A Regulatory Required Non Interventional Study to Monitor the Safety and Effectiveness of Once Daily Treatment of Orally Inhaled Vahelva Respimat (Tiotropium + Olodaterol Fixed Dose Combination 2.5µg/2.5µg Per Puff (2 Puffs Comprise One Medicinal Dose)) for Korean Patients With COPD (Chronic Obstructive Pulmonary Disease)
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
TITLE PAGE
Non-interventional Study Protocol
TITLE PAGE
Document Number:
c13799423-02
BI Study Number:
1237.60
BI Investigational
Product(s):
Vahelva® Respimat® 
(Tiotropium bromide + Olodaterol hydrochloride)
Title:
A regulatory required non interventional study to monitor the 
safety and effectiveness of once daily treatment of orally inhaled 
Vahelva® Respimat® (Tiotropium + Olodaterol fixed dose 
combination 2.5µg/2.5µg per puff (2 puffs comprise one 
medicinal dose)) for Korean patients with COPD (Chronic 
Obstructive Pulmonary Disease)
Brief lay title
Vahelva® Respimat® rPMS in Korean patients with COPD
Protocol version 
identifier:
2.0
Date of last version of 
protocol:
Not applicable
PASS:
Yes
EU PAS register 
number:
EUPAS14956
Active substance:
Tiotropium bromide 
Olodaterol hydrochloride
Medicinal product:
Tiotropium + Olodaterol fixed dose combination solution for 
inhalation-Respimat®
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Joint PASS:
No
Research question and 
objectives:
To monitor the safety profile and effectiveness of Vahelva® 
Respimat® (tiotropium + olodaterol) in Korea patients with 
COPD (Chronic Obstructive Pulmonary Disease) in a routine 
clinical practice setting

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Country(-ies) of study:
Multi-Centre study conducted in Korea
Author:
Phone:
  Fax:
Marketing authorisation 
holder(s):
MAH contact person:
EU-QPPV:
Signature of EU-QPPV:
The signature of the EU-QPPV is provided electronically
Date:
08 October 2020
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© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior 
written permission

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1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 6
3.
RESPONSIBLE PARTIES.................................................................................... 8
4.
ABSTRACT........................................................................................................... 9
4.1
FLOW CHART............................................................................................... 11
5.
AMENDMENTS AND UPDATES..................................................................... 12
6.
MILESTONES..................................................................................................... 15
7.
RATIONALE AND BACKGROUND................................................................ 16
7.1
RATIONALE.................................................................................................. 16
7.2
BACKGROUND ............................................................................................ 16
7.3
INDICATIONS............................................................................................... 17
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 18
8.1
PRIMARY OBJECTIVE ................................................................................ 18
8.2
SECONDARY OBJECTIVE.......................................................................... 18
9.
RESEARCH METHODS .................................................................................... 19
9.1
STUDY DESIGN............................................................................................ 19
9.1.1
Method of assigning patients to treatment groups .................................. 19
9.1.2
Dosage and Administration..................................................................... 19
9.1.3
Concomitant therapy, Restrictions, And rescue...................................... 19
9.1.3.1
Rescue medication, emergency procedures, and additional treatments20
9.2
SETTING........................................................................................................ 20
9.2.1
Study sites ............................................................................................... 20
9.2.2
Study population ..................................................................................... 20
9.2.2.1
Main diagnosis for study entry......................................................... 20
9.2.2.2
Inclusion criteria............................................................................... 20
9.2.2.3
Exclusion criteria ............................................................................. 20
9.2.2.4
Subjects of special investigation ...................................................... 20
9.2.3
Study visits .............................................................................................. 21
9.2.3.1
Screening and run-in periods ........................................................... 21
9.2.3.2
Visit 1 - Baseline Visit ..................................................................... 21
9.2.3.3
Visit 2 - 24±2 weeks from Visit 1.................................................... 21

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9.2.3.4
Visit 3 - 52±2 weeks from Visit 1.................................................... 22
9.2.3.5
End of study and follow-up period................................................... 22
9.2.4
Study discontinuation.............................................................................. 22
9.3
VARIABLES .................................................................................................. 22
9.3.1
Safety....................................................................................................... 22
9.3.1.1
Outcome(s) of safety........................................................................ 22
9.3.2
Effectiveness ........................................................................................... 23
9.3.2.1
Outcome(s) of effectiveness............................................................. 23
9.3.2.2
Assessment of Effectiveness............................................................ 23
9.3.3
Items of Investigation.............................................................................. 23
9.3.3.1
Demographic data ............................................................................ 23
9.3.3.2
Medical history................................................................................. 24
9.3.3.3
Concomitant medication .................................................................. 24
9.3.3.4
Drug administration status ............................................................... 24
9.3.3.5
Information on the site ..................................................................... 24
9.3.3.6
Result of laboratory tests(if applicable) ........................................... 25
9.3.3.7
Overall evaluation ............................................................................ 25
9.3.4
Outcomes of subjects Evaluation............................................................ 25
9.3.4.1
Subject evaluation items .................................................................. 25
9.4
DATA SOURCES........................................................................................... 26
9.5
STUDY SIZE.................................................................................................. 26
9.6
DATA MANAGEMENT................................................................................ 26
9.7
DATA ANALYSIS......................................................................................... 27
9.7.1
Statistical design – model........................................................................ 27
9.7.2
Demographic baseline data ..................................................................... 27
9.7.3
Analysis of Safety ................................................................................... 27
9.7.4
Analysis of Effectiveness........................................................................ 28
9.7.4.1
Main outcome analyses.................................................................... 28
9.7.4.2
Other outcome analyses ................................................................... 28
9.7.5
Interim analyses....................................................................................... 28
9.7.6
Handling of missing data......................................................................... 28
9.8
QUALITY CONTROL................................................................................... 29
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 29
9.9.1
Follow up loss ......................................................................................... 29
9.9.2
Channeling bias....................................................................................... 29

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9.9.3
Confounding............................................................................................ 29
9.10
DATA PROTECTION, STUDY RECORDS................................................. 29
9.10.1
Data quality assurance............................................................................. 30
9.10.2
Study records........................................................................................... 30
9.10.2.1
Source documents ............................................................................ 30
9.10.2.2
Direct access to source data and documents .................................... 31
9.10.2.3
Storage period of records ................................................................. 31
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 32
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 32
10.2
STATEMENT OF CONFIDENTIALITY...................................................... 32
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 33
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 33
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 34
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 37
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 38
13.
REFERENCES .................................................................................................... 39
13.1
PUBLISHED REFERENCES......................................................................... 39
13.2
UNPUBLISHED REFERENCES................................................................... 39
13.3
WEB SITE ...................................................................................................... 39
14.
APPENDICES ..................................................................................................... 40
14.1
ELECTRONIC CASE REPORT FORM........................................................ 40
14.2
SAE/ NON-SERIOUS ADVERSE REACTION REPORT ........................... 40
14.3
PREGNANCY MONITORING FORM ......................................................... 40
14.4
VAHELVA® RESPIMAT® PRESCRIPTION INFORMATION FOR KOREA40
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 41
ANNEX 2. MODIFIED MEDICAL RESEARCH COUNCIL(mMRC)...................... 42
ANNEX 3. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 43

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
BD
Bronchodilator
BI
Boehringer Ingelheim
BP
Blood Pressure
CA
Competent Authority
CML
Local Clinical Monitor
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DMP
Data Management Plan
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EU
European Union
EU PAS
European Union Post-Authorization Safety
EU-QPPV
European Union – Qualified Person for Pharmacovigilance
FDC
Fix Dose Combination
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GPP
Good Pharmacy Practice
IC50
Inhibitory Concentration
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File
KNHANES
Korean National Health and Nutrition Examination Survey 
LPVM
Local PV Manager

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MAH
Marketing Authorisation Holder Activities
MedDRA
Medical Dictionary for Drug Regulatory Activities
MFDS
The Ministry of Food and Drug Safety
NCE
New Chemical Entity
NIS
Non-Interventional Study
NSADR
Non Serious Adverse Drug Reaction
OPU
Operative Unit
PASS
Post Authorization Safety Studies 
PFT
Pulmonary Function Test
PMS
Post Marketing Surveillance
rNIS
Regulatory Non-Interventional Study
SADR
Serious Adverse Drug Reaction
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TMF
Trial Master File
TMM
Team Member Medicine

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3.
RESPONSIBLE PARTIES
Boehringer Ingelheim(BI) has appointed a Trial Clinical Monitor(TCM), responsible for 
coordinating all required activities, in order to

Manage the study in accordance with applicable regulations and internal standard 
operating procedures(SOPs).

Direct the study team in the preparation, conduct, and reporting of the trial,

Order the materials as needed for the study,

Ensure appropriate training and information of Local Clinical Monitors(CMLs), 
Clinical Research Associate(CRAs), and Investigators of participating countries.
Data Management and Statistical Evaluation will be done by CRO according to CRO’s SOPs.
The organization of the study in the participating countries will be done by the respective 
local BI- operative unit(OPU) or by a Contract Research Organization(CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the study. In each local BI OPU participating in this study, a CML will be appointed 
responsible for coordinating the activities required in order to manage the study in 
accordance with applicable regulations and internal SOPs in the countries covered by the 
respective BI OPU. On-site monitoring will be performed by BI or a CRO appointed by BI.
An Investigator Site File(ISF) containing all relevant study related documentation will be
maintained according to local regulations and BI SOPs at each study site. A copy of the ISF 
documents will also be kept as an electronic Trial Master File(TMF) at BI according to BI 
SOPs. Documents related to participating physician and other important participants,
especially their curricula vitae, will be filed in the TMF.

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4.
ABSTRACT
Name of company:
Name of finished medicinal product:
Vahelva® Respimat®
Name of active ingredient:
Tiotropium + Olodaterol fixed-dose 
combination solution for inhalation - Respimat®
Protocol date:
Study number:
Version/Revision:
Version/Revision 
date:
09 November 2016
1237.60
2.0
08 October 2020
Title of study:
A regulatory required non interventional study to monitor the safety and 
effectiveness of once daily treatment of orally inhaled Vahelva® 
Respimat® (Tiotropium + Olodaterol fixed dose combination 2.5µg/2.5µg
per puff(2 puffs comprise one medicinal dose)) for Korean patients with 
COPD(Chronic Obstructive Pulmonary Disease)
Rationale and 
background:
According to the local regulations, when a new chemical entity(NCE) is 
registered, a regulatory non interventional study(NIS) of an extended 
period(6 years) should be conducted. Such rNIS can provide 
supplementary data to monitor the safety of NCEs in a real-world
situation. Data collected in randomized clinical study with strict 
inclusion/exclusion criteria and rigorous monitoring schemes have 
limitations.
Research question 
and objectives:
To monitor the safety profile and effectiveness of Vahelva® Respimat® in 
Korean patients with COPD in a routine clinical practice setting
Study design:
Observational prospective, non-interventional, open-label, multi-centre 
study
Population:
Patients diagnosed with COPD will be included.
Inclusion criteria:

Patients who have been started on Vahelva® Respimat® in 
accordance with the approved label in Korea

Age ≥18 years at enrolment

Patients who have signed on the data release consent form
Exclusion criteria:

Patients with hypersensitivity to Vahelva® Respimat® or to any of 
the excipients.

Patients with a history of hypersensitivity to atropine or its 
derivatives(e.g. ipratropium, oxitropium, glycopyrronium, 
aclidinium, umeclidinium)

Patients with asthma 

Current participation in other clinical trials
Patients for whom Vahelva® Respimat® is contraindicated according 

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Name of company:
Name of finished medicinal product:
Vahelva® Respimat®
Name of active ingredient:
Tiotropium + Olodaterol fixed-dose 
combination solution for inhalation - Respimat®
Protocol date:
Study number:
Version/Revision:
Version/Revision 
date:
09 November 2016
1237.60
2.0
08 October 2020
local label of Vahelva® Respimat®.
Variables:
Outcomes of safety
All reported adverse events in patients who take at least once of 
Vahelva® Respimat® will be noted.
Outcomes of effectiveness
Change from baseline in (pre-dose) FEV1, (Post Bronchodilator 
Predicted %) FEV1, mMRC scale after 24±2 weeks and/or 52±2 weeks, 
conditionally. And overall evaluation after 24±2 weeks and/or 52±2
weeks of treatment will be noted.
Data sources:
Field study with new data collection
Study size:
N=3,000 approximately
Sample size of 3,000 patients is based on the requirement of the local 
regulatory authority (MFDS).
Data analysis:
In this non-interventional study, all statistical analyses will be 
descriptive. Data of characteristics and other status of patients will be 
described and proportions including the confidence intervals will be 
provided.
Milestones:
Study duration: 6 years (MFDS sets Vahelva® Respimat® re-examination 
period from 31 August 2015 to 30 Aug 2021. Interim report planned 
biannually for the initial two years and annually thereafter by November 
2021.

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4.1
FLOW CHART
Data points
Baseline
Follow-up 1
Follow-up 2
Visit Number
1
2
3
Week/s
0
24±2
52±2
Informed consent
X
Diagnosis
X
Inclusion / exclusion criteria
X
Demographics
X
Medical history
X
PFT value
-
FEV1/FVC pred (%)
-
(Pre-dose) FEV1
X
Physical examination
X
X
X
Concomitant medications
X
X
X
Vahelva® Respimat® administration status
X
X
X
(Pre-dose) FEV1
X
XA
XA
(Post Bronchodilator Predicted %) FEV1
X
XA
XA
Assessment of mMRC scale
XA
XA
XA
Laboratory data
XA
XA
XA
Adverse events
X
X
Study completion
X
X
Overall evaluation
XA
XA
A : If applicable

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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study protocol
Amendment or update
Reason
2
17 
September 
2020
9.2.3.2 visit 1 
– Baseline 
visit
Effectiveness outcomes: (pre-
dose) FEV1, BDI(within 1 
month(30 days) prior to 
baseline date)
Was changed to:
Effectiveness outcomes: (pre-
dose) FEV1, (Post 
Bronchodilator Predicted % ) 
FEV1, mMRC scale(within 1 
month(30 days) prior to 
baseline date)
Reflect to HA’s 
feedback and 
epidemiology 
team’s 
feedback
2
17 
September 
2020
9.2.3.3 Visit 2 
- 24±2 weeks 
from Visit 1
Effectiveness assessment: (pre-
dose) FEV1, TDI
Was changed to:
Effectiveness assessment: (pre-
dose) FEV1, (post 
bronchodilator predicted %) 
FEV1, mMRC scale
Reflect to HA’s 
feedback and 
epidemiology 
team’s 
feedback
2
17 
September 
2020
9.2.3.4 Visit 3 
- 52±2 weeks 
from Visit 1
Effectiveness assessment: (pre-
dose) FEV1, TDI
Was changed to:
Effectiveness assessment: (pre-
dose) FEV1, (post 
bronchodilator predicted %) 
FEV1, mMRC scale
Reflect to HA’s 
feedback and 
epidemiology 
team’s 
feedback
2
17 
September 
2020
9.3.2.1.1 Main 
outcome
Change from baseline in (pre-
dose) FEV1 after 24 weeks 
and/or 52 weeks of treatment
Was changed to:
Change from baseline in (Post 
Bronchodilator Predicted % ) 
FEV1 after 24 weeks and/or 52 
weeks of treatment
Reflect to HA’s 
feedback and 
epidemiology 
team’s 
feedback
2
17 
September 
9.3.2.1.2
Other 
Change from baseline in TDI 
after 24 weeks and/or 52 
Reflect to HA’s 
feedback and 

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2020
outcomes
weeks of treatment
Was changed to:
Change from baseline in Pre-
dose FEV1 after 24 weeks 
and/or 52 weeks of treatment
Change from baseline in 
mMRC score after 24 weeks 
and/or 52 weeks of treatment
epidemiology 
team’s 
feedback
2
17 
September 
2020
9.3.2.2
Assessment of 
Effectiveness

(pre-dose) FEV1 (Forced 
Expiratory Volume in one 
second): (pre-dose) FEV1 
should be collected within 1 
month(30 days) prior to 
baseline and after 24 weeks 
and/or 52 weeks of 
treatment.

BDI/TDI(Baseline Dyspnea 
Index/Transition Dyspnea
Index): BDI/TDI should be 
collected within 1 month(30 
days) prior to baseline and 
after 24 weeks and/or 52 
weeks of treatment.

Overall evaluation: Overall 
evaluation will be assessed 
after 24 weeks or 52 weeks 
of treatment.
Was changed to:

Post Bronchodilator 
Predicted % FEV1(Forced 
Expiratory Volume in one 
second): Post BD FEV1 
should be collected within 
1 month(30 days) prior to 
baseline and after 24 
weeks and/or 52 weeks of 
treatment.

(pre-dose) FEV1 (Forced 
Expiratory Volume in one 
second): (pre-dose) FEV1
should be collected within 
1 month(30 days) prior to 
baseline and after 24
weeks and/or 52 weeks of 
Reflect to HA’s 
feedback and 
epidemiology 
team’s 
feedback

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treatment.

mMRC scale: mMRC 
scale should be collected
within 1 month(30 days)
prior to baseline and after 
24 weeks and/or 52 weeks
of treatment.

Overall evaluation: 
Overall evaluation will be 
assessed after 24 weeks or 
52 weeks of treatment.

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
30 Jul 2016
End of data collection
30 Aug 2021
Interim report 1
30 Apr 2016
Interim report 2
30 Oct 2016
Interim report 3
30 Apr 2017
Interim report 4
30 Oct 2017
Interim report 5
30 Oct 2018
Interim report 6
30 Oct 2019
Interim report 7
30 Oct 2020
Registration in the EU PAS register
29 Aug 2016
Final report of study results:
30 Nov 2021

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7.
RATIONALE AND BACKGROUND
7.1
RATIONALE
According to the local regulations, when a new chemical entity(NCE) is registered, a 
regulatory non interventional study(NIS) of an extended period(6 years) should be conducted. 
Such rNIS can provide supplementary data to monitor the safety of NCEs in a real-world
situation. Data collected in randomized clinical study with strict inclusion/exclusion criteria 
and rigorous monitoring schemes have limitations.
This is an open-label, multi-centre and national non-interventional study based on newly 
collected data. It will provide additional safety information of Vahelva® Respimat®
(Tiotropium + Olodaterol) in Korean patients with COPD(Chronic Obstructive Pulmonary 
Disease) in a routine clinical practice setting.
7.2
BACKGROUND
Chronic obstructive pulmonary disease(COPD) is a leading cause of morbidity and mortality
worldwide and results in an economic and social burden that is both substantial and
increasing. COPD prevalence, morbidity and mortality vary across countries and across
different groups within countries[P12-01205].
The prevalence of COPD in Korea increased from 12.5% in 2011 to 13.7% in 2012 and 12.8% 
in 2013. The Korean National Health and Nutrition Examination Survey(KNHANES, 2013)
reported that approximately 12.8% of the population who were ≥40 years old. In addition, 
27.7 of 100,000 persons die because of respiratory diseases, including COPD which was the 
fifth leading cause of death in Korea(Statistics Korea, 2009).
COPD is the result of cumulative exposure over decades; often, the prevalence of COPD is 
directly related to the prevalence of tobacco smoking, although in several countries, outdoor, 
occupational and indoor pollution are major risk factors.
The prevalence and burden of COPD are projected to increase in the coming decades due to 
continued exposure to COPD risk factors and the changing age structure of the world’s
population, with more people living longer and therefore expressing the long-term effects of
exposure to COPD risk factors[P12-01205].
The combination of Tiotropium and Olodaterol in a single Respimat® Inhaler device provides
a rational target for optimizing bronchodilator treatment of COPD. 
Tiotropium(18μg) inhalation powder capsule (Spiriva®) has been approved in more than 100 
countries worldwide as an antimuscarinic bronchodilator with a once daily posology. An
alternative aqueous formulation for use in the Respimat® device (tiotropium 5μg qd) has
recently been approved in Europe and Japan. Olodaterol, a long acting β2–agonist in clinical
development(Phase III) by Boehringer Ingelheim, has a clinical profile with a 24-hour
duration of action. The recently completed Phase III clinical program in COPD showed that
Olodaterol at doses of 5μg and 10μg once daily is safe, well tolerated and efficacious;
Olodaterol 5μg was identified as the optimal choice of dose for once daily maintenance

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bronchodilator treatment in patients with COPD[U04-0202].
Safety data from the supportive Phase III 12 week trial and the 6-week crossover trials were
consistent with the data from the 52-week pooled dataset. In conclusion, Tiotropium + 
Olodaterol 5/5μg and Tiotropium + Olodaterol 2.5/5μg delivered via the RESPIMAT inhaler 
were safe and well-tolerated in patients with moderate to very severe COPD[c01735808-12].
7.3
INDICATIONS
A maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic 
obstructive pulmonary disease(COPD). 

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8.
RESEARCH QUESTION AND OBJECTIVES
8.1
PRIMARY OBJECTIVE
The primary objective of this study is to monitor the safety profile of Vahelva® Respimat®
(tiotropium + olodaterol fixed dose combination 2.5µg/2.5µg per puff (2 puffs comprise one 
medicinal dose)) in Korean patient with COPD in a routine clinical setting. 
8.2
SECONDARY OBJECTIVE
The secondary objective of this study is to monitor the effectiveness of Vahelva® Respimat®
(tiotropium + olodaterol fixed dose combination 2.5µg/2.5µg per puff (2 puffs comprise one 
medicinal dose)) by evaluation the change from baseline to outcome in the (pre-dose)
FEV1(Forced Expiratory Volume in one second), (Post Bronchodilator Predicted % ) 
FEV1(Forced Expiratory Volume in one second) and mMRC(Modified Medical Research 
Council) scale of Korean COPD patients.
.

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9.
RESEARCH METHODS
This rNIS is an observational prospective, non-interventional, open-label, multi-centre and 
national study. As per regulation, the re-examination period extends from 31 August 2015 
until 30 August 2021. However, active enrolment is to be initiated in 2016 after finalizing the 
re-imbursement agreement with the authority. Before initiation of the study, any newly 
reported adverse events collected from other sources such as spontaneous cases, literature 
cases etc will be closely monitored. The last patient follow up is expected in August 2021.
This study will be carried out in the manner of successive survey that the investigator will be 
asked to successively write in the case report forms(CRFs) from the subject who was initially 
administered the drug following the study start date to the requested number of subjects 
without omission. Prior to initiation of the study, written contract shall be concluded, and this 
contract shall be concluded with the head of the site or the investigator with his/her consent.
Patients will be managed according to the local practice guidelines. The choice of treatment 
will be solely at the discretion of the participating physician. Vahelva® Respimat®will be 
administered according to the approved label in Korea. Hence there are no additional risks to 
patients by participating in this rNIS.
9.1
STUDY DESIGN
This is a NIS based on newly collected data with Vahelva® Respimat®.
Vahelva® Respimat®will be prescribed according to the local label and at the discretion of the 
treating physician. Since this is a NIS, the drug will not be supplied by the sponsor. 
Furthermore, the sponsor will not cover the expenses related to other medications taken by 
the patient, interventions, procedures or diagnostic test.
9.1.1
Method of assigning patients to treatment groups
The choice of treatment is fully at the discretion of the physician and the patient. There is no 
treatment assignment by a third party.
9.1.2
Dosage and Administration 
The starting dose is based on the current authorized label in Korea.
The recommended dose for adults is 5 microgram Tiotropium and 5 microgram Olodaterol 
given as two puffs from the Respimat® inhaler once daily at the same time of the day(see 
Instructions for Use).
9.1.3
Concomitant therapy, Restrictions, And rescue
The protocol will allow additional drugs considered necessary for the patient’s welfare to be 
prescribed at the discretion of the treating physician. It is required, however, to record the 
details of all concomitant medication administered to the patient during the course of 
treatment in eCRF. This includes concomitant therapies started one month prior to Vahelva®
Respimat® initiation until the patient completes the final follow-up visit.

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9.1.3.1
Rescue medication, emergency procedures, and additional treatments
Please refer to the current local label.
9.2
SETTING
As per regulations, enrolled patients will be followed up for 24weeks or 52 weeks treatment 
period. There will be a visit window of ±2weeks. 
9.2.1
Study sites
A total of 3,000 patients will be enrolled at approximately 50 sites by as many as 50 or more 
NIS physicians. To minimize the selection bias at the site level, the goal is to have 
participating centers reflect a balance between general hospitals and clinics for surveillance. 
The treating physicians will mainly be Respiratory Internists. To minimize the selection bias, 
consecutive patients from each site who meet inclusion criteria will be enrolled in this study.
9.2.2
Study population
9.2.2.1
Main diagnosis for study entry
Patients diagnosed with COPD will be included.
9.2.2.2
Inclusion criteria

Patients who are new initiators of Vahelva® Respimat® in accordance with the 
approved label in Korea

Age ≥18 years at enrolment

Patients who have signed on the data release consent form
9.2.2.3
Exclusion criteria

Patients with hypersensitivity to Vahelva® Respimat® or to any of the excipients.

Patients with a history of hypersensitivity to atropine or its derivatives (e.g. 
ipratropium, oxitropium, glycopyrronium, aclidinium, umeclidinium)

Patients with asthma

Current participation in other clinical trials

Patients for whom Vahelva® Respimat® is contraindicated according to the local 
label of Vahelva® Respimat®
9.2.2.4
Subjects of special investigation
The patient who have signed on the data release consent form, subjects of special 
investigation(Pediatric or Adolescent(Younger than 18 years), Geriatric(Older than 65 years), 
Pregnant Women, renal impairment, hepatic impairment and other special population) among 
the patients who conducted investigation for safety assessment after the administration of 
Vahelva® Respimat® can be further investigation into cases collected from this study may be 
taken into account according to the outcome of retrospective analysis.

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9.2.3
Study visits
9.2.3.1
Screening and run-in periods
This section is not applicable as this is a non-interventional study.
9.2.3.2
Visit 1 - Baseline Visit
Upon patient enrolment, the following will be recorded on the patient’s eCRF.

Visit date

Informed consent form: Date of Informed consent

Diagnosis: Date of the diagnosis of COPD

Inclusion / Exclusion criteria

Demographic data: Initial, year of birth(age), gender, pregnancy, previous allergy, 
height, weight, smoking status

Medical history: history of cardiovascular disease, metabolic disease, respiratory 
disease, any malignancy, renal dysfunction and other concomitant disease within 6
months.

Physical examination: Blood pressure, pulse rate, body temperature

PFT value for diagnosis of COPD: FEV1/FVC predicted (%), (pre-dose) FEV1 (within 6
months(180 days) prior to baseline date)

Effectiveness outcomes : (pre-dose) FEV1, (Post Bronchodilator Predicted % ) FEV1, 
mMRC scale(within 1 month(30 days) prior to baseline date)

Concomitant medications: Record all medications have been taken at least once since 
one month(30 days) prior to the baseline visit.

Dose of Vahelva® Respimat® given
At visit 1, the patient will be requested to contact the treating physician in the event of any 
adverse events noted after initiating Vahelva® Respimat® treatment.
9.2.3.3
Visit 2 - 24±2 weeks from Visit 1
After 24±2 weeks from Visit 1, the patients will return for follow-up. The followings will be 
noted and recorded in the eCRF.

Visit date

Physical examination: Blood pressure, pulse rate, body temperature

Effectiveness assessment: (pre-dose) FEV1, (post bronchodilator predicted %) FEV1,
mMRC scale

Any change of Vahelva® Respimat® given

Concomitant medications including new medications taken since last visit : any 
change in the concomitant medications(dose and dosing intervals)

Any changes in laboratory tests if there is any lab result which was clinically 
significant compared to data before Vahelva® Respimat® therapy (This data is 
collected on the basis of medical need, i.e. independent of the NIS) 

Any adverse events noted

Study completion status

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
Overall evaluation

NIS physician’s electronic signature for data integrity(if applicable)
9.2.3.4
Visit 3 - 52±2 weeks from Visit 1
After 52±2 weeks from Visit 1, the patients will return for follow-up. The followings will be 
noted and recorded in the eCRF.

Visit date

Physical examination: Blood pressure, pulse rate, body temperature

Effectiveness assessment: (pre-dose) FEV1, post bronchodilator predicted %) FEV1,
mMRC scale

Any change of Vahelva® Respimat® given

Concomitant medications including new medications taken since last visit: any 
change in the concomitant medications(dose and dosing intervals)

Any changes in laboratory tests if there is any lab result which was clinically 
significant compared to data before Vahelva® Respimat® therapy (This data is 
collected on the basis of medical need, i.e. independent of the NIS) 

Any adverse events noted

Study completion status

NIS physician’s electronic signature for data integrity
9.2.3.5
End of study and follow-up period
Patients with adverse events noted at the final follow-up visit or upon premature 
discontinuation of Vahelva® Respimat® will be monitored further until the resolution of those 
adverse events. Alternatively, those patients will be followed up until the NIS physician and 
sponsor agree that no further follow-up is necessary.
9.2.4
Study discontinuation
reserves the right to discontinue the study overall or at a 
particular study site at any time for the following reasons:
•
Emergence of any effectiveness/safety information that could significantly affect 
continuation of the study
•
Violation of applicable local regulations, the NIS protocol, or the contract by a study 
site or participating physician, disturbing the appropriate conduct of the study.
9.3
VARIABLES
9.3.1
Safety
9.3.1.1
Outcome(s) of safety
All reported adverse events in patients who take at least once of Vahelva® Respimat® will be 
noted.

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Outcomes pertaining to safety will be presented as incidence rates of adverse events and will 
include:

Adverse events

Unexpected adverse events

Serious adverse events

Adverse Drug Reactions

Adverse events leading to discontinuation

Adverse events by intensity, outcome of the events, causality
9.3.2
Effectiveness
9.3.2.1
Outcome(s) of effectiveness
9.3.2.1.1
Main outcome

Change from baseline in (Post Bronchodilator Predicted % ) FEV1 after 24 weeks
and/or 52 weeks of treatment
9.3.2.1.2
Other outcomes

Change from baseline in Pre-dose FEV1 after 24 weeks and/or 52 weeks of 
treatment

Change from baseline in mMRC score after 24 weeks and/or 52 weeks of 
treatment

Overall evaluation(Improved, unchanged, aggravated or unassessible) by 
investigator based on overall clinical assessment including change from baseline 
in effectiveness assessment((Post bronchodilator predicted % of) FEV1, (pre-dose)
FEV1, mMRC scale) after 24 weeks or 52 weeks of treatment. ‘Improved’ is 
assessed as “Effective”, ‘Unchanged, Aggravated’ are assessed as “Invalid”.
9.3.2.2
Assessment of Effectiveness

Post Bronchodilator Predicted % FEV1(Forced Expiratory Volume in one second): 
Post BD FEV1 should be collected within 1 month(30 days) prior to baseline and 
after 24 weeks and/or 52 weeks of treatment.

(pre-dose) FEV1 (Forced Expiratory Volume in one second): (pre-dose) FEV1
should be collected within 1 month(30 days) prior to baseline and after 24 weeks 
and/or 52 weeks of treatment.

mMRC scale: mMRC scale should be collected within 1 month(30 days) prior to 
baseline and after 24 weeks and/or 52 weeks of treatment.

Overall evaluation: Overall evaluation will be assessed after 24 weeks or 52 
weeks of treatment.
9.3.3
Items of Investigation
9.3.3.1
Demographic data
For demographic evaluation, following background information of subjects shall be recorded:  

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
Subject signed date 

Subject study number

Initial

Gender

Pregnancy

Height

Weight

Year of birth(age)

Smoking status
9.3.3.2
Medical history
The medical history to be collected prior to administration of this drug includes:

Check hepatic or renal impairment

Diagnosis

Severity(Mild, Moderate, Severe)

Date of diagnosis or date of surgery

End date or continuation
9.3.3.3
Concomitant medication
Information on concomitant medication that is to be collected includes:

Brand name

generic name

Route of medication

Daily dose

Unit

Purpose of administration

Indication

Start date

Date of discontinuation or continuation 
9.3.3.4
Drug administration status
Information on the drug administration status includes:

Dose

Unit

Start date

Date of discontinuation or continuation
9.3.3.5
Information on the site
Information on the site includes:

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
Hospital name 

Department 

Physician name 
9.3.3.6
Result of laboratory tests(if applicable)
Information on the result of laboratory tests includes:

Name of lab test

Range of normal(Unit, Maximum and minimum data)

Result of lab test before treatment

Result of lab test after treatment
9.3.3.7
Overall evaluation
Information on the overall evaluation includes:

Improved: If determined as there is any effect of maintaining or improving symptoms.

Unchanged: If symptoms have not been changed compared with before 
administration, and not determined as there is any effect of maintaining symptoms.

Aggravated: If symptoms are worse than before administration.

Unassessible: If it cannot be determined due to insufficient information 
collected(Even though there are any objective indicators present, it is possible to 
belong to this grade.).
9.3.4
Outcomes of subjects Evaluation
9.3.4.1
Subject evaluation items
9.3.4.1.1
Number of cases who accepted the study
This number means the planned number of cases as specified in the contract concluded with 
the investigator(physician) prior to initiation of the study.
9.3.4.1.2
Number of cases subject who collected CRF
This number means the number of cases who signed the informed consent form to participate 
in the study as subject, and have record of taking Vahelva® Respimat® once at least.
9.3.4.1.3
Number of dropouts
These cases include those who signed the informed consent form to participate in this study 
as subject but did not meet any of the inclusion criteria, do not have any prescription record 
of Vahelva® Respimat®, have prescription record but have not been followed up by the 
physician following prescription and started administration prior to the signed date.

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9.3.4.1.4
Number of cases subject to safety evaluation
These cases include those who signed the informed consent form to participate in this study 
as subject, took Vahelva® Respimat® once at least, and were completed follow up by the 
physician once or more.
9.3.4.1.5
Number of cases subject to effectiveness evaluation
These cases include those who signed the informed consent form to participate in this study 
as subject, visited as per the study schedule, took Vahelva® Respimat®, the cases included in 
safety evaluation, and were evaluated for the effectiveness including overall evaluation(if the 
case assessed as ‘unassessible’ will be excluded).
9.3.4.1.6
Subjects of special investigation
The patient who have signed on the data release consent form, subjects of special 
investigation(Pediatric or Adolescent(Younger than 18 years), Geriatric(Older than 65 years), 
Pregnant Women, renal impairment, hepatic impairment and other special population) among 
the patients who conducted investigation for safety assessment after the administration of 
Vahelva® Respimat® can be further investigation into cases collected from this study may be 
taken into account according to the outcome of retrospective analysis.
9.4
DATA SOURCES
This study will be carried out in the manner of successive survey that the investigator will be 
asked to successively write in the case report forms(CRFs) from the subject who was initially 
administered the drug following the study start date to the requested number of subjects 
without omission. Prior to initiation of the study, written contract shall be concluded, and this 
contract shall be concluded with the head of the site or the investigator with his/her consent.
9.5
STUDY SIZE
Sample size of 3,000 patients is based on the requirement of the local regulatory authority
(MFDS). Since COPD is chronic disease it might be restrictive to collect data in just short-
term (24±2weeks) period. The local regulatory authority(MFDS) recommends long-term(at 
least 52±2weeks) surveillance for maintaining approved indication. Thus all patients will be 
enrolled for long-term(52±2weeks) surveillance, basically.
Considering total surveillance size of 3,000 cases, at least 20%(600 cases) of total would be 
enrolled for long-term(52±2weeks) surveillance, even considering follow up loss in real 
world practice. Every institution will be contract for only one option of follow up 
period(short-term surveillance or long-term surveillance). It will be decided by feasibility 
check before to decide participation.
9.6
DATA MANAGEMENT
Patients’ data will be gathered by eCRF. The data management procedures to ensure the 
quality of the data are described in detail in the data management plan (DMP) available in 
TMF. Data management and statistics will be outsourced to a qualified contract research 
organization (CRO).

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9.7
DATA ANALYSIS
The safety evaluation will be performed on the “safety set” that will include all patients who 
have received treatment of Vahelva® Respimat® at least one time except those who are found 
to have no observation after enrolment, invalid registration, or invalid contract with the site. 
The effectiveness evaluation will be performed on the “effectiveness set”, a subset of the 
safety set, which will include all patients in the “safety set” except those who have no 
available effectiveness data and/or who do not suffer from COPD.
Medico-pharmaceutical assessment will be described with results of multiple regression 
analysis, 95% confidence intervals of every sub-analysis items of safety and effectiveness
assessment.
Details are provided in the Statistical Analysis Plan (SAP).
9.7.1
Statistical design – model
In this NIS, all statistical analyses will be descriptive.
The level of statistical significance (p-value) and the precision (confidence interval) for the 
statistical analysis method used for exploratory purposes will be presented. Confirmatory 
hypothesis will not be conducted.
9.7.2
Demographic baseline data
Descriptive statistics will be performed that is data of demographics and medical health status 
of safety assessed cases. Average, standard deviation, min value, max value and median will 
be displayed for continuous data. The frequency will be conducted from categorical data.
Baseline characteristics (Demographics(all), co-morbidity, initial (pre-dose)FEV1, (post 
bronchodilator predicted % of) FEV1, mMRC, co-medications, etc.) will be compared 
between the “long-term group” (patients who will be followed up for 52 weeks) and the 
“short-term group” (patients who will be followed up for 24 weeks) to put the data into 
perspective.
9.7.3
Analysis of Safety
Demographic and baseline characteristics will be summarized descriptively for the entire 
cohort of eligible patients.
Adverse events(AEs) from demographic data of safety assessment cases;
-
Number of subjects and cases of AEs will be counted and incidence rate, 95% CI 
calculation.
-
Calculate 95% confidence interval and rate of AEs. Analysis by one of methods of 
chi square test, fisher’s exact test or logistic regression analysis methods in each item
to find difference of AEs’ rate or find factor that influence to safety profile.
Adverse Events (AEs) will be coded according to the latest version of Medical Dictionary for 
Drug Regulatory Affairs (MedDRA) coding system. The study database will not be locked 
until coding is complete.

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Safety analyses will be based on all patients treated, i.e. all patients who received at least one 
dose of Vahelva® Respimat®. However, if data for patients who have been treated with 
Vahelva® Respimat® beyond the scope of approved label are collected, separate safety 
analyses will be performed. Safety analyses will be performed based on demographics and 
baseline characteristics.
Patients lost to follow up will be characterized compared to the remaining patients and reason 
and time point of loss to follow up will be evaluated.
9.7.4
Analysis of Effectiveness
Effectiveness assessment of short-term and long-term cases will be analysis. Effectiveness
rate and 95% confidence interval of demographic data will be calculated. One of methods of 
chi square test, fisher’s exact test or logistic regression analysis methods will be use 
appropriately.
9.7.4.1
Main outcome analyses
A descriptive analysis of effectiveness outcomes is planned. For patients treated with 
Vahelva® Respimat®, the change of Post Bronchodilator Predicted % FEV1 from baseline 
and last follow-up visit will be calculated. Effectiveness analysis will be performed based on 
demographic characteristics and baseline characteristics.
9.7.4.2
Other outcome analyses
A descriptive analysis of effectiveness outcome is planned. For patient treated with Vahelva 
Respimat, the change of (pre-dose) FEV1 from baseline and last follow up visit will be 
calculated. Effectiveness analysis will be performed based on demographic characteristics 
and baseline characteristics.
A descriptive analysis of effectiveness outcome is planned. For mMRC, descriptive statistics 
will be calculated. Effectiveness analysis will be performed based on demographic 
characteristics and baseline characteristics.
A descriptive analysis of effectiveness outcomes is planned. For overall evaluation, 
descriptive statistics will be calculated for assessed one of the items(improved, unchanged, 
worsen or not applicable) by investigator with medical opinion of each individual component 
and the changes from scores before first administration. Effectiveness analysis will be 
performed based on demographic characteristics and baseline characteristics.
9.7.5
Interim analyses
In accordance with local regulation for rNIS, interim analyses are planned biannually for the 
initial two years and annually thereafter.
9.7.6
Handling of missing data
As this is a NIS, there are no required investigations and diagnostic procedure (e.g. lab, 
ultrasound).

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Maximum attempt will be made to ensure the completeness of data collection. All available 
data will be used in the data analysis. Missing or incomplete AE dates are imputed according 
to BI standard.
9.8
QUALITY CONTROL
All entries in the eCRF and the existing coding will be stored in a database. The structure of 
the database is based on the division into sections and entry fields defined in the eCRF. To 
improve and ensure data quality, data checks will be performed automatically in the eCRF 
directly on electronic entry at the study site.
Plausible value ranges for numerical data entries and logical data and list entries will be filed 
in the eCRF. The tests for consistency and completeness based on this will be performed 
during entry in the eCRF. The validity of the recorded data will therefore be ensured by the 
validations incorporated in the documentation system, which highlight incorrect or 
implausible entries to the data entry clerk/doctor.
If corrections are necessary after the data are saved, these will be documented in an audit 
trail.
For the further quality assurance of the documented patient observations, a sample-based 
source data comparison might be performed on about 10% of the sites. An additional 
inspection/quality assurance check of this NIS can be performed in case of any deviation.
9.9
LIMITATIONS OF THE RESEARCH METHODS
9.9.1
Follow up loss
All efforts will be made to minimize lost to follow up, particularly in the tracking of lost 
patients. To the extent possible, occurrence of adverse event, at minimum, for patients lost to 
follow up will be obtained. This allows assessing the impact of informative censoring due to 
treatment discontinuation. Also, patients lost to follow up will be characterized compared to 
the remaining patients and reason and time point of loss to follow up will be evaluated.
9.9.2
Channeling bias
Channeling bias can occur due to preferential prescribing in relation to different risks for the 
events of interest: e.g., if Vahelva® Respimat®(tiotropium + olodaterol) would be more often 
prescribed to higher risk patients compared to other treatments, higher incidences of outcome 
events were then expected in the Tiotropium + Olodaterol group.
9.9.3
Confounding
As in any NIS, confounding may affect the estimation of associated between drug exposure 
and outcome of interest and statistical techniques. However, as only major confounders for 
selected research questions can be captured, residual (unmeasured) confounding may remain.
9.10
DATA PROTECTION, STUDY RECORDS
The International Conference on Harmonization/Harmonized Tripartite Guideline for Good 
Clinical Practice (ICH/GCP) does not often apply to NIS as most elements are relevant for 

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controlled clinical trials. However, in this NIS, all attempts will be made to adhere, as close 
as possible, to the standards of ICH/GCP. 
The protocol of this regulatory requisite NIS will be submitted to the Ministry of Food And 
Drug Safety (MFDS) for notification. It is not a local requirement in Korea to obtain 
Institutional Review Board (IRB) approval for the conduct of regulatory requisite NIS. All of 
sites will be selected which has own IRB in hospital. The protocol of this NIS will be 
submitted to IRBs whenever required or requested by these institutions. This study will be 
conducted in accordance with the Standards for Re-examination of New Medicines notified 
by MFDS, Korean Pharmaceutical Affairs Code (KPAC), Enforcement Regulation of KPAC 
and other applicable local laws and industry code (including but not limited to the 
Regulations on Fair Competition in the Trade of Medicines of KPMA and KRPIA). 
will submit periodic reports during re-examination period, and 
the final report to MFDS upon study completion. The periodic report for the final year will be 
substituted with the final report. When required, the interim reports and the final report will 
be submitted to the IRBs as well.
9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s study-related files and 
correspondence, and the informed consent documentation of this non-interventional study.
9.10.2
Study records
All of the clinical data will be captured via a web-based EDC (Electronic Data Capture) 
System. The site staff will enter and edit the data via a secure network, with secure access 
features (username, password and secure identification – an electronic password system). A 
complete electronic audit trail will be maintained. The treating physician will approve the 
data using an electronic signature.
Patients will not be identified on the eCRF by name. Appropriate code identification (i.e., 
patient number) will be used. The treating physician will make a separate confidential record 
of these details (patient identification code list) to permit identification of all patients enrolled 
in this study in case follow-up is required. Likewise, any supporting documentation will be 
redacted of any patient identifying information, and the patient ID number clearly written on 
the documents. 
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 reported on the eCRFs must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study; current medical records must also be available.
For the eCRF, the following data need to be derived from source documents:

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
Patient identification(gender, age, initial)

Patient participation in the study(study number, patient number, date patient was 
informed)

Dates of Patient’s visits, including dispensing of study medication

Medical history(including study indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events(onset date(mandatory), and end date(if available))

Serious adverse events(onset date(mandatory), and end date(if available))

Concomitant therapy(start date, changes)

Laboratory results(if applicable)

Completion of Patient’s Participation in the study
9.10.2.2 Direct access to source data and documents
The Investigator / institution will permit study-related monitoring, audits, IRB review and 
regulatory inspection, providing direct access to all related source data / documents. eCRF 
and all source documents must be available at all times for review by the Sponsor’s non 
interventional study specialist(NIS specialist), auditor and inspection by health authorities 
(e.g. MFDS). The NIS specialist and auditor may review all eCRF, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
section 9.10.2.1.
9.10.2.3
Storage period of records
The NIS physician and the site are jointly responsible for maintaining essential study 
documents for 3 years after completion of the study (defined as termination date of re-
examination period) by the Pharmaceutical Affairs Law and shall take measures to prevent 
accidental or premature destruction of these documents.

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10.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the applicable sections of GCP, relevant BI 
Standard Operating Procedures and local regulations. Standard medical care(prophylactic, 
diagnostic and therapeutic procedures) remains in the responsibility of the treating physician 
of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/International Conference on Harmonization(ICH) GCP / GPP if applicable.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract.
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board(IRB) / Independent Ethics 
Committee(IEC) and Competent Authority(CA) according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the study, written informed consent must be obtained from 
each patient(or the patient’s legally accepted representative) according to the regulatory and 
legal requirements of the participating country. Each signature must be personally dated by 
each signatory and the informed consent retained by the investigator as part of the study 
records. A signed copy of the informed consent and any additional patient information must 
be given to each patient or the patient’s legally accepted representative.
The patient must be informed that his/her personal study-related data will be used by BI in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors(NIS Specialist) or Clinical Quality Assurance auditors appointed by BI, by 
appropriate IRB / IEC members, and by inspectors from regulatory authorities.
10.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study will be considered 
confidential and disclosure to third parties will be prohibited with the exceptions noted 
below. Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data will be made available to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated from the 
study will be made available for inspection on request by the participating physicians, the 
sponsor and/or its representatives and/or designees, by the IRBs/IECs and the regulatory 
authorities.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. 
Adverse 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(SAE) is defined as any AE which:
•
results in death,
•
is life-threatening,
•
requires inpatient hospitalization or 
•
prolongation of existing hospitalization,
•
results in persistent or significant disability or incapacity,
•
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 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 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.
Non Serious Adverse Drug Reaction
Non Serious Adverse Drug Reaction(NSADR) is defined as any adverse reaction which does 
not meet the SAE criteria.

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AESI (Adverse Event of Special interest)
No AESI (Adverse Event of Special interest) 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 authorization. Sufficient data from controlled 
interventional studies are available to support the evidence on the safety and effectiveness of 
the studied Vahelva® Respimat®. For this reason the following AE collection and reporting 
requirements have been defined.
Reporting will be done according to the specific definitions and instructions detailed in the 
‘Adverse Event Reporting’ section of the site materials (that include all necessary documents, 
the protocol, instructions for conducting NIS, the package insert etc.).
All adverse events occurred from the signing date on data release consent form to last visit 
date of monitoring period need to be collected, documented and reported to the sponsor using 
the AE page of eCRF(Attachment 1). It will then be automatically reported to the sponsor via 
email as ‘AE Alert’. All SAEs must be reported with details of relevant non-serious AEs, 
within 24 hours of occurrence via Electronic Data Capture system to the Local PV 
Manager(LPVM) of
using the NIS AE report form(Attachment 2). If any new or 
further information to these events is available, a follow-up NIS AE report has to be sent to 
BI. All SAEs and non-serious AEs must include a causal relationship assessment from the 
physician.
Contact details:
Local PV Manager(LPVM)
Tel: 
Fax:
Address:
(Postal code: 
The investigator carefully assesses whether an AE constitutes an Adverse Reaction using the 
information below. 
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an AE. An adverse reaction, in 
contrast to an AE, is characterised by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected. 

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Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative etiologies that could explain the event(e.g. 
preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs(e.g. Stevens-Johnson syndrome).
•
An indication of dose-response(i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal
relationship could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
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.
The causal relationship must be provided by the Investigator for all potential study drugs, i.e. 
the BI study drug and for all other study drugs.
The reason for the decision on causal relationship needs to be provided in the (e)CRF and on 
the NIS AE form (if applicable).
Related
a.
Certain: An event occurring in a plausible time relationship to drug administration 
and that cannot be explained by concurrent disease or other drugs or chemicals. The 
response to withdrawal of the drug (dechallenge) should be clinically plausible. The 
event must be definitive pharmacologically or phenomenologically, using a 
satisfactory rechallenge procedure if necessary,
b.
Probable/Likely: An event with a reasonable time sequence to administration of the 
drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and 
which follows a clinically reasonable response on withdrawal(dechallenge). 
Rechallenge information is not required to fulfill this definition.

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c.
Possible: An event with a reasonable time sequence to administration of the drug, but 
which could also be explained by concurrent disease or other drugs or chemicals. 
Information on drug withdrawal may be lacking or unclear.
d.
Conditional/Unclassifiable: Case of requiring more data or reviewing the additional 
data for the appropriate assessment
e.
Unassessable/ Unclassifiable: Case that it cannot be judged and complemented or 
confirmed due to the insufficient or contradictory information
Unrelated
a.
Unlikely: An event with a temporal relationship to drug administration which makes 
a causal relationship improbable, and in which other drugs, chemicals or underlying 
disease provide plausible explanations.
Intensity of AE
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 study medication, VAHELVA® 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’s LPVM 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. 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form and not the NIS AE form is to be completed. If there is 
an SAE associated with the pregnancy then the SAE has to be reported on the NIS AE form 
in addition. 
The ISF will contain the Pregnancy Monitoring Form (Part A and B).
Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS AE form from signing the 
informed consent onwards until the end of the study:
Type of Report
Timeline
All Serious Adverse Events (SAEs) 
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to Vahelva® Respimat® (Tiotropium 
+ Olodaterol)
immediately within 24 hours

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All non-serious Adverse Drug Reaction
associated with Vahelva® Respimat®
(Tiotropium + Olodaterol)
7 calendar days
All Drug exposure during pregnancy
7 calendar days
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor upfront via telephone. 
This does not replace the requirement to complete the AE page of the eCRF.
Information required
For each reportable AE, the investigator should provide the information requested on the 
appropriate (e)CRF pages and the NIS AE form.
Reporting of related AEs associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other than
Vahelva® 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 rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalization of the Study Report.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P12-01205
Global Initiative for Chronic Obstructive Lung Disease (GOLD). 
Global strategy for the diagnosis, management, and prevention of 
chronic obstructive pulmonary disease (revised 2011).
R96-2117
Mahler DA, Weinberg DH, Wells CK, Reinstein AR, The measurement 
of dyspnea. Contents, interobserver agreement, and physiologic 
correlates of two new clinical indexes. Chest 85(6), 751-758(1984)
13.2
UNPUBLISHED REFERENCES
U04-0202             
BI 1744 CL: Investigator's Brochure. 1222.P1.
c01735808-12
Tiotropium + Olodaterol fixed dose combination Investigator’s 
Brochure
No. 0287-01
SPIOLTO® RESPIMAT® Company Core Data Sheet
13.3
WEB SITE
1.
Korean National Health and Nutrition Examination Survey (2013)
http://knhanes.cdc.go.kr
2.
Statistics Korea: 2009 statistical results about cause of death.
http:// www.index.go.kr 

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14.
APPENDICES
14.1
ELECTRONIC CASE REPORT FORM
See the Attachment 1.
14.2
SAE/ NON-SERIOUS ADVERSE REACTION REPORT
See the Attachment 2.
14.3
PREGNANCY MONITORING FORM
See the Attachment 3.
14.4
VAHELVA® RESPIMAT® PRESCRIPTION INFORMATION FOR 
KOREA
See the Attachment 4.

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

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ANNEX 2. MODIFIED MEDICAL RESEARCH COUNCIL(MMRC)
Difficulty breathing in daily life is evaluated by the mMRC level consisting of five scores, 
and it is divided into a score without difficulty breathing (score 0) and inability to live normal 
life (score 4).
Score
Level of Breathlessness
0
Only breathlessness with strenuous exercise
1
Shortness of breath hurrying or walking up a slight hill
2
Walks slower than age group or has to stop for breath when walking on level 
ground at own pace
3
Stops for breath after walking 100 meters or a few minutes on level ground
4
Breathless when dressing/undressing or too breathless to leave the house

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ANNEX 3. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Doc.Ref. EMA/540136/2009 
ENCePP Checklist for Study Protocols (Revision 2, amended)
Adopted by the ENCePP Steering Group on 14/01/2013
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)
welcomes innovative designs and new methods of research. This Checklist has been developed by 
ENCePP to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist is intended to 
promote the quality of such studies, not their uniformity. 
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. 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). 
Study title:
A regulatory required non interventional study to monitor the safety and effectiveness of once daily 
treatment of orally inhaled VAHELVA® RESPIMAT® (Tiotropium + Olodaterol fixed dose 
combination 2.5µg/2.5µg per puff (2 puffs comprise one medicinal dose) for Korean patients with 
COPD (Chronic Obstructive Pulmonary Disease)
Study reference number:
1237.XX
Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
1.1 Does the protocol specify timelines for 
1.1.1 Start of data collection
1.1.2 End of data collection
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.
13
13
13
13
13
13
Comments:
Section 2: Research question
Yes
No
N/A
Page 
Number(s)
2.1 Does the formulation of the research question and 
objectives clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address an 
important public health concern, a risk identified in the risk 
management plan, an emerging safety issue)
2.1.2 The objective(s) of the study?
14
16
2.1.3 The target population? (i.e. population or 
18

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Section 2: Research question
Yes
No
N/A
Page 
Number(s)
subgroup to whom the study results are intended to be 
generalised)
2.1.4 Which formal hypothesis(-es) is (are) to be 
tested?
2.1.5 If applicable, that there is no a priori
hypothesis?
Comments:
Section 3: Study design
Yes
No
N/A
Page 
Number(s)
3.1 Is the study design described? (e.g. cohort, case-
control, randomised controlled trial, new or alternative design) 
17
3.2 Does the protocol specify the primary and 
secondary (if applicable) endpoint(s) to be 
investigated?
16
3.3 Does the protocol describe the measure(s) of 
effect? (e.g. relative risk, odds ratio, deaths per 1000 
person-years, absolute risk, excess risk, incidence rate ratio, 
hazard ratio, number needed to harm (NNH) per year)
21
Comments:
Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1 Is the source population described?
18
4.2 Is the planned study population defined in terms 
of:
4.2.1 Study time period?
4.2.2 Age and sex?
4.2.3 Country of origin?
4.2.4 Disease/indication?
4.2.5 Co-morbidity?
4.2.6 Seasonality?
17
18
18
18
4.3 Does the protocol define how the study population 
will be sampled from the source population? (e.g. 
event or inclusion/exclusion criteria)  
18
Comments:
Section 5: Exposure definition and measurement
Yes
No
N/A
Page 
Number(s)
5.1 Does the protocol describe how exposure is 
defined and measured? (e.g. operational details for 

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Section 5: Exposure definition and measurement
Yes
No
N/A
Page 
Number(s)
defining and categorising exposure)
5.2 Does the protocol discuss the validity of exposure 
measurement? (e.g. precision, accuracy, prospective 
ascertainment, exposure information recorded before the 
outcome occurred, use of validation sub-study)
5.3 Is exposure classified according to time windows?
(e.g. current user, former user, non-use)
5.4 Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
5.5 Does the protocol specify whether a dose-
dependent or duration-dependent response is 
measured?
Comments:
Section 6: Endpoint definition and measurement
Yes
No
N/A
Page 
Number(s)
6.1 Does the protocol describe how the endpoints are 
defined and measured? 
21
6.2 Does the protocol discuss the validity of endpoint 
measurement? (e.g. precision, accuracy, sensitivity, 
specificity, positive predictive value, prospective or 
retrospective ascertainment, use of validation sub-study)
21
Comments:
Section 7: Confounders and effect modifiers
Yes
No
N/A
Page 
Number(s)
7.1 Does the protocol address known confounders?
(e.g. collection of data on known confounders, methods of 
controlling for known confounders)
7.2 Does the protocol address known effect modifiers?
(e.g. collection of data on known effect modifiers, anticipated 
direction of effect)
Comments:
Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.1 Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
8.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview, etc.)
8.1.2 Endpoints? (e.g. clinical records, laboratory markers 
or values, claims data, self-report, patient interview including 
22

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Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
scales and questionnaires, vital statistics, etc.)
8.1.3 Covariates?
22
8.2 Does the protocol describe the information 
available from the data source(s) on:
8.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose,  number of days of supply prescription, daily dosage,  
prescriber)
8.2.2 Endpoints? (e.g. date of occurrence, multiple event, 
severity measures related to event)
8.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, life style, etc.)
23
23
8.3 Is a coding system described for:
8.3.1 Diseases? (e.g. International Classification of 
Diseases (ICD)-10)
8.3.2 Endpoints? (e.g. Medical Dictionary for Regulatory 
Activities (MedDRA) for adverse events)
8.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC)Classification System)
18
25
25
8.4 Is the linkage method between data sources 
described? (e.g. based on a unique identifier or other)
Comments:
Section 9: Study size and power
Yes
No
N/A
Page 
Number(s)
9.1 Is sample size and/or statistical power calculated? 
Comments:
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1 Does the plan include measurement of excess 
risks?
24
10.2 Is the choice of statistical techniques described? 
24
10.3 Are descriptive analyses included?
24
10.4 Are stratified analyses included?
24
10.5 Does the plan describe methods for adjusting for 
confounding?
26
10.6 Does the plan describe methods addressing 
effect modification?
26
Comments:

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Non-interventional Study Protocol
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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Section 11: Data management and quality 
control
Yes
No
N/A
Page 
Number(s)
11.1 Is information provided on the management of 
missing data?
26
11.2 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
29
11.3 Are methods of quality assurance described?
28
11.4 Does the protocol describe possible quality 
issues related to the data source(s)?
28
11.5 Is there a system in place for independent 
review of study results? 
Comments:
Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
12.1 Does the protocol discuss:
12.1.1 Selection biases?
12.1.2 Information biases?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods)
25
25
12.2 Does the protocol discuss study feasibility? (e.g. 
sample size, anticipated exposure, duration of follow-up in a 
cohort study, patient recruitment)
23
12.3 Does the protocol address other limitations? 
25
Comments:
Section 13: Ethical issues
Yes
No
N/A
Page 
Number(s)
13.1 Have requirements of Ethics 
Committee/Institutional Review Board approval 
been described?
28
13.2 Has any outcome of an ethical review procedure 
been addressed?
28
13.3 Have data protection requirements been 
described?
28
Comments:
Section 14: Amendments and deviations
Yes
No
N/A
Page 
Number(s)
14.1 Does the protocol include a section to document 

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Non-interventional Study Protocol
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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Section 14: Amendments and deviations
Yes
No
N/A
Page 
Number(s)
future amendments and deviations? 
Comments:
Section 15: Plans for communication of study 
results
Yes
No
N/A
Page 
Number(s)
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)?
33
15.2 Are plans described for disseminating study 
results externally, including publication?
36
Comments:
Name of the main author of the protocol:
Date: 17/Sep/2020
Signature: