Specific Use-result Surveillance of Spiriva Respimat in Asthmatics (Patients With Severe Persistent Asthma)
Conditions: Asthma
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
Non-interventional Study Protocol
TITLE PAGE
Document Number:
c02810760-01  
BI Study Number:
205.525
BI Investigational
Product:
Tiotropium inhalation solution – Respimat Inhaler (Ba 679 BR 
Respimat)
Title:
Specific Use-Result Surveillance of Spiriva Respimat in 
asthmatics(patients with severe persistent asthma)
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
Not applicable
PASS:
Yes
EU PAS register 
number:
To be registered
Active substance:
R03BB04 : Tiotropium
Medicinal product:
Spiriva® 2.5 μg Respimat® 60 puffs (hereinafter referred to as 
Spiriva Respimat)
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder:
Joint PASS:
No
Research question and 
objectives:
This PMS is designed:
To investigate the safety and effectiveness of Spiriva Respimat
in patients with severe persistent asthma under real-world use.
Country of study:
Japan
Author:
Marketing authorisation 

Boehringer Ingelheim
Page 2 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
holder:
MAH contact person:
EU-QPPV:
Signature of EU-
QPPV:
(e-signature is on BIRDS)
Date:
22 April 2015
Page 1 of 38
Proprietary confidential information
© 2015 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
TBD = to be determined

Boehringer Ingelheim
Page 3 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 6
4.
ABSTRACT........................................................................................................... 7
5.
AMENDMENTS AND UPDATES....................................................................... 9
6.
MILESTONES..................................................................................................... 10
7.
RATIONALE AND BACKGROUND................................................................ 11
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 13
9.
RESEARCH METHODS .................................................................................... 14
9.1
STUDY DESIGN............................................................................................ 14
9.1.1
Outcomes: effectiveness.......................................................................... 14
9.1.1.1
Primary outcome .................................................................................. 14
9.1.1.2
Secondary outcome .............................................................................. 14
............................................................................... 14
9.1.1.4
Assessment of effectiveness................................................................. 15
9.1.2
Outcomes for safety ................................................................................ 15
9.1.2.1
Primary Outcome ................................................................................. 15
9.2
SETTING........................................................................................................ 15
9.2.1
Site selection: .......................................................................................... 15
9.2.2
Selection of population............................................................................ 16
9.2.2.1
Inclusion/Exclusion criteria:................................................................. 16
9.2.2.2
Patient registration method................................................................... 16
9.2.2.3
Registration period ............................................................................... 16
9.2.3
Observations............................................................................................ 17
9.2.5
Discontinuation of the study by the sponsor ........................................... 17
9.3
VARIABLES .................................................................................................. 17
9.4
DATA SOURCES........................................................................................... 18
9.5
STUDY SIZE.................................................................................................. 18
9.6
DATA MANAGEMENT................................................................................ 18
9.7
DATA ANALYSIS......................................................................................... 19

Boehringer Ingelheim
Page 4 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.7.1
Analyses of outcome events.................................................................... 19
9.7.2
Safety analyses ........................................................................................ 19
9.7.3
Analyses of other variables ..................................................................... 19
9.7.4
Interim analyses....................................................................................... 20
9.8
QUALITY CONTROL................................................................................... 20
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 20
9.10
OTHER ASPECTS ......................................................................................... 20
9.10.1
INFORMED CONSENT, DATA PROTECTION, STUDY RECORDS20
9.10.1.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT.......................................................................................................... 20
9.10.1.2 DATA QUALITY ASSURANCE ....................................................... 20
9.10.1.3 RECORDS............................................................................................ 21
9.10.1.3.1
Source documents ......................................................................... 21
9.10.1.3.2
Direct access to source data and documents ................................. 21
9.10.1.4 STATEMENT OF CONFIDENTIALITY........................................... 21
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 22
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 23
11.1
Definitions of adverse events.......................................................................... 23
11.2
Adverse event and serious adverse event COLLECTION AND REPORTING24
11.3
Time windows................................................................................................. 26
11.4
Documentation of adverse events and patient narratives................................ 26
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 27
13.
REFERENCES .................................................................................................... 28
13.1
PUBLISHED REFERENCES......................................................................... 28
13.2
UNPUBLISHED REFERENCES................................................................... 28
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 29
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS ................................. 30
ANNEX 3. FLOW CHART OF VARIABLES ............................................................ 37

Boehringer Ingelheim
Page 5 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
CI
Confidence Interval
CRF
Case Report Form
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EudraCT
European Clinical Trials Database
EU-QPPV
European Union – Qualified Person for Pharmacovigilance
FAS
Full Analysis Set
FEV1
Forced Expiratory Volume in one second 
GCP
Good Clinical Practice
GPSP
Good Post- marketing Study Practice
FVC
Forced Vital Capacity
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File
J-PAL
Japanese Pharmaceutical Affairs Law
J-RMP
Japan Risk Management Plan
MedDRA
Medical Dictionary for Regulatory Activities
MR
Medical Representative
NBI
Nippon Boehringer Ingelheim Co. Ltd.
OPU
Operative Unit
PEFR
Peak Expiratory Flow Rate
PMDA
Pharmaceuticals and Medical Devices Agency
PMS
Post Marketing Surveillance
SAE
Serious Adverse Event
SPC
Summary of Product Characteristics
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
TMM
Team Member Medicine
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan

Boehringer Ingelheim
Page 6 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
3.
RESPONSIBLE PARTIES
Sponsor

Boehringer Ingelheim
Page 7 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
SPIRIVA Respimat
Name of active ingredient:
Tiotropium bromide
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
15 April 2015
205.525
Ver 1.0
n.a.
Title of study:
Specific Use-Result Surveillance of Spiriva Respimat in 
asthmatics(patients with severe persistent asthma)
Rationale and 
background:
The safety of Spiriva® 2.5 μg Respimat® 60 puffs (hereinafter referred 
to as Spiriva® Respimat®) in patients with severe persistent asthma 
under the real-world use was not confirmed in clinical trials.
Research question 
and objectives:
This PMS is designed;
To investigate the safety and effectiveness of Spiriva Respimat in 
patients with severe persistent asthma under real-world use.
Study design:
Non-interventional, observational study based on new data collection
Population:
Inclusion criteria:
• Patients diagnosed with severe persistent bronchial asthma
• Patient aged ≥15 years old
• Patients who are naive to Spiriva respimat and receive Spiriva 
Respimat for the first time for the treatment of bronchial asthma on 
top of at least ICS treatment.
Variables:
Demographics
Medical history/baseline conditions
Previous/concomitant therapies
Pulmonary function test (peak expiratory flow rate, forced expiratory 
volume in 1 second, forced vital capacity), if available
Asthma severity and asthma control status, if available
ACQ 6 score, if available
Spiriva Respimat administration
Adverse event
Safety laboratory test (if corresponding AEs are reported)
Data sources:
Patients data will be gathered by electronic Case Report Form on EDC
Study size:
300 (safety set)
Data analysis:
Descriptive
Milestones:
Final report will be made by 1 Apr 2018
Study result in re-examination will be submitted to PMDA (Jan. 2019)

Boehringer Ingelheim
Page 8 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 9 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.
AMENDMENTS AND UPDATES
There are currently no amendments to the protocol.

Boehringer Ingelheim
Page 10 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.
MILESTONES
Milestone
Planned Date
Start of data collection
1 Jun 2015
End of data collection
31 Aug 2017
Study progress report
None
<Registration in the EU 
PAS register>
To be registered
Final report of study results:
1 Apr 2018
(Study result in re-examination will be submitted to PMDA 
by Jan. 2019)

Boehringer Ingelheim
Page 11 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.
RATIONALE AND BACKGROUND
Tiotropium is one of the most widely used long-acting bronchodilators worldwide for the 
treatment of COPD, and now, after systematic clinical investigation, it is proposed to be 
designated for relief of various symptoms associated with the obstructive impairment of 
airways due to the following diseases: chronic obstructive pulmonary disease (chronic 
bronchitis, emphysema), bronchial asthma.
Tiotropium delivered via the RESPIMAT inhaler once daily demonstrated consistent and 
significantly improved lung function parameters in the Phase III trials despite the fact that the 
requirement for stable asthma maintenance therapy at baseline and throughout the treatment 
period might impose limitations on the effect size that can be achieved with an additional 
treatment. In addition to the improvements in lung function, patients who remained 
symptomatic despite treatment with at least a high-dose ICS+LABA or medium-dose ICS 
were shown to have a symptomatic benefit from taking tiotropium [U13-1598-01].
Tiotropium delivered via the RESPIMAT inhaler once daily also demonstrated acceptable 
long-term safety and tolerability when administered at a dose of 5 µg (Tio R5) to adult 
patients with asthma. Exposure to tiotropium in the clinical program covered more than 1000 
patient-years in more than 2200 patients. The overall frequencies of AEs, drug-related AEs, 
and SAEs were similar across all treatment groups in trials with the same duration and patient 
population. In general, no specific concerns with regard to abnormal vital signs were raised 
for patients who took tiotropium. There were no consistent patterns of increases in particular 
AEs for the tiotropium treatment groups compared to the placebo in any subgroup analysis. 
No deaths were reported during the entire clinical program [U13-1598-01].
According to the current guidelines for the treatment of asthma, although various treatment 
options are available for long-term asthma management including ICS as the first-line 
therapy and other additional therapies depending on asthma severity (e.g., LABA, leukotriene 
receptor antagonist, theophyllines, antihistamines, oral steroids, anti-IgE), improvement of 
symptoms is insufficient in many patients (i.e., uncontrolled and/or at potential risk of asthma 
exacerbation), and there is a growing medical need for additional therapeutic options for the 
treatment of asthma [! "#$"%"&%]. Responding to the medical needs, inhaled administration of 
anticholinergic bronchodilator Tio R5 as a new additional maintenance therapy in patients 
with asthma who remain symptomatic despite treatment with at least ICS has significance in 
managing lung function and symptoms of asthma patients more appropriately and may be an 
important paradigm shift in the treatment of asthma patients.
Result of PMDA review
PMDA judged that the 5-μg dosage form was suitable only for patients with severe persistent 
asthma and the 2.5-μg dosage form was suitable for patients with mild to moderate persistent 
asthma. But the 2.5-μg dosage form is not established for marketing and the 5-μg dosage 
form has no data to ensure the dose of 2.5 μg in one inhalation because Respimat inhaler can 
only maintain quality assurance with two inhalations at a time.
For the above reason including PMDA review, Spiriva Respimat (5-μg dosage form) for use 
in severe persistent asthmatics age 15 or over was approved on November 18 2014 in Japan. 

Boehringer Ingelheim
Page 12 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
PMDA instructed NBI to conduct the PMS with sever persistent ashmatics at age 15 or over 
as an approval condition in J-RMP.
Japanese regulation related to Post Marketing Surveillance (PMS)
This PMS study is planned according to the Japanese Law for Ensuring the Quality, Efficacy, 
and Safety of Drugs and Medical. The law requires in principle that data on the safety and 
effectiveness of all launched products to be accumulated under real-world clinical practice. 
The data collected in the PMS study are required to be submitted to the Pharmaceuticals and 
Medical Devices Agency (PMDA), the local regulatory agency in Japan, according to the 
process of re-examination which will take place 4 years after approval of registration. The 
PMS study is a part of the local Risk Management Plan in Japan (J-RMP) to be submitted to 
PMDA at New Drug Application.

Boehringer Ingelheim
Page 13 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.
RESEARCH QUESTION AND OBJECTIVES
As the submission data package for registration in Japan, we participated in two studies in 
adult patients  with severe persistent asthma  (Studies 205.416 and 205.417) and two studies 
(Studies 205.418 and 205.419)  in adult patients with moderate persistant asthma , and we 
comparatively investigated the dose response between Japanese and non-Japanese by using 
two doses (Tio R2.5 and Tio R5). With the addition of the domestic long-term administration 
study in Japanese patients (Study 205.464), we investigated the validity of selecting a dose of 
5 μg in Japanese asthma patients [U13-1598-01].
In the clinical trials, 212 Japanese patients with asthma received Tio R5 up to 52 weeks and 
some concomitant asthma therapies were allowed. However the clinical trials reflected a 
limited controlled experiment that might not generalize to the population, setting or condition 
and might not be reflected due to prohibited concomitant drugs or exclusion criteria of
complicating diseases. The primary aim of clinical trials is to measure the key clinical 
efficacy as an end point in a limited population and clinical setting. PMS is likely to improve 
data monitoring and can collect post-marketing safety data in response to specific safety 
concerns. Even though there was no safety concern reported in patients with asthma based on 
the results of clinical trials, PMDA directed NBI to conduct PMS to fulfill regulatory 
obligations established as a condition of marketing approval.
The objective of this PMS is to investigate the safety and effectiveness of Spiriva Respimat in 
patients with severe persistent asthma under real-world use. 

Boehringer Ingelheim
Page 14 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a non-interventional study based on newly collected data under routine medical 
practice.
This PMS is designed to investigate the safety and effectiveness of Spiriva Respimat in 
patients with severe persistent asthma on top of at least ICS maintenance treatment under  real-
world use. 
9.1.1
Outcomes: effectiveness
9.1.1.1
Primary outcome
There is no primary outcome for effectiveness as the primary objective of a PMS is 
evaluating safety. The primary outcome for safety is described in Section 9.1.2.1.
9.1.1.2
Secondary outcome

Change from baseline in asthma control status at Week 52  

Boehringer Ingelheim
Page 15 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.1.1.4
Assessment of effectiveness
Asthma control status:
Asthma control status will be assessed based on the “Asthma prevention and management 
guideline” [ ! "#$"%"&%] .
  
9.1.1.4: 1 Asthma control status Table 
Patients control status
Well-controlled
Insufficiently-
controlled
Poorly-controlled
Meet all the 
criteria
Meet 1 or 2 
criteria
Meet all of 3
Criteria
Asthma symptoms (in the 
daytime or at night)
None
Once or more a 
week
Once or more a 
week
Use of reliever
None
Once or more a 
week
Once or more a 
week
Limitation of activities, 
including exercise
None
Restricted
Restricted
9.1.2
Outcomes for safety
9.1.2.1
Primary Outcome
The primary Outcome is the absolute and relative (%) frequency of patients with suspected 
adverse drug reactions (ADRs).
Safety will be assessed by use of the following other parameters of interest: 

Adverse events irrespective of seriousness

Laboratory tests (if corresponding AEs are reported)
9.2
SETTING
9.2.1
Site selection:
NBI will nominate the candidate sites which satisfied the following criteria and NBI  ask the 
nominated sites to participate in the study.
1. Spiriva Respimat has been delivered to the site.
2. The observation of peak expiratory flow meter is done as part of the usual medical 
practice.
Planned number of sites: Approximately 25 Sites

Boehringer Ingelheim
Page 16 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
A medical representative will explain the objectives, subjects and methods of the surveillance 
to the investigator at the site and exchange a written contract with the head of the site (e.g., 
hospital director).
9.2.2
Selection of population
9.2.2.1
Inclusion/Exclusion criteria:
Inclusion criteria:
•
Patients diagnosed with severe persistent bronchial asthmaPatient aged ≥15 years
•
Patients who are naive to Spiriva Respimat and receive Spiriva Respimat for the first 
time for treatment of bronchial asthma on top of at least ICS treatment.
  *:Asthma severity is defined by “Table 6 Classification of asthma severity based on 
the present treatment (adult)” of “Japanese Guideline for Adult Asthma 2014”[P14-
15105]. Most severe persistent asthma is included in “Severe persistent asthma” 
indication in J-PI of Spiriva Respimat.
Exclusion criteria:
•
Patients who have a contraindication to Spiriva Respimat defined in the package 
insert for Spiriva Respimat
•
Patients who have been enrolled this study before. 
9.2.2.2
Patient registration method
The registration method will be a continuous investigation system. Patients who begin 
treatment with Spiriva Respimat after the conclusion of the contract will be registered by 
entering necessary information in the EDC within 14 days whenever possible from the day of 
treatment initiation (inclusive).
The necessary variable for registration is gender, date of birth, start date of administration and
the reason for use. And ICS treatment as of inclusion criteria will be checked in the EDC 
system. 
Patient registration will be stopped when the target number of the study is reached. After the 
end of the registration period, investigators will use a signed form to confirm that patients 
will be registration continuously at the site. A log of all patients included into the study will 
be maintained at the site.
9.2.2.3
Registration period
From June 2015 to May 2016

Boehringer Ingelheim
Page 17 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.2.3
Observations
After start of the treatment with Spiriva Respimat, each patient will be observed for 52 weeks 
(approximately 12 months) or at premature discontinuation from the PMS. Observations are 
made at the following time points: before first administration of Spiriva Respimat (this visit is 
defined as baseline), 4 weeks, 12 weeks and 52 weeks after the start of treatment, or at 
discontinuation.
 
9.2.5
Discontinuation of the study by the sponsor
NBI reserves the right to discontinue the PMS overall or at a particular PMS study site at any 
time for the following reasons:
1. Failure to meet expected registration overall goals or goals at a particular study site,
2. Emergence of any effectiveness/safety information that could significantly affect 
continuation of the PMS,
3. Violation of Good Post-marketing Study Practice (GPSP) or the contract of a study site or 
investigator, thereby disturbing the appropriate conduct of the PMS.
The investigator / the PMS site will be reimbursed for reasonable expenses incurred as a 
result of PMS termination (except in case of the third reason).
9.3
VARIABLES
The investigator will enter the following patient data into the eCRF for registration. 

Patient’s ID, gender, date of birth, start date of administration, indication, asthma 
severity
The observation items include the following:

Demographics

Medical history/baseline conditions

Previous/concomitant therapies

Spiriva Respimat administration

Pulmonary function test (peak expiratory flow rate, forced expiratory volume in 1 
second, forced vital capacity), if available

Asthma severity and asthma control status[! "#$"%"&%], if available

ACQ 6 score, if available

Boehringer Ingelheim
Page 18 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Adverse event

Laboratory test (if corresponding AEs are reported)
Additional variable will also be included in the CRF such as cardiovascular risk factors 
including smoking and weight.
See ANNEX 3 for more details.
9.4
DATA SOURCES
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via the 
Electronic Data Capture (EDC) system.
Three case books will be used. The first book is for registry (Book 1), the second book is for 
baseline, 4 and 12 weeks (Book 2) and the third book is for 52 weeks (Book 3).
Data are to be transmitted immediately after being entered into the eCRF at 12 weeks and 52 
weeks after the start of treatment or at discontinuation. In the case that any adverse events
occur, the data should be immediately entered into eCRF and transmitted.
9.5
STUDY SIZE
It is planned to enroll 360 patients with severe persistent asthma: 360 patients will initiate the 
Spiriva Respimat treatment, assuming 60 patients out of 360 patients will be dropped out 
without any data being collected.
The planned number of patients is not driven by a formal sample size calculation but is 
primarily based on the availability of patients eligible for Spiriva Respimat treatment.
300 patients will be registered for this study. The frequently observed ADR (>1.0%) in
special use surveillance for Spiriva Respimat in patients with COPD was Coughing (1.2%). 
The frequently observed ADRs (>1.0%) in the clinical trial in Japanese patients with asthma 
were asthma (1.8%), dysphonia (1.8%) and dry mouth (1.8%). In the number of cases to be 
surveyed, it is evaluated if there is no possibility that the trend of incidence of these main 
adverse events would be largely increased compared to that of COPD patients.
  
9.6
DATA MANAGEMENT
Data are gathered using EDC.

Boehringer Ingelheim
Page 19 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.7
DATA ANALYSIS
This is a non-interventional, observational study to collect new real-world data (i.e., data 
under routine medical practice) on safety and effectiveness of Spiriva Respimat treatment in 
patients. Analyses are descriptive in nature. Due to the nature of the observational study, no 
confirmatory statistical testing is foreseen in this study.
Per local regulation, any patient who meets one of the following criteria is treated as 
ineligible for all analyses: 
•
No safety observation was documented after registration
•
No required registration procedure was followed
•
No valid site contract was available
9.7.1
Analyses of outcome events
The analysis of outcome events will include all patients registered in the study and receiving 
the Spiriva Respimat treatment. All outcome events are based on reported AE data which will 
be handled according to BI standards. 
9.7.2
Safety analyses
The safety analysis will include all patients registered in the study and receiving the Spiriva 
Respimat treatment. In general, safety analyses will be descriptive in nature, will be based on 
BI standards, and will focus on ADRs related to the Spiriva Respimat treatment.
AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be based on the concept of treatment emergent AEs. To this 
end, all AEs occurring between the first intake of Spiriva Respimat prescribed at baseline 
visit and within 30 days (inclusive) after the last intake will be considered ‘treatment 
emergent’. An AE is considered to be ADR if either the physician who has reported the AE 
or the sponsor assesses its causal relationship as ‘related’.
The frequency of AEs/ADRs will be tabulated by system organ class and preferred term for 
overall and for subgroups based on the important baseline characteristics. 
No imputation is planned for missing AE data except for missing onset dates which will be 
handled according to BI standard.
9.7.3
Analyses of other variables
Descriptive statistics will be calculated for all outcomes.
A missing score for an item may be replaced as the mean score of the available data. In case 
of a missing ACQ 6 score, the missing score will not be imputed.
For other variables, missing data will not be imputed.

Boehringer Ingelheim
Page 20 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.7.4
Interim analyses
Several interim analyses will be performed for the purpose of creating periodic safety update 
reports to the local authority (every 6 to 12 months depending on the time from the approval).
9.8
QUALITY CONTROL
All processes are conducted according to GPSP SOPs and GPSP working instruction. 
Appropriate records and documents are stored based on the GPSP SOPs and these processes
are checked by internal self-check. 
9.9
LIMITATIONS OF THE RESEARCH METHODS
No randomized assignment of patients to the survey is implicated. This may induce selection 
bias. The site will be nominated by the availability of conducting the study with a peak flow 
meter, and might have a more intensive observation compared with the non-selected site.
9.10
OTHER ASPECTS
9.10.1
INFORMED CONSENT, DATA PROTECTION, STUDY RECORDS
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the patient’s treating physician.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this PMS are described in the contract. 
9.10.1.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
The review by IRB is not mandatory for conducting PMS in Japanese GPSP. The sponsor 
will enter into a contract with a representative (e.g., head of hospital) in accordance with 
GPSP. Written informed consent prior to patient participation in the trial is not a regulatory or 
legal requirement in accordance with GPSP.
9.10.1.2
DATA QUALITY ASSURANCE
This PMS is to be conducted in accordance with both the in-house PMS SOP and working 
instructions which are in compliance with GPSP. This study should be conducted in 
compliance with SOP 001-MCS-90-118.

Boehringer Ingelheim
Page 21 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.10.1.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via the 
Electronic Data Capture (EDC) system.
9.10.1.3.1 Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the study; also current 
medical records must be available.
For eCRFs, all data must be derived from source documents.
9.10.1.3.2 Direct access to source data and documents
Direct access to source data and documents for PMS is not allowed in Japan.
9.10.1.4
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this PMS 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.
Data generated as a result of the PMS needs to be available for inspection on request by the 
regulatory authorities.

Boehringer Ingelheim
Page 22 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
10.
PROTECTION OF HUMAN SUBJECTS
There is no regulation or requirement for ensuring the well-being and rights of participants in 
a non-interventional observational study.

Boehringer Ingelheim
Page 23 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a study who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.  An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product.
Adverse Drug Reaction (ADR)
A response to a medicinal product which is noxious and unintended.
Response in this context means that a causal relationship between a medicinal product and an 
adverse event is at least a reasonable possibility.
Adverse reactions may arise from use of the product within or outside the terms of the 
marketing authorisation or from occupational exposure. Conditions of use outside the 
marketing authorisation include off-label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event - is defined as any AE which
-
results in death, 
-
-is immediately life-threatening,
-
-requires in-patient hospitalization, or
-
prolongation of existing hospitalization
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.

Boehringer Ingelheim
Page 24 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Every new occurrence of cancer will be is to be considered as SAE regardless of the duration 
between discontinuation of the study medication and the occurrence of the cancer.
Adverse Event of Special Interest (AESI)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this 
study, e.g. the potential for AEs based on knowledge from other compounds in the same class. 
No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection and Reporting of AEs:
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorisation. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined.
The following must be collected by the investigator in the (e)CRF via EDC system from first 
intake of Spiriva Respimat prescribed at baseline visit and within 30 days (inclusive) after the 
last intake: 
-
all ADRs (serious and non-serious) as soon as possible,
-
all AEs with fatal outcome in patients exposed to Spiriva Respimat as soon as 
possible,
-
all AEs which are relevant for a serious ADR or an AE with fatal outcome in 
patients exposed to Spiriva Respimat as soon as possible 
All ADRs including those persisting after study completion must be followed up until they 
are resolved, have been sufficiently characterized, or no further information can be obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.
Causal relationship of adverse event:
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 

Boehringer Ingelheim
Page 25 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug 
exposure.
•
Evidence that the event is reproducible when the drug is re-
introduced
•
No medically sound alternative etiologies that could explain the 
event (e.g. preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general 
population not exposed to drugs (e.g. Stevens-Johnson syndrome).
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 its pharmacological properties of the compound 
(e.g. after 5 half-lives).
•
Of note, this criterion may not be applicable to events whose time 
course is prolonged despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative 
explanation (e.g. situations where other drugs or underlying diseases 
appear to provide a more likely explanation for the observed event than 
the drug concerned).
•
Disappearance of the event even though the study drug treatment 
continues or remains unchanged.
   Intensity of adverse event
   The intensity of the AE should be judged based on the following:
    Mild:
             Awareness of sign(s) or symptom(s) which is/are easily tolerated
    Moderate 
Enough discomfort to cause interference with usual activity
    Severe:              Incapacitating or causing inability to work or to perform usual activities
The intensity of adverse events should be classified and recorded according to the above 
referenced definition in the (e)CRF.

Boehringer Ingelheim
Page 26 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Pregnancy
In rare cases, pregnancy might occur in a study. Once a subject, has been enrolled into the 
study after having taken Spiriva Respimat, the investigator must report any drug exposure 
during pregnancy which occurred in a female subject or in a partner to a male subject to the 
Sponsor by means of Part A of the Pregnancy Monitoring Form. The outcome of the 
pregnancy associated with the drug exposure during pregnancy must be followed up and 
reported by means of Part B of the Pregnancy Monitoring Form. 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed. 
The investigator will report the Pregnancy Monitoring Forms to sponsor as soon as possible 
via the unique entry point described in the Site Materials. 
Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other than 
the Spiriva Respimat according to the local regulatory requirements for spontaneous AE 
reporting at the investigator’s discretion by using the locally established routes and AE report 
forms. The term AE includes drug exposure during pregnancy, and, regardless of whether an 
AE occurred or not, any abuse, off-label use, misuse, medication error, occupational 
exposure, lack of effect, and unexpected benefit.
11.3
TIME WINDOWS
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "expected" (i.e., is a known side effect of the drug or 
not). Therefore a unique reference document for the evaluation of expectedness needs to be 
provided. For the study product, this is the current version of the Japan PI (package inserts). 
The current versions of these reference documents are to be provided in the Site material. 
11.4
DOCUMENTATION OF ADVERSE EVENTS AND PATIENT 
NARRATIVES
Expedited reporting of serious adverse events (e.g., suspected unexpected serious adverse 
reactions (SUSARs) to health authorities) will be done according to local regulatory 
requirements. Further details regarding this reporting procedure are provided in the Site
material.

Boehringer Ingelheim
Page 27 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The progress reports and final reports will be submitted to PMDA in Japan PSR (Periodic
safety report). And also the final report will be submitted in re-examination documents.
This study is planned for the publication based on the final report.

Boehringer Ingelheim
Page 28 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
13.
REFERENCES
13.1
PUBLISHED REFERENCES
! "#$"%"&%'()* +, -.(/0123 4, 5*6*0323 78/9 3:/03 ;1< =98:) =2)(>* ?&"#,=::3<@1:1@A 
-0),
?&"#,BCD?EC$CCC
13.2
UNPUBLISHED REFERENCES
U13-1598-01 2.5 Clinical Overview, Spiriva Respimat, addition of asthma indication, 25 July 
2013

Boehringer Ingelheim
Page 29 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference 
Number
Date
Title
None

Boehringer Ingelheim
Page 30 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
ANNEX 2. ENCEPP CECKLIST FOR STUDY PROTOCOLS
Doc.Ref. EMEA/540136/2009 
ENCePP Checklist for Study Protocols (Revision 2, amended)
Adopted by the ENCePP Steering Group on 14/01/2013
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) 
welcomes innovative designs and new methods of research. This Checklist has been developed by 
ENCePP to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist is intended to 
promote the quality of such studies, not their uniformity. The user is also referred to the ENCePP 
Guide on Methodological Standards in Pharmacoepidemiology which reviews and gives direct 
electronic access to guidance for research in pharmacoepidemiology and pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the page number(s) of the protocol where 
this issue has been discussed should be specified. It is possible that some questions do not apply 
to a particular study (for example in the case of an innovative study design). In this case, the 
answer ‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section 
should be used to explain why. The “Comments” field can also be used to elaborate on a “No” 
answer. 
This Checklist should be included as an Annex by marketing authorisation holders when submitting 
the protocol of a non-interventional post-authorisation safety study (PASS) to a regulatory 
authority (see the Guidance on the format and content of the protocol of non-interventional post-
authorisation safety studies). Note, the Checklist is a supporting document and does not replace 
the format of the protocol for PASS as recommended in the Guidance and Module VIII of the Good 
pharmacovigilance practices (GVP). 
Study title: 
Specific Use-Result Surveillance of Spiriva Respimat in asthmatics (patients with severe 
persistent asthma)
Study reference number: BI Study Number: 205.525
Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
European Network of Centres for 
Pharmacoepidemiology and 
Pharmacovigilance

Boehringer Ingelheim
Page 31 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
1.1 Does the protocol specify timelines for 
1.1.1 Start of data collection1
1.1.2 End of data collection2
1.1.3 Study progress report(s) 
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
1.1.6 Final report of study results.
10
10
10
10
10
10
Comments:
     none
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2 Date from which the analytical dataset is completely available.
Section 2: Research question
Yes
No
N/A
Page 
Number(s)
2.1 Does the formulation of the research question and 
objectives clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address an 
important public health concern, a risk identified in the risk 
management plan, an emerging safety issue)
2.1.2 The objective(s) of the study?
11
13
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
2.1.4 Which formal hypothesis(-es) is (are) to be 
tested? 
2.1.5 If applicable, that there is no a priori
hypothesis?
16
Comments:
none
Section 3: Study design
Yes
No
N/A
Page 
Number(s)
3.1 Is the study design described? (e.g. cohort, case-
control, randomised controlled trial, new or alternative design) 
14
3.2 Does the protocol specify the primary and 
secondary (if applicable) endpoint(s) to be 
investigated?
14,15

Boehringer Ingelheim
Page 32 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Section 3: Study design
Yes
No
N/A
Page 
Number(s)
3.3 Does the protocol describe the measure(s) of 
effect? (e.g. relative risk, odds ratio, deaths per 1000 
person-years, absolute risk, excess risk, incidence rate ratio, 
hazard ratio, number needed to harm (NNH) per year)
Comments:
     none
Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1 Is the source population described?
4.2 Is the planned study population defined in terms 
of:
4.2.1 Study time period?
4.2.2 Age and sex?
4.2.3 Country of origin?
4.2.4 Disease/indication? 
4.2.5 Co-morbidity?
4.2.6 Seasonality?
16
17
17
17
4.3 Does the protocol define how the study population 
will be sampled from the source population? (e.g. 
event or inclusion/exclusion criteria)  
15
Comments:
     none
Section 5: Exposure definition and measurement
Yes
No
N/A
Page 
Number(s)
5.1 Does the protocol describe how exposure is 
defined and measured? (e.g. operational details for 
defining and categorising exposure)
5.2 Does the protocol discuss the validity of exposure 
measurement? (e.g. precision, accuracy, prospective 
ascertainment, exposure information recorded before the 
outcome occurred, use of validation sub-study)
5.3 Is exposure classified according to time windows? 
(e.g. current user, former user, non-use)
5.4 Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
5.5 Does the protocol specify whether a dose-
dependent or duration-dependent response is 
measured?
Comments:
none

Boehringer Ingelheim
Page 33 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Section 6: Endpoint definition and measurement
Yes
No
N/A
Page 
Number(s)
6.1 Does the protocol describe how the endpoints are 
defined and measured? 
6.2 Does the protocol discuss the validity of endpoint 
measurement? (e.g. precision, accuracy, sensitivity, 
specificity, positive predictive value, prospective or 
retrospective ascertainment, use of validation sub-study)
Comments:
none
Section 7: Confounders and effect modifiers
Yes
No
N/A
Page 
Number(s)
7.1 Does the protocol address known confounders? 
(e.g. collection of data on known confounders, methods of 
controlling for known confounders)
17
7.2 Does the protocol address known effect modifiers? 
(e.g. collection of data on known effect modifiers, anticipated 
direction of effect)
17
Comments:
none
Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.1 Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
8.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview, etc.)
8.1.2 Endpoints? (e.g. clinical records, laboratory markers 
or values, claims data, self-report, patient interview including 
scales and questionnaires, vital statistics, etc.)
8.1.3 Covariates? 
18
8.2 Does the protocol describe the information 
available from the data source(s) on:
8.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose,  number of days of supply prescription, daily dosage,  
prescriber)
8.2.2 Endpoints? (e.g. date of occurrence, multiple event, 
severity measures related to event)
8.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, life style, etc.)
17
14
17
8.3 Is a coding system described for:
8.3.1 Diseases? (e.g. International Classification of 
Diseases (ICD)-10)
8.3.2 Endpoints? (e.g. Medical Dictionary for Regulatory 
Activities (MedDRA) for adverse events)
8.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC)Classification System)
19
19

Boehringer Ingelheim
Page 34 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.4 Is the linkage method between data sources 
described? (e.g. based on a unique identifier or other)
Comments:
none    
Section 9: Study size and power
Yes
No
N/A
Page 
Number(s)
9.1 Is sample size and/or statistical power calculated? 
18
Comments:
none    
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1 Does the plan include measurement of excess 
risks?
10.2 Is the choice of statistical techniques described? 
10.3 Are descriptive analyses included?
19
10.4 Are stratified analyses included?
10.5 Does the plan describe methods for adjusting for 
confounding?
10.6 Does the plan describe methods addressing 
effect modification?
Comments:
   none  
Section 11: Data management and quality 
control
Yes
No
N/A
Page 
Number(s)
11.1 Is information provided on the management of 
missing data?
19
11.2 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
18
11.3 Are methods of quality assurance described?
20
11.4 Does the protocol describe possible quality 
issues related to the data source(s)?
20
11.5 Is there a system in place for independent 
review of study results? 
Comments:

Boehringer Ingelheim
Page 35 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
none
Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
12.1 Does the protocol discuss:
12.1.1 Selection biases?
12.1.2 Information biases?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods)
20
12.2 Does the protocol discuss study feasibility? (e.g. 
sample size, anticipated exposure, duration of follow-up in a 
cohort study, patient recruitment)
12.3 Does the protocol address other limitations? 
Comments:
   none 
Section 13: Ethical issues
Yes
No
N/A
Page 
Number(s)
13.1 Have requirements of Ethics 
Committee/Institutional Review Board approval 
been described?
20
13.2 Has any outcome of an ethical review procedure 
been addressed?
20
13.3 Have data protection requirements been 
described?
Comments:
  none   
Section 14: Amendments and deviations
Yes
No
N/A
Page 
Number(s)
14.1 Does the protocol include a section to document 
future amendments and deviations? 
Comments:
none 
Section 15: Plans for communication of study 
results
Yes
No
N/A
Page 
Number(s)
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)? 
27
15.2 Are plans described for disseminating study 
results externally, including publication?
27
Comments:
     none

Boehringer Ingelheim
Page 36 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

Boehringer Ingelheim
Page 37 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
ANNEX 3. FLOW CHART OF VARIABLES
1. Observation period
     
Time 
    Item
Observation period1
Before first 
administration of
Spiriva Respimat 
4W 
12W (or 
at 
disconti
nuation)
52 W (or at 
discontinua
tion)
Patient registration
X2
Patient demographics
X
Administration of Spiriva  
Respimat
X (to be recorded throughout the observation period)
Medical history/baseline 
conditions
X
Previous/concomitant 
therapies
X (to be recorded throughout the observation period)
Pulmonary function test
FEV1
FVC
PEFR3
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
Asthma severity
X
Asthma Control Status
（X）
（X）
（X）
（X）
QOL (ACQ 6 score)
(X)
(X)
(X)
(X)
Adverse events
X (to be recorded throughout the observation period)
Laboratory tests4
associated with AE
(X)
EDC transmitted time5
                                                              X
X
(X): If applicable
1: Time points during the observation period are approximate. Collected data should be 
reported as of the closest available visit.

Boehringer Ingelheim
Page 38 of 38
Non-interventional Study Protocol
BI Study Number 205.525
c02810760-01
Proprietary confidential information © 2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
2: Patients administered Spiriva Respimat will be registered within 14 days from whenever 
the day of first administration is possible.
3: PEFR is defined as the mean of the PEFR values of the 7 days before each visit.
4: When laboratory related AE is reported, Laboratory tests associated with AE are 
reported.
5: eCRF (electronic case report form): Data are to be transmitted immediately after being 
entered into the eCRF at 12 weeks and 52 weeks after the start of treatment or at 
discontinuation. In case of occurrence of any adverse events, the data should be 
immediately entered into the eCRF and transmitted.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number:  
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02810760
1.0
non-interventional-study-protocol
Specific Use-Result Surveillance of Spiriva Respimat in asthmatics(patients with
severe persistent asthma)
Author-Trial Clinical Monitor
23 Apr 2015 13:19 CEST
Approval-Pharmacovigilance
23 Apr 2015 13:19 CEST
Approval-Team Member Medical
Affairs
23 Apr 2015 13:27 CEST
Approval-Therapeutic Area 
23 Apr 2015 13:30 CEST
Approval-EU Qualified Person
Pharmacovigilance
23 Apr 2015 13:31 CEST
Approval-Project Statistician
23 Apr 2015 13:56 CEST
Approval-
 Safety Evaluation
Therapeutic Area
23 Apr 2015 14:07 CEST
Approval-
 of Global
Epidemiology
23 Apr 2015 18:05 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02810760
1.0
Approval-Medical 
24 Apr 2015 01:28 CEST
Author-Trial Statistician
24 Apr 2015 02:13 CEST
Approval-Dept 
 or 
 or
24 Apr 2015 02:59 CEST