Specific Use-Result Surveillance of Spiriva Respimat in Asthmatics (Patients With Mild and Moderate Persistent Asthma)
Conditions: Asthma
Sponsor: Boehringer Ingelheim

ABCD
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TITLE PAGE
Non-interventional Study Protocol
Document Number:
c14514897-01
BI Study Number:
0205-0536
BI Investigational
Product(s):
Tiotropium inhalation solution – Respimat Inhaler (Ba 679 BR 
Respimat) 
Title:
Specific Use-Result Surveillance of Spiriva Respimat in 
asthmatics (patients with mild to moderate persistent asthma)
Brief lay title
Specific Use-result Surveillance of Spiriva Respimat® in mild to 
moderate persistent asthmatic patients
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® 1.25 μg Respimat® 60 puffs
Spiriva® 2.5 μg Respimat® 60 puffs
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Joint PASS:
No
Research question and 
objectives:
This PMS is designed:
To investigate the safety and effectiveness of Spiriva Respimat
in patients with mild to moderate persistent asthma under real-
world use.
Country(-ies) of study:
Japan
Author:

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Marketing authorisation 
holder(s):
MAH contact person:
EU-QPPV:
Signature of EU-
QPPV:
The signature of the EU-QPPV is provided electronically
Date:
16 January 2017
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 6
4.
ABSTRACT........................................................................................................... 7
5.
AMENDMENTS AND UPDATES....................................................................... 8
6.
MILESTONES....................................................................................................... 9
7.
RATIONALE AND BACKGROUND................................................................ 10
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 11
9.
RESEARCH METHODS .................................................................................... 12
9.1
STUDY DESIGN............................................................................................ 12
9.2
SETTING........................................................................................................ 12
9.2.1
Study sites ............................................................................................... 12
9.2.2
Study population ..................................................................................... 12
9.2.2.1
Inclusion/Exclusion criteria ............................................................. 12
9.2.2.2
Patient registration method .............................................................. 12
9.2.2.3
Registration period........................................................................... 13
9.2.3
Study visits .............................................................................................. 13
9.2.4
Study discontinuation.............................................................................. 13
9.3
VARIABLES .................................................................................................. 13
9.3.1
Exposures ................................................................................................ 13
9.3.2
Outcomes................................................................................................. 14
9.3.2.1
Primary outcome .............................................................................. 14
9.3.2.2
Secondary outcome .......................................................................... 14
9.3.3
Covariates................................................................................................ 15
9.4
DATA SOURCES........................................................................................... 16
9.5
STUDY SIZE.................................................................................................. 16
9.6
DATA MANAGEMENT................................................................................ 16
9.7
DATA ANALYSIS......................................................................................... 16
9.7.1
Main analysis........................................................................................... 17
9.7.3
Interim analyses....................................................................................... 17

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9.8
QUALITY CONTROL................................................................................... 18
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 18
9.10
OTHER ASPECTS ......................................................................................... 18
9.10.1
Data quality assurance............................................................................. 18
9.10.2
Study records........................................................................................... 18
9.10.2.1
Source documents ............................................................................ 18
9.10.2.2
Direct access to source data and documents .................................... 18
9.10.3
Completion of study................................................................................ 18
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 19
10.1
Study approval, patient information, and informed consent........................... 19
10.2
Statement of confidentiality............................................................................ 19
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE
REACTIONS....................................................................................................... 20
11.1
Definitions of adverse events.......................................................................... 20
11.2
Adverse event and serious adverse event collection and reporting................. 21
11.3
Reporting to health Authorities....................................................................... 23
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 24
13.
REFERENCES .................................................................................................... 25
13.1
PUBLISHED REFERENCES......................................................................... 25
13.2
UNPUBLISHED REFERENCES................................................................... 25
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 26
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 27
ANNEX 3. FLOW CHART OF VARIABLES ............................................................ 33

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special interest
CA
Competent Authority
CCDS
Company Core Data Sheet
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
eCRF
Electronic Case Report Form
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
EU-QPPV
European Union – Qualified Person for Pharmacovigilance
FDA
Food and Drug Administration
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
GPSP
Good Post- marketing Study Practice
GVP
Good Pharmacovigilance Practices
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
J-PAL
Japanese Pharmaceutical Affairs Law
J-RMP
Japan Risk Management Plan
J-PSR
Japanese Periodic Safety Report
MedDRA
Medical Dictionary for Regulatory Activities
MAH
Marketing Authorisation Holder
NIS
Non-Interventional Study
PASS
Post-Authorization Safety Study
PMDA
Pharmaceuticals and Medical Devices Agency
PMS
Post Marketing Surveillance
SAE
Serious Adverse Event
TSAP
Trial Statistical Analysis Plan

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3.
RESPONSIBLE PARTIES
Sponsor

Boehringer Ingelheim
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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:
16 January 2017
0205-0536
1.0
NA
Title of study:
Specific Use-Result Surveillance of Spiriva Respimat in asthmatics
(patients with mild to moderate persistent asthma)
Rationale and 
background:
The safety of Spiriva® 1.25 μg Respimat® 60 puffs and Spiriva® 2.5 μg 
Respimat® 60 puffs (hereinafter referred to as Spiriva Respimat) in
patients with mild to moderate 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 mild to moderate persistent asthma under real-world use.
Study design:
Non-interventional, observational study based on new data collection
Population:
Inclusion criteria:
• Patients diagnosed with mild to moderate 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:
150 (safety set)
Data analysis:
Descriptive
Milestones:
Final report will be prepared by 31 July 2019

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5.
AMENDMENTS AND UPDATES
None
Number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
-
-
-
-
-

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
01 July 2017
End of data collection
31 December 2018
Study progress report
None
Study interim report 1
08 January 2018 (J-PSR)
Study interim report 2
08 January 2019 (J-PSR)
Study interim report 3
17 February 2019 (re-examination report for Spiriva 
Respimat in asthmatics)
Registration in the EU PAS 
register
To be registered
Final report of study results:
31 July 2019

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7.
RATIONALE AND BACKGROUND
Tiotropium is one of the most widely used long-acting bronchodilators worldwide for the
treatment of COPD (including chronic bronchitis and emphysema), 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 bronchial asthma.
Tiotropium delivered via the Respimat® inhaler once daily demonstrated consistent and
significant improvement in 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 high-dose ICS+LABA or medium-dose ICS were shown 
to have a symptomatic benefit from taking tiotropium.
Tiotropium delivered via the Respimat® inhaler once daily also demonstrated long-term 
safety and tolerability compared with that of placebo when administered at a daily dose of 2.5 
and 5 μg 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 dose 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 patterns of 
increased particular AEs for the tiotropium treatment groups compared with that of placebo 
in any subgroup analysis. No deaths were reported during the entire clinical program.
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 tiotropium is a new additional maintenance therapy in patients 
with asthma who remain symptomatic despite treatment with at least ICS. Treatment with 
tiotropium improves lung function and symptoms of asthma patients more appropriately and 
may be an important paradigm shift in the treatment of asthma patients.
Japanese regulation related to Post Marketing Surveillance (PMS)
This PMS 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 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 10 years after approval of registration. The 
PMS is a part of the local Risk Management Plan in Japan (J-RMP) to be submitted to 
PMDA at New Drug Application.

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8.
RESEARCH QUESTION AND OBJECTIVES
The objective of this PMS is to investigate the safety and effectiveness of Spiriva Respimat in 
patients with mild to moderate persistent asthma under real-world use.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
Non-interventional observational study based on newly collected data under real-world use.
9.2
SETTING
9.2.1
Study sites
 will nominate the candidate sites which satisfied the following criteria and 
 ask the 
nominated sites to participate in the study.
•
Spiriva Respimat has been delivered to the site.
•
The observation of peak expiratory flow meter is done as part of the usual medical 
practice.
Planned number of sites: Approximately 25 Sites
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
Study population
9.2.2.1
Inclusion/Exclusion criteria
Inclusion criteria:
•
Patients diagnosed with mild to moderate persistent bronchial asthma
•
Patient 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]. 
Exclusion criteria:
•
Patients who have a contraindication to Spiriva Respimat defined in the package 
insert for Spiriva Respimat
•
Patients who have been enrolled in 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 

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entering necessary information in the EDC within 14 days whenever possible from the day of 
treatment initiation (inclusive).
The necessary variables for registration are 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 use a signed form to confirm that patients have 
been registered 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 July 2017 to June 2018
9.2.3
Study visits
After start of the treatment with Spiriva Respimat, each patient will be observed for 12 weeks 
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 and 12 weeks after the start of treatment, or at discontinuation.
9.2.4
Study discontinuation
reserves the right to discontinue the PMS overall or at a particular study site at any time 
for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular study site
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the 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 study site will be reimbursed for reasonable expenses incurred in case 
of PMS termination (except in case of the third reason).
9.3
VARIABLES
9.3.1
Exposures
This PMS is conducted under real-world use of Spiriva® 1.25 μg Respimat® 60 puffs and 
Spiriva® 2.5 μg Respimat® 60 puffs following the labeling (Japanese package insert).

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9.3.2
Outcomes
9.3.2.1
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)
There is no primary outcome for effectiveness as the primary objective of a PMS is 
evaluating safety.
9.3.2.2
Secondary outcome
•
Change from baseline in asthma control status at Week 12
Asthma control status:
Asthma control status will be assessed based on the “Asthma prevention and management 
guideline” [ P14-15105]
9.3.2.2: 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

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9.3.3
Covariates
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
Demographics
At baseline:
Patient background including weight, height and smoking history
Medical history/baseline conditions
(Ischaemic heart disease, Cardiac failure, Myocardial infarction, Angina pectoris, Cardiac 
arrhythmia, Renal failure)
Previous /concomitant therapies
Pulmonary function test (PEFR (peak expiratory flow rate), FEV1 (forced expiratory volume 
in 1 second), FVC (forced vital capacity), if available
Asthma severity and asthma control status, if available [ P14-15105]
ACQ 6 score, if available
Spiriva Respimat® administration, dose
At week4:
Concomitant therapies
Pulmonary function test (PEFR, FEV1, FVC), if available
Asthma severity and asthma control status, if available [ P14-15105]
ACQ 6 score, if available
Spiriva Respimat® administration, dose, particularly any changed in dose with details 
provided
At week12:
Concomitant therapies
Pulmonary function test (PEFR, FEV1, FVC), if available
Asthma severity and asthma control status, if available [ P14-15105]
ACQ 6 score, if available
Spiriva Respimat® administration, dose, particularly any changed in dose with details 
provided
Observation period and follow-up period by 30 days:
Adverse events
Priority survey items:
Cardiovascular adverse events
Anticholinergic-related adverse events
Asthma related death/hospitalization/intubation
Safety laboratory test (if corresponding AEs are reported)
See ANNEX 3 for more details.

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9.4
DATA SOURCES
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via the 
Electronic Data Capture (EDC) system.
One case book is used. Book 1 is for baseline, Week 4 and Week 12.
Data is to be transmitted immediately after being entered into the eCRF at 12 weeks after the 
start of treatment or at discontinuation. When any adverse events occur, the data should be 
immediately entered into eCRF and transmitted.
9.5
STUDY SIZE
It is planned to enroll 180 patients with mild to moderate persistent asthma to ensure the 
number of 150 patients as safety analysis set at least.
150 (safety set)
150 patients will be set as a safety analysis set. The main ADR (about 2.0%) in clinical trials 
were asthma (1.8%), dysphonia (1.8%) and dry mouth (1.8%). With 150 patients, the 
incidence of the main adverse events would be evaluated.
9.6
DATA MANAGEMENT
Data is gathered by the EDC system provided by external vendor below.
Table 9.6: 1
Contract research organizations 1
Contract research organizations 2
Name
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 including means, standard deviation, Q1, medians, 

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Q3, frequency and percentages. For safety outcomes, incidence rates with corresponding 95% 
confidence interavals will also be calculated. 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
Main analysis
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. 
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
Interim analyses
Several interim analyses will be performed for the purpose of creating periodic safety update 
reports to the local authority (see 6. MILESTONES).

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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
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.
9.10.2
Study records
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, via EDC. 
9.10.2.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the study; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
9.10.2.2
Direct access to source data and documents
Direct access to source data and documents for PMS is not allowed in Japan.
9.10.3
Completion of study
When the study is completed, the investigator should inform the head of the study site of the 
completion in writing, and the head of the study site should promptly inform the IRB and 
sponsor of the completion in writing.

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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.
10.1
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.
10.2
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.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Procedures for the collection, management and reporting of individual cases of adverse 
events/adverse reactions (see 001-MCS-05-501-RD-01 for collection requirements) and of 
any new information that might influence the evaluation of the benefit-risk balance of the 
product while the study is being conducted. 
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavourable 
and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product 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 authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which
-
results in death, 
-
is life-threatening, 
-
requires in-patient hospitalization, or
-
prolongation of existing 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 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 

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development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
An AE which possibly leads to disability will be reported as an SAE.
No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing 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. When any adverse events
occur, the data should be immediately entered into eCRF and transmitted. : 
-
all adverse drug reaction (ADRs) (serious and non-serious), 
-
all AEs with fatal outcome, 
All ADRs, including those persisting after study completion must be followed up until they 
are resolved, have been sufficiently characterized, or no further information can be obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is 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

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•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal
relationship could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g.
situations where other drugs or underlying diseases appear to provide a more likely
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Pregnancy:
In rare cases, pregnancy might occur in a 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, 
otherwise the NIS AE form is to be completed and forwarded as well as soon as possible. 
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate (e)CRF pages.
Reporting of related Adverse Events associated with any other BI drug

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The investigator is encouraged to report all adverse events related to any BI drug other than 
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
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local
and international regulatory requirements.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The progress reports and final reports will be submitted to PMDA in Japan PSR (Periodic
safety report). And also the interim report for this PMS is included in re-examination 
documents.
This study is planned for the publication based on the final report.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P14-15105  Ohta K, Ichinose M, Japanese Guideline for Adult Asthma 2014, Allergology Int, 
2014,63:293-333
13.2
UNPUBLISHED REFERENCES
U13-1598-01  2.5 Clinical Overview, Spiriva Respimat, addition of asthma indication, 25 
July 2013
001-MCS-05-501-RD-01  “Individual Case Safety Report (ICSR) collection, processing and 
reporting by Source”, version 4.0, date 03 Oct 2016

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
ENCePP Checklist for Study Protocols (Revision 3)
Adopted by the ENCePP Steering Group on 01/07/2016
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 section number 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). 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 mild to moderate
persistent asthma)
Study reference number:
BI Study Number: 0205-0536
Section 1: Milestones
Yes
No
N/A
Section 
Number
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.
6
6
6
6
6
6
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.

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Section 2: Research question
Yes
No
N/A
Section 
Number
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?
7
8
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 hypothesis(-es) is (are) to be tested? 
2.1.5 If applicable, that there is no a priori
hypothesis?
9.2
Comments:
Section 3: Study design
Yes
No
N/A
Section 
Number
3.1 Is the study design described? (e.g. cohort, case-
control, cross-sectional, new or alternative design) 
9
3.2 Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection?
9
3.3 Does the protocol specify measures of occurrence? 
(e.g. incidence rate, absolute risk)
9
3.4 Does the protocol specify measure(s) of 
association? (e.g. relative risk, odds ratio, excess risk, 
incidence rate ratio, hazard ratio, number needed to harm 
(NNH) per year)
3.5 Does the protocol describe the approach for the 
collection and reporting of adverse events/adverse 
reactions? (e.g. adverse events that will not be collected in 
case of primary data collection)
11
Comments:
none
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
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?
6
9.3
9.3

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Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.2.4 Disease/indication? 
4.2.5 Duration of follow-up?
9.3
4.3 Does the protocol define how the study population 
will be sampled from the source population? (e.g. 
event or inclusion/exclusion criteria)  
9.2
Comments:
none
Section 5: Exposure definition and measurement
Yes
No
N/A
Section 
Number
5.1 Does the protocol describe how the study 
exposure is defined and measured? (e.g. operational 
details for defining and categorising exposure, measurement of 
dose and duration of drug exposure)
9.3
5.2 Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, 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?
Comments:
none
Section 6: Outcome definition and measurement
Yes
No
N/A
Section 
Number
6.1 Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated?
9.3
6.2 Does the protocol describe how the outcomes are 
defined and measured? 
9.3
6.3 Does the protocol address the validity of outcome 
measurement? (e.g. precision, accuracy, sensitivity, 
specificity, positive predictive value, prospective or 
retrospective ascertainment, use of validation sub-study)
6.4 Does the protocol describe specific endpoints 
relevant for Health Technology Assessment? (e.g. 
HRQoL, QALYs, DALYS, health care services utilisation, burden 
of disease, disease management)
Comments:
none
Section 7: Bias
Yes
No
N/A
Section 
Number

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Section 7: Bias
Yes
No
N/A
Section 
Number
7.1 Does the protocol describe how confounding will 
be addressed in the study?
7.1.1. Does the protocol address confounding by 
indication if applicable?  
7.2 Does the protocol address:
7.2.1. Selection biases (e.g. healthy user bias)
7.2.2. Information biases (e.g. misclassification of 
exposure and endpoints, time-related bias)
7.3 Does the protocol address the validity of the study 
covariates?
Comments:
none
Section 8: Effect modification
Yes
No
N/A
Section  
Number
8.1 Does the protocol address effect modifiers? (e.g. 
collection of data on known effect modifiers, sub-group analyses, 
anticipated direction of effect)
Comments:
none
Section 9: Data sources
Yes
No
N/A
Section  
Number
9.1 Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview, etc.)
9.1.2 Outcomes? (e.g. clinical records, laboratory markers 
or values, claims data, self-report, patient interview including 
scales and questionnaires, vital statistics, etc.)
9.1.3 Covariates? 
9.2 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 Outcomes? (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.)
9.3
9.3
9.3
9.3 Is a coding system described for:
9.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC)Classification System)
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD)-10, Medical Dictionary for Regulatory Activities 
(MedDRA)) 
9.7

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Section 9: Data sources
Yes
No
N/A
Section  
Number
9.3.3 Covariates?
9.4 Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)
Comments:
none
Section 10: Analysis plan
Yes
No
N/A
Section  
Number
10.1 Is the choice of statistical techniques described? 
10.2 Are descriptive analyses included?
9.7
10.3 Are stratified analyses included?
10.4 Does the plan describe methods for adjusting for 
confounding?
10.5 Does the plan describe methods for handling 
missing data?
9.7
10.6 Is sample size and/or statistical power 
estimated?
9.5
Comments:
none
Section 11: Data management and quality 
control
Yes
No
N/A
Section 
Number
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
9.10
11.2 Are methods of quality assurance described?
9.10
11.3 Is there a system in place for independent 
review of study results? 
9.10
Comments:
none
Section 12: Limitations
Yes
No
N/A
Section  
Number
12.1
Does the protocol discuss the impact on the 
study results of:
12.1.1 Selection bias?
12.1.2 Information bias?
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods)
9.9

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Section 12: Limitations
Yes
No
N/A
Section  
Number
12.2 Does the protocol discuss study feasibility? (e.g. 
study size, anticipated exposure, duration of follow-up in a 
cohort study, patient recruitment)
Comments:
none
Section 13: Ethical issues
Yes
No
N/A
Section  
Number
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described?
13.2 Has any outcome of an ethical review procedure 
been addressed?
13.3 Have data protection requirements been 
described?
Comments:
none
Section 14: Amendments and deviations
Yes
No
N/A
Section 
Number
14.1 Does the protocol include a section to document 
amendments and deviations? 
5
Comments:
none
Section 15: Plans for communication of study 
results
Yes
No
N/A
Section 
Number
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)? 
12
15.2 Are plans described for disseminating study 
results externally, including publication?
12
Comments:
none

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ANNEX 3. FLOW CHART OF VARIABLES
1. Observation period
Time 
Item
Observation period1
Before first 
administration of
Spiriva Respimat 
4W 
12W (or at 
discontinuation)
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)
Asthma severity
X
Asthma Control Status
（X）
（X）
（X）
QOL (ACQ 6 score)
(X)
(X)
(X)
Adverse events
X (to be recorded throughout the observation period)
Laboratory tests4 
associated with AE
(X)
EDC transmitted time5
X
(X): If applicable
1: Time points during the observation period are approximate. Collected data should be 
reported as of the closest available visit.
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 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.