG PROFILE
Tiotropium bromide is the first once-daily, long-acting anticholinergic bronchodilator for the 
maintenance therapy of patients with COPD and is available in two formulations in many 
countries: an aqueous solution (5 μg) delivered via the Respimat® SMI [XX] and a dry powder 
(18 μg) delivered via the breath-actuated Spiriva® HandiHaler®
device (DPI, both 
formulations: Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim am Rhein, Germany)
[XXI].
Numerous controlled trials, including either or both formulations, have shown that tiotropium 
provides at least a 24-hour sustained improvement in airflow, reduced hyperinflation, and 
shortness of breath, as well as a reduced risk of exacerbations and associated hospitalizations, 
resulting in an increased HRQoL [XXII-XXVIII].
6.3
ASSESSMENT OF QUALITY OF LIFE
Various questionnaires on HRQoL are used to try assessing COPD patients’ health status and 
physical state. The Clinical COPD questionnaire (CCQ) has been developed and validated in 
the Netherlands especially for COPD patients by Jan Kocks et al. in 2006 [XXIX] to categorize 

Boehringer Ingelheim
Page 16 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
patients’ impairments generally and focus patients’ treatment on their specific needs. 
The CCQ is easy to administer, and it takes less than a few minutes to complete. CCQ is used 
to monitor the clinical control of COPD covering the last 7 days prior to request. It consists of 
10 questions, covering 3 domains: symptom domain (4 items [#’s 1,2,5,6]); functional status 
domain (4 items [#’s 7,8,9,10]) and mental status domain (2 items [#’s 3,4]). The questionnaire 
is responsive to intervention and has been translated and validated in over 140 languages 
[XXX]. In a head-to-head comparison of COPD Assessment Test (CAT) and CCQ the patients 
preferred the latter as it reflected their status better than CAT by giving more details on 
breathing problems which was more important for them than sleep or energy [XXX]. CCQ has 
been given maximum ranking in “COPD wellness tools” overview by the International Primary 
Care Respiratory Group (IPCRG) [XXXI]. The clinical CCQ is a well-established tool to 
evaluate COPD patients self-reported outcomes [XXIX, XXXII, XXXIII]]. A difference from 
-0.2 points corresponds to 50% of the minimal clinically important difference for a CCQ of -
0.4 points [XXIX, XXXII]. Patients with a worse CCQ (score of ≥2) are expected to have a 
CCQ score that is on average 0.2 points higher (i.e., worser health status) than patients with an 
acceptable CCQ score for moderate disease (score of <2) [XXXIV]. Thus, a change of -0.2 
points will be used in this NIS to explore whether there is an improvement in CCQ after 
switching the device without changing the pharmacological compound although the setting in 
this NIS is different from the validation studies.
6.4
SITUATION IN SWITZERLAND
In Switzerland, both devices, the Spiriva® Respimat® SMI as well as the Spiriva® HandiHaler®
DPI, are approved treatment options for COPD patients. Beside similar exacerbation and 
bronchodilator efficacy [XXIV, XXVIII], their safety and pharmacokinetic profiles are similar 
to each other [XXXV, XXXVI, XXXVII]. However, in Switzerland, life expectancy is one of 
the highest in Europe [XXXVIII] and therefore, it can be considered that mean age in Swiss 
COPD patients might be higher than in the other European countries. Thus, Swiss COPD 
patients might be faced with difficulties in preparation and handling of the device. The 
Respimat® device was developed to fulfil patients´ and physicians´ needs for an easy usability 
and might be an appropriate device in older patients who suffer from comorbidities correlated 
to impaired mobility such as Parkinson´s disease, arthritis/arthrosis, and rheumatism [XXXIX].
In those patients, it seems to be important to follow up the ability for correct usage of their 
device to ensure adequate COPD maintenance therapy. Since there are no other Tiotropium
devices (generic drugs) available on the Swiss market, COPD patients from Switzerland 
represent an ideal cohort to assess whether there is an improvement in clinical control of COPD 
when switching the patients from the DPI to the respective SMI without changing the active 
agent.

Boehringer Ingelheim
Page 17 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
6.5
RATIONALE
The current non-interventional study (NIS) aims to evaluate whether in a real-world COPD 
patient setting and by not altering the pharmacological compound the change from the Spiriva®
HandiHaler® to the Respimat® will lead to improvements in HRQoL including physical 
function, and dyspnea.
Based on the previous mentioned background, this NIS has been designed to assess whether 
changing COPD patients from a dry powder inhaler (HandiHaler®) to a soft mist inhaler 
(Respimat®), without changing the pharmacological compound, will lead to an improvement 
in HRQoL. Therapeutic success will be assessed at week 8 which is the mean time between 
two medical appointments in COPD patients. The well-established and commonly used CCQ 
will be used to assess changes in HRQoL in switching patients. 
 
 
 will be collected to characterize 
the population of COPD patients which is intended for a switch to the SMI device.

Boehringer Ingelheim
Page 18 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
7.
RESEARCH QUESTION AND OBJECTIVES
The objective of this non-interventional, observational study is to assess whether changing 
COPD patients from a dry powder inhaler (HandiHaler®) to a soft mist inhaler (Respimat®), 
without changing the pharmacological compound, will lead to an improvement in CCQ score*
and in the scores of the three subdomains: symptoms (4 items), functional state (4 items) and 
mental state (2 items) during a study period of approximately 8 weeks. Each of the 10 CCQ 
questions is scored by the patient on a 7-point scale between 0 and 6 at baseline and at the end 
of the observation after approximately 8 weeks. The sum of the scores divided by 10 gives the 
CCQ score, which measures the health and functional status. 
The functional state score is a calculation of the sum of the 4 items (#’s 7, 8, 9, 10) divided by 
4, the symptom score is calculation of the sum of the 4 items (#’s 1, 2, 5, 6) divided by 4 and 
the mental state score is a calculation of the sum of the 2 items (#’s 3, 4) divided by 2. More 
details, e.g., how to handle missing data, will be described in the statistical analysis plan.
CCQ values can be interpreted as: acceptable (CCQ < 1); acceptable for moderate disease (1 ≤ 
CCQ <2); instable-severe limited (2 ≤ CCQ < 3); very instable-very severe limited (CCQ ≥ 3) 
[XVI,XVII]. As a CCQ ≥ 2 is as well associated with an increased mortality [XXVIII], this 
value will be used as the cut-off for the current non-interventional study.
Our hypothesis is that patients with a worse CCQ (= high CCQ of ≥2) at baseline will benefit 
the most when changing from the DPI Spiriva® HandiHaler® to the SMI Spiriva® Respimat®.
Note: Patients will be included into the study independently of their CCQ at baseline.
*CQQ score means CCQ overall score, unless otherwise stated
Primary objective:
The primary objective of the NIS is to assess proportion of patients achieving a 0.2 points 
decrease in the CCQ score between baseline and after approximately 8 weeks of treatment) in 
patients with high CCQ baseline score (≥2).
Secondary objectives:
Secondary objectives of the NIS are the assessment of the proportion of patients achieving a
0.2 points decrease in the CCQ score between baseline and after approximately 8 weeks of 
treatment independently from CCQ baseline score, the mean change in CCQ score and in the 
three CCQ domains symptom, mental state, and functional state domain in all patients and in 
patients with high CCQ baseline score (≥ 2) between baseline and visit 2 (approximately at 
week 8 after visit 1), breathlessness based on mMRC score at baseline, visit 2 (approximately 
at week 8 after visit 1), and change in mMRC score between baseline and visit 2 (approximately 
at week 8 after visit 1), 

Boehringer Ingelheim
Page 19 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
 
 
 
 
 
 
 
Safety data of COPD patients switching from Spiriva® HandiHaler® to Spiriva® Respimat® will 
be collected descriptively and are not a separate objective of the NIS.
8.
RESEARCH METHODS
8.1
STUDY DESIGN
This is a national, multicenter, non-interventional, observational, cohort study based on newly 
collected data with an observational period of at least 8 weeks until switch or discontinuation 
of Spiriva® Respimat® treatment or up to 52 weeks after baseline visit whatever occurs first. 
This NIS is designed as single-arm study without a specific comparator in a parallel arm. All 
included patients must have been on treatment with Spiriva® HandiHaler® for at least 6 weeks 
prior to study inclusion. Therefore, patient could serve as their own control (baseline values) 
and a parallel arm being on Spiriva® HandiHaler® is not obligatory to address the primary 
objective of the NIS.
The study is non-interventional on the therapeutic strategy as the decision to switch the patient 
from Spiriva® HandiHaler® to Spiriva® Respimat® device is made by the treating physician 
prior to study inclusion due to patient´s individual needs. Patients will be treated within clinical 
routine practice and according to the current standard of care to assess the real-world situation 
in Swiss clinical practice. The patients included in the study will be followed for 1 year 
(approximately 52 weeks) after switching to the Respimat® device with no fixed study visit 
schedule. The treating physician will be asked to record data for study endpoint assessments in 
week 8 after baseline to assess therapeutic success of the switch to the Respimat® device.
Patients who discontinued Spiriva® Respimat® treatment or who were switched to another 
treatment will be asked to perform an end-of-treatment (EoT) visit (= follow-up visit).
This national study will be conducted as a multicenter study to collect information on current 
status, and characteristics of patients switching from HandiHaler® to Respimat® device from 

Boehringer Ingelheim
Page 20 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
various sites to achieve balanced data with regard to geographic distribution, type of clinical 
setting (e.g., academic versus community health centers), and prescriber specialty which are 
representative for the larger patient and prescriber community.
8.2
SETTING
8.2.1
Study sites
It is planned that data of approximately 225 patients from approximately 40 sites will be 
collected. Site selection will be performed to reflect routine COPD care to secure 
representativeness of the Swiss COPD population. As described in section study design,
achievement of balanced data regarding geographic distribution, type of clinical setting (e.g., 
academic versus community health centers), and prescriber specialty which are representative 
for the larger patient and prescriber community will be considered for site selection.
A log of all patients included into the study (i. e., having given informed consent form) will 
be maintained in the investigator´s site file at the investigational site irrespective of whether 
they have been switched or not.
8.2.2
Study population
Patients will be enrolled consecutively in the study. The decision to switch the patient from 
Spiriva® HandiHaler® to Spiriva® Respimat® will be made by the treating physician to the 
patient’s need and to the standard of best medical practice prior to the inclusion into the study.
Patients with COPD planned to be switched according to the respective SmPC and consenting 
to participate in the study are eligible. To avoid any selection bias, all eligible patients will be 
invited to participate in this study, in the order in which their eligibility is determined. A time 
window of 1 years is foreseen for recruitment of the patients. Patients will be treated within 
clinical routine practice and according to the current standard of care. Patients who discontinue 
from treatment before the visit at week 52 will be asked to complete an EoT visit.
Inclusion criteria:
Patients can be included if all following criteria are met:
!
Participants ≥40 years of age at baseline visit
!
Patients with confirmed diagnosis of COPD* 
!
Patients who have been on Spiriva® HandiHaler® for ≥ 6 weeks at baseline visit
!
Patients for whom a switch from Spiriva® HandiHaler® to Spiriva® Respimat® was 
planned prior to study inclusion. If additional inhalative COPD drugs (AICDs) are 

Boehringer Ingelheim
Page 21 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
used: AICD treatment must have been stable for at least 6 weeks before study 
inclusion
!
Signed written informed consent form to participation
*Confirmed by spirometry: FEV1/FVC <0.7 (last available FEV1 and FVC including % predicted)
Exclusion criteria:
!
Patients who have contraindications to Spiriva® Respimat® according to the current 
prescribing information label/ summary of product characteristics (SmPC)
!
Patients who have signs of a current, acute respiratory tract infection 2 weeks prior 
visit 1
!
Patients for whom further follow-up will not be possible at the enrolling site during the 
planned observational period (of approximately 8 weeks)
!
Patients with confirmed diagnosis of only asthma
!
Patients who had > 1 moderate to severe exacerbation(s) within the last 6 weeks prior 
to study inclusion
!
Patients who are pregnant or breastfeeding
!
Patients participating in an ongoing interventional study
8.2.3
Study visits
Eligible patients who sign the informed consent form (ICF) will undergo the baseline visit.
Patients will be followed up over an observational period of approximately 52 weeks after 
baseline visit (visit 1). During the observational period, 2 further visits will be performed. Visit 
2 will be approximately in week 8, visit 3 will be performed in week 52 as follow-up visit. 
Patients who discontinue from the treatment before the visit at week 52 will be asked to 
complete an EoT visit.
Figure 8.2.3:1 provides a study flow chart. Table 8.2.3:1 gives an overview about the 
parameters collected during the study.

Boehringer Ingelheim
Page 25 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
2. Emergence of any effectiveness/safety information that could significantly affect 
continuation of the study, or any other administrative reasons, i.e., lack of recruitment
3. Violation of Good Pharmacoepidemiology Practice (GPP), the study protocol, or the 
contract by a study site, investigator, or research collaborator, disturbing the appropriate 
conduct of the study
The investigator/the study site/research collaborator will be reimbursed for reasonable 
expenses incurred in case of study/site termination (except in case of the third reason).
Patients who discontinue from the study before the visit at week 52 will be asked to complete 
an EoT visit.
8.3
VARIABLES
The following parameters will be collected and assessed at visit 1 and/ or visit 2 and/or visit 3:
!
Patient demographics (age, gender, height & weight)
!
Concomitant diseases / comorbidities (relevant comorbidities such as cardiovascular 
diseases, diabetes mellitus type 2, depression and diseases affecting the preparing and 
handling of the Respimat® device)
!
Date of confirmed COPD diagnosis [year]
!
Start with inhalative bronchodilators for COPD treatment [year]
!
Concomitant COPD medication including AICDs (dosage, date of onset) up to 6 weeks 
before baseline visit
!
Changes in COPD treatment scheme (date, reason(s))
!
Last available FEV1 (value and date measured) and FVC including % predicted (value 
and date measured, closest to the date of baseline visit)
!
Reported moderate-to-severe exacerbations based on medical history in the last 12 
months and exacerbations leading to hospitalization in the last 12 months
!
Smoking history (number of pack years) and status (never, former, current)
!
Assessment of the severity of breathlessness based on the mMRC questionnaire
!
GOLD spirometric classifications (1, 2, 3, 4) and GOLD patient groups (A, B, C, D) 
based on GOLD 2022
!
Clinical control based on CCQ score and CCQ symptom, mental state, and functional 
state domain scores

Boehringer Ingelheim
Page 27 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
!
Time frame: between baseline (= visit 1) to approximately 8 weeks after switching from 
Spiriva® HandiHaler® to Spiriva® Respimat® (= visit 2)
!
Safety Issue: No
8.3.2.2
Secondary outcomes
!
Outcome type: secondary
!
Outcome name: “Improvement” defined as 0.2 points decrease in the CCQ score 
between baseline and visit 2 in patients independently from CCQ baseline score 
!
Time frame: between baseline (= visit 1) to approximately 8 weeks after switching from 
Spiriva® HandiHaler® to Spiriva® Respimat® (= visit 2)
!
Safety Issue: No
!
Outcome type: secondary
!
Outcome name: “Changes in clinical control” [XXXIII] defined as mean change in 
the in CCQ score and in the scores of the 3 CCQ subdomains symptom (items 1, 2, 5, 
6 of the CCQ), mental state (items 3, 4 of the CCQ), and functional state domain (CCQ-
4, items 7, 8, 9 and 10 of the CCQ), in all patients independently from CCQ baseline 
score 
!
Time frame: 
o
between baseline (= visit 1) and approximately 8 weeks after switching from 
Spiriva® HandiHaler® to Spiriva® Respimat® (= visit 2)
!
Safety Issue: No
!
Outcome type: secondary
!
Outcome name: “Changes in clinical control” defined as mean change in the in CCQ 
score and in the scores of the 3 CCQ subdomains symptom (items 1, 2, 5, 6 of the CCQ), 
mental state (items 3, 4 of the CCQ), and functional state domain (CCQ-4, items 7, 8, 
9 and 10 of the CCQ), in patients with high CCQ baseline score (≥2)
!
Time frame: 
o
between baseline (= visit 1) and approximately 8 weeks after switching from 
Spiriva® HandiHaler® to Spiriva® Respimat® (= visit 2)
!
Safety Issue: No

Boehringer Ingelheim
Page 28 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
!
Outcome type: secondary
!
Outcome name: “Breathlessness of the patients” assessed by the mMRC scale 
completed by all patients
!
Time frame: Assessment will be performed at baseline (= visit 1), approximately 8 
weeks after switching from Spiriva® HandiHaler® to Spiriva® Respimat® (= visit 2)
!
Safety Issue: No
!
Outcome type: secondary
!
Outcome name: “Changes in breathlessness of the patients” assessed by the mMRC 
scale completed by all patients
o
Time frame: between baseline (= visit 1) to approximately 8 weeks after 
switching from Spiriva® HandiHaler® to Spiriva® Respimat® (= visit 2)
!
Safety Issue: No

Boehringer Ingelheim
Page 29 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
8.3.3
Covariates
Not applicable.
8.4
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 

Boehringer Ingelheim
Page 30 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
demographics, smoking history, collection of previous COPD medication, concomitant 
diseases, and previous exacerbation history.
All patients will be enrolled consecutively. The study physician has the ultimate responsibility 
for the collection and reporting of all clinical and patient data through the case report forms 
(CRFs) as well as ensuring that they are accurate and complete.
Start of treatment will be assessed by a yes/no question at visit 2. If treatment was started, date 
of treatment onset will be asked by the physician.
The CCQ comprises 10 items. Each question can be scored by patients on a 7-point scale 
between 0 and 6. The sum of the scores divided by 10 gives the CCQ score. For the functional 
status calculation, the sum of the 4 items (# 7, 8, 9, 10) is divided by 4, for the symptom domain 
the sum of the 4 items (# 1, 2, 5, 6) is divided by 4, and for the mental state domain the sum of 
the 2 items (# 3, 4) is divided by 2.   This questionnaire will be filled out by the patient and 
entered in the database by trained personnel from the Clinical Research Organization. Patients 
will be asked to complete the CCQ to evaluate their clinical control before, approximately 8 
weeks after treatment with Spiriva® Respimat®.
 
 
The modified Medical Research Council (mMRC) scale will be used to assess the 
breathlessness state of the patient before switching the device, and approximately 8 weeks after 
device switch. The mMRC stage (0 to 4) collected from the patient as well as the exacerbation 
history will be used to calculate the GOLD patient group (B, C, or D) in the CRF.
 
 
8.5
STUDY SIZE
It is expected that half of the patients included will have CCQ score of ≥2 (high CCQ).
Primary endpoint: Assuming 40% of high CCQ score patients have a 0.2 improvement in 
CCQ score from baseline at 8 weeks on treatment, then with a sample size of 100, the 95% CI 
for the response rate will be: (0.304, 0.496).

Boehringer Ingelheim
Page 31 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Secondary endpoint: Assuming 30% of all patients have a 0.2 improvement in CCQ score 
from baseline at 8 weeks on treatment, then with a total sample size of 200, the 95% CI for the 
response rate will be (0.236, 0,364).   
With a dropout rate of 10%, a total of about 225 patients will be needed.
Sample size assumes that Respimat® is better compared to HandiHaler® and patients will 
improve 
their 
CCQ 
scores 
once 
switched 
to 
Respimat®.
The 
sample 
size 
calculation/justification can only provide a rough estimate of the statistical power in such an 
exploratory real-world setting. Recruitment will continue until the minimum sample size is 
achieved.
8.6
DATA MANAGEMENT
The data management plan is summarized below. Full details of the data management plan are 
documented in a separate NIS-Data Management and Review Plan (NIS-DMRP).
A data management plan (DMP) will be created to describe all functions, processes, and 
specifications for data collection, cleaning, and validation. Boehringer-Ingelheim will check 
CRFs for correctness at date of collection. The CRFs will be sent to the vendor or Clinical 
Research Organization (CRO) and will be computed by trained staff from the vendor/CRO
including programmable edits to obtain immediate feedback if data are missing (also negative 
answers, unknown), out of range, illogical or potentially erroneous. These rules may 
encompass simple checks such as range validation or presence/absence of data. 
Concurrent manual data review may be performed based on parameters dictated by the DMP. 
Ad hoc queries to the sites may be generated and followed up for resolution. A source data 
quality audit may be initiated to ensure that the data in the database is accurate. Source data 
verification (SDV) will be performed at sites identified by a risk-based approach as needed.
The database will be housed in a physically and logically secure computer system maintained 
in accordance with a written security policy. The system will meet the standards of the 
International Committee on Harmonization guideline E6R1 regarding electronic study data 
handling and the safety requirements of the FDA (US Food & Drug Administration) concerning 
systems for the data acquisition of clinical studies in accordance with "Title 21 Code of Federal 
Regulations (21 CFR Part 11): Electronic Records; Electronic Signatures”. Patient 
confidentiality will be strictly maintained.
8.7
DATA ANALYSIS
This section provides specifications for the preparation of the final statistical analysis plan 
(SAP), which will be issued prior to database lock. Any differences compared to this statistical 
section should be identified and documented in the final SAP.

Boehringer Ingelheim
Page 32 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
The following data handling conventions will be followed:
!
Baseline assessments are those that were completed at the baseline visit (visit 1).
!
The following analysis time windows will be utilized in the analysis: 
o
Assessments scheduled to be done:
o
Approximately 8 weeks after treatment start (= visit 2): 8 weeks ± 2 weeks
o
Approximately 52 weeks after treatment start (= visit 3, follow-up visit): 52 
weeks ± 4 weeks
o
If patients discontinue or switched from Spiriva® Respimat® treatment, they will 
be asked to perform an EoT visit (= visit 3) nearby to the date of stopping 
Spiriva® Respimat® treatment
No formal hypothesis testing will be performed since this is a self-controlled study. The 
analysis of the data will be of descriptive and explorative character. Variables will be 
summarized using appropriate statistical methods
The statistical characteristics presented in the end-of-text tables will be N / mean / SD / min / 
median / max for continuous variables. Tabulations of relative and absolute frequencies will 
be presented for categorical variables. Proportions and 95% CI will be given when appropriate.
At baseline, the following data will be collected as available in routine clinical practice:
Patient demographics and medical history:
!
Patient demographics (gender, age, height, weight) 
!
Comorbidities (main diagnosis and concurrent diagnosis according to 
MedDRA, version valid at the time of database closure)
!
COPD related concomitant medication (according to the WHO classification, 
version valid at the time of database closure)
!
Details of treatment with inhaled respiratory agents before the study 
!
History of smoking 
!
GOLD spirometric classifications (1, 2, 3, 4) and GOLD patient groups (A, B, 
C, D), date of confirmed COPD diagnosis
Data collection at baseline:
!
Breathlessness based on mMRC score at visit 1; secondary endpoint

Boehringer Ingelheim
Page 33 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
!
CCQ score and CCQ symptom, mental state, and functional state scores; 
secondary endpoint
 
 
The following data will be collected as available in routine clinical practice at visit 2:
!
Assessment of treatment start with date of onset, if applicable
!
Breathlessness based on mMRC score, secondary endpoint
!
CCQ score and CCQ symptom, mental state, and functional state scores; 
secondary endpoint
 
 
 
 
 
!
Reasons for ending treatment during the observational period 
!
Details of treatment continuation / discontinuation
!
Adverse Drug Reactions (ADR & SADR), fatal AEs, pregnancies (descriptive 
collection, no endpoint of the current study).
The following data will be collected as available in routine clinical practice at visit 3 (follow-
up visit)/EoT vis:
!
Details of treatment with respiratory agents during the study and changes (if 
applicable)
!
Reasons for ending treatment during the observational period 
!
Details of treatment continuation / discontinuation

Boehringer Ingelheim
Page 34 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
!
Adverse Drug Reactions (ADR & SADR), fatal AEs, pregnancies (descriptive 
collection, no endpoint of the current study).
All statistical analyses will be pre-specified in the SAP. Statistical analysis will be performed 
by using SAS Version 9.4 or higher.
8.7.1
Main analysis
For the primary outcome, the proportion of patients (%) with a CCQ decrease of at least 0.2 
points and a high CCQ baseline score of ≥ 2 will be presented together with the 95% confidence 
interval.

Boehringer Ingelheim
Page 35 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
8.7.3
Safety Analysis
All adverse events and adverse drug reactions collected per study protocol will be included 
and summarized in the in the final study report according to local requirements.
8.8
QUALITY CONTROL
All details are documented in the NIS-DMRP.
Every physician shall allow an authorized personal or staff from Boehringer Ingelheim 
(Schweiz) GmbH to make regular visits to monitor the study. The monitor will either use 
interviewing techniques for monitoring or perform source data verification. The CRF entries 
will be compared with the data given in the patient files. Therefore, in order to perform an 
extend source data verification the monitor shall have access to the patient files. Furthermore, 
the CRFs will be controlled for completeness and accuracy.
Visiting of the study and laboratory facilities will likewise be allowed. 
During data entry, incomplete or non-valid data will be identified, and data clarification 
requests will be sent to the physician.
Completed CRFs should be returned at the end of each month to the responsible study manager 
to accelerate the process of data entry and evaluation. In case of return after more than 3 months 
after completion acceptance of the CRF cannot be ensured. The physician/investigator or a 
qualified designee will be responsible for recording and verifying the accuracy and correctness 
of patient data within the CRF via signature. 
Data will be entered and verified for accuracy by trained personal from Boehringer Ingelheim 
(Schweiz) GmbH / CRO /vendor according to the data entry manual. A sample of 10% of all 
CRFs will be double-checked by an independent person. Data will be checked during patient 
enrolment for consistency, plausibility, and out-of-range values by responsible Data 
Management staff. These checks will be performed through programs and range checks within 
the EDC system.
8.9
LIMITATIONS OF THE RESEARCH METHODS
The intention of this NIS is to collect data on the changes in HRQoL in patients with COPD 
after switching from Spiriva® HandiHaler® to Spiriva® Respimat® in a real-world setting.
A NIS appears the most suitable instrument for obtaining information about the use of 
medicines in everyday therapeutic practice and thus for investigating future questions in 
everyday therapeutic practice.

Boehringer Ingelheim
Page 36 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Consecutive enrolment will be employed to minimize selection bias. The entry criteria are non-
restrictive which will permit the enrolment of a broad patient population. The choice of 
treatment is at the discretion of the investigator.
Selection bias could occur at the site level and the patient level. To minimize the site level 
selection bias, the goal is to have participating centers that have access to all available treatment 
options which are approved for use in Switzerland for the targeted COPD patients. To minimize 
selection bias at the patient level, consecutive enrolment is performed. Information bias will be 
minimized using standard CRF, questionnaire and physicians’ training on the study protocol.
 
 
8.10
OTHER ASPECTS
8.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Board (IRBs) / Independent Ethics Committee 
(IECs) or by regulatory authorities. The quality assurance auditor will have access to all 
medical records, the investigator’s study-related files and correspondence, and the informed 
consent documentation of this study.
8.10.2
Study records
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, in paper 
or electronic Form.
8.10.2.1
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 reported on the CRFs 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 CRFs, the following data need to be derived from source documents:
!
Patient identification (gender, date of birth)
!
Patient participation in the study (substance, study number, patient 
number, date patient was informed)

Boehringer Ingelheim
Page 37 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
!
Dates of patient’s visits, including prescription of study medication
!
Medical history (including study indication and concomitant diseases, if 
applicable)
!
COPD medication history
!
Adverse events and outcome events (onset date (mandatory), and end 
date (if available))
!
Serious adverse events (SAEs) (onset date (mandatory), and end date (if 
available))
!
Originals or copies of laboratory results (in validated electronic format, 
if available)
!
Conclusion of patient’s participation in the study
!
Questionnaires and surveys completed by the patient
8.10.2.2
Direct access to source data and documents
The investigator/institution will permit study-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes and copies of laboratory and medical test results 
must be available at all times for review by the sponsor’s clinical study monitor, auditor and 
inspection by health authorities (e.g., Swissmedic). BI study staff and auditor may review all 
CRFs and written informed consents. The accuracy of the data will be verified by reviewing 
the documents described in Section 8.10.2.1. 
8.10.3
Completion of study
The IEC/competent authority in Switzerland needs to be notified about the end of the study
(last patient/patient out, unless specified differently in Section 9.1) or early termination of the 
study. 
8.10.4
Protocol deviations
Protocol deviations will be specified in the SAP. Patients with protocol deviations will be 
excluded from the full analysis set.
9.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, Guidelines for Good Pharmacoepidemiology Practice (GPP), and the 
relevant BI Standard Operating Procedures (SOPs). Standard medical care (prophylactic, 

Boehringer Ingelheim
Page 38 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
diagnostic and therapeutic procedures) remains 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.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File).
9.1
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.
Prior to patient participation in the study, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent, and any additional patient-
information form retained by the investigator as part of the study records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of disclosure 
must also be explained to the patient. The patient must be informed that his / her medical 
records may be examined by authorized monitors (CML/CRA) or Quality Medicine auditors 
appointed by Boehringer Ingelheim, by appropriate IRB / IEC members, and by inspectors 
from regulatory authorities.
9.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained because 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 because of the study need to be 
available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities i.e., the CA.

Boehringer Ingelheim
Page 39 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
10.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
10.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether, or not considered related to the 
medicinal product. 
Adverse drug reaction
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is 
noxious and unintended. Response in this context means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility. Adverse reactions 
may arise from use of the product within or outside the terms of the marketing authorization or 
from occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse, and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which
!
results in death, 
!
is life-threatening, 
!
requires in-patient hospitalization, or
!
prolongation of existing hospitalization, 
!
results in persistent or significant disability or incapacity, or 
!
is a congenital anomaly/birth defect 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 

Boehringer Ingelheim
Page 40 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
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.

Boehringer Ingelheim
Page 41 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
10.2
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 investigator carefully assesses whether an AE constitutes an ADR using the information 
below. 
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse reaction, 
in contrast to an adverse event, is characterized by the fact that a causal relationship between a 
medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases, and relevant history. 
Arguments that may suggest a reasonable causal relationship could be:
!
The event is consistent with the known pharmacology of the drug 
!
The event is known to be caused by or attributed to the drug class
!
A plausible time to onset of the event relative to the time of drug exposure
!
Evidence that the event is reproducible when the drug is re-introduced
!
No medically sound alternative etiologies that could explain the event (e.g.,
preexisting, or concomitant diseases, or co-medications)
!
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g., Stevens-Johnson syndrome)
!
An indication of dose-response (i.e., greater effect size if the dose is increased, 
smaller effect size if dose is diminished)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
!
No plausible time to onset of the event relative to the time of drug exposure is 
evident (e.g., pre-treatment cases, diagnosis of cancer or chronic disease within 
days/weeks of drug administration; an allergic reaction weeks after discontinuation 
of the drug concerned)

Boehringer Ingelheim
Page 42 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
!
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).
o
Of note, this criterion may not be applicable to events whose time course is 
prolonged despite removing the original trigger.
!
Additional arguments amongst those stated before, like alternative explanation 
(e.g., situations where other drugs or underlying diseases appear to provide a more 
likely explanation for the observed event than the drug concerned).
!
Disappearance of the event even though the study drug treatment continues or 
remains unchanged.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Pregnancy:
In rare cases, pregnancy might occur in a NIS. Once a patient has been enrolled in the study 
and has taken study medication, the investigator must report any drug exposure during 
pregnancy in a study participant within 7 days by means of Part A of the Pregnancy Monitoring 
Form to the sponsor’s unique entry point. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form (Part B). 
The ISF will contain the Pregnancy Monitoring Form (Part A and B). As pregnancy itself is 
not to be reported as an AE, in the absence of an accompanying serious ADR and/or AESI, 
only the Pregnancy Monitoring Form and not the NIS AE form is to be completed. If there is 
a serious ADR and/or AESI associated with the pregnancy a NIS AE form must be completed 
in addition.
The following must be reported on the NIS AE Form and/or Pregnancy Monitoring Form for 
Studies in case such AE/drug exposure during pregnancy information is identified during the 
review of the individual records:

Boehringer Ingelheim
Page 43 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
All serious ADRs associated with the 
Spiriva® Respimat®
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to Spiriva® Respimat®
immediately within 24 hours
All protocol specified AESIs Spiriva®
Respimat®
immediately within 24 hours
All non-serious ADRs associated with the 
Spiriva® Respimat®
7 calendar days
Drug exposure during pregnancy
7 calendar days
The same timelines apply if follow-up information becomes available for the respective events. 
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 CRF from signing the informed 
consent onwards until the end of the study: 
!
all adverse drug reactions (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. 
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate CRF pages and the (S)AE NIS form.
Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other than the 
Spiriva® 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.

Boehringer Ingelheim
Page 44 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Expedited Reporting of AEs and Drug Exposure during Pregnancy to BI Pharmacovigilance
The following must be reported by the investigator on the NIS AE form and/or Pregnancy 
Monitoring Form from signing the informed consent onwards until the end of the study and 
provide to BI unique entry point: 
Type of Report
Timeline
All serious ADRs associated with the 
Spiriva® Respimat®
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to Spiriva® Respimat®
immediately within 24 hours
All protocol specified AESIs Spiriva®
Respimat®
Immediately within 24 hours
All non-serious ADRs associated with the 
Spiriva® Respimat®
7 calendar days
Drug exposure during pregnancy
7 calendar days
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor upfront via telephone. 
This does not replace the requirement to complete and fax the NIS AE form.
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate CRF page and the NIS AE form.
10.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the Marketing Authorization 
Holder (MAH) according to local and international regulatory requirements.
11.
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.

Boehringer Ingelheim
Page 45 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
12.
REFERENCES
I
GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national 
incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and 
territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018 
Nov; 392(10159):1789-1858. 
II
Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, 
management, and prevention of chronic obstructive pulmonary disease (updated 2021). Available at: 
http://goldcopd.org/gold-reports/ (access date: 06 January 2022).
III
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS 
Med. 2006 Nov; 3(11):e442.
IV
Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: 
systematic review and meta-analysis. Eur Respir J. 2006 Sep;28(3):523-32.
V
from: Herold G et al.: Innere Medizin 2012; S. 343ff
VI
Troosters T, Sciurba F, Battaglia S, Langer D, Valluri SR, Martino L et al. Physical inactivity in patients 
with COPD, a controlled multi-center pilot-study. Respir Med. 2010 Jul; 104(7): 1005 – 1011.
VII
Tantucci C, Modina D. Lung function decline in COPD. Int J Chron Obstruct Pulmon Dis. 2012; 7:95-
9.
VIII
Capstick TG & Clifton IJ. Inhaler technique and training in people with chronic obstructive pulmonary 
disease and asthma. Expert Rev Respir Med 2012; 6:91–103.
IX
Darbà J, Ramírez G, Sicras A, Francoli P, Torvinen S, Sánchez-de la Rosa R. The importance of inhaler 
devices: the choice of inhaler device may lead to suboptimal adherence in COPD patients. Int J Chron 
Obstruct Pulmon Dis. 2015 Oct 29; 10:2335-45. 
X
Hanania NA, Braman S, Adams SG, Adewuya R, Ari A, Brooks J, Mahler DA, Ohar JA, Peters J, Sanjar 
S. The Role of Inhalation Delivery Devices in COPD: Perspectives of Patients and Health Care 
Providers. Chronic Obstr Pulm Dis. 2018 Apr 1;5(2):111-123. Usmani O. Treating the small airways. 
Respiration 2012; 84:441–453.
XI
Usmani O, et al. Choosing an appropriate inhaler device for the treatment of adults with asthma or 
COPD. Guidelines.co.uk 2017. Available at: https://www.guidelines.co.uk/respiratory/inhaler-choice-
guideline/455503.article (access date: 06 January 2022).
XII
Usmani O. Choosing the right inhaler for your asthma or COPD patient. Ther Clin Risk Manag 2019; 
15:461–472.
XIII
Ghosh S, Pleasants RA, Ohar JA, Donohue JF, Drummond MB. Prevalence and factors associated with 
suboptimal peak inspiratory flow rates in COPD. Int J Chron Obstruct Pulmon Dis. 2019 Mar 1; 14:585-
595.
XIV
Ciciliani AM, Langguth P, Wachtel H. In vitro dose comparison of Respimat® inhaler with dry powder 
inhalers for COPD maintenance therapy. Int J Chron Obstruct Pulmon Dis. 2017 May; 12:1565-1577.
XV
Mahler DA, Ludwig-Sengpiel A, Ferguson GT, de la Hoz A, Ritz J, Shaikh A, Watz H. TRONARTO: 
A Randomized, Placebo-Controlled Study of Tiotropium/Olodaterol Delivered via Soft Mist Inhaler in 
COPD Patients Stratified by Peak Inspiratory Flow. Int J Chron Obstruct Pulmon Dis. 2021 Aug; 
16:2455-2465.

Boehringer Ingelheim
Page 46 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
XVI
Hodder R, Price D. Patient preferences for inhaler devices in chronic obstructive pulmonary disease: 
experience with Respimat Soft Mist inhaler. Int J Chron Obstruct Pulmon Dis. 2009; 4:381-390. 
XVII
 
 
XVIII
 
 
XIX
Baloira A, Abad A, Fuster A, García Rivero JL, García-Sidro P, Márquez-Martín E, Palop M, Soler N, 
Velasco JL, González-Torralba F. Lung Deposition and Inspiratory Flow Rate in Patients with Chronic 
Obstructive Pulmonary Disease Using Different Inhalation Devices: A Systematic Literature Review 
and Expert Opinion. Int J Chron Obstruct Pulmon Dis. 2021 Apr; 16:1021-1033.
XX
Spiolto® Respimat® Summary of Product Characteristics. Version Dec 2018 Available at: 
https://www medicines.org.uk/emc/medicine/30495#gref Version Dec 2020 (access date: 06 January 
2022)
XXI
Spiriva® HandiHaler® Summary of Product Characteristics. Version Dec 2018 Available at:
https://www medicines.org.uk/emc/medicine/10039#gref Version Jan 2019 (access date: 06 January 
2022)
XXII
Maltais F, Hamilton A, Marciniuk D, Hernandez P, Sciurba FC, Richter K, Kesten S, O'Donnell D. 
Improvements in symptom-limited exercise performance over 8 h with once-daily tiotropium in patients 
with COPD. Chest. 2005 Sep; 128(3):1168-78.
XXIII
Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M; UPLIFT Study 
Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 
2008 Oct; 359(15):1543-54.
XXIV
van Noord JA, Cornelissen PJ, Aumann JL, Platz J, Mueller A, Fogarty C. The efficacy of tiotropium 
administered via Respimat Soft Mist Inhaler or HandiHaler in COPD patients. Respir Med. 
2009;103(1):22–9.
XXV
Bateman ED, Tashkin D, Siafakas N, Dahl R, Towse L, Massey D, Pavia D, Zhong NS. A one-year trial 
of tiotropium Respimat plus usual therapy in COPD patients. Respir Med. 2010 Oct; 104(10):1460-72. 
XXVI
Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Mölken MP, Beeh KM, Rabe KF, Fabbri 
LM; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of 
COPD. N Engl J Med. 2011 Mar; 364(12):1093-1103.
XXVII
Cooper CB, Celli BR, Jardim JR, Wise RA, Legg D, Guo J, Kesten S. Treadmill endurance during 2-
year treatment with tiotropium in patients with COPD: a randomized trial. Chest. 2013 Aug; 144(2):490-
497.
XXVIII
Wise R, Calverley PM, Dahl R, Dusser D, Metzdorf N, Müller A, Fowler A, Anzueto A. Safety and 
efficacy of tiotropium Respimat versus HandiHaler in patients naive to treatment with inhaled 
anticholinergics: a post hoc analysis of the TIOSPIR trial. NPJ Prim Care Respir Med. 2015 Nov; 
25:15067.
XXIX
Kocks JW, Tuinenga MG, Uil SM, van den Berg JW, Ståhl E, van der Molen T. Health status 
measurement in COPD: the minimal clinically important difference of the clinical COPD questionnaire. 
Respir Res. 2006 Apr; 7(1):62.

Boehringer Ingelheim
Page 47 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
XXX
Tsiligianni IG, van der Molen T, Moraitaki D, Lopez I, Kocks JW, Karagiannis K, Siafakas N, Tzanakis 
N. Assessing health status in COPD. A head-to-head comparison between the COPD assessment test 
(CAT) and the clinical COPD questionnaire (CCQ). BMC Pulm Med. 2012 May; 12:20
XXXI
Cave AJ, Atkinson L, Tsiligianni IG, Kaplan AG. Assessment of COPD wellness tools for use in primary 
care: an IPCRG initiative. Int J Chron Obstruct Pulmon Dis. 2012; 7:447-56.
XXXII
Kocks JW, Kerstjens HA, Snijders SL, de Vos B, Biermann JJ, van Hengel P, Strijbos JH, Bosveld HE, 
van der Molen T. Health status in routine clinical practice: validity of the clinical COPD questionnaire 
at the individual patient level. Health Qual Life Outcomes. 2010 Nov; 8:135. 
XXXIII
van der Molen T, Willemse BW, Schokker S, ten Hacken NH, Postma DS, Juniper EF. Development, 
validity and responsiveness of the Clinical COPD Questionnaire. Health Qual Life Outcomes. 2003 Apr; 
1:13. doi: 10.1186/1477-7525-1-13.
XXXIV
Leving M, Wouters H, de la Hoz A, Bosnic-Anticevich S, Dekhuijzen R, Gardev A et al. Impact of PIF, 
Inhalation Technique and Medication Adherence on Health Status and Exacerbations in COPD: Protocol 
of a Real-World Observational Study (PIFotal COPD Study). Pulm Ther. 2021 Dec; 7(2):591-606.
XXXV
Caillaud D, Le Merre C, Martinat Y, Aguilaniu B, Pavia D. A dose-ranging study of tiotropium delivered 
via Respimat Soft Mist Inhaler or HandiHaler in COPD patients. Int J Chron Obstruct Pulmon Dis. 
2007; 2(4):559–65.
XXXVI
Ichinose M, Fujimoto T, Fukuchi Y. Tiotropium 5 lg via Respimat and 18 lg via HandiHaler; efficacy 
and safety in Japanese COPD patients. Respir Med. 2010; 104(2):228–36.
XXXVII
Hohlfeld JM, Sharma A, van Noord JA, et al. Pharmacokinetics and pharmacodynamics of tiotropium 
solution and tiotropium powder in chronic obstructive pulmonary disease. J Clin Pharmacol. 2014; 
54(4):405–14.
XXXVIII
De Pietro C, Camenzind P, Sturny I, Crivelli L, Edwards-Garavoglia S, Spranger A, Wittenbecher F, 
Quentin W. Switzerland: Health System Review. Health Syst Transit. 2015;17(4):1-288, xix.
XXXIX
Tschacher A, Cadus C, Schildge S, Diedrich JP, Chhajed PN, Leuppi-Taegtmeyer AB, Leuppi JD. 
Switching COPD patients from the disposable to the new reusable Respimat soft mist inhaler: a real-
world study from Switzerland. Curr Med Res Opin. 2021 Nov;37(11):2019-2033.

Boehringer Ingelheim
Page 48 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 50 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
3. Clinical COPD Questionnaire

Boehringer Ingelheim
Page 51 of 51
Non-Interventional Study (NIS) Protocol
BI Study No.: 0205-0549                                                                                 c38251083-01
Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020

 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
F

FOLQLFDOWULDOSURWRFROYHUVLRQ
6ZLWFKLQJ&23'3DWLHQWVIURP6SLULYD+DQGL+DOHUPDLQWHQDQFHWKHUDS\WR
6SLULYD5HVSLPDWDQRQ,QWHUYHQWLRQDO5HDOZRUOGFOLQLF$ORX7FRPH
DVV(VVPHQW1,63,5$7(
$SSURYDO&OLQLFDO7ULDO/HDGHU
0DU&(7
$SSURYDO7HDP0HPEHU0HGLFLQH
0DU&(7
$SSURYDO7HDP0HPEHU'UXJ
6DIHW\
0DU&(7
$SSURYDO2QEHKDOIRI
RU
RU
0DU&(7
$SSURYDO
0DU&(7
$SSURYDO%LRVWDWLVWLFV
0DU&(7

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