Post-marketing Surveillance (PMS) on Long-term Use of Tiotropium+Olodaterol Fixed Dose Combination (Tio+Olo FDC) 5µg/5µg in Patients With Chronic Obstructive Pulmonary Disease (Chronic Bronchitis, Emphysema) in Japan
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
Non-interventional Study Protocol
Document Number:
c02840643-02
BI Study Number:
1237.34
BI Investigational
Product(s):
Tiotropium+olodaterol fixed dose combination solution for 
inhalation -RESPIMAT
Title:
Post-marketing surveillance (PMS) on long-term use of 
tiotropium+olodaterol fixed dose combination (Tio+Olo FDC)
5µg/5µg in patients with chronic obstructive pulmonary disease 
(chronic bronchitis, emphysema) in Japan
Protocol version 
identifier:
Ver 2.0
Date of last version of 
protocol:
15 November 2015
PASS:
Yes
EU PAS register 
number:
NA
Active substance:
Tiotropium:R03BB04
Olodaterol:R03AC19
Medicinal product:
Spiolto RESPIMAT 28 puffs
(Tio+Olo FDC solution for inhalation-RESPIMAT)
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
.
Joint PASS:
No
Research question and 
objectives:
The study objective is to assess the long-term safety and 
effectiveness of Tio+Olo FDC 5µg/5µg in patients with chronic 
obstructive pulmonary disease (chronic bronchitis, emphysema)
in real-world setting.
Country(-ies) of study:
Japan
Author:
(Trial Clinical Monitor, Patient Safety 3 , 
 

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Marketing authorisation 
holder(s):
In case of PASS, add:
MAH contact person:
 
In case of PASS, add:
<EU-QPPV:>
In case of PASS, add:
<Signature of EU-
QPPV:>
e-signature is on BIRDS
Date:
10 MAY 2016
Page 1 of 34
Proprietary confidential information
© 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
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
9.2
SETTING .............................................................................................................15
9.2.1
Site selection:................................................................................................15
9.2.2
Selection of population.................................................................................15
9.2.2.1
Inclusion/ exclusion criteria.......................................................................15
9.2.2.2
Registration period.....................................................................................15
9.2.2.3
Patient registration method........................................................................15
9.2.3
Discontinuation of the study by the sponsor ................................................16
9.2.4
Priority survey items.....................................................................................16
9.3
VARIABLES........................................................................................................16
9.3.1
Exposure.......................................................................................................16
9.3.2
Outcomes......................................................................................................17
9.4
DATA SOURCES................................................................................................19
9.5
STUDY SIZE .......................................................................................................19
9.6
DATA MANAGEMENT.....................................................................................20
9.7
DATA ANALYSIS ..............................................................................................20
9.7.1
Analyses of outcome events .........................................................................20
9.7.2
Analyses of Safety........................................................................................20
9.7.3
Analyses of effectiveness .............................................................................21
9.7.4
Interim analyses............................................................................................21
9.8
QUALITY CONTROL ........................................................................................21
9.9
LIMITATIONS OF THE RESEARCH METHODS ...........................................21

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9.10
OTHER ASPECTS...............................................................................................21
9.10.1
Informed consent, data protection, study records.........................................21
9.10.1.1 Study approval, patient information, and informed consent......................22
9.10.1.2 Data quality assurance ...............................................................................22
9.10.1.3 Records ......................................................................................................22
9.10.1.4 Source documents......................................................................................22
9.10.1.5 Direct access to source data and documents..............................................22
9.10.1.6 Statement of confidentiality.......................................................................22
10.
PROTECTION OF HUMAN SUBJECTS................................................................23
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ............................................................................................................24
11.1
Definitions of adverse events ...............................................................................24
11.2
Adverse event and serious adverse event reporting .............................................24
11.3
RePORTING TO HEALTH AUTHORITIES......................................................26
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS27
13.
REFERENCES..........................................................................................................28
13.1
PUBLISHED REFERENCES..............................................................................28
13.2
UNPUBLISHED REFERENCES ........................................................................28
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS ...................................................30
ANNEX 2. FLOW CHART OF VARIABLES..................................................................31
ANNEX 3. COPD ASSESMENT TEST (CAT)................................................................33

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
CAT
COPD Assessment Test
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EU-QPPV
European Union – Qualified Person for Pharmacovigilance
FDC
Fix Dose Combination
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity
GPSP
Good Post- marketing Study Practice
ICS
Inhaled Corticosteroid
IRB
Institutional Review Board
J-PAL
Japanese Law for Ensuring the Quality, Efficacy, and Safety of 
Drugs and Medical Devices
J-RMP
Japan Risk Management Plan
LABA
Long Acting Beta2 Agonist
LAMA
Long Acting Muscarinic Antagonist
MedDRA
Medical Dictionary for Drug Regulatory Activities
PMDA
Pharmaceuticals and Medical Devices Agency
PMS
Post Marketing Surveillance
SAE
Serious Adverse Event

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3.
RESPONSIBLE PARTIES
Contact details and the list of all investigators will be kept in a stand-alone document. This
document will be managed in the PMS tracking system which manage the contracts with site 
and investigators name.

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat 28 puffs/ Spiolto 
Respimat 60 puffs
Name of active ingredient:
Tiotropium + olodaterol fixed-dose 
combination solution for inhalation -
RESPIMAT
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
15 November 2015
1237.34
Ver 2.0
10 MAY 2016
Title of study:
Post Marketing Surveillance (PMS) on long-term use of 
tiotropium+olodaterol fixed dose combination (Tio+Olo FDC) 5µg
/5µg in patients with chronic obstructive pulmonary disease (chronic 
bronchitis, emphysema) in Japan
Rationale and 
background:
The number of patients exposed to Tio+Olo FDC 5µg /5µg is limited
in clinical trials. In addition, the clinical trial setting had some 
limitations compared to the real-world setting, such as 
inclusion/exclusion criteria defined patient’s background and 
restriction of concomitant medications. In addition it is important to 
understand treatment patterns in routine clinical practice.
Research question 
and objectives:
The study objective is to assess the long-term safety and effectiveness 
of Tio+Olo FDC 5µg/5µg in patients with chronic obstructive 
pulmonary disease (chronic bronchitis, emphysema) in real-world 
setting.
Study design:
Observational study based on newly collected data for 52 weeks.
Population:
- Inclusion criteria

Patients who have been diagnosed with chronic obstructive 
pulmonary disease (chronic bronchitis, emphysema) by physician
and need to be treated co-administration of a long-acting 
inhalational anticholinergic and a long-acting inhalational β2-
agonist to relief of various symptoms associated with the 
obstructive impairment of airways.

Patients who are prescribed Tio+Olo FDC 5µg /5µg for the first 
time
- Exclusion criteria

Patients who have already been registered in this study once (re-
entry of patients is not allowed)

Patients who are participating in a clinical trial or registry.

Patients who have a contraindication to Tio+Olo FDC 5µg /5µg

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defined in the package insert for Tio+Olo FDC 5µg /5µg.
Variables:
Baseline characteristics
Demographics
Duration from indication
COPD status (severity (i.e. GOLD stage))
Tio+Olo FDC 5µg /5µg administration status
Medical history/ baseline conditions
Previous /concomitant therapies
Concomitant/ past medications (start/stop date, dosage, unknown)
Chronic obstructive pulmonary disease (chronic bronchitis, 
emphysema) medications (ICS, LABA, LAMA, other, unknown)
other medications (start/stop date, dosage, unknown)
CAT (COPD Assessment Test)
FVC and FEV1 (if the data is available at sites with information of 
pulmonary medication (i.e. pre-dose or post-dose))
Pregnancy
Data sources:
Patients’ data will be collected by electronic Case Report Form (eCRF) 
on EDC system
Study size:
1000 (safety set)
Data analysis:
Analyses are descriptive in nature. AEs are described with their 
incidence and incidence rate per treatment time. Subgroup analyses are 
performed for suitable sized samples with regard to patient 
characteristics and AE groups of medical interest. Due to the nature of 
the observational study, no confirmatory statistical testing is foreseen 
in this study.
Milestones:
Study Report planned to be archived in 3Q 2019
Study result based on study report is submitted in the re-examination 
document to PMDA in 4Q 2023.

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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
2.0
10 MAY 2016
Abstract
Change the 
indication
To comply 
with J-PI
Milestones
Change the study 
period
Delay of EDC 
system setup
Physicians’ 
global 
assessment
Add “( compared 
to the day before 
initiation of 
Tio+Olo FDC 5µg
/5µg)”
To make the 
rule clearer
Data 
management
Change name of 
CRO
CRO changed 
their name
9.1 STUDY 
DESIGN
Updated
Added visits 
based on the 
requirement 
from PMDA.

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
23 August 2016
(Launch of the investigated product: 3 December 
2015)
End of data collection
30 November 2018
Registration in the EU PAS 
register
To be registered
Final report of study results:
July 2019

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7.
RATIONALE AND BACKGROUND
This PMS study is planned according to the requirement by the Pharmaceutical Affairs Law 
in Japan (J-PAL). 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 8 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.
The results of clinical trials and PMS studies related to Tio mono or Tio+Olo FDC are
summarised below.
Clinical trials evaluating Tio mono until re-examination:
Until now, there were five clinical trials [P05-08673][U03-3113][U03-3144][U08-3718][P09-
15298] in Japanese patients with COPD for Tio HandiHaler and Tio Respimat as indicated in 
Table 7: 1.
Table7: 1
Study list of Tiotropium mono until re-examination
Study type [reference], BI study number
Treatment
period
Number of  Japanese 
patients (safety set)
Phase II, dose finding study [P05-08673], 
205.139
Single dose
HandiHaler, 27 
Phase III, DBT [U03-3113], 205.226
4 weeks
HandiHaler, 67
Phase III for long term administration, open trial
for safety [U03-3144], 205.227
1 year
HandiHaler, 110
Phase IIIb, UPLIFT trial [U08-3718], 205.235
4 years
HandiHaler, 100
Phase II, crossover trial for equivalence between 
HandiHaler and Respimat [P09-15298], 205.291
4 weeks
HandiHaler, 81
Respimat, 76
A total of 385 Japanese patients received Tio in these clinical trials. Even though there were 
no reports of safety concern to Tio in patients with COPD based on the results of clinical 
trials, PMDA directed 
 to conduct PMS to fulfil regulatory obligations established as a 
condition of marketing approval. Therefore two PMS studies [U09-1849-01] [U09-2234-01] 
for Tio HandiHaler and 1 PMS study [U12-2679-01] for Tio Respimat were conducted. A 
total of 4130 patients received Tio in these PMS studies.

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Clinical trials evaluating Tio+Olo FDC:
A total of 238 Japanese patients were treated with Tio+Olo FDC (5µg/ 5µg; the planned 
registered dose) up to 52 weeks in 3 phase III trials for Tio+Olo FDC program [U13-1759-
01][U13-1760-01] [U13-1762-01]. Clinical trials of Tio+Olo FDC also include 149 Japanese
patients receiving Olo mono 5µg and 76 Japanese patients receiving Tio mono 5µg. 
There were no safety concerns of Tio+Olo FDC, Olo mono and Tio mono in these clinical 
trials in Japanese patients compared to the respective global safety experience. However, 
clinical trials have limitations in comparison to real-world clinical practice due to the 
restriction of concomitant drugs and the exclusion of complicating severe diseases. In 
addition, no safety experience beyond 1-year of exposure is currently available from clinical 
trials with Tio+Olo FDC
Therefore, PMDA directed 
 to conduct PMS to collect mainly safety data from real-world 
clinical practice to fulfil regulatory obligations established as a condition of marketing 
approval.
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 8 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.

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8.
RESEARCH QUESTION AND OBJECTIVES
This PMS study is one of the action plans of collecting post-marketing safety information  
focused on the following risks and information of Tio+Olo FDC 5µg/5µg in the J-RMP. 

Important identified risks: Cardiac failure, atrial fibrillation and extrasystoles, Ileus, 
Angle closure glaucoma, Anaphylaxis

Important potential risks: Cardiac disorder (Myocardial ischaemia, Cardiac arrhythmia), 
Intubation and mortality related to asthma

Important missing information: none specified
The study objective is to assess the long-term safety and effectiveness of Tio+Olo FDC 
5µg/5µg in patients with chronic obstructive pulmonary disease (chronic bronchitis, 
emphysema) in real-world setting.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is an observational study based on newly collect real-world data (i.e., data under real-
world practice) to evaluate safety and effectiveness of Tio+Olo FDC 5µg/5µg in patients with 
chronic obstructive pulmonary disease (chronic bronchitis, emphysema). 
The study will be initiated after marketing of Tio+Olo FDC 5µg/5µg in Japan. The study will 
consist of a baseline visit and further visits in a 52-week follow-up for patients who have 
initiated the Tio+Olo FDC 5µg/5µg treatment.
As this is an observational study, no specific treatment is mandated or withheld from the 
patients. The choice of maintenance treatment for chronic obstructive pulmonary disease 
(chronic bronchitis, emphysema) must be according to regular medical practice and at 
discretion of physician (i.e., no randomised assignment of patient to treatment [Tio+Olo FDC 
or other treatment] is performed). In total, approximately 1100 patients are planned to be 
registered at approximately 200 study sites in the study.
Patients participating in the subsequent follow-up will undergo regular observations. These 
observations should be reported after 4, 12, 24 and 52 weeks since the initiation of Tio+Olo 
FDC 5µg/5µg as long as they continue to receive the treatment. Patients will not be followed 
any longer once they are reported to have discontinued the Tio+Olo FDC 5µg/5µg treatment.
Patients who experience adverse events will be followed up until detailed information on the 
outcome of the adverse event is collected.
The primary outcome of this study is the incidence and exposure-time adjusted incidence rate 
of adverse drug reactions (ADRs).
The secondary outcome of this study is:
•
COPD assessment test (CAT) at 12 weeks.

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9.2
SETTING
9.2.1
Site selection:
Tio+Olo FDC 5µg/5µg has been delivered to the sites and PMS Director who is assigned on 
Good Post- marketing Study Practice (GPSP) will decide sites to participate in the study 
based on the site selection checklist. 
Planned number of site: Approximately 200 Sites
A medical representative will explain the objective and design of this study to investigators at 
each study site and exchange a written contract with the head of the study site (e.g., hospital 
director).
9.2.2
Selection of population
9.2.2.1
Inclusion/ exclusion criteria
Patients who fulfil the following criteria will be included.

Patients who have been diagnosed with chronic obstructive pulmonary disease (chronic 
bronchitis, emphysema) by physician and need to be treated co-administration of a long-
acting inhalational anticholinergic and a long-acting inhalational β2-agonist to relief of 
various symptoms associated with the obstructive impairment of airways

Patients who are prescribed Tio+Olo FDC 5µg/5µg for the first time
Patients who present the following criteria will be excluded.

Patients who have been registered once in this study (i.e., re-entry of patients is not 
allowed).

Patients who are participating or registry in a clinical trial.

Patients who have a contraindication to Tio+Olo FDC 5µg/5µg defined in the package 
insert for Tio+Olo FDC 5µg/5µg.
9.2.2.2
Registration period
From August 2016 to August 2017
9.2.2.3
Patient registration method
Patients will neither be selected randomly nor assigned to treatment randomly. At each study 
site, patients who are judged by investigator eligible to the study will be consecutively 
registered. Investigators register patients sequentially who are prescribed Tio+Olo FDC 

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5µg/5µg treatment according to regular medical practice to reach the number of contract with
site.
Patients will be registered by entering necessary information into the EDC immediately or 
within 14 days whenever possible from the day of treatment initiation (inclusive). The 
necessary information for registration is gender, date of birth, start date of administration and 
the reason for use.
Investigators will use a signed form to confirm that the patients will be registered 
continuously at the site.
End of registration
Patient registration will be stopped when the target number of study is reached. A log of all 
patients included into the survey will be maintained at the sites.
9.2.3
Discontinuation of the study by the sponsor
reserves the right to discontinue the study overall or at a 
particular study site at any time for the following reasons:
1.
Failure to meet expected enrolment overall goals or goals at a particular study site,
2.
Emergence of any efficacy/safety information that could significantly affect 
continuation of the study or any other administrative reasons.
3.
Violation of GPSP, the NIS protocol, or the contract by study site or investigator, 
disturbing the appropriate conduct of the study.
The study site will be reimbursed for reasonable expenses incurred in case of study 
termination (except in case of the third reason).
9.2.4
Priority survey items
The following outcomes of interest are set with particular priority as priority survey items. 

Cardiovascular adverse events

Anticholinergic-related adverse events

Beta2 agonist-related events
9.3
VARIABLES
9.3.1
Exposure
Exposure to Tio+Olo FDC 5µg/5µg is estimated as time from the day Tio+Olo FDC 5µg/5µg
is initiated until the day the drug is last administrated on a patient-level (or the final contact 
with the patient during the regular observation period).

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9.3.2
Outcomes
The following events are considered important outcomes. 
Safety:
Safety will be assessed with the incidence (n and % in treatment group) and treatment
exposure time adjusted incidence rate (n in 100 patient years) of AEs in patients treated with 
Tio+Olo FDC (treatment emergent). Results will be stratified by different treatment types 
prior to baseline and age as a general risk factor.
•
Adverse Drug Reactions (ADRs) (primary outcome) : related AEs as judged by the 
investigator or sponsor with a suspected causal relationship with the Tio+Olo FDC 
5µg/5µg treatment
•
AEs leading to death
•
AEs leading to discontinuation of the Tio+Olo FDC 5µg/5µg treatment)
•
Serious Adverse Events(SAEs)
•
Priority survey items: Cardiovascular adverse events, Anticholinergic-related adverse 
events, Beta2 agonist-related adverse events
Section 11 covers how to assess and report AEs including the definitions.
Additional subgroup analyses/ safety outcomes might be included based on new information 
that could become available during the course of the study.
Effectiveness:
Patient’s global rating (PGR)
Patients will be asked to rate their health (respiratory condition) at 4 weeks, 12 weeks, 24
weeks and 52 weeks (compared to the day before they commenced treatment with study drug) 
on the following 7-point scale.

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1
2
3
4
5
6
7
very 
much 
better
much 
better
a little 
better
no change
a little 
worse
much 
worse
very 
much 
worse
COPD Assessment Test (CAT)
    See ANNEX 3
Physicians’ global assessment
Effectiveness of the Tio+Olo FDC 5µg/5µg treatment will be comprehensively assessed 
(compared to the day before initiation of the Tio+Olo FDC 5µg/5µg) according to the 
following scale based on the observed symptoms and results of pulmonary function test. 
1. Improved, 2.Unchanged, 3.Deteriorated, 4. Not assessable
FVC and FEV1
If the data is available at sites with information of pulmonary medication (i.e. pre-dose or 
post-dose)

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    See ANNEX 2 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.
In EDC system, two casebooks will be set up; Book 1 includes baseline, 4 weeks, and 12 
weeks.  Book 2 includes 24 weeks and 52 weeks.
The data are to be transmitted immediately after being entered into EDC at 12 weeks (Book 1) 
and 52 weeks (Book 2) after the start of treatment or at discontinuation.
For any adverse events, the data should be immediately entered into EDC and transmitted.
9.5
STUDY SIZE
Study size is 1000 patients with chronic obstructive pulmonary disease (chronic bronchitis, 
emphysema) analysed (safety analysis set). As approximately 10 % of the patients are 
assumed to drop out without any data (just registered), therefore, 1100 patients is planned to 
be registered.
This is a descriptive study and no confirmatory tests are planned. 
The proportion of overall patients with serious cardiovascular events was 2.6% in Tio+Olo 
FDC 5µg/5µg group in the pooled data of trials 1237.5, 1237.6 and 1237.22. With 1000 
patients, the 95% confidence interval of serious cardiovascular events could be estimated with 
a width of 2.0% to 2.8% (Wilson interval) if the proportion of patients with serious 
cardiovascular events is between 2.6% and 5.2%.
If the true proportion of patients with serious cardiovascular events is assumed to be 2-fold 
(i.e., 5.2%), the sample size of 873 is required to have 98% power for rejecting the null 
hypothesis of incidence=2.6% by using one sample chi-square test with a 0.05 two-sided 
significance level.

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9.6
DATA MANAGEMENT
Patients’ data will be gathered by EDC system provided by external vendor below.
Contract 1
Contract 2
Company Name
Outsourced work
EDC system setting
Patient registration
Clinical Data Management
Document management of 
contract with site.
9.7
DATA ANALYSIS
This is an observational study to collect real-world data (i.e., data under routine medical 
practice) on safety and effectiveness of Tio+Olo FDC 5µg/5µg treatment. Analyses are 
descriptive in nature, including confidence intervals. Due to the nature of the observational 
study, no confirmatory statistical testing is foreseen in this study. Subgroup analyses are also 
performed if sample size allows.
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 Tio+Olo FDC 5µg/5µg treatment. All outcome events are based on reported AE data 
which will be handled according to BI standards (see the section below).
9.7.2
Analyses of Safety
The safety analysis will include all patients registered in the study and receiving the Tio+Olo 
FDC 5µg/5µg treatment except for patients who meet the ineligible criteria (see section9.7). 
In general, safety analyses will be descriptive in nature, be based on BI standards, and focus
on AEs related to the Tio+Olo FDC 5µg/5µg treatment.
AEs will be coded using the current version of the Medical Dictionary for Drug Regulatory 
Activities (MedDRA) and will be based on the concept of treatment emergent AEs. To this 
end, all AEs occurring between the initiation of Tio+Olo FDC 5µg/5µg prescribed at baseline 
visit and 21 days (inclusive) after the last administration will be considered ‘treatment 
emergent’. An AE is considered to be an ADR if either the physician/investigator who has 
reported the AE or the sponsor assesses its causal relationship as ‘related’.

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The incidence (n and % in treatment group) and treatment exposure time adjusted incidence 
rate (n in 100 patient years) of AEs in patients treated with Tio-Olo FDC (treatment emergent 
including 21 days after discontinuation of Tio+Olo FDC medication) will be tabulated by 
MedDRA SOC and PT for overall and for subgroups based on the important baseline 
characteristics, if sample size allows (see9.3.3)
9.7.3
Analyses of effectiveness
For patients’ global rating and physicians’ global assessment, the frequency of patients with 
each score will be tabulated. 
For CAT, descriptive statistics will be calculated for the total score and the score of each 
individual component and the changes from scores at week 12 before first administration.
9.7.4
Interim analyses
Several interim analyses (AEs’ tabulate) will be performed for the purpose of submission of 
periodic safety update reports to PMDA in project (status update of using Spiolto not only 
with this trial but all usage, every 6 month in two years after approval and every 12 months
afterward. The submission date is 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
The general objective of this observational study is to obtain an estimate of the effect of a 
drug exposure on the occurrence of the events of interest in the population of the study. Due 
to the nature of a single cohort observational study, however, there are issues that may impose 
threats in particular on the validity of the assessment based on the study data, such as 
selection bias, loss to follow up, channeling bias and information and recall bias, and these 
issues should be fully taken into account as limitations of this study design when, conducting,
analyzing and interpreting the study. In addition interpretation of results may be challenging 
due to the lack of a comparator.
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.

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The rights of the investigator and of the sponsor with regard to publication of the results of 
this PMS study are described in the contract. As a general rule, no PMS study results should 
be published prior to finalization of the Study Report.
9.10.1.1
Study approval, patient information, and informed consent
The review by IRB is not mandatory for conducting PMS study according to GPSP. The 
sponsor will enter into a contract with a study site representative (e.g. head of hospital) in 
accordance with GPSP. Informed consent prior to patient participation in the study 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 SOP and working 
instructions which are in compliance with GPSP.
9.10.1.3
Records
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via 
Electronic Data Capture (EDC) system.
9.10.1.4
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 study site. For the CRFs, all 
of the data must be derived from source documents.
9.10.1.5
Direct access to source data and documents
Direct access to source data and documents for PMS study is not allowed in Japan.
9.10.1.6
Statement of confidentiality
Individual patient’s medical information obtained as a result of this PMS study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Data generated as a result of this PMS study need to be submitted on request by the regulatory 
authorities.

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10.
PROTECTION OF HUMAN SUBJECTS
There is no need for a clinical trial type insurance of well-being and rights of 
participants because this is a non-interventional study and there is no risk of an 
experimental treatment. There is no regulation or requirement for ensuring the well-
being and rights of participants.  

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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 unfavorable 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) is a response to a medicinal product which is noxious and 
unintended.
Response in this context means that a causal relationship between a medicinal product and an
adverse event is at least a reasonable possibility.
Adverse reactions may arise from use of the product within or outside the terms of the
marketing authorization or from occupational exposure. Conditions of use outside the
marketing authorization include off-label use, overdose, misuse, abuse and medication errors.
Serious Adverse Event (SAE) - 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 judgment should be exercised in deciding whether other situations
should be considered serious reactions, such as important medical events that might not be
immediately life threatening or result in death or hospitalization but might jeopardize the
patient or might require intervention to prevent one of the other outcomes listed above.
Examples of such events are intensive treatment in an emergency room or at home for
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or
development of dependency or abuse. Any suspected transmission via a medicinal product of
an infectious agent is also considered a serious adverse reaction.
.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files.

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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 authorization. Sufficient data from controlled
interventional trials are available to support the evidence on the safety and efficacy of the
studied BI drug. For this reason the following AE collection and reporting requirements have
been defined.
The following must be collected by the investigator in the (e) CRF via EDC system from first
intake of Tio+Olo FDC 5µg/5µg prescribed at baseline visit and within 21 days (inclusive) 
after the last intake:
- all AEs (serious and non-serious) as soon as possible,
- all AEs with fatal outcome in patients exposed to Spiolto Respimat as soon as possible,
- all AEs which are relevant for a serious ADR or an AE with fatal outcome in patients
exposed to Spiolto 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
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge,
confounding factors such as concomitant medication, concomitant diseases and relevant
history.
Arguments that may suggest a reasonable causal relationship could be:
• The event is consistent with the known pharmacology of the drug
• The event is known to be caused by or attributed to the drug class.
• A plausible time to onset of the event relative to the time of drug exposure.
• Evidence that the event is reproducible when the drug is reintroduced
• 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 

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evident (e.g. pre-treatment cases, diagnosis of cancer or chronic disease within 
days/weeks of drug administration; 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.
Pregnancy
In rare cases, pregnancy might occur in a study. Once a subject, has been enrolled into the
study after having taken Spiolto Respimat, the investigator must report any drug exposure
during pregnancy which occurred in a female subject or in a partner to a male subject to the
Sponsor by means of Part A of the Pregnancy Monitoring Form. The outcome of the
pregnancy associated with the drug exposure during pregnancy must be followed up and
reported by means of Part B of the Pregnancy Monitoring Form.
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 Spiolto Respimat according to the local regulatory requirements for spontaneous AE
reporting at the investigator’s discretion by using the locally established routes and AE report
forms. The term AE includes drug exposure during pregnancy, and, regardless of whether an
AE occurred or not, any abuse, off-label use, misuse, medication error, occupational
exposure, lack of effect, and unexpected benefit.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to the 
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 final report will be submitted in re-examination documents.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P05-08673
Hirata K, Kurihara N, Irino T, Yoshikawa J.Dose ranging study of a new 
long-acting bronchodilator tiotropium in single administration, double 
blind, 4-treatment and 4-period crossover design in patients with chronic 
obstructive pulmonary disease (COPD).Original in Japanese.
J Clin Ther Med 20(9),925-939(2004).
P09-15298
Ichinose M, Fujimoto T, Fukuchi Y Tiotropium 5 mcg via Respimat and 
18 mcg via HandiHaler; efficacy and safety in Japanese COPD patients.
Respir Med 104 (2), 228 - 236 (2010)
P11-06784
Fukuchi Y, Fernandez L, Kuo HP, Mahayiddin A, Celli B, Decramer M, 
Kesten S, Liu D, Tashkin DEfficacy of tiotropium in COPD patients from
Asia: a subgroup analysis from the UPLIFT trial.Respirology 16 (5), 825 -
835 (2011).
P11-08788
Antoniu SA. Effects of inhaled therapies on health-related quality of life in 
stable chronic obstructive pulmonary disease. Expert Rev 
Pharmacoeconomics Outcomes Res 2010;10(2):155-162.
R13-0957
CAT: COPD assessment test (healthcare professional user guide), expert 
guidance on frequently asked questions (issue 3: February 2012). 
http://www.catestonline.org/images/UserGuides/CATHCPUser%20gui 
deEn.pdf (access date: 28 February 2013) ; GlaxoSmithKline; 2012.
13.2
UNPUBLISHED REFERENCES
U03-3113
, A Multiple Dose Comparison of 18 µg, 36 µg of 
Ba679BR (Tiotropium) Inhalation Capsules and Oxitropium Metered Dose 
Inhaler (2 puffs of 100µg) in a 4-week, Double-Blind, Double-Dummy, 
Safety and Efficacy Study in Patients with Chronic Obstructive Pulmonary 
Disease (COPD).205.226, 12 May 2003 
U03-3144
, A Multiple Dose Comparison of Tiotropium 18µg 
Inhalation Capsules and Oxitropium MDI (2 puffs of 100µg) in a One-year, 
Open-Label, Safety and Efficacy Study in Patients with COPD, 205.227, 
11 June 2003
U08-3718
 
UPLIFT®: Understanding Potential Long-term Impacts on Function with 
Tiotropium  / A randomized, double-blind, placebo-controlled, parallel 
group trial assessing the rate of decline of lung function with tiotropium 18 
mcg inhalation capsule once daily in patients with chronic obstructive 
pulmonary disease (COPD), 205.235, 28 October 2008
U09-1849-01
, Drug Use Results Survey of Tiotropium bromide. 
205.314 20 November 2009
U09-2234-01
, Special Survey Long-term Treatment of Tiotropium. 
205.315 30 October 2009.

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U12-2679-01
Post Marketing Surveillance on Long-Term Drug Use of 
Spiriva 2.5 μg Respimat® 60 puffs in Patients with Chronic Obstructive 
Pulmonary Disease. 205.463 18 December 2012
U13-1759-01
A randomised, double-blind, parallel group study to 
assess the efficacy and safety of 52 weeks of once daily treatment of orally 
inhaled tiotropium + olodaterol fixed dose combination (2.5 μg / 5 μg;5 μg 
/5 μg) (delivered by the Respimat® Inhaler) compared with the individual 
components (2.5 μg and 5 μg tiotropium, 5 μg olodaterol) (delivered by the 
Respimat® Inhaler) in patients with Chronic Obstructive Pulmonary 
Disease (COPD) [TOnado™ 1]. 1237.5, 10 April 2014. (c01735218-02)
U13-1760-01
, A randomised, double-blind, parallel group study to 
assess the efficacyand safety of 52 weeks of once daily treatment of orally 
inhaled tiotropium + olodaterol fixed dose combination (2.5 μg / 5 μg;5 μg 
/5 μg) (delivered by the Respimat® Inhaler) compared with theindividual 
components (2.5 μg and 5 μg tiotropium, 5 μg olodaterol) (delivered by the 
Respimat® Inhaler) in patients with ChronicObstructive Pulmonary 
Disease (COPD) [TOnado™ 2]. 1237.6, 10 April 2014. (c01735249-02)
U13-1762-01
, A randomised, double-blind, parallel-group study to 
assess the safetyand efficacy of 52 weeks of once daily treatment of orally 
inhaled tiotropium + olodaterol fixed-dose combination (2.5 μg/ 5 μg, 5 
μg/5 μg) and olodaterol (5 μg) delivered by the Respimat® inhaler in
Japanese patients with Chronic Obstructive Pulmonary Disease(COPD). 
1237.22, 03 April 2014. (c02099166-02)

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference Number
Date
Title
None
None

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ANNEX 2. FLOW CHART OF VARIABLES
      
Time 
    Item
Observation period
Before first 
administration of
Tio+Olo FDC 
5µg/5µg
4W
12W
(or at 
discontinu
ation)
24W
52W
(or at 
discontinu
ation)
Patient 
registration
X
Patients visit 
date
X
X
X
X
X
Patient 
demographics
X
COPD 
Characteristics
X
Administration
of Tio+Olo FDC 
5µg/5µg
X (to be recorded throughout the observation period)
Medical 
history/baseline 
conditions
X
Previous/conco
mitant therapies 
X (to be recorded throughout the observation period)
Prescribed 
medication for 
chronic 
obstructive 
pulmonary 
disease (chronic 
bronchitis, 
emphysema) 
treatment
X (to be recorded throughout the observation period)
Concomitant 
medications
X (to be recorded throughout the observation period)
CAT
X
X
X
X
X
Patient’s global 
rating (PGR)
X
X
X
X
Physician’s 
global 
assessment
X
X
X
X
FVC and FEV1*
(X)
(X)
(X)
(X)
(X)
Adverse events
X (to be recorded throughout the observation period)
Laboratory tests
associated with 
AE
X
EDC transfer
time
Xa
X
(Book 1)
X
( Book 2)

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a: At patient registration: Patient’s ID, gender, date of birth, start date of administration, 
indication and registration group will be entered into eCRF and transmitted.
*if the data is available at sites with information of pulmonary medication (i.e. pre-dose or 
post-dose)

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ANNEX 3. COPD ASSESMENT TEST (CAT)
The COPD Assessment Test™ (CAT)
The COPD Assessment Test™ (CAT) is a short 8-item questionnaire for assessment and 
monitoring of COPD health status in routine practice. Its scale is 0-40 (high score = poor 
health). The CAT questionnaire has the advantage of a reduced number of items and could be 
used to assess the effects of inhaled therapies [P11-08788]. The CAT is attached following
The CAT will be performed at Visit 1 and each subsequent clinic visits until the last study 
treatment visit. The questionnaire will be paper based.
The test will be performed according to the “HEALTHCARE PROFESSIONAL USER 
GUIDE; CATTM; COPD Assessment Test; Expert guidance on frequently asked questions; 
Issue 3; February 2012” [R13-0957]. The CAT translated Japanese version will be used.
Site staff will check the answered CAT questionnaire for completeness. Site staff must not 
exercise any influence on the patient what to answer.
The patient’s answers on the CAT questionnaire will be transcribed in the eCRF. The CAT 
score is the sum of the values corresponding to the answers to the eight questions.

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APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02840643
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non-interventional-study-protocol-1237-34
Post-marketing surveillance (PMS) on long-term use of tiotropium+olodaterol fixed
dose combination (Tio+Olo FDC) 5µg/5µg in patients with chronic obstructive
pulmonary disease (chronic bronchitis, emphysema) in Japan
Author-Trial Clinical Monitor
07:29 CEST
Approval-Medical 
07:38 CEST
Approval-
 Pharmacovigilance
07:54 CEST
Approval-
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Therapeutic Area
08:41 CEST
Author-Trial Statistician
09:02 CEST
Approval-EU Qualified Person
Pharmacovigilance
11:54 CEST
Approval-Team Member Medicine
13:43 CEST
Approval-Therapeutic Area 
17:09 CEST

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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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