A Real-world Non-interventional Study to Assess Patient Satisfaction With and Preference for Re-usable Respimat Soft Mist Inhaler in Patients With Chronic Obstructive Pulmonary Disease.
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
TITLE PAGE
PAGE
Non-interventional Study Protocol
Document Number:
c28180323-01
BI Study Number:
1237-0097
BI Investigational
Product(s):
Re-usable Respimat® Soft MistTM inhaler
Title:
A real-world non-interventional study to assess patient 
satisfaction with and preference for re-usable Respimat 
Soft Mist inhaler in patients with chronic obstructive 
pulmonary disease.
Brief lay title
Re-usable Respimat® Soft MistTM inhaler study
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
N/A
PASS:
No
EU PAS register 
number:
Study not registered
Active substance:
(1) Tiotropium; (2) Olodaterol; and (3) Tiotropium /
Olodaterol
Medicinal product:
Re-usable (1) Spiriva® Respimat® 2.5 microgram, inhalation 
solution; (2) Striverdi® Respimat® 2.5 microgram, 
inhalation solution; and (3) Spiolto® Respimat® 2.5 
microgram / 2.5 microgram, inhalation solution
Product reference:
(1) Spiriva® Respimat®: NL/H/0718/001; (2) Striverdi®
Respimat®: NL/H/2498/001; and (3) Spiolto® Respimat®: 
NL/H/3157/001
Procedure number:
N/A
Marketing 
authorisation 
holder(s):
Study Sponsor
Joint PASS:
No
Research question and 
objectives:
The overall aim of this study is to assess patient 
satisfaction with inhaler attributes of the re-usable 
Respimat® Soft MistTM Inhaler (SMI) in adult patients 

Boehringer Ingelheim
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Non-interventional Study Protocol
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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
with chronic obstructive pulmonary disease (COPD), 
including patients who are Respimat SMI-experienced 
and Respimat SMI-naïve. This study also aims to examine 
patient preference for the re-usable Respimat SMI 
compared to the disposable Respimat SMI in Respimat 
SMI-experienced patients switching from a disposable to 
a re-usable Respimat SMI product at study entry.
Primary Objective: 
The primary objective of the study is to assess patient 
satisfaction with the re-usable Respimat SMI, assessing 
the mean total score of the validated Patient Satisfaction 
and Preference Questionnaire (PASAPQ) at study end.
Secondary Objectives:
For all patients
1. To examine the individual domains of the PASAPQ: 
total performance score, total convenience score, the 
overall satisfaction question and the question on 
willingness to continue with inhaler at study end
2. To examine ease of handling of the re-usable 
Respimat SMI at study end
Additionally, for Respimat SMI-experienced patients 
switching from a disposable to a re-usable Respimat SMI 
at study entry
3. To compare the difference in mean total PASAPQ 
score between baseline and study end
4. To examine patient preference for the re-usable 
Respimat SMI, through single question asking 
patients their preference for the re-usable compared to 
the disposable Respimat SMI at study end
Countries of study:
Up to 10 European countries using Respimat SMI to treat 
COPD, including but not restricted to Belgium, Denmark, 
Finland, Germany, Netherlands, Norway, Romania and 
Sweden.
Author:
Date:
11 Jun 2019
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© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated 
companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or 
otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE..................................................................................................................1
1.
TABLE OF CONTENTS.......................................................................................3
1.1
LIST OF TABLES............................................................................................6
1.2
LIST OF FIGURES ..........................................................................................6
2.
LIST OF ABBREVIATIONS................................................................................7
3.
RESPONSIBLE PARTIES....................................................................................8
4.
ABSTRACT.........................................................................................................10
5.
AMENDMENTS AND UPDATES.....................................................................18
6.
MILESTONES.....................................................................................................19
7.
RATIONALE AND BACKGROUND................................................................20
8.
RESEARCH QUESTION AND OBJECTIVES .................................................22
8.1
STUDY OBJECTIVES...................................................................................22
9.
RESEARCH METHODS ....................................................................................23
9.1
STUDY DESIGN............................................................................................23
9.2
SETTING........................................................................................................25
9.2.1
Study period ............................................................................................25
9.2.2
Study sites ...............................................................................................25
9.2.3
Study population .....................................................................................25
9.2.4
Study visits / assessments........................................................................26
9.2.5
Patient withdrawal...................................................................................27
9.2.6
Study discontinuation..............................................................................27
9.3
VARIABLES ..................................................................................................27
9.3.1
Exposures ................................................................................................29
9.3.2
Outcomes.................................................................................................29
9.3.2.1
Primary outcome ..............................................................................29
9.3.2.2
Secondary outcomes.........................................................................29
9.3.3
Covariates................................................................................................30
9.4
DATA SOURCES...........................................................................................31
9.4.1
Demographic and clinical details............................................................31
9.4.1.1
Validation of receipt of re-usable Respimat SMI Question.............31
9.4.2
Patient Reported Outcome (PRO) assessment ........................................32
9.4.2.1
Patient Satisfaction and Preference Questionnaire (PASAPQ)........32

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9.4.2.2
Ease of handling questions...............................................................34
9.4.2.3
Question on patient preference for re-usable or disposable in 
Respimat SMI-experienced patients ...................................................................34
9.4.3
Adverse events ........................................................................................36
9.5
STUDY SIZE..................................................................................................36
9.6
DATA MANAGEMENT................................................................................37
9.7
DATA ANALYSIS.........................................................................................37
9.7.1
Main analysis...........................................................................................38
9.7.1.1
Primary outcome ..............................................................................38
9.7.1.2
Secondary outcomes.........................................................................38
9.7.3
Handling of missing data.........................................................................39
9.8
QUALITY CONTROL...................................................................................39
9.9
LIMITATIONS OF THE RESEARCH METHODS......................................40
9.10
OTHER ASPECTS .........................................................................................40
9.10.1
Data quality assurance.............................................................................40
9.10.2
Study records...........................................................................................41
9.10.2.1
Source documents ............................................................................41
9.10.2.2
Direct access to source data and documents ....................................41
9.10.3
Completion of study................................................................................41
9.11
STATEMENT OF CONFIDENTIALITY......................................................41
10.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS.......................................................................................................42
10.1
DEFINITIONS OF ADVERSE EVENTS......................................................42
10.2
COLLECTION AND REPORTING OF ADVERSE EVENTS, SERIOUS 
ADVERSE 
EVENTS, 
AND 
OTHER 
SAFETY-RELEVANT 
INFORMATION.............................................................................................44
10.3
REPORTING TO HEALTH AUTHORITIES................................................48
11.
PLANS 
FOR 
DISSEMINATING 
AND 
COMMUNICATING 
STUDY 
RESULTS............................................................................................................49
12.
REFERENCES ....................................................................................................50
12.1
PUBLISHED REFERENCES.........................................................................50
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS..............................................52
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ..............................53
ANNEX 3. PATIENT SATISFACTION AND PREFERENCE QUESTIONNAIRE 
(PASAPQ) DIRECT VERSION .........................................................................54

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1.1
LIST OF TABLES
Table 1: Visit flow chart and data variables to be collected...........................................28
Table 2: Validation of receipt of re-usable Respimat SMI.............................................32
Table 3: PASAPQ questions and scoring .......................................................................33
Table 4: Ease of handling questions and patient preference (for Respimat SMI-
experienced patients switching from disposable to re-usable Respimat SMI at 
the time of study entry) ..................................................................................35
Table 5: Sample size scenarios for detecting difference in total PASAPQ score means36
Table 6: Definitions for other reportable safety events ..................................................43
1.2
LIST OF FIGURES
Figure 1. Study design ....................................................................................................24
Figure 2. Timing of the PRO data collection..................................................................34
Figure 3. Collection and Reporting of Safety-Relevant Information .............................48

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
BI
Boehringer Ingelheim
CA
Competent Authority
CAT
COPD Assessment Test
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
DMP
Data Management Plan
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EU
European Union
FAS
Full Analysis Set
FEV
Forced Expiratory Volume
FVC
Forced Vital Capacity
GOLD
Global Initiative for Chronic Obstructive Lung Disease
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LABA
Long-Acting Beta-Agonist
LAMA
Long-Acting Muscarinic Antagonist
LPCO
Local Pharmaceutical Complaint Officer
MAH
Marketing Authorisation Holder
MedDRA
Medical Dictionary for Regulatory Activities
NIS
Non-Interventional Study
PASAPQ
Patient Satisfaction and Preference Questionnaire
PRO
Patient Reported Outcome
PT
Preferred Term
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SMI
Soft MistTM Inhaler
SOC
System Organ Class
TM
Team Member
TPC
Technical Product Complaint

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3.
RESPONSIBLE PARTIES
Name
Role in Study
Affiliation
Email Address
Team Member 
Medical Affairs 
(TM MA) global 
Team Member 
Epidemiology (TM 
Epi)
GPV study 
coordination
Trial Statistician 
(TSTAT)
Coordinating
investigator
Project Oversight
Project 
Evidence Strategy 
Epidemiology 
Senior 
Epidemiology 
Oversight
 
Biostatistician
Pharmacovigilance 

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Name
Role in Study
Affiliation
Email Address
Site Strategy 

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Re-usable (1) Spiriva® Respimat® 2.5 
microgram inhalation solution; (2) 
Striverdi® Respimat® 2.5 microgram 
inhalation solution; and (3) Spiolto® 
Respimat® 2.5 microgram / 2.5 microgram 
inhalation solution
Name of active ingredient:
(1) Tiotropium; (2) olodaterol; and (3) 
tiotropium/olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
11 Jun 2019
1237-0097
1.0
N/A
Title of study:
A real-world non-interventional study to assess patient satisfaction with
and preference for re-usable Respimat Soft Mist inhaler in patients with 
chronic obstructive pulmonary disease.
Rationale and 
background:
Inhaled medications are the mainstay of pharmacological treatment (both 
rescue therapy and maintenance treatment) for patients with chronic 
obstructive pulmonary disease (COPD). A number of inhaler devices are 
available, and their selection is based on patients’ needs and preferences, 
depending on device characteristics and patient capabilities.
The Respimat® Soft MistTM inhaler (SMI) (Spiriva®, Striverdi® or 
Spiolto®) has been available since 2004 for the delivery of treatments to 
patients with COPD or asthma and has gained widespread use. While 
Respimat SMI was initially available as a ‘disposable’ inhaler that patients 
were only able to use for the labelled number of doses following insertion 
of the cartridge, feedback from patients and physicians resulted in 
modification of the disposable Respimat SMI to become an 
environmentally friendly re-usable inhaler.
Studies have shown that greater treatment satisfaction is associated with 
improved adherence and persistence with medication;
critical to 
improving health outcomes for patients. Therefore, as part of the post-
marketing evaluation of the re-usable Respimat SMI, it is important to 
assess patients’ satisfaction and preference for the re-usable features of 
the device in the real-world setting.

Boehringer Ingelheim
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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Re-usable (1) Spiriva® Respimat® 2.5 
microgram inhalation solution; (2) 
Striverdi® Respimat® 2.5 microgram 
inhalation solution; and (3) Spiolto® 
Respimat® 2.5 microgram / 2.5 microgram 
inhalation solution
Name of active ingredient:
(1) Tiotropium; (2) olodaterol; and (3) 
tiotropium/olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
11 Jun 2019
1237-0097
1.0
N/A
Research question 
and objectives:
The overall aim of this study is to assess patient satisfaction with the 
inhaler attributes of the re-usable Respimat SMI (Spiriva, Striverdi or 
Spiolto) in patients with COPD, including patients who are Respimat 
SMI-experienced and Respimat SMI-naïve. This study also aims to 
examine patient preference for the re-usable Respimat SMI compared to 
the disposable Respimat SMI in Respimat SMI-experienced patients 
switching from a disposable to a re-usable Respimat SMI product at study 
entry.
Primary Objective: 
The primary objective of the study is to assess patient satisfaction with the 
re-usable Respimat SMI, assessing the mean total score of the validated 
Patient Satisfaction and Preference Questionnaire (PASAPQ), at study 
end.
Secondary Objectives: 
For all patients
1.
To examine the individual domains of the PASAPQ:
total 
performance score, total convenience score, the overall satisfaction 
question and the question on willingness to continue with inhaler at 
study end
2.
To examine ease of handling of the re-usable Respimat SMI at study 
end
Additionally, for Respimat SMI-experienced patients switching from a 
disposable to a re-usable Respimat SMI at study entry
3.
To compare the difference in mean total PASAPQ score between 
baseline and study end
4.
To examine patient preference for the re-usable Respimat SMI,
through a single question asking patients their preference for the re-
usable compared to the disposable Respimat SMI at study end

Boehringer Ingelheim
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Non-interventional Study Protocol
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Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Re-usable (1) Spiriva® Respimat® 2.5 
microgram inhalation solution; (2) 
Striverdi® Respimat® 2.5 microgram 
inhalation solution; and (3) Spiolto® 
Respimat® 2.5 microgram / 2.5 microgram 
inhalation solution
Name of active ingredient:
(1) Tiotropium; (2) olodaterol; and (3) 
tiotropium/olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
11 Jun 2019
1237-0097
1.0
N/A
Study design:
A multi-centre, open-label, prospective, real-world non-interventional 
study will be conducted over a 6 month period on patients with COPD 
who receive the re-usable Respimat SMI. 
It will include two patient cohorts: (1) Respimat SMI-experienced, 
defined as patients who have been on maintenance treatment with a 
Respimat SMI product (Spiriva, Striverdi or Spiolto) and receive a refill 
prescription  at study entry; and (2) Respimat SMI-naïve, defined as 
patients who have not previously used a Respimat SMI product and  
receive their first prescription at study entry. The prescription at study 
entry for both cohorts should be for a re-usable Respimat SMI product.
The Respimat SMI-experienced patient cohort will further be divided into 
two subgroups: (1a) patients on maintenance treatment with a re-usable 
Respimat SMI at study entry; and (1b) patients on maintenance treatment 
with a disposable Respimat and switching to a re-usable Respimat SMI at 
study entry.
Patients will be followed from study entry (enrolment visit) for a period 
of approximately 4-6 weeks (follow-up assessment, study end). The 
minimum pack size for the re-usable Respimat SMI is 30 days (4 weeks), 
after which the follow-up assessment will be conducted. An additional 2
week follow-up window has been included to account for scheduling of 
clinic visits and/or provision of time for the patient to complete the 
PASAPQ and the questions on the ease of handling of the re-usable 
Respimat SMI. 
All patients will complete the PASAPQ and ease of handling questions at 
the follow-up assessment (study end). Additionally, Respimat-
experienced patients switching from a disposable to a re-usable Respimat 
SMI product at study entry will complete the PASAPQ at baseline and the 
individual question on patient preference for the re-usable or disposable 
Respimat SMI at follow-up assessment.
PASAPQ, ease of handling questions and the patient preference question 
will be administered electronically, with the provision for administration 
in paper format, if required, providing the ability to be completed offsite 
(remotely).
Safety data (serious and non-serious adverse drug reactions [ADR], 
adverse events [AE] with a fatal outcome and other reportable safety 
events) will be collected for all patients throughout the study period.

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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Re-usable (1) Spiriva® Respimat® 2.5 
microgram inhalation solution; (2) 
Striverdi® Respimat® 2.5 microgram 
inhalation solution; and (3) Spiolto® 
Respimat® 2.5 microgram / 2.5 microgram 
inhalation solution
Name of active ingredient:
(1) Tiotropium; (2) olodaterol; and (3) 
tiotropium/olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
11 Jun 2019
1237-0097
1.0
N/A
Population:
Patients aged 40 years or older with COPD residing in one of the target 
countries, who have been prescribed a re-usable Respimat SMI during the 
study period, in the course of standard clinical practice.
Inclusion criteria:
Patients fulfilling all the following inclusion criteria will be eligible for 
participation in the study:
-
Provision of signed informed consent prior to study data collection
-
Patient with COPD aged 40 years or older
-
Patient prescribed (or already receiving the disposable Respimat 
SMI and switched to) one of the following re-usable Respimat SMI 
products per the standard clinical practice: Spiriva 2.5 microgram 
inhalation solution; (2) Striverdi 2.5 microgram inhalation solution; 
and (3) Spiolto 2.5 microgram / 2.5 microgram inhalation solution
-
Patient unlikely to change their Respimat therapy during the 
observation period (in the opinion of the investigator)
Exclusion criteria:
Patients fulfilling any of the following exclusion criteria will not be 
eligible for participation in the study:
-
Patient using a disposable Respimat SMI product during the study 
period, after study entry
-
Patient who have had a severe COPD exacerbation requiring 
hospitalisation in the immediate 3 months prior to study entry
-
Patient participating in a clinical trial or any other non-interventional 
study of a drug or device at the time of enrolment
-
Visual, cognitive, motor or health impairment that, as judged by the 
investigator, may cause concern regarding the patient's ability to 
complete the questionnaires
-
Patient not fluent and literate in one of the main languages of the 
country

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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Re-usable (1) Spiriva® Respimat® 2.5 
microgram inhalation solution; (2) 
Striverdi® Respimat® 2.5 microgram 
inhalation solution; and (3) Spiolto® 
Respimat® 2.5 microgram / 2.5 microgram 
inhalation solution
Name of active ingredient:
(1) Tiotropium; (2) olodaterol; and (3) 
tiotropium/olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
11 Jun 2019
1237-0097
1.0
N/A
Variables:
Exposures:
The re-usable Respimat SMI administered with one of the 3 products: 
Spiriva 2.5 microgram inhalation solution (tiotropium), Striverdi 2.5 
microgram inhalation solution (olodaterol) or Spiolto 2.5 microgram / 2.5 
microgram inhalation solution (tiotropium / olodaterol).
The Respimat SMI product prescribed to the patient (Spiriva, Striverdi or 
Spiolto) and the inhaler version (disposable or re-usable) will be recorded.
Outcomes:
Primary outcome
The primary outcome of the study is the mean total PASAPQ score with 
re-usable Respimat SMI at study end (follow-up assessment)
Secondary outcomes
-
Total performance PASAPQ score for all patients at study end (follow-
up assessment)
-
Total convenience PASAPQ score for all patients at study end (follow-
up assessment)
-
Overall satisfaction question for all patients at study end (follow-up 
assessment)
-
Question on willingness to continue with inhaler for all patients at study 
end (follow-up assessment)
-
Questions on ease of handling re-usable Respimat SMI for all patients 
at study end (follow-up assessment)
-
Difference in the mean total PASAPQ score between study entry 
(baseline visit) and study end (follow-up assessment) in the Respimat 
SMI-experienced patients switching from a disposable to a re-usable 
Respimat SMI product at study entry
-
Question on preference for re-usable or disposable Respimat SMI at 
study end (follow-up assessment) in Respimat SMI-experienced 
patients switching from a disposable to a re-usable Respimat SMI 
product at study entry

Boehringer Ingelheim
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Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Re-usable (1) Spiriva® Respimat® 2.5 
microgram inhalation solution; (2) 
Striverdi® Respimat® 2.5 microgram 
inhalation solution; and (3) Spiolto® 
Respimat® 2.5 microgram / 2.5 microgram 
inhalation solution
Name of active ingredient:
(1) Tiotropium; (2) olodaterol; and (3) 
tiotropium/olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
11 Jun 2019
1237-0097
1.0
N/A
Covariates:
-
Patient demographics (e.g. age, gender, height, weight, highest level of 
educational attainment), at study entry
-
Duration of COPD, at study entry
-
Number of COPD exacerbations, based on medical history, in the 12 
months prior to study entry and  during study period
-
Pulmonary function (post-bronchodilator forced expiratory volume in 
one second [FEV1] and forced vital capacity [FVC]), based on most 
recent spirometry test in the 12 months prior to study entry (if 
available)
-
COPD Assessment Test (CAT) or Modified Medical Research Council 
(mMRC) score, at study entry (if available)
-
COPD severity (grade [1-4] and patient group [A, B, C or D]), based on 
the 2019 Global Initiative for Chronic Obstructive Lung Disease 
(GOLD) grade and group, at study entry
-
Respimat SMI type used during study period (disposable or re-usable)
-
Duration of treatment with disposable Respimat SMI (for Respimat 
SMI-experienced patients), at study entry (if available) 
-
Last day of use of disposable Respimat SMI (for Respimat SMI-
experienced patients), at study entry
-
Date of first prescription of re-usable Respimat SMI, at study entry
-
COPD-related and other concomitant medications, based on medical 
prescription history, in the 6 months prior to study entry and during the 
study period
-
Comorbidities, at study entry and during the study period
-
Serious and non-serious ADRs, AEs with a fatal outcome and other 
reportable safety events during the study period 
-
Smoking status/history (current smokers, former smokers, and never 
smokers) and pack-years (for current smokers), at study entry and at 
study end
-
Details of discontinuation of the re-usable Respimat SMI during the 
study period (if applicable)

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Re-usable (1) Spiriva® Respimat® 2.5 
microgram inhalation solution; (2) 
Striverdi® Respimat® 2.5 microgram 
inhalation solution; and (3) Spiolto® 
Respimat® 2.5 microgram / 2.5 microgram 
inhalation solution
Name of active ingredient:
(1) Tiotropium; (2) olodaterol; and (3) 
tiotropium/olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
11 Jun 2019
1237-0097
1.0
N/A
Data sources:
Patient medical records, collected through the routine clinical care, will be 
used to assess the eligibility criteria of patients and to collect information
on patient demographics, smoking history, COPD duration, exacerbation 
history, pulmonary function, the Respimat SMI prescribed and duration of 
treatment with Respimat SMI (in Respimat SMI-experienced patients), 
COPD-related concomitant medications and comorbidities, where 
available.
If available, the CAT or mMRC score, along with the exacerbation history 
and the post-bronchodilator spirometry measurement, will be used to 
sappraise the COPD severity using the GOLD criteria.
The validation question to confirm patients’ use of the re-usable Respimat 
SMI will be asked at study end to all patients.
The patients’ satisfaction with the re-usable Respimat SMI (measured by 
the self-administered PASAPQ) and the questions on ease of handling of 
the re-usable Respimat SMI will be completed by all patients at study end 
(follow-up assessment). Additionally, for the Respimat SMI-experienced 
patients  switching from a disposable to a re-usable Respimat SMI product
at study entry, PASAPQ will be administered at study enrolment (baseline 
visit) to assess the difference in the mean total PASAPQ score between 
study enrolment and study end.
The patient preference question for the re-usable or disposable Respimat 
SMI will be administered at the follow-up assessment (study end) to the 
Respimat-experienced patients switching from a disposable to a re-usable 
Respimat SMI product at study entry.
The safety data will be extracted from the medical records and/or 
collected from a telephone interview (held by the Investigator’s staff) at 
the time of the follow-up assessment and entered into the electronic case 
report form (eCRF) where it will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and grouped by system organ class 
(SOC) and preferred term (PT).
Study size:
It is planned that approximately 250 COPD patients (Respimat SMI-
experienced and Respimat SMI-naïve) from Europe will be enrolled in 
this study.  It is anticipated that at least half the patients will be Respimat 
SMI-experienced.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal product:
Re-usable (1) Spiriva® Respimat® 2.5 
microgram inhalation solution; (2) 
Striverdi® Respimat® 2.5 microgram 
inhalation solution; and (3) Spiolto® 
Respimat® 2.5 microgram / 2.5 microgram 
inhalation solution
Name of active ingredient:
(1) Tiotropium; (2) olodaterol; and (3) 
tiotropium/olodaterol
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
11 Jun 2019
1237-0097
1.0
N/A
Data analysis:
The total PASAPQ and the domain scores (total performance score, total 
convenience score, overall patient satisfaction score  and the rating of 
willingness to continue with the inhaler) will be summarised using 
descriptive statistics for continuous variables.
The difference in the mean total PASAPQ score between baseline and 
study end, in Respimat SMI-experienced patients switching from a
disposable to a re-usable Respimat SMI product at study entry, will be 
compared using a two-tailed paired t-test or an appropriate non-parametric 
test (e.g. Wilcoxon signed ranks test), depending on the distributions of 
the count / score data.Responses to the questions on the ease of handling
of the re-usable Respimat SMI will be summarised using descriptive 
statistics for categorical or continuous variables, as appropriate.
Results for both primary and secondary outcomes will be presented as the 
total study population, Respimat SMI-experienced and Respimat SMI-
naïve patients (where applicable). Additional subgroup analyses by key 
patient characteristics (e.g. age, GOLD patient group, type of re-usable 
Respimat SMI prescribed, smoking status, etc.) may be performed, 
provided the subgroups of interest include more than 20% of all patients.
The safety data will be reported by summarising counts and frequencies of  
non-serious ADRs, serious ADRs, AEs with a fatal outcome, other 
reportable safety events, grouped by MedDRA SOC and PT.
Milestones:
Final protocol: May 2019
Planned first patient in: August-2019
Planned last patient in: December-2019
Planned last patient out: February-2020
Planned final study report: June-2020

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5.
AMENDMENTS AND UPDATES
None.

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6.
MILESTONES
Milestone
Planned Date
Final protocol
May 2019
Planned first patient in
August 2019
Planned last patient in
December 2019
Planned last patient out
February 2020
Planned final study report
June 2020

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7.
RATIONALE AND BACKGROUND
Chronic obstructive pulmonary disease (COPD) is the third-leading cause of mortality 
worldwide and is associated with significant morbidity (Rabe and Watz 2017). The 2017
global prevalence of COPD is estimated to be 299 million cases, with a 23.8% increase in 
prevalence between 2007 to 2017 (GBD 2017 Disease and Injury Incidence and Prevalence 
Collaborators 2018). COPD is more prevalent in the older population and in men than in 
women, with tobacco smoking as the main cause, particularly in high-income countries (Rabe 
and Watz 2017).
Inhaled medications are the mainstay of pharmacological treatment (both rescue therapy and 
maintenance treatment) for patients with COPD (Mirza et al. 2018). This provides efficient 
and targeted drug delivery to the site of action, providing increased efficacy and safety. 
Lower doses are required, with fewer systemic adverse effects than oral therapy (Dhand et al. 
2018). An important component of treatment selection includes appropriate inhaler device 
selection. A number of inhaler devices are available, and selection should be based on 
patients’ needs and preferences, depending on inhaler characteristics and patient capabilities
(Dhand et al. 2018).
Since 2004, the Respimat® Soft MistTM inhaler (SMI) has been available across many regions 
worldwide, for the delivery of treatments for patients with COPD or asthma and has gained 
widespread use (over 10 million patient-years across all products) (Dhand et al. 2019). The 
range of drugs and drug combinations available in Respimat SMI include Spiriva®
(tiotropium; long-acting muscarinic receptor antagonist [LAMA]), Striverdi® (olodaterol; 
long-acting 
beta-agonist 
[LABA]), 
Spiolto®
(tiotropium–olodaterol),
Berodual®
(ipratropium–fenoterol hydrobromide) and Combivent® (albuterol; short-acting beta-agonist 
[SABA])–ipratropium; short-acting muscarinic receptor antagonist [SAMA]). Respimat SMI 
is a hand-held, propellant-free inhaler that provides a slow-moving, long-lasting mist of drug 
for inhalation, featuring a high fine-particle fraction independent of inspiratory airflow, with 
optimal aerosol velocity and generation time. These features result in ease of inhalation and 
higher drug deposition compared to dry-powder or pressurised metered-dose inhalers (Dalby 
et al. 2011). To date, the Respimat SMI has been well received by patients, with high 
acceptance and satisfaction (Schürmann et al. 2005), largely as a result of its higher drug 
delivery capabilities requiring lower doses, and providing increased control of symptoms and 
increased therapeutic ratio (Caillaud et al. 2007).
Respimat was initially available as a ‘disposable’ inhaler that patients were able to use only 
for the labelled number of doses following insertion of the cartridge. However, feedback 
from patients and physicians resulted in modification of the disposable Respimat SMI into a 
next-generation, environmentally friendly re-usable inhaler. The enhanced features include
simplified assembly and daily use, optimisation of the dose indicator, and use with up to 6

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cartridges together with an intuitive cartridge exchange mechanism, that aim to improve both 
the usability and environmental impact of the Respimat SMI product. At the same time, the 
basic functions of the inhaler, such as its unique pharmaceutical performance and reliable 
drug delivery are preserved (Dhand et al. 2019). A recently published study reported 
comparable average delivered dose and fine-particle dose between the re-usable and 
disposable Respimat SMI (Dhand et al. 2019). Further, in study of 65 people, which included
11 healthcare professionals and 54 patients with COPD, asthma or mixed airway disease,
usability of the re-usable Respimat SMI was reported to be improved, with regard to 
assembly and daily use (Dhand et al. 2019). In addition, a sub-sample of patients who had 
previously used the disposable Respimat SMI, 81% (n=13/16) reported preferring the re-
usable inhaler (Dhand et al. 2019).
Studies have shown that greater treatment satisfaction is associated with improved adherence 
and persistence with medication; critical to improving health outcomes for patients (Dias 
Barbosa et al. 2012, Chrystyn et al. 2014). In a study by Chrystyn et al., the satisfaction of 
1443 patients with COPD with their inhaler, was shown to be associated with increased 
treatment compliance, increased health status and less frequent exacerbations (Chrystyn et al. 
2014). Therefore, as part of the post-marketing evaluation of the re-usable Respimat SMI, it 
is important to assess patients’ satisfaction and preference for the re-usable SMI features, in 
the real-world setting.

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8.
RESEARCH QUESTION AND OBJECTIVES
The overall aim of this study is to assess patient satisfaction with the inhaler attributes of the 
re-usable Respimat SMI (Spiriva® 2.5 microgram inhalation solution, Striverdi® 2.5 
microgram inhalation solution or Spiolto® 2.5 microgram / 2.5 microgram inhalation 
solution) in adult patients with COPD, including patients who are Respimat SMI-experienced 
and Respimat SMI-naïve (see Section 9.1 for definitions of Respimat SMI-experienced and 
Respimat SMI-naïve cohorts). This study also aims to examine patient preference for the re-
usable Respimat SMI compared to the disposable Respimat SMI in Respimat SMI-
experienced patients switching from a disposable to a re-usable Respimat SMI product at 
study entry.
8.1
STUDY OBJECTIVES
Primary Objective:
The primary objective of the study is to assess patient satisfaction with the re-usable 
Respimat SMI, assessing the mean total score of the validated Patient Satisfaction and 
Preference Questionnaire (PASAPQ) at study end.
The PASAPQ is a self-administered multi-item instrument, which includes a performance 
domain (7 items), a convenience domain (6 items), an overall satisfaction question (Item 14)
and a question on willingness to continue with inhaler (Item 15). It has been developed and 
validated to measure respiratory inhalation device satisfaction and preference in patients with 
asthma and COPD (Kozma et al. 2005).
Secondary Objectives: The secondary objectives of the study are:
For all patients
1. To examine the individual domains of the PASAPQ: total performance score, total 
convenience score, the overall satisfaction question and the question on willingness 
to continue with inhaler at study end 
2. To examine the ease of handling of the re-usable Respimat SMI at study end
Additionally, for Respimat SMI-experienced patients switching from a disposable to a re-
usable Respimat SMI at study entry
3. To compare the difference in the mean total PASAPQ score between study entry and 
study end
4. To examine patient preference for the re-usable Respimat SMI, through a single 
question asking patients their preference for the re-usable compared to the disposable 
Respimat SMI at study end

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
A multi-centre, open-label, prospective, real-world non-interventional study over a 6 month 
period of patients with COPD prescribed re-usable Respimat® SMI, will be conducted. 
It will include two patient cohorts: (1) Respimat SMI-experienced, defined as patients who 
have been on maintenance treatment with a Respimat SMI product (Spiriva®, Striverdi® or 
Spiolto®) and receive a refill prescription at study entry and (2) Respimat SMI-naïve, defined 
as patients who have not previously used a Respimat SMI product and receive their first 
prescription at study entry. The prescription at study entry for both cohorts should be for a re-
usable Respimat SMI product.
The Respimat SMI-experienced patient cohort will further be divided into two subgroups: 
(1a) patients on maintenance treatment with a re-usable Respimat SMI at study entry; and 
(1b) patients on maintenance treatment with a disposable Respimat and switching to a re-
usable Respimat SMI at study entry (Figure 1).
Patients will be followed from the time of study entry (enrolment visit) for a period of 
approximately 4-6 weeks (study period) (Figure 1). The minimum pack size for the re-usable 
Respimat SMI is 30 days (4 weeks), after which the follow-up assessment will be conducted. 
An additional 2 week follow-up window has been included to account for scheduling of clinic 
visits and/or provision of time for the patient to complete the PASAPQ and the questions on 
the ease of handling of the re-usable Respimat SMI.
The primary outcome is satisfaction with the re-usable Respimat SMI attributes in patients 
with COPD, which will be measured by the PASAPQ total score (from 13 questions) at the
end of the study period (follow-up assessment, Figure 1) for all patients.
Secondary outcomes will include individual domains of the PASAPQ: total performance 
score (from 7 individual questions), total convenience score (from 6 individual questions), the 
overall satisfaction question and the question on willingness to continue with inhaler. The 
ease of  handling of the re-usable Respimat SMI will also be assessed in all patients at the end 
of the study period. Additionally, the study will compare the PASAPQ total score at study 
enrolment (baseline visit) with the PASAPQ score during the follow-up assessment in the
Respimat SMI-experienced patients switching from a disposable to a re-usable Respimat SMI 
product at study entry; and assess patient preference for the re-usable Respimat SMI through 
a single question asking patients their preference for the re-usable compared to the disposable 
Respimat SMI (Figure 2).

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Safety data (serious and non-serious adverse drug reactions [ADR], adverse events [AE] with 
a fatal outcome and other reportable safety events) of the re-usable Respimat SMI will be 
collected for all patients throughout the study period.
COPD: Chronic Obstructive Pulmonary Disease; PASAPQ: Patient Satisfaction and Preference Questionnaire; 
SMI: Soft Mist Inhaler.
Figure 1. Study design
The study population will be identified by the participating physicians involved in the 
diagnosis, treatment and management of COPD patients (general practitioners and/or 
specialist physicians including pneumologists). Eligible patients must be prescribed and use a
re-usable Respimat SMI product (as per the routine clinical practice of the participant sites). 
Patients will be Respimat SMI-experienced or Respimat SMI-naïve (see Section 9.1 for 
definitions of Respimat SMI-experienced and Respimat SMI-naïve cohorts) and evaluated as 
stable (or unlikely to change their COPD Respimat treatment) for the duration of the study 
period (approximately 4-6 weeks). Eligible patients will be asked to provide written informed 
consent prior to inclusion in the study.
Patients will be enrolled consecutively, following informed consent, and followed over the 
4-6 weeks (approximately) study period. The enrolment will be competitive, i.e. the sites are 
free to enrol as many Respimat SMI-experienced and Respimat SMI-naïve patients as 
available. It is not required that all countries will have both cohorts represented at the site or 
at the country level. It is, however, anticipated that at least half the patients will be Respimat 
SMI-experienced. This will be monitored throughout patient recruitment and capped where 
necessary.

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Patients will be followed prospectively from the time of enrolment until the earliest of: death, 
loss to follow-up or end of the study period (i.e. approximately 4-6 weeks after the enrolment 
visit). Patients who are alive and not lost to follow-up, will have a follow-up assessment at 
the end of the study period (Figure 1).
9.2
SETTING
9.2.1
Study period
Patient enrolment will commence in August 2019 and is expected to end in December 2019 
(see Section 6 for details of study milestones). The last patient last assessment is expected in 
February 2020.
9.2.2
Study sites
It is planned that approximately 250 patients (Respimat SMI-experienced and Respimat SMI-
naïve) from approximately 32 sites in up to 10 European countries, potentially including (but 
not limited to) Belgium, Denmark, Finland, Germany, Netherlands, Norway, Romania and 
Sweden, will be enrolled in this study. Site selection will be performed to reflect the 
distribution of routine COPD care in the participating countries in order to secure a 
representative population of COPD patients. This may include public and private hospitals 
and clinics, university hospitals, specialist medical centres, and community-dwelling general 
practitioners and specialists. Patients may be treated by general practitioners or specialist 
physicians, including pneumologists.
9.2.3
Study population
The study population will include patients (aged 40 and above) with COPD, who are residing 
in one of the target countries and follow the routine clinical practice of the participant sites 
(see Section 9.2.2 for list of target countries). Patients should be prescribed a re-usable 
Respimat SMI product, during the study period (see Section 9.2.1), in the course of standard 
medical practice. Patients must be able to inhale the medication in a competent manner from 
the Respimat SMI according to the Clinical investigator's judgement, which will be recorded 
in the electronic case report form (eCRF) as per standard clinical practice.
Inclusion criteria:
Patients fulfilling all the following inclusion criteria will be eligible for participation in the 
study:
-
Provision of signed informed consent prior to study data collection

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-
Patient with COPD aged 40 years or older
-
Patient prescribed (or already receiving the disposable Respimat SMI and switched to) 
1 of the following re-usable Respimat SMI products per the standard clinical practice: 
Spiriva 2.5 microgram inhalation solution, Striverdi 2.5 microgram inhalation solution
or Spiolto 2.5 microgram / 2.5 microgram inhalation solution
-
Patient unlikely to change their Respimat therapy during the observation period (in 
the opinion of the investigator)
Exclusion criteria:
Patients fulfilling any of the following exclusion criteria will not be eligible for participation 
in the study:
-
Patient using a disposable Respimat SMI product during the study period, after study 
entry
-
Patient who have had a severe COPD exacerbation requiring hospitalisation in the 
immediate 3 months prior to study entry
-
Patient participating in a clinical trial or any other non-interventional study of a drug 
or inhaler at the time of enrolment
-
Visual, cognitive, motor or health impairment that, as judged by the investigator, may 
cause concern regarding the patient's ability to complete the questionnaires
-
Patient not fluent and literate in one of the main languages of the country
Where allowed by local regulations, a patient screening log will be kept at each site, 
recording basic information such as age at COPD diagnosis, gender, information on the 
eligibility (or reasons for non-eligibility/non-enrolment, including a reason for refusal [if 
known]). In addition, a log of all patients included into the study (i.e. having provided 
informed consent) will be maintained in the Investigator Site File irrespective of whether they 
have completed the study or not.
9.2.4
Study visits / assessments
Patients will have two assessments: one at study enrolment (baseline visit) corresponding to 
their routine clinic visits for treatment of COPD, and one at end of the study period (follow-
up assessment), which will occur approximately 4-6 weeks after the baseline visit. The 
follow-up assessment can be completed during the routine clinic visit or remotely (by 
telephone) if the patient does not visit the site (clinic) within 4-6 weeks of the baseline visit. 
No additional clinic visits or assessments are mandated or recommended for this study.

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All patients will have the PASAPQ administered at study end (follow-up assessment). The 
PASAPQ will be administered in electronic format, with the provision for administration in 
paper format, if required. For the Respimat SMI-experienced patients switching from a 
disposable to a re-usable Respimat SMI product at study entry, the PASAPQ will be 
administered twice: (1) at study enrolment (baseline visit); and (2) at study end (follow-up 
assessment). 
The pack size for the re-usable Respimat will cover 30 days (1 month), or 90 days (3
months), depending on the country. It is therefore anticipated that patients prescribed larger 
pack sizes may not return to the clinic at the time of follow-up assessment. Therefore, the 
PASAPQ, as well as the questions on the ease of handling of the re-usable Respimat SMI and 
patient preference, will be administered either electronically or mailed to patients (depending 
on patient preference) to be completed offsite (remotely) (see Section 9.4.2.1).
9.2.5
Patient withdrawal
Patients are free to discontinue or withdraw from the study at any time. Reason for 
discontinuation or withdrawal will be collected; however, reasons for withdrawal of consent 
do not have to be disclosed. Unless otherwise requested by the participant, all data obtained 
up to that point (i.e. before the consent withdrawal) will be retained.
9.2.6
Study discontinuation
Boehringer Ingelheim (BI) reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
-
Failure to meet expected enrolment goals overall or at a particular study site
-
Emergence of any efficacy/safety information that could significantly affect the 
continuation of the study, or any other administrative reasons, i.e. lack of recruitment
-
Violation of the study protocol, or the contract by a study site or investigator, or 
applicable laws and regulations for non-interventional studies, which could disturb the 
appropriate conduct of the study
9.3
VARIABLES
This is a non-interventional study design enrolling consented patients with COPD who will 
be treated with a re-usable Respimat product (Spiriva, Striverdi or Spiolto), according to their
approved summary of product characteristics. Patients will be enrolled consecutively and will 
be followed over a period of approximately 4-6 weeks (Figure 1). Data, as listed in Table 1,
will be collected, where available.

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Table 1: Visit flow chart and data variables to be collected
Study entry
(Baseline)
Follow-up 
assessment 
(4-6 weeks after 
baseline)
Informed Consent
X
Inclusion / Exclusion Criteria
X
Patient demographics (e.g. age, gender, height, weight)
X
Duration of COPD
X
CAT or mMRC score (if available)
X
Pulmonary function (based on most recent spirometry test in the 12
months prior to study entry1) (if available)
X
Disease severity based on 2019 GOLD grade and group2
X
Respimat® SMI product prescribed (Spiriva®, Striverdi® or Spiolto®)
X
Duration of treatment with disposable Respimat SMI3
X
Last day of use of disposable Respimat SMI3
X
Date of first prescription of re-usable Respimat SMI
X
Number of COPD exacerbations (in the 12 months prior to study entry) 
and during the study period
X
X
COPD-related and other concomitant medications (in the 6 months prior 
to study entry and during the study period4)
X
X
Comorbidities
X
X
Smoking status / history
X
X
PASAPQ completed by the patient5
X
X
Respimat SMI type used during study period (disposable or re-usable)
X
Questions on the ease of handling of re-usable Respimat SMI 
X
Question on Respimat SMI preference (disposable vs re-usable)5
X
Safety: Serious and non-serious ADRs, AEs with a fatal outcome and 
other reportable safety events
X
Details of discontinuation of the re-usable Respimat SMI during the study 
period4 (if applicable)
X
1 If more than one measurement is available in the 12-month period prior to study entry, the measurement closest to the study 
entry will be included.
2 GOLD grade (1-4) and patient group (A, B, C or D) will be appraised based on available exacerbation history, assessment 
of symptoms based on CAT, and GOLD spirometry classification of airflow limitation based on post-bronchodilator 
spirometry results, if available (GOLD 2019).
3 This will be assessed in Respimat SMI-experienced patients only.
4 The study period starts with the baseline visit and ends with the follow-up assessment, which is approximately 4-6 weeks.
5 PASAPQ at study enrolment (baseline visit) and the question on Respimat SMI preference (disposable vs re-usable) will be 
administered only to the Respimat SMI-experienced patients switching from a disposable to a re-usable Respimat SMI 
product at study entry.

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ADR: Adverse Drug Reaction; AE: Adverse Event; CAT: COPD Assessment Test; COPD: Chronic Obstructive Lung 
Disease; GOLD: Global Initiative for Chronic Obstructive Lung Disease; mMRC: modified Medical Research Council
PASAPQ: Patient Satisfaction and Preference Questionnaire; SMI: Soft MistTM Inhaler.
9.3.1
Exposures
The exposures of interest in this study are the re-usable Respimat SMI administered with one 
of the 3 products: Spiriva 2.5 microgram inhalation solution (tiotropium), Striverdi 2.5 
microgram inhalation solution (olodaterol) or Spiolto 2.5 microgram / 2.5 microgram 
inhalation solution (tiotropium / olodaterol).
In this study, all patients will follow the usual clinical practice of the participating sites and 
will receive their treatment (Spiriva, Striverdi or Spiolto) in a re-usable Respimat SMI after 
being prescribed a Respimat SMI product for the first time in the course of standard clinical 
practice (Respimat SMI-naïve patients) or after having been on maintenance treatment with a 
Respimat SMI product and receive a refill prescription at study entry (Respimat SMI-
experienced patients).
The Respimat SMI product prescribed to the patient (Spiriva, Striverdi or Spiolto) and the 
inhaler version (disposable or re-usable) will be recorded in the eCRF.
9.3.2
Outcomes
9.3.2.1
Primary outcome
The primary outcome of the study is the mean total PASAPQ score with re-usable Respimat 
SMI at study end (follow-up assessment) (see Section 9.4.2.1 and Table 3 for the PASAPQ 
questions and scoring).
9.3.2.2
Secondary outcomes
-
Total performance PASAPQ score for all patients at study end (follow-up assessment)
(see Table 3)
-
Total convenience PASAPQ score for all patients at study end (follow-up assessment)
(see Table 3)
-
Overall satisfaction question with inhaler for all patients at study end (follow-up 
assessment) (see Table 3)
-
Question on willingness to continue with inhaler for all patients at study end (follow-
up assessment) (see Table 3)
-
Questions on ease of handling of the re-usable Respimat SMI for all patients at study 
end (follow-up assessment) (see Table 4)

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-
Difference in the mean total PASAPQ score between study entry (baseline visit) and 
study end (follow-up assessment) in Respimat SMI-experienced patients switching 
from a disposable to a re-usable Respimat SMI product at study entry
-
Question on preference for re-usable or disposable Respimat SMI at study end 
(follow-up assessment) in Respimat SMI-experienced patients switching from a 
disposable to a re-usable Respimat SMI product at study entry (see Section 9.4.2.3)
9.3.3
Covariates
The following covariates, where available, will be collected and assessed at study enrolment 
(baseline visit) and/or study end (follow-up assessment). See Table 1 for the timing of data 
collection:
-
Patient demographics (e.g. age, gender, height, weight, highest level of educational 
attainment)
-
Duration of COPD
-
Number of COPD exacerbations, based on medical history, in the 12 months prior to 
study entry or in the study period
-
Pulmonary function (post-bronchodilator expiratory volume in one second [FEV1] and 
forced vital capacity [FVC]), based on most recent spirometry test in the 12 months 
prior to study entry (if available)
-
COPD Assessment Test (CAT) score or modified Medical Research Council (mMRC) 
dyspnoea scale (if available)
-
COPD severity (grade [1-4] and patient group [A, B, C or D]) based on the 2019 
Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade (GOLD 2019)
-
Respimat SMI type used during study period (disposable or re-usable)
-
Duration of treatment with Respimat SMI (for Respimat SMI-experienced patients)
(if available)
-
Last day of use of disposable Respimat SMI (for Respimat SMI-experienced patients)
-
Date of first prescription of re-usable Respimat SMI
-
COPD-related and other concomitant medications, based on medical prescription 
history, in the 6 months prior to study entry and during the study period
-
Comorbidities such as cardiovascular diseases, malignancies (e.g. lung cancer), 
diabetes mellitus, musculoskeletal diseases, renal diseases, liver diseases, 
osteoporosis, gastroesophageal reflux, other respiratory diseases (e.g. asthma, 
pulmonary fibrosis, pneumonia), or mental health conditions (e.g. depression, anxiety)

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-
Serious and non-serious ADRs, AEs with a fatal outcome, pregnancies and other 
reportable safety events (as outlined in Section 10.2) during the study period
-
Smoking status/history (current smokers, former smokers, and never smokers) and 
pack-years (for current smokers)
-
Details of discontinuation of the re-usable Respimat SMI during the study period (if 
applicable)
9.4
DATA SOURCES
9.4.1
Demographic and clinical details
Patient medical records, collected through the routine clinical care, will be used to assess the 
eligibility criteria of patients (see Section 9.2.3 for the details of the study inclusion and 
exclusion criteria). Medical records will also be used to collect information on patient 
demographics, smoking history, COPD duration, exacerbation history, post-bronchodilator 
FEV1, FVC, the Respimat product prescribed, COPD-related and other concomitant 
medications, and comorbid conditions (where available).
The GOLD criteria of COPD severity (GOLD Grade 1-4 and Stage A, B, C and D) will be 
appraised based on available exacerbation history, assessment of symptoms based on the 
CAT score or mMRC dyspnoea scale (where available) and GOLD spirometry classification 
of airflow limitation based on the most recent post-bronchodilator spirometry measurement, 
if available (GOLD 2019).
The CAT consists of 8 items, covering a wide range of disease severity. Each of the 8 items is 
formatted into a semantic 6-point differential scale, which makes it easy for the patients to 
complete the overall score ranges from 0-40 (Jones et al. 2009).
The mMRC assesses the grading of severity of breathlessness during daily activities. The 
scores range from 0-4, with a score of 0 representing ‘I only get breathless with strenuous 
exercise’ and a score of 4 representing ‘I am too breathless to leave the house or I am 
breathless when dressing or undressing’ (Fletcher 1960).
9.4.1.1
Validation of receipt of re-usable Respimat SMI Question
The re-usable Respimat SMI can be differentiated from the disposable Respimat SMI through 
the position of the dose indicator. In the re-usable Respimat SMI the dose indicator is 
attached to the base of the cartridge and in the disposable Respimat SMI, the dose indicator is 
located on the side of the inhaler. Patients will be advised to contact the sites if they are not 
dispensed a re-usable Respimat SMI product at study entry. 

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Additionally, at the time of the follow-up visit, single question will be asked to all patients to 
confirm the re-usable version of Respimat SMI was being used during the study period 
(Table 2).
Table 2: Validation of receipt of re-usable Respimat SMI
Validation of receipt of re-usable Respimat SMI
Scoring
Type of inhaler 
What type of inhaler have you been using since 
commencing the study?
- Re-usable inhaler
- Disposable inhaler
9.4.2
Patient Reported Outcome (PRO) assessment
9.4.2.1
Patient Satisfaction and Preference Questionnaire (PASAPQ)
The patients’ satisfaction with regard to the handling of the re-usable Respimat SMI will be 
measured by the self-administered, 15-item PASAPQ that includes a performance domain (7
items), a convenience domain (6 items), an overall satisfaction question (Item 14) and a 
question on willingness to continue with inhaler (Item 15). Only the questions in the 
performance and convenience domains count towards the total score. Questions 1-14 are 
answered using a 7-point ordinal scale with divisions from very dissatisfied to very satisfied; 
question 15 is answered using a value from 0-100, with zero indicating that the patient would 
not be willing to continue using the inhaler and 100 indicating that the patient would 
definitely be willing to continue using the inhaler (Kozma et al. 2005). The PASAPQ has 
been translated and validated for use in all the main languages of the study countries. 
To calculate the total score, the sum of the 13 items of the two domains (performance and 
convenience; items 1-13) are transformed to a 0- (least) to 100- (most) point scale, with 
higher scores indicating greater satisfaction. Missing data in the PASAPQ is handled as 
follows (Miravitlles et al. 2016): 
-
If half or more than half of the questions in the individual domains (performance and 
convenience) of the PASAPQ are missing for a patient, no score is calculated and the 
PASAPQ domain score is marked as missing.
-
If a patient answers at least half of the questions in the domain, values for missing 
questions will be imputed using the mean of the remaining, non-missing questions in 
that domain.
The PASAPQ will be administered to all patients (Respimat SMI-experienced and Respimat
SMI-naïve) at the follow-up assessment. Additionally, for the Respimat SMI-experienced 

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patients switching from a disposable to a re-usable Respimat SMI product at study entry, 
PASAPQ will be administered at the baseline visit (see Figure 2).
The PASAPQ will be administered in electronic format, with the provision for administration
in paper format, if required. The electronic questionnaire will be designed using a mobile-
first approach. The patients will receive a link to the PASAPQ via email, which they can 
complete using their hand-held electronic devices (such as smartphone, iPad or tablet), laptop 
or desktop computer. The link will be provided as follows:

At baseline visit (study entry): to the Respimat SMI-experienced patients switching 
from a disposable to a re-usable Respimat SMI product at study entry – the link will 
be valid for up to 3 days after the baseline visit.

At study end (i.e. 4 weeks after the baseline visit): to all patients (Respimat SMI-
experienced and Respimat SMI-naïve) – the link be valid for up to 2 weeks after study 
end.
Patients unable to complete the PASAPQ electronically may be provided with a paper 
version of the PASAPQ at study enrolment (baseline visit), if applicable. It can also be
mailed (with a pre-paid return envelope) to patients to be completed up to 2 weeks after study 
completion (follow-up assessment).
Table 3: PASAPQ questions and scoring
Domain
Question
Scoring
Performance
Q1: Overall feeling of inhaling your 
medicine
Items scored on a 7-point 
Likert scale: 
1 = Very dissatisfied
2 = Dissatisfied
3 = Somewhat dissatisfied
4 = Neither satisfied nor 
dissatisfied 
5 = Somewhat satisfied
6 = Satisfied
7 = Very satisfied
Q2: Inhaled dose goes to lungs 
Q3: Amount of medication left 
Q4: Works reliably
Q5: Ease of inhaling a dose 
Q10: Using the inhaler 
Q11: Speed medicine comes out
Convenience
Q6: Instructions for use
Q7: Size of inhaler
Q8: Durability of inhaler
Q9: Ease of cleaning inhaler
Q12: Ease of holding during use
Q13: Convenience of carrying
Overall 
Q14: Overall satisfaction with the inhaler
Total Score

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Domain
Question
Scoring
satisfaction 
question
Question on 
willingness to 
continue 
with inhaler
Q15: Willingness to continue using the 
inhaler that was used during the study
Score ranges from 0-100, 
with 0 indicating that the 
patient would not be willing 
to continue using this inhaler 
and 100 indicating that the 
patient would definitely be 
willing to continue
COPD: Chronic Obstructive Pulmonary Disease; PASAPQ: Patient Satisfaction and Preference Questionnaire; 
SMI: Soft Mist Inhaler.
Figure 2. Timing of the PRO data collection
9.4.2.2
Ease of handling questions
For all patients, the ease of handling of the re-usable Respimat SMI will be completed at the 
time of follow-up assessment, using a set of individual questions with answers to each 
question scored on a 7-point ordinal scale, with divisions from very dissatisfied to very 
satisfied (see Table 4 for details). 
9.4.2.3
Question on patient preference for re-usable or disposable in Respimat SMI-
experienced patients
A single question will be asked only to the Respimat-experienced patients switching from a 
disposable to a re-usable Respimat SMI product at study entry, to determine their preference 

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for the type of Respimat SMI: re-usable vs the disposable Respimat SMI (see Table 4 for 
details).
Table 4: Ease of handling questions and patient preference (for Respimat SMI-experienced 
patients switching from disposable to re-usable Respimat SMI at the time of study entry)
For all patients
Scoring
Ease of handling
Q1: How satisfied are you with the ease of 
removing the clear base?
All items scored on a 7-point 
Likert scale: 
1 = Very dissatisfied 
2 = Dissatisfied 
3 = Somewhat dissatisfied 
4 = Neither satisfied nor 
dissatisfied 
5 = Somewhat satisfied 
6 = Satisfied 
7 = Very satisfied
Q2: How satisfied are you with the grip of the 
cartridge?
Q3: How satisfied are you with inserting a new 
cartridge?
Q4: How satisfied are you with the readability 
of the dose indicator?
Q5: How satisfied are you with recognising 
when you need to replace the cartridge?
Q6: How satisfied are you with automatic 
detachment of the clear base when the cartridge 
is empty?
Q7: How satisfied are you with automatic 
return to the start-use position when replacing 
the clear base?
Q8: How satisfied are you with the overall ease 
of handling the inhaler?
Q9: 
How 
satisfied 
are 
you 
with 
the 
sustainability (eco-friendly) concept of the 
inhaler, due to re-use ability?
Q10: How satisfied are you with recognising 
when to replace the inhaler?
1 = Very dissatisfied 
2 = Dissatisfied 
3 = Somewhat dissatisfied 
4 = Neither satisfied nor 
dissatisfied 
5 = Somewhat satisfied 
6 = Satisfied 
7 = Very satisfied
8 = Not applicable
Only for Respimat SMI-Experienced patients switching from disposable to re-usable Respimat SMI at 
the time of study entry
Rating of inhaler 
preference 
Q1: Comparing the re-usable with disposable 
inhaler, please indicate which inhaler do you 
prefer to use?
- Re-usable inhaler
  - Disposable inhaler
  - No preference

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9.4.3
Adverse events
The safety data including serious and non-serious ADRs, AEs with a fatal outcome and other 
reportable safety events (see Table 6 and Section 10.2 for further details) will be extracted 
from the medical records and/or collected from a telephone interview (held by the 
Investigator’s staff) at the time of the follow-up assessment and entered into the eCRF where 
it will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
grouped by system organ class (SOC) and preferred term (PT).
9.5
STUDY SIZE
The primary objective of this study is to assess patient satisfaction for the re-usable Respimat 
SMI, measured by the total mean score of PASAPQ. Assuming a population standard 
deviation (SD) of 18 points, and a 95% confidence interval (CI), a sample size of at least 50 
patients will enable the estimation of a population mean total PASAPQ score within a margin 
of error (precision) of ±5.0 points. Assuming that 10% of patients will not have evaluable 
data (i.e. loss to follow-up), a total number of 56 patients is required.
To test for differences in the mean total PASAPQ score in Respimat SMI-experienced 
patients switching from a disposable to a re-usable Respimat SMI product at study entry, the 
minimum clinically important difference for PASAPQ, which has been previously reported as 
8-10 points, will be used (Hodder and Price 2009). A sample size of 56 patients will have a 
90% power to detect a minimum 8-point difference in total PASAPQ score means assuming 
SD of differences of 18 points, using a paired t-test with a 5% two-sided significance level. 
To account for potential 10% of patients with no evaluable data, a total sample size of 
minimum 63 patients is required. If the difference in the mean total PASAPQ score is further 
reduced to 6 points, the sample size will increase to 107 patients, accounting for a potential 
10% patients with no evaluable data at follow-up assessment. Different scenarios, depending 
on the desired power (80% or 90%) and mean difference of total PASAPQ score (6-, 8- and 
10-point difference) and considering an 18-point SD of differences are presented in Table 5.
Table 5: Sample size scenarios for detecting difference in total PASAPQ score means
Scenario 1
Scenario 2
Scenario 3
Scenario 4
Scenario 5
Scenario 6
Significance level (α)
0.05
0.05
0.05
0.05
0.05
0.05
Mean difference of
total PASAPQ score
6
6
8
8
10
10
SD of differences
18
18
18
18
18
18
Power (%)
80
90
80
90
80
90
Sample size, n
73
97
42
56
28
37

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In this study, a total of 250 patients will be enrolled, which is adequate to meet the primary 
and the secondary outcomes of the study. Further, subgroup analyses will be performed only
if the subgroups of interest include more than 20% of all patients.
9.6
DATA MANAGEMENT
A data management plan (DMP) will be created to describe all functions, processes, and 
specifications for data collection, cleaning and validation. All data will be collected and 
entered directly into the electronic data capture (EDC) system.
All participating sites will have access to the data entered regarding the individual site of its 
own enrolled patients. All sites will be fully trained on using the online data capture system, 
including the eCRF completion guidelines and help files. Sites will be responsible for 
entering extracted patient data into a secure internet-based EDC registry database via the 
eCRF. For electronic patient reported outcomes (ePROs), the data entered by the patients will 
be directly captured into the EDC.
The eCRFs will include programmable edits to obtain immediate feedback if data are missing 
(also negative answers, unknown), out of range, illogical or potentially erroneous. These rules 
may encompass simple checks such as range validation or presence/absence of data. 
Concurrent manual data review may be performed based on parameters dictated by the DMP.
High data quality standards will be maintained, and processes and procedures utilised to 
repeatedly ensure that the data are as clean and accurate as possible when presented for 
analysis. Data quality will be enhanced through a series of programmed data quality checks 
that automatically detect out of range or anomalous data.
9.7
DATA ANALYSIS
A comprehensive statistical analysis plan (SAP) will be prepared before database lock. The 
SAP will detail the most appropriate statistical methodology and analyses to be performed in 
accordance with the study design and objectives. 
All patients who have received at least one dose of their re-usable Respimat SMI product will 
be included in the analysis; this is the full analysis set (FAS). All analyses will be performed 
on the FAS. If a patient withdraws consent, the patient’s data collected before the consent 
withdrawal will remain in the dataset.
Results for both primary and secondary outcomes will be presented as the total study 
population, Respimat SMI-experienced patients switching from a disposable to a re-usable 
Respimat SMI product at study entry, Respimat SMI-experienced patients on maintenance 

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therapy with a re-usable Respimat SMI product at study entry and Respimat SMI-naïve 
patients (where applicable and if the sufficient number of patients are available). Further 
details will be provided in the SAP.
Qualitative variables will be summarised by frequency counts (n) and percentages (%) of 
patients in each category (unless otherwise specified) and 95% CIs, when applicable. Counts 
of missing data will be provided in all tables for information only. Percentages will not 
include the missing category and are calculated over the number of patients with available 
(non-missing) data. Continuous variables will be summarised by descriptive statistics (mean 
and SD, first quartile [Q1], median, third quartile [Q3], minimum and maximum). The 
number of non-missing and missing observations for each variable will also be reported.
Whenever applicable, two-sided 95% CIs will be calculated for the difference of means.
9.7.1
Main analysis
9.7.1.1
Primary outcome
The primary outcome is the mean total PASAPQ score at study end (follow-up assessment,
4-6 weeks after study entry), which will be summarised using descriptive statistics for 
continuous variables. The mean will be estimated together with a corresponding 95% CI.
9.7.1.2
Secondary outcomes
The total performance PASAPQ score, the total convenience PASAPQ score, the overall 
patient satisfaction score and the rating of willingness to continue with the inhaler at the 
follow-up assessment will be summarised using descriptive statistics for continuous 
variables.
Responses to the questions on the ease of handling of the re-usable Respimat SMI for all 
patients and patient preference for the re-usable or disposable Respimat SMI in Respimat
SMI-experienced patients switching from a disposable to a re-usable Respimat SMI product
at study entry will be summarised using descriptive statistics for categorical or continuous 
variables, as appropriate.
The change in total PASAPQ score from baseline to the end of the study period in the 
Respimat SMI-experienced patients switching from a disposable to a re-usable Respimat SMI
product at study entry will be analysed. The difference in the means of the total score and the 
performance and convenience domain scores between study entry and the follow-up 
assessment will be calculated along with the 95% CIs and compared using a two-tailed paired 
t-test or an appropriate non-parametric test (e.g. Wilcoxon signed ranks test), depending on 
the distributions of the count / score data.

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9.7.3
Handling of missing data
Due to the nature of the study, missing data (i.e. data that are not collected or documented in 
the patient medical record) may be observed for some variables. In general, missing data will 
not be imputed (except for dates). Partial dates will be imputed using the rules described in 
the SAP.
Missing data in the PASAPQ will be handled as per the rules outlined in Section 9.4.2.1.
9.8
QUALITY CONTROL
A study monitoring plan (Clinical Operations Plan), including for-cause monitoring, that is 
appropriate for the study design will be developed and implemented. 
During the remote site initiation visit, the monitor will provide training on the conduct of the 
study to the investigator, co-investigator(s), and all site staff involved in the study. Remote 
Site monitoring will be performed to examine compliance with the protocol and adherence to 
the data collection procedures, to assess the accuracy and completeness of submitted clinical 
data, and to verify that records and documents are being properly maintained for the duration 
of the study.
No regular source data verification is planned in this study. However, in case of decreasing 
compliance (i.e. of missing data, data discrepancies, protocol violations, etc.) a for-cause 
audit or risk-based monitoring visit will be performed.

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9.9
LIMITATIONS OF THE RESEARCH METHODS
The intention of this non-interventional study (NIS) is to collect data on patient satisfaction 
and preference for the re-usable Respimat SMI in a real life setting in patients with COPD.
However, heterogeneities in health-seeking behaviour, treatment and reporting practices 
between countries and sites within countries may introduce selection and information bias. 
Moreover, due to the real-world nature of the study and due to variabilities in efficiency and 
completeness of records, missing data are likely to be present and this may vary by country 
and/or site.
The sites selected will be a convenience sample and may not be representative of the 
geographic distribution or the clinic/hospital type or size in each of the participating 
countries. The enrolment will be competitive, although there may be capping at the country 
level to ensure that all countries are represented.
At the patient level, consecutive enrolment will be employed to minimise selection bias. 
Potential selection bias arising from the lack of complete enrolment of potentially eligible 
patients will be reduced by maintaining screening logs at sites. The eligibility criteria are 
largely non-restrictive, which will permit the enrolment of a broad COPD-patient population. 
The choice of treatment is at the discretion of the investigator, reflective of real-world clinical 
practice.
Information bias will be minimised by using standard eCRF, questionnaires and physicians’ 
training on the study protocol. The patients’ interpretation and understanding of the 
questionnaires and different educational backgrounds may also influence the results. Further, 
while the PASAPQ questionnaire has been validated (Kozma et al. 2005), the additional 
questions on the ease of handling of the re-usable Respimat SMI is a self-designed BI
questionnaire.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the Sponsor or 
Sponsor’s designees or by the 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.

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9.10.2
Study records
Case Report Forms (CRFs) for individual patients will be provided by the Sponsor, either on 
paper or via remote data capture.
9.10.2.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered (or reported) in the eCRFs that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study; also, current medical records must be available.
9.10.2.2
Direct access to source data and documents
The investigator/institution will permit study-related monitoring, audits, IRB/IEC review, and 
regulatory inspection, providing direct access to all related source data/documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of medical test 
results must be available at all times for review by the Sponsor’s clinical study monitor, 
auditor and inspection by health authorities. The Clinical Research Associate/Clinical 
Monitor Local and the auditor may review all CRFs/eCRFs and written informed consents.
9.10.3
Completion of study
The IRB/IEC/competent authority (CA) in each participating European Union (EU) member 
state needs to be notified about the end of the study (last patient/patient out, unless specified 
differently in Section 9.2) or early termination of the study.
9.11
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the 
study need to be available for inspection on request by the participating physicians, the 
Sponsor’s representatives, by the IRB/IEC and the regulatory authorities, i.e. the CA.

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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 AE can therefore be any unfavourable and 
unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an AE is at least a reasonable possibility. Adverse reactions may arise from the 
use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorisation include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event (SAE)
A SAE is defined as any AE which
-
results in death, 
-
is life-threatening, 
-
requires in-patient hospitalisation, or
-
prolongation of existing hospitalisation, 
-
results in persistent or significant disability or incapacity, or 
-
is a congenital anomaly/birth defect 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life-threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 

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allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a SAE.
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.
Other Reportable Safety Events
If occurring in conjunction with an AE, other reportable safety events (defined in Table 6) 
should be captured in the CRF/eCRF.
Table 6: Definitions for other reportable safety events
Safety Event
Definition
Overdose/Under dose
The patient has taken (accidentally or intentionally) above the maximal / 
below  the minimal recommended dose as stated in the product label / 
authorised product information
Drug Interaction
Includes an interaction with another drug, device, disease, food or alcohol
Exposure
Accidental exposure to BI product
Medication Error
Inappropriate use of BI product that was not intended. This may be an actual 
error that occurred, an error that was intercepted (near miss) or an error that 
could occur (potential)
Product Confusion
Type of medication error involving confusion between BI products or 
confusion between BI product with another manufacturer’s product
Use of Product outside of 
Product Label / Authorised 
Product Information
May be intentional (e.g. off-label use, misuse or abuse), unintentional (e.g. 
medication error) or the intention is not known
Lack (or Loss) of Effect
BI drug was ineffective (did not work) or the expected effect was not 
achieved 
Unexpected Therapeutic 
Benefit / Effect
Beneficial effect of a product aside from the use for which it has been given
BI: Boehringer Ingelheim.

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Technical Product Complaints
The term technical product complaints (TPC) refers to any indication of a product defect 
involving the possible failure of a product to meet any of its specifications or functionalities. 
TPC may have their origin in the design, materials and substances used, production, 
packaging, storage, or distribution of a product
10.2
COLLECTION AND REPORTING OF ADVERSE EVENTS, SERIOUS 
ADVERSE EVENTS, AND OTHER SAFETY-RELEVANT 
INFORMATION
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorisation. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason, the following AE collection and reporting requirements have 
been defined.
The following must be collected by the investigator in the eCRF from signing the informed 
consent onwards until the end of the study: 
-
All serious and non-serious ADRs related to the re-usable Respimat SMI products 
(Spiriva, Striverdi, Spiolto)
-
All AEs with a fatal outcome
-
All AEs occurring in conjunction with other reportable safety events (cf Table 6)
-
Pregnancy
All ADRs, including those persisting after study completion must be followed up until they 
are resolved, have been sufficiently characterised, or no further information can be obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an AE. An adverse reaction, in 
contrast to an AE, is characterised by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected.

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Medical judgement 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 aetiologies that could explain the event (e.g. 
pre-existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population
not exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is 
evident (e.g. pre-treatment cases, diagnosis of cancer or chronic disease within 
days/weeks of drug administration; an allergic reaction weeks after 
discontinuation of the drug concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives)
Of note, this criterion may not be applicable to those events where the 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

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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 study. Once a patient has been enrolled into the 
study, after having taken Spirivia Respimat, Striverdi Respimat or Spiolto Respimat, in scope 
of the study, the investigator must report any drug exposure during pregnancy, which 
occurred in a female patient or in a partner to a male subject to the Sponsor by means of Part 
A of the Pregnancy Monitoring Form. The outcome of the pregnancy associated with the 
drug exposure during pregnancy must be followed up and reported by means of Part B of the 
Pregnancy Monitoring Form. 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 
Expedited reporting of AEs and drug exposure during pregnancy
The following must be reported by the investigator on the NIS AE form from signing the 
informed consent onwards until the end of the study: 
Type of Report
Timeline
All serious ADRs associated with Spiriva®
Respimat®, Striverdi® Respimat or Spiolto®
Respimat
Immediately within 24 hours
All AEs with fatal outcome in patients exposed to 
Spiriva Respimat, Striverdi Respimat or Spiolto 
Respimat
Immediately within 24 hours
All non-serious ADRs associated with Spiriva
Respimat, Striverdi Respimat or Spiolto Respimat
7 calendar days
All pregnancy monitoring forms
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 AE, the investigator should provide the information requested on the 
appropriate eCRF pages and the NIS AE form.

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Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all AEs related to any BI drug other than the Spiriva
Respimat, Striverdi Respimat or Spiolto Respimat, according to the local regulatory 
requirements for spontaneous AE reporting at the investigator’s discretion by using the 
locally established routes and AE report forms. The term AE includes drug exposure during 
pregnancy, and, regardless of whether an AE occurred or not, any abuse, off-label use, 
misuse, medication error, occupational exposure, lack of effect, and unexpected benefit.
Reporting of other events
Other reportable safety events (for definitions see Table 6) are to be captured only if they 
occur in conjunction with an AE, and are documented in the eCRF as additional information 
regarding that AE.
Reporting of Technical Product Complaints (TPC)
In case of a potential Technical Product Complaint (TPC), please inform the Local 
Pharmaceutical Complaint Officer (LPCO) of the Marketing Site where the complaint was 
received within 24 hours and provide the necessary information. If the potential TPC also 
involves a reportable AE, including lack of efficacy, off-label use or if the wrong dosage was 
taken, the investigator must ensure that the relevant information is provided on the 
appropriate eCRF pages and the NIS AE form is completed and forwarded as well within the 
respective timelines outlined under expedited reporting.
Overview on Collection and Reporting of Safety-relevant Information
Figure 3 provides an overview of the requirements and processes described above.

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Figure 3. Collection and Reporting of Safety-Relevant Information
10.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local
and international regulatory requirements.

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11.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The rights of the investigator and of the Sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalisation of the Study Report.
A study specific publication plan will be developed to describe planned publications.

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12.
REFERENCES
12.1
PUBLISHED REFERENCES
[1]
Caillaud D, Le Merre C, Martinat Y, Aguilaniu B and Pavia D (2007). "A dose-ranging 
study of tiotropium delivered via Respimat Soft Mist inhaler or HandiHaler in COPD 
patients." Int J Chron Obstruct Pulmon Dis 2(4): 559-565.
[2]
Chrystyn H, Small M, Milligan G, Higgins V, Gil EG and Estruch J (2014). "Impact of 
patients’ satisfaction with their inhalers on treatment compliance and health status in 
COPD." Respir Med 108(2): 358-365. 
[3]
Dalby RN, Eicher J and Zierenberg B (2011). "Development of Respimat(®) Soft 
Mist™ inhaler and its clinical utility in respiratory disorders." Med Devices 4: 145-155. 
[4]
Dhand R, Cavanaugh T and Skolnik N (2018). "COPD in Primary Care: Key 
Considerations for Optimized Management: Considerations for Optimal Inhaler Device 
Selection in Chronic Obstructive Pulmonary Disease." J Fam Pract. 67(2 Suppl): S19-
s27. 
[5]
Dhand R, Eicher J, Hansel M, Jost  I, Meisenheimer M and Wachtel H (2019). 
"Improving usability and maintaining performance: human-factor and aerosol-
performance studies evaluating the new reusable Respimat inhaler." Int J Chron 
Obstruct Pulmon Dis. 14: 509-523. 
[6]
Dias Barbosa C, Balp M-M, Kulich K, Germain N and Rofail D (2012). "Literature 
review to explore the link between treatment satisfaction and adherence, compliance, 
and persistence." Patient Prefer Adherence 6: 39-48. 
[7]
Fletcher CM (1960). "Standardised questionnaire on respiratory symptoms: a statement 
prepared and approved by the MRC Committee on the Aetiology of Chronic Bronchitis 
(MRC breathlessness score)." Br Med J 2: 1665. 
[8]
GBD 2017 Disease and Injury Incidence and Prevalence Collaborators (2018). "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 392(10159): 1789-1858. 
[9]
GOLD (2019). "Global Strategy for the Diagnosis, Management and Prevention of 
COPD, Global Initiative for Chronic Obstructive Lung Pulmonary Disease (GOLD) 
(2019 Report)." (https://goldcoped.org/. Accessed April 10, 2019).
[10] Hodder R and Price D (2009). "Patient preferences for inhaler devices in chronic 
obstructive pulmonary disease: experience with Respimat Soft Mist inhaler." Int J 
Chron Obstruct Pulmon Dis. 4: 381-90. 
[11] Jones PW, Harding G, Berry P, Wiklund I, Chen WH and Kline Leidy N (2009). 
"Development and first validation of the COPD Assessment Test." Eur Respir J 34(3): 
648-654. 
[12] Kozma CM, Slaton TL, Monz BU, Hodder R and Reese PR (2005). "Development and 
validation of a patient satisfaction and preference questionnaire for inhalation devices." 
Treat Respir Med 4(1): 41-52.
[13] Miravitlles M, Montero-Caballero J, Richard F, Santos S, Garcia-Rivero JL, Ortega F 
and Ribera X (2016). " A cross-sectional study to assess inhalation device handling and 
patient satisfaction in COPD." Int J Chron Obstruct Pulmon Dis 11: 407-415. 
[14] Mirza, S., R. D. Clay, M. A. Koslow and P. D. Scanlon (2018). "COPD Guidelines: A 
Review of the 2018 GOLD Report." Mayo Clin Proc 93(10): 1488-1502. 

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[15] Rabe KF and Watz H (2017). "Chronic obstructive pulmonary disease." Lancet 389: 
1931-1940. 
[16] Schürmann W, Schmidtmann S, Moroni P, Massey D and Qidan M (2005). "Respimat 
Soft Mist inhaler versus hydrofluoroalkane metered dose inhaler: patient preference and 
satisfaction." Treat Respir Med 4(1): 53-61.

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
The stand-alone documents for this non-interventional study are:

Informed Consent Form

Patient Satisfaction and Preference Questionnaire (PASAPQ)

Statistical Analysis Plan (SAP)

Serious Adverse Event Report in Non-Interventional Studies - (S)AE NIS Form

Pregnancy Monitoring Form
All of the above documents will be archived in the Trial Master File in its original English 
master version.

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable.

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ANNEX 
3. 
PATIENT
SATISFACTION
AND
PREFERENCE
QUESTIONNAIRE (PASAPQ) DIRECT VERSION
PART 1: RATING OF SATISFACTION WITH INHALER ATTRIBUTES
Instructions: For the following questions, please check the response that best describes how 
satisfied you are with each of the following items.  Please take as much time 
as you need to answer each question.
Very
Dissatisfied
Dissatisfied
Somewhat 
Dissatisfied
Neither Satisfied
nor Dissatisfied
Somewhat Satisfied
Satisfied
Very
Satisfied
How satisfied are you…
1.
With the overall feeling of inhaling 
your medicine?
Inhaler
2.
With the feeling that the inhaled 
dose goes to your lungs?
Inhaler
3.
That you can tell the amount of 
medication left in your inhaler?
Inhaler
4.
That the inhaler works reliably?
Inhaler
5.
With the ease of inhaling a dose 
from the inhaler?
Inhaler
6.
With the instructions for use?
Inhaler
7.
With the size of your inhaler?
Inhaler
8.
That the inhaler is durable (hard 
wearing)?
Inhaler
▼
Please go to the next page 

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Very
Dissatisfied
Dissatisfied
Somewhat Dissatisfied
Neither Satisfied
nor Dissatisfied
Somewhat Satisfied
Satisfied
Very
Satisfied
9.
With the ease of cleaning your 
inhaler?
Inhale
r
10.
With using the inhaler?
Inhale
r
11.
With the speed at which medicine 
comes out of the inhaler?
Inhale
r
12.
With the ease of holding the inhaler 
during use?
Inhale
r
13.
With the overall convenience of 
carrying the inhaler with you?
Inhale
r
14.
Overall, how satisfied are you with 
your inhaler?
Inhale
r
▼
Please go to the next page 

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PART 2: RATING OF WILLINGNESS TO CONTINUE WITH INHALER
15.
How would you feel about continuing to use the inhaler?
Please indicate your willingness to continue using the inhaler that you used during the 
study by providing a value between 0 and 100.
0 indicates that you would not be willing to continue using this inhaler and 100 
indicates that you would definitely be willing to continue.
Please write in a number in the box that is between 0 and 100.
Inhaler
The box should contain a number between 0 and 100.