Safety Profile of Tiotropium + Olodaterol Used as Maintenance Treatment in COPD Patients in Taiwan: a Non-interventional Study Based on the Taiwan National Health Insurance (NHI) Data
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

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ABCD
Non-Interventional Study (NIS) Protocol 
TITLE PAGE
Document Number:
c38644780-01 
BI Study Number:
1237-0109
BI Investigational 
Product(s):
Spiolto Respimat
Title:
Safety profile of Tiotropium + Olodaterol used as 
maintenance treatment in COPD patients in Taiwan: a 
non-interventional study based on the Taiwan National 
Health Insurance (NHI) data
Brief lay title:
Safety of Tiotropium + Olodaterol in COPD patients in 
Taiwan: a non-interventional study based on the Taiwan 
National Health Insurance (NHI) data
Protocol version 
identifier:
1.0  
Date of last version of 
protocol:
Not applicable
PASS:
Yes
EU PAS register
number:
Study not registered
Active substance:
Tiotropium + Olodaterol (R03AL06)
Medicinal product:
Spiolto Respimat
Product reference:
BC26735443
Procedure number:
Not applicable
Marketing authorization 
holder(s):
Boehringer Ingelheim International GmbH
Joint PASS:
No
Research question and 
objectives:
To estimate the incidence of safety outcomes in patients with 
COPD who initiated Tiotropium / Olodaterol (Tio/Olo)
Country(-ies) of study:
TCM (The Chinese Market)

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Author:
Principle Investigator
Email: 
Email: 
Marketing authorization
holder(s):
Boehringer Ingelheim International GmbH
In case of PASS, add:
MAH contact person:
Email: 
EU-QPPV: 
Phone: 
Fax: 
E-mail:
Mobile phone: 
24-hour phone contact: 
Signature of EU-QPPV:
Date:
11 May 2022
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Proprietary confidential information
© 2022 Boehringer Ingelheim Group of 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...............................................................................................5
3.
RESPONSIBLE PARTIES...................................................................................................6
4.
ABSTRACT..........................................................................................................................7
5.
AMENDMENTS AND UPDATES....................................................................................17
6.
MILESTONES....................................................................................................................17
7.
RATIONALE AND BACKGROUND...............................................................................17
8.
RESEARCH QUESTION AND OBJECTIVES ................................................................18
9.
RESEARCH METHODS ...................................................................................................18
9.1
STUDY DESIGN .........................................................................................................18
9.2
SETTING......................................................................................................................19
9.2.1 Study sites .................................................................................................................19
9.2.2 Study population .......................................................................................................19
9.2.3 Study visits................................................................................................................20
9.2.4 Study discontinuation................................................................................................20
9.3
VARIABLES................................................................................................................20
9.3.1 Exposures..................................................................................................................20
9.3.2 Outcomes ..................................................................................................................20
9.3.2.1 Primary outcomes .............................................................................................20
9.3.2.2 Secondary outcomes .........................................................................................20
9.3.3 Covariates..................................................................................................................21
9.4
DATA SOURCES ........................................................................................................23
9.5
STUDY SIZE................................................................................................................24
9.6
DATA MANAGEMENT .............................................................................................25
9.7
DATA ANALYSIS.......................................................................................................25
9.7.1 Main analysis ............................................................................................................25

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9.7.3 Safety Analysis .........................................................................................................26
9.8
QUALITY CONTROL.................................................................................................26
9.9
LIMITATIONS OF THE RESEARCH METHODS....................................................26
9.10 OTHER ASPECTS.......................................................................................................27
9.10.1 Data quality assurance.............................................................................................27
9.10.2 Study records...........................................................................................................27
9.10.2.1 Source documents...........................................................................................27
9.10.2.2 Direct access to source data and documents...................................................27
10.
PROTECTION OF HUMAN SUBJECTS .........................................................................28
10.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED CONSENT28
10.2 STATEMENT OF CONFIDENTIALITY....................................................................28
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS......................................................................................................................29
11.1 DEFINITIONS OF ADVERSE EVENTS....................................................................29
11.2 ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING................................................................................................................29
11.3 REPORTING TO HEALTH AUTHORITIES .............................................................29
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ........30
13.
REFERENCES ...................................................................................................................31
13.1 PUBLISHED REFERENCES ......................................................................................31
13.2 UNPUBLISHED REFERENCES.................................................................................31
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................................32
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................................33
ANNEX 3. ADDITIONAL INFORMATION.............................................................................41
ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES..................................................42

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2.
LIST OF ABBREVIATIONS
AE
Adverse Event
CA
Competent Authority
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
ENCePP
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance
GPP
Good Pharmacoepidemiology Practice
GVP
Good Pharmacovigilance Practices
ICS
Inhaled corticolsteroids 
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LABA
Long-acting β2-agonists
LAMA
Long-acting muscarinic antagonists
MAH
Marketing Authorization Holder
NHI
Taiwan National Health Insurance
NHIRD               Taiwan National Health Insurance Research Database
NIS
Non-Interventional Study
Olo
Olodaterol
PASS
Post-Authorization Safety Study
SAE
Serious Adverse Event
Tio
Tiotropium 

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3.
RESPONSIBLE PARTIES
Principle Investigator
Email: 
BI NIS Lead (Scientific)
Email: 
BI NIS Lead (Operation)
Email: 

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4.
ABSTRACT
According to requirement by local regulatory authority, the safety information of newly 
approved drugs is to be collected to provide supplementary data to those identified in 
randomized clinical studies within 5 years period after approval. This is a non-
interventional study based on existing data. It will provide the safety information of 
Spiolto (tiotropium+olodaterol) in Chinese patients with chronic obstructive pulmonary 
disease (COPD) in routine clinical practice in Taiwan.
Data used in this study will come from the Taiwan National Health Insurance (NHI) 
claims data between 2014 and 2019. There will be around 4,000 patients using 
Tiotropium/ Olodaterol (Tio+Olo) in the Taiwan National Health Insurance Research 
Database (NHIRD) that can be enrolled in this study. The primary outcome of this study 
will be incidence of adverse events in patients with COPD treated with Tio+Olo. Other 
outcomes include the baseline characteristics of patients who initiated Tio+Olo and 
comparing the baseline characteristics of patients who initiated Tio+Olo with those 
treated with other LAMA/LABAs in the Taiwan NHIRD database.

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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat  
Name of active ingredient: 
Tiotropium + Olodaterol {R03AL06}
Protocol date:
11 May 2022
Study 
number:
1237.0109
Version/Revision:
1.0
Version/Revision date:
NA
Title of study:
Safety profile of Tiotropium + Olodaterol used as maintenance 
treatment in COPD patients in Taiwan: a non-interventional study 
based on the Taiwan National Health Insurance (NHI) data
Rationale and 
background:
According to requirement by local regulatory authority, the safety 
information of newly approved drugs is to be collected to provide 
supplementary data to those identified in randomized clinical studies 
within 5 years period after approval. 
This is a non-interventional study based on existing data. It will 
provide the safety information of Spiolto (tiotropium+olodaterol) in 
Chinese patients with chronic obstructive pulmonary disease (COPD) 
in routine clinical practice in Taiwan.
COPD is a leading cause of morbidity and mortality throughout the 
world and now is the third leading cause of mortality in China. The 
prevalence of COPD in China was 13.7% in population who were ≥40 
years old [R22-0908].
Spiriva Respimat® (tiotropium 5μg qd) has been approved worldwide 
for over one decade and provides improvements on lung function and 
symptoms, and prevents exacerbations for patients with COPD
[P13-11053]. Olodaterol, a long acting β2–agonist, in the completed 
global clinical development for COPD, has shown a 24-hour duration 
of action profile, rapid onset of action, and an optimized inhaled 
LABA profile. Also, olodaterol at doses of 5μg once daily is safe and 
well tolerated [P05-10481].
The combination of tiotropium and olodaterol in a single Respimat®

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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat  
Name of active ingredient: 
Tiotropium + Olodaterol {R03AL06}
Protocol date:
11 May 2022
Study 
number:
1237.0109
Version/Revision:
1.0
Version/Revision date:
NA
Inhaler device provides a rational target for optimizing bronchodilator 
treatment of COPD, the safety and efficacy profile of which has been 
demonstrated in large clinical development program with no concerns 
of any new safety issues comparing with placebo and its mono-
components [P15-03344, P18-02990].China participated Tio+Olo 
Respimat® inhaler pivotal trials. In Chinese patients, the safety finding 
is in line with those in total trial population and the efficacy is similar 
to that in all trial population [c03489048-01].
In conclusion, the safety and efficacy profile of tiotropium + 
olodaterol (Tio+Olo) 5/5μg delivered via the RESPIMAT inhaler has 
been demonstrated in entire completed global clinical program 
(Tio+Olo) with no concerns of any new safety issues and well-
tolerated.
Research 
question and 
objectives:
Primary objective:
•
To estimate the incidence rate of safety outcomes in Chinese 
patients with COPD who initiated Tio/Olo between 1st January 
2014 and 31st December 2019;
Secondary objective:
•
To compare the baseline characteristics of patients between those 
treated with Tio/Olo and those with other LAMA/LABAs FDC 
(Vilanterol/Umeclidinium; INDACATEROL/ 
GLYCOPYRRONIUM) or (LABA: Salmeterol; 
Formoterol; Procaterol; Indacaterol; Olodaterol, LAMA: Tiotropium 
bromide; Glycopyrrolate; Umeclidinium) free combination;
Study design:
This study will be a non-interventional cohort study based on existing 
data (NISed).

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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat  
Name of active ingredient: 
Tiotropium + Olodaterol {R03AL06}
Protocol date:
11 May 2022
Study 
number:
1237.0109
Version/Revision:
1.0
Version/Revision date:
NA
Population:
Inclusion criteria:
1.
At least one prescription for Tio+Olo (fixed dose combination 
(FDC) or free combination) as a new initiation between 1st January 
2014 and 31st December 2019.
2.
Aged ≥ 40 years on the index date (The first dispensing of 
Tio/Olo combined inhaler will be defined as the index date);
3.
At least one diagnosis of COPD (ICD9: 491.x, 492.x, 496; 
ICD10: J41.x, J42, J43.x, J44.x) at any time prior to or on the index 
date;
4.
At least one year of continuous medical and health insurance 
plan prior to the index date will be required to allow for a look-back 
period for the covariates and identification of new use of the study 
drugs;
5.
At least one record in the health insurance system database.
Exclusion criteria:
1.
Any use of Tio+Olo in free or fixed form within one year prior 
to the index date;
2.
Individuals with asthma, allergic rhinitis, lung cancer, interstitial 
lung disease, or lung transplant identified at any time prior to the 
index date.
Another cohort of patients using other LAMA/LABA (FDC or free 
combination) will also be enrolled to collect the information of 
baseline characteristics to be compared with those of patients treated 
with Tio+Olo. The Inclusion/Exclusion criteria are similar with those 
of Tio+Olo, which include:
Inclusion criteria:
1. At least one prescription for LAMA+LABA (FDC or free 
combination) other than Tio/Olo as a new initiation between 1st 

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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat  
Name of active ingredient: 
Tiotropium + Olodaterol {R03AL06}
Protocol date:
11 May 2022
Study 
number:
1237.0109
Version/Revision:
1.0
Version/Revision date:
NA
January 2014 and 31st December 2019. 
2. Aged ≥ 40 years on the index date; 
3. At least one diagnosis of COPD at any time prior to or on the index 
date; 
4. At least one year of continuous medical and health insurance plan 
prior to the index date will be required to allow for a look-back 
period for the covariates and identification of new use of the study 
drugs;  
5. At least one record in the health insurance system database.
Exclusion criteria:
1. Any use of LAMA+LABA in free or fixed form for one year prior to 
the index date; 
2. Individuals with asthma, allergic rhinitis, lung cancer, interstitial 
lung disease, or lung transplant identified at any time prior to the
index date.
Variables:
Exposures:
Exposure of this study is defined as new initiation of 
Tiotropium/Olodaterol during the study period between 1st January 
2014 and 31st December 2019.
Outcomes:
Primary outcome:
•
Incidence rate of adverse events in patients with COPD treated with 
Tio+Olo 
Secondary outcomes: 
•
To describe the baseline characteristics of patients who initiated 
Tio+Olo;

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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat  
Name of active ingredient: 
Tiotropium + Olodaterol {R03AL06}
Protocol date:
11 May 2022
Study 
number:
1237.0109
Version/Revision:
1.0
Version/Revision date:
NA
•
To compare the baseline characteristics of patients who initiated 
Tio+Olo with those treated with other LAMA/LABAs in the Taiwan 
NHIRD database;
Covariates:
Including sex, age, calendar year of cohort entry, season of index date 
(winter, spring, summer, fall)
Additional characteristics will be defined during the 1 year pre-index 
baseline period: 
specific previous COPD treatments, previous COPD exacerbation, 
hospitalizations caused by exacerbation of heart failure, all-cause 
hospitalizations, comorbidities, Charlson Comorbidity Index (CCI), 
history of medications dispensed.
Data sources:
Data used in this study will come from the Taiwan National Health 
Insurance (NHI) claims data between 2014 and 2019. 
Data sources include Taiwan NHI, Taiwan cancer registry (TCR) and 
Taiwan Mortality Data. Taiwan Department of Statistics, Ministry of 
Health and Welfare is the unit designated by the government to 
manage health and social welfare statistical databases, and to develop 
data platform for academic research. Through the services provided by 
the Health and Welfare Data Science Center (HWDSC) of the 
Department of Statistics, researchers may access a wide range of health 
and welfare data, including claims, mortality (with cause of death) and 
Taiwan Cancer Registry (TCR). The HWDSC staff encrypt the 
national ID for all individuals according to a secure encryption 
algorithm that is not made known to the public. The encrypted ID is 
unique for all individuals and will be used for linkage between 
databases.

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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat  
Name of active ingredient: 
Tiotropium + Olodaterol {R03AL06}
Protocol date:
11 May 2022
Study 
number:
1237.0109
Version/Revision:
1.0
Version/Revision date:
NA
(a) National Health Insurance claims data
Taiwan National Health Insurance (NHI) started in 1995 and is a 
publicly funded single payer health insurance program for all residents. 
Health insurance for individuals is required by law and coverage is 
more than 99%. The majority of healthcare providers in Taiwan 
contract with the National Health Insurance Agency in Taiwan to 
provide a wide range of medical services. Geographic locations of 
health care claims are broadly classified into 6 regions in Taiwan. 
Salary range, which serves as the basis for enrollees’ premium 
calculation, can serve as a proxy indicator for
socioeconomic status. Bundled payment according to the Diagnosis-
Related Group system only applies in limited number of disease 
conditions, therefore detailed drug use information during 
hospitalization is also available. An added advantage of the NHI data 
source is the low membership turnover rate, which is particularly 
important for long-term follow-up study. NHI claims were based on 
International Classification of Disease, ninth revision, clinical 
modification (ICD-9-CM) codes till the end of 2015, and then switched 
to International Classification of Disease, tenth revision, clinical 
modification (ICD-10-CM) codes after 2016. Specific NHI data 
column please see file column_note_in_TW_NHI_20210824 
[No document #] in the database (confidential and only can be 
accessed by PI).
(b) Mortality data
The household registration system in Taiwan maintain birth, marital 
status, and death information and is administrated by the Department 
of Household Registration, Ministry of the Interior. Death certificates 
are collected through this system and transferred to the Ministry of 
Housing and Works (MOHW) for coding of cause of death and 
maintenance of the mortality database. The cause of death was coded 
in the ICD-9-CM format from 1990 to 2009, and in ICD-10-CM 

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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat  
Name of active ingredient: 
Tiotropium + Olodaterol {R03AL06}
Protocol date:
11 May 2022
Study 
number:
1237.0109
Version/Revision:
1.0
Version/Revision date:
NA
format from 2010 to 2019. This study will use the cause of death files 
in years 2012-2019, primarily focusing on the date of death of study 
subjects. 
(c) Taiwan Cancer Registry data
In Taiwan, the population-based cancer registry was founded in 1979. 
Since then, the registry collected basic information, referred to the “20 
items short-form system,” on incident cancer cases (including cancer-
in-situ) within one year after the initial diagnosis from hospitals with 
more than 50-bed capacity throughout the country. Recorded items 
include date of birth, gender, time and method of diagnosis, cancer site 
and morphology, treatment summary and death. From 2002
onward, a “long-form” system was established to collect more 
detailed information of cancer staging, treatment and follow-up data 
from hospitals with more than 500 new cancer cases diagnosed 
annually. The number of recorded items increased from 20 to 65 in 
2002, further to 95 in 2007, and to 114 in 2011. In 2003, Cancer 
Control Act was introduced with all reporting hospitals mandated to 
submit cancer patient information to the cancer registry. To ensure 
quality of cancer registries and enhancing the quality of cancer 
registry data, Taiwan Society of Cancer Registry was established in 
2006, conducting random medical record review to ensure data 
accuracy since 2010. TCR data from 2000 through 2018 will be used 
for this study.
Study size:
There will be around 4,000 patients using Tio+Olo in the Taiwan 
NHIRD that can be enrolled in this study.
The following table provides an estimation and 95% CI for incidence 
rate of each AE among new users of Spiolto® Respimat® for the study 

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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat  
Name of active ingredient: 
Tiotropium + Olodaterol {R03AL06}
Protocol date:
11 May 2022
Study 
number:
1237.0109
Version/Revision:
1.0
Version/Revision date:
NA
duration of 6 years.
Adverse 
events
Inciden
ce rates 
per 100 
patient 
years
N
95% CI
Lowe
r
Uppe
r
Pneumonia
4.69
400
0
4.308
5.083
COPD 
exacerbation
55.42
400
0
54.09
2
56.75
8
Arrhythmia
1.82
400
0
1.583
2.067
Supraventricul
ar tachycardia
1.16
400
0
0.975
1.358
Data analysis:
All variables, including patient characteristics, baseline measures, and 
outcomes, will be analysed descriptively.
We will first describe formation of the study cohort. Patient 
characteristics at baseline will be described using standard descriptive 
statistics. For the analysis of primary outcome, the incidence rates of 
AEs during entire follow-up period will be calculated based on the 
following formula:
(Total number of patients in the Tio+Olo cohort experiencing an 
event of interest for the first time during the given time period) / 
(Total person-time at risk from current use of Tio+Olo during the 
given period)
Absolute standardized differences (ASDs) will be used to compare the 

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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat  
Name of active ingredient: 
Tiotropium + Olodaterol {R03AL06}
Protocol date:
11 May 2022
Study 
number:
1237.0109
Version/Revision:
1.0
Version/Revision date:
NA
baseline characteristics between the two groups, in which a >0.1 ASD 
indicates a meaningful difference.
As an objective of the study was to compare the clinical attributes of 
patients in each study group. The standardized difference will be used 
as a parameter to quantify the between-group differences for each 
clinical attribute. This metric is commonly used in studies utilizing 
secondary health data, in which a standardized difference of larger 
than 0.1 indicates a meaningful difference with respect to the clinical 
attribute between the two study groups.
Milestones:
Feasibility assessment: 2020. Q3
EU PAS Registration: 01-Jun-2022
Full analysis:
•
Touching the data: 15-Jun-2022
•
Study result: 30-Jul-2022
Publication’s timeline:
Abstract: 2023 ATS

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5.
AMENDMENTS AND UPDATES
None
6.
MILESTONES
Milestone
Planned Date
IRB/IEC approval
Oct 2020 (completed)
Feasibility assessment
Qct 2020 (completed)
EU PAS Registration
01/Jun/2022
Full analysis
Accessing the data 
15/Jun/2022
Complete data analysis
30/June/2022 
Final report of study results:
15/Oct/2022
7.
RATIONALE AND BACKGROUND
According to requirement by local regulatory authority, the safety information of newly 
approved drugs is to be collected to provide supplementary data to those identified in 
randomized clinical studies within 5 years period after approval. 
This is a non-interventional study based on existing data. It will provide the safety 
information of Spiolto (tiotropium+olodaterol) in Chinese patients with chronic 
obstructive pulmonary disease (COPD) in routine clinical practice in Taiwan.
COPD is a leading cause of morbidity and mortality throughout the world and now is the 
third leading cause of mortality in China. The prevalence of COPD in China was 13.7% 
in population who were ≥40 years old [R22-0908].
Spiriva Respimat® (tiotropium 5μg qd) has been approved worldwide for over one 
decade and provides improvements on lung function and symptoms, and prevents 
exacerbations for patients with COPD [P13-11053]. Olodaterol, a long acting β2–
agonist, in the completed global clinical development for COPD, has shown a 24-hour 
duration of action profile, rapid onset of action, and an optimized inhaled LABA profile. 

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Also, olodaterol at doses of 5μg once daily is safe and well tolerated [P05-10481].
The combination of tiotropium and olodaterol in a single Respimat® Inhaler device 
provides a rational target for optimizing bronchodilator treatment of COPD, the safety 
and efficacy profile of which has been demonstrated in large clinical development 
program with no concerns of any new safety issues comparing with placebo and its 
mono-components [P15-03344, P18-02990]. China participated Tio+Olo Respimat® 
inhaler pivotal trials. In Chinese patients, the safety finding is in line with those in total 
trial population and the efficacy is similar to that in all trial population [c03489048-01].
In conclusion, the safety and efficacy profile of tiotropium + olodaterol (Tio+Olo) 5/5μg 
delivered via the RESPIMAT inhaler has been demonstrated in entire completed global 
clinical program (Tio+Olo) with no concerns of any new safety issues and well-
tolerated.
8.
RESEARCH QUESTION AND OBJECTIVES
Primary objective:
•
To estimate the incidence rate of safety outcomes in Chinese patients with COPD who 
initiated Tio/Olo;
Secondary objective:
•
To compare the baseline characteristics of patients between those treated with Tio/Olo
and those with other LAMA/LABAs;
9.
RESEARCH METHODS
9.1
STUDY DESIGN
This study will be a non-interventional cohort study based on existing data (NISed).
The aim of this real world study is to assess the safety profile of tiotropium/olodaterol 
(Tio/Olo). The primary outcome of this study will be the incidence rate of adverse 
events in patients with COPD treated with Tio+Olo. Other outcomes include the baseline 
characteristics of patients who initiated Tio+Olo and comparing the baseline 
characteristics of patients who initiated Tio+Olo with those treated with other 
LAMA/LABAs in the Taiwan NHIRD database.

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9.2
SETTING
9.2.1
Study sites
Data used in this study will come from the Taiwan National Health Insurance (NHI) 
claims data between 2014 and 2019. 
9.2.2
Study population
Inclusion criteria:
1.
At least one prescription for Tio+Olo (FDC or free combination) as a new 
initiation between 1st January 2014 and 31st December 2019.
2.
Aged ≥ 40 years on the index date;
3.
At least one diagnosis of COPD at any time prior to or on the index date;
4.
At least one year of continuous medical and health insurance plan prior to the 
index date will be required to allow for a look-back period for the covariates and 
identification of new use of the study drugs;
5.
At least one record in the health insurance system database;
Exclusion criteria:
1.
Any use of Tio+Olo in free or fixed form within one year prior to the index date;
2.
Individuals with asthma, allergic rhinitis, lung cancer, interstitial lung disease, or 
lung transplant identified at any time prior to the index date;
Another cohort of patients using other LAMA/LABAs (FDC or free combination) will also 
be enrolled to collect the information of baseline characteristics to be compared with those 
of patients treated with Tio+Olo. The Inclusion/Exclusion criteria are similar with those of 
Tio+Olo, which include:
Inclusion criteria:
1. At least one prescription for LAMA+LABA (FDC or free combination) other than 
Tio/Olo as a new initiation between 1st January 2014 and 31st December 2019. 
2. Aged ≥ 40 years on the index date; 
3. At least one diagnosis of COPD at any time prior to or on the index date; 
4. At least one year of continuous medical and health insurance plan prior to the index 
date will be required to allow for a look-back period for the covariates and identification 
of new use of the study drugs; 
5. At least one record in the health insurance system database.
Exclusion criteria:
1. Any use of LAMA+LABA in free or fixed form for one year prior to the index date; 
2. Individuals with asthma, allergic rhinitis, lung cancer, interstitial lung disease, or lung 

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transplant identified at any time prior to the index date.
9.2.3
Study visits
Not applicable.
9.2.4
Study discontinuation
Boehringer Ingelheim reserves the right to discontinue the study at any time for the 
following reasons: violation of Good Pharmacoepidemiology Practice (GPP), the study 
protocol, or the contract by a study site, investigator or research collaborator, disturbing the 
appropriate conduct of the study.
9.3
VARIABLES
9.3.1
Exposures
Exposure of this study is defined as new initiation of Tio/Olo during the study period
between 1st January 2014 and 31st December 2019. The duration of exposure is defined as 
the period between the index date and the end of follow-up which is described in
section 9.7.1.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
-
Outcome type: Primary
-
Outcome Name: Incidence rate of adverse events in patients with COPD treated 
with Tio+Olo  
-
Time Frame: 2014~2019 
-
Safety Issue (Yes/No): Yes
9.3.2.2
Secondary outcomes
-
Outcome type: Secondary
-
Outcome Name: Baseline characteristics of patients who initiated Tio+Olo or other 
LAMA/LABA
-
Time Frame: 2014~2019 
-
Safety Issue (Yes/No): No

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9.3.3
Covariates
Covariates:
•
Sex
•
Age
•
Calendar year of cohort entry
•
Season of index date (winter, spring, summer, fall)
Additional characteristics will be defined during the 1 year pre-index baseline period:
•
Specific previous COPD treatments

LAMA monotherapy

LABA monotherapy

ICS monotherapy

LAMA/ICS combination therapy

LAMA+LABA free combinations
•
Use of other respiratory drugs

Mucolytics

Theophylline

Short-acting beta-agonists

Short-acting muscarinic antagonists
•
Previous acute COPD exacerbation (measured both 12 months and in the 30 days 
prior to cohort entry), categorized as 0, 1, or 2+.

All exacerbations (Moderate+Severe)

An outpatient visit with a diagnosis code for COPD in any field + a prescription 
for an oral corticosteroid or an antibiotic for respiratory infections (Moderate)

Hospitalizations or emergency room visits with a primary diagnosis for COPD 
(Severe)
•
Hospitalizations caused by exacerbation of COPD in 12 months prior to index 
date:

0;

1;

>=2;
•
All-cause hospitalizations in 12 months prior to index date;
•
Comorbidities:

Cardiovascular disease

Cerebrovascular disease

Diabetes

Chronic kidney disease

Pneumonia

Cancer

Cirrhosis
•
Charlson Comorbidity Index (CCI)

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•
History of medications dispensed in the 12 months before or on the index date 
will be identified from the pharmacy dispensing history:

Cardiovascular drugs: 
antihypertensives,
antiarrhythmics,
nitrates,
heart failure medications 

Lipid-lowering medications

Blood glucose-lowering medications

Anticoagulants and antiplatelet agents

Antibiotics

Antineoplastic agents

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9.4
DATA SOURCES
Data used in this study will come from the Taiwan National Health Insurance (NHI) 
claims data between 2014 and 2019. 
Data sources include Taiwan NHI, Taiwan cancer registry (TCR) and Taiwan Mortality 
Data. Taiwan Department of Statistics, Ministry of Health and Welfare is the unit 
designated by the government to manage health and social welfare statistical databases, 
and to develop data platform for academic research. Through the services provided by 
the Health and Welfare Data Science Center (HWDSC) of the Department of Statistics, 
researchers may access a wide range of health and welfare data, including claims, 
mortality (with cause of death) and Taiwan Cancer Registry (TCR). The HWDSC staff 
encrypt the national ID for all individuals according to a secure encryption algorithm 
that is not made known to the public. The encrypted ID is unique for all individuals and 
will be used for linkage between databases.
(a) National Health Insurance claims data
Taiwan National Health Insurance (NHI) started in 1995 and is a publicly funded single 
payer health insurance program for all residents. Health insurance for individuals is 
required by law and coverage is more than 99%. The majority of healthcare providers in 
Taiwan contract with the National Health Insurance Agency in Taiwan to provide a wide 
range of medical services. Geographic locations of health care claims are broadly classified 
into 6 regions in Taiwan. Salary range, which serves as the basis for enrollees’ premium 
calculation, can serve as a proxy indicator for socioeconomic status. Bundled payment 
according to the Diagnosis-Related Group system only applies in limited number of disease 
conditions, therefore detailed drug use information during hospitalization is also available. 
An added advantage of the NHI data source is the low membership turnover rate, which is 
particularly important for long-term follow-up study. NHI claims were based on 
International Classification of Disease, ninth revision, clinical modification (ICD-9-CM) 
codes till the end of 2015, and then switched to International Classification of Disease, 
tenth revision, clinical modification (ICD-10-CM) codes after 2016. Specific NHI data 
column please see file column_note_in_TW_NHI_20210824 [No document #] in the 
database (confidential and only can be accessed by PI).
(b) Mortality data
The household registration system in Taiwan maintain birth, marital status, and death 
information and is administrated by the Department of Household Registration, Ministry of 
the Interior. Death certificates are collected through this system and transferred to the 
Ministry of Housing and Works (MOHW) for coding of cause of death and maintenance of 
the mortality database. The cause of death was coded in the ICD-9-CM format from 1990 to 

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2009, and in ICD-10-CM format from 2010 to 2019. This study will use the cause of death 
files in years 2012-2019, primarily focusing on the date of death of study subjects. 
(c) Taiwan Cancer Registry data
In Taiwan, the population-based cancer registry was founded in 1979. Since then, the 
registry collected basic information, referred to the “20 items short-form system,” on 
incident cancer cases (including cancer-in-situ) within one year after the initial diagnosis 
from hospitals with more than 50-bed capacity throughout the country. Recorded items 
include date of birth, gender, time and method of diagnosis, cancer site and morphology, 
treatment summary and death. From 2002 onward, a “long-form” system was established to 
collect more detailed information of cancer staging, treatment and follow-up data from 
hospitals with more than 500 new cancer cases diagnosed annually. The number of 
recorded items increased from 20 to 65 in 2002, further to 95 in 2007, and to 114 in 2011. 
In 2003, Cancer Control Act was introduced with all reporting hospitals mandated to submit 
cancer patient information to the cancer registry. To ensure quality of cancer registries and 
enhancing the quality of cancer registry data, Taiwan Society of Cancer Registry was 
established in 2006, conducting random medical record review to ensure data accuracy 
since 2010. TCR data from 2000 through 2018 will be used for this study. 
9.5
STUDY SIZE
There will be around 4,000 patients using Tio+Olo in the Taiwan NHIRD that can be 
enrolled in this study. 
Assuming that observed incidence rates of each AE from Ferguson paper could be 
replicated, and 4000 patients were enrolled in the study in a uniform distribution from 0 
to 6 years. The estimation and 95% CI for incidence rate of each AE among new users 
of Spiolto® Respimat® for the study duration of 6 years were calculated based on 
Poisson distribution and provided as the following table.
Table 1         Incidence rate of AEs
Adverse events
Incidence 
rate per 
100 
patient 
years
N
95% CI
Lower
Upper
Pneumonia
4.69
4000
4.308
5.083
COPD 
exacerbation
55.42
4000
54.092
56.758
Arrhythmia
1.82
4000
1.583
2.067
Supraventricul
ar tachycardia
1.16
4000
0.975
1.358

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Incidence rate of AEs from Ref: G.T. Ferguson, et al., Respiratory Medicine 143 (2018) 
67–73.
9.6
DATA MANAGEMENT
Full details of the data management plan are documented in a separate NIS-Data 
Management and Review Plan (NIS-DMRP).
9.7
DATA ANALYSIS
Full details of the statistical analysis will be documented in the SEAP, which will be 
finalized before the end of data collection.
9.7.1
Main analysis
All variables, including patient characteristics, baseline measures, and outcomes, will 
be analysed descriptively.
•
For all analyses, variables will be reported as follows: Continuous variables (e.g., 
age) will be presented as means (with standard deviation, SD) and/or medians 
(with interquartile range, IQR), minimum, maximum.
•
Categorical variables (e.g., sex) will be presented as absolute and relative 
frequencies.
We will first describe formation of the study cohort. Patient characteristics at baseline 
will be described using standard descriptive statistics. Absolute standardized 
differences (ASDs) will be used to compare the characteristics between the two 
groups, in which a >0.1 ASD indicates a meaningful difference.
As an objective of the study was to compare the clinical attributes of patients in each 
study group. The standardized difference will be used as a parameter to quantify the 
between-group differences for each clinical attribute. This is metric is commonly used 
in studies utilizing secondary health data, in which a standardized difference of larger 
than 0.1 indicates a meaningful difference with respect to the clinical attribute 
between the two study groups.
For the analysis of primary outcome, the incidence rates of AEs during entire follow-
up period will be calculated based on the following formula:

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(Total number of patients in the Tio+Olo cohort experiencing an event of interest for 
the first time during the given time period) / (Total person-time at risk from current 
use of Tio+Olo during the given period)
For the analysis of the primary outcome, individuals will be followed up from the 
index date until the earliest of the date of the follows, whichever occurs first 1) 
disenrollment; 2) the end of the study period; 3) death; 4) discontinuation of the index 
drug; 5) adding ICS mono on top of Tio/Olo.
9.7.3
Safety Analysis
Based on current guidelines from the International Society for Pharmacoepidemiology
[R11-4318] and the EMA [R13-1970], non-interventional studies such as the one 
described in this protocol, conducted using health care records, do not require expedited 
reporting of suspected adverse events/reactions. Specifically, as stated in section 
VI.C.1.2.1 of Guideline on Good Pharmacovigilance Practices (GVP), Module VI –
Management and Reporting of Adverse Reactions to Medicinal Products, for non-
interventional study designs, which are based on use of secondary data, reporting of 
adverse reactions is not required.
9.8
QUALITY CONTROL
The study will strictly follow relevant BI SOPs. In addition, this study will follow key 
elements of the Guideline for Good Pharmacoepidemiology Practices (GPP) and the 
Guideline for Good Pharmacovigilance Practices (GVP).
The statistical analytic approach will be reviewed/repeated by a second analyst to ensure 
quality control. The study report will be reviewed, approved and archived per BI SOP.
Greater details are documented in the NIS-DMRP.
9.9
LIMITATIONS OF THE RESEARCH METHODS
In this study, we will describe the incidence rate of AEs among patients who initiate 
Spiolto. Patients taking Spiolto might be different from patients taking only 

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maintenance therapies (so-called channelling) in terms of their baseline characteristics, 
which makes it difficult to interpret the results. To help put the results into perspective, 
we will compare the baseline characteristics between patients who initiated Spiolto and 
patients treated with other LAMA/LABAs to understand the potential channelling.
In a database study like this, we can only rely on the available information to define 
outcomes, exposure and covariates. Misclassification may happen during this process.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Board (IRBs) / Independent Ethics 
Committee (IECs) or by regulatory authorities. The quality assurance auditor will have 
access to the investigator’s study-related files and correspondence.
9.10.2
Study records
9.10.2.1 Source documents
Not applicable.
Data were provided by Health and Welfare Data Science Center, Ministry of Health and 
Welfare, Taiwan. Data access was only available through dedicated data analysis areas 
within the Ministry. Individual level data are not allowed to be brought outside of the 
Ministry.
9.10.2.2 Direct access to source data and documents
Not applicable.
Data were provided by Health and Welfare Data Science Center, Ministry of Health and 
Welfare, Taiwan. Data access was only available through dedicated data analysis areas 
within the Ministry. Individual level data are not allowed to be brought outside of the 
Ministry.

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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, Guidelines for Good Pharmacoepidemiology Practice 
(GPP), and the relevant BI Standard Operating Procedures (SOPs).
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This NIS 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.
10.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted 
below. Patient confidentiality will be ensured by using patient identification code 
numbers.
Data generated as a result of the study need to be available for inspection on request 
by the participating physicians, the sponsor’s representatives, by the IRB/IEC and the 
regulatory authorities.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Not applicable.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT 
COLLECTION AND REPORTING
Not applicable based on secondary use of data without any potential that any employee of 
BI or agent working on behalf of BI will access individually identifiable patient data.This 
study is a non-interventional study based on secondary data without involving review or 
analysis of any individual patient level data. The data is extracted and analyzed in an 
aggregate manner. 
11.3
REPORTING TO HEALTH AUTHORITIES
This study is a non-interventional study based on secondary data, which will 
not involve individual medical record review. Therefore, no AE collection of 
this study will be performed and reported to Chinese regulatory authorities.
This study was classified as a post authorization safety study, and the study 
report would be reported to health authorities as drug intensive monitoring
according to local regulation.

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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
R22-0908 Wang C, Xu J, Yang L, et al. Prevalence and risk factors of chronic 
obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study) a 
national cross-sectional study. Lancet, 2018, 391(10131): 1706-1717. 
P13-11053 Torchio, Roberto. (2013). Tiotropium Respimat inhaler and the risk of 
death in COPD.. New England Journal of Medicine. 369. 1491.
P05-10481 Hochrainer D, Hölz H, Kreher C, Scaffidi L, Spallek M, Wachtel H. 
Comparison of the aerosol velocity and spray duration of Respimat Soft Mist inhaler and 
pressurized metered dose inhalers. J Aerosol Med. 2005 Fall;18(3):273-82. doi: 
10.1089/jam.2005.18.273. PMID: 16181002.
P15-03344 Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose 
combination versus mono-components in COPD (GOLD 2-4) [published correction appears 
in Eur Respir J. 2015 Jun;45(6):1763]. Eur Respir J. 2015;45(4):969-979. 
doi:10.1183/09031936.00136014
P18-02990 Calverley PMA, Anzueto AR, Carter K, Grönke L, Hallmann C, Jenkins C, 
Wedzicha J, Rabe KF. Tiotropium and olodaterol in the prevention of chronic obstructive 
pulmonary disease exacerbations (DYNAGITO): a double-blind, randomized, parallel-
group, active-controlled trial. Lancet Respir Med. 2018 May;6(5):337-344. doi: 
10.1016/S2213-2600(18)30102-4. Epub 2018 Apr 5. PMID: 29605624.
R11-4318 Guidelines for Good Pharmacoepidemiology Practices (GPP) (revision 3: June 
2015). Guidelines for Good Pharmacoepidemiology Practices (GPP) - International Society 
for Pharmacoepidemiology (access date: 1st March 2022) ; International Society for 
Pharmacoepidemiology (ISPE); 2015.
R13-1970 European Medicines Agency (EMA), Heads of Medicines Agencies (HMA); 
Guideline on good pharmacovigilance practices (GVP): module VI - management and 
reporting of adverse reactions to medicinal products (28 July 2017 EMA/873138/2011 Rev 
2). Guideline on good pharmacovigilance practices (GVP) - Module VI – Collection, 
management and submission of reports of suspected adverse reactions to medicinal 
products (Rev 2) (europa.eu) (access date: 1st March 2022); European Medicines Agency 
(EMA), Heads of Medicines Agencies (HMA); 2017.
13.2
UNPUBLISHED REFERENCES
c03489048-01 China Clinical Overview. 7 Apr 2015
No document # Taiwan National Health Insurance, column_note_in_TW_NHI_20210824. 
24 Aug 2021

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

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Study title:
Safety profile of Tiotropium + Olodaterol used as maintenance treatment in COPD patients in Taiwan: 
a non-interventional study based on the Taiwan National Health Insurance (NHI) data
EU PAS Register® number:
Study reference number (if applicable): 1237-0109
Section 1: Milestones
Yes
No
N/A
Section 
Number
1.1
Does the protocol specify timelines for 
1.1.1 Start of data collection0F1
1.1.2 End of data collection1F2
1.1.3 Progress report(s)
1.1.4 Interim report(s)
1.1.5 Registration in the EU PAS Register®
6
1.1.6 Final report of study results.
6
Comments:
Milestone is updated in protocol.
Section 2: Research question
Yes
No
N/A
Section 
Number
2.1
Does the formulation of the research 
question and objectives clearly 
explain: 
2.1.1 Why the study is conducted? (e.g. to 
address an important public health concern, a risk 
identified in the risk management plan, an 
emerging safety issue)
7
2.1.2 The objective(s) of the study?
8
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to 
be generalized)
9.2.2
2.1.4 Which hypothesis(-es) is (are) to be 
tested?
2.1.5 If applicable, that there is no a priori
hypothesis?
                                                     
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2 Date from which the analytical dataset is completely available.

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Comments:
Section 3: Study design
Yes
No
N/A
Section 
Number
3.1
Is the study design described?
(e.g. cohort, case-control, cross-sectional, other 
design) 
9.1
3.2
Does the protocol specify whether the 
study is based on primary, secondary 
or combined data collection?
9.4
3.3
Does the protocol specify measures of 
occurrence? (e.g., rate, risk, prevalence)
9.3.2
3.4
Does the protocol specify measure(s) 
of association? (e.g. risk, odds ratio, excess 
risk, rate ratio, hazard ratio, risk/rate 
difference, number needed to harm (NNH))
9.7.1
3.5
Does the protocol describe the 
approach for the collection and 
reporting of adverse events/adverse 
reactions? (e.g. adverse events that will not 
be collected in case of primary data collection)
9.7.3/11
Comments:
3.5  Secondary data for observational study
Section 4: Source and study 
populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
9.4
4.2
Is the planned study population 
defined in terms of:
4.2.1 Study time period
9.2.2
4.2.2 Age and sex
9.2.2
4.2.3 Country of origin
9.4
4.2.4 Disease/indication
9.2.2
4.2.5 Duration of follow-up
9.7.1
4.3
Does the protocol define how the 
study population will be sampled from 
the source population? (e.g. event or 
inclusion/exclusion criteria)
9.2.2

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Comments:
Section 5: Exposure definition and 
measurement
Yes
No
N/A
Section 
Number
5.1
Does the protocol describe how the 
study exposure is defined and 
measured? (e.g. operational details for defining 
and categorizing exposure, measurement of dose 
and duration of drug exposure)
9.3.1
5.2
Does the protocol address the validity 
of the exposure measurement? 
(e.g. precision, accuracy, use of validation sub-
study)
5.3
Is exposure categorized according to 
time windows? 
5.4
Is intensity of exposure addressed? 
(e.g. dose, duration)
5.5
Is exposure categorized based on 
biological mechanism of action and 
taking into account the 
pharmacokinetics and 
pharmacodynamics of the drug?
5.6
Is (are) (an) appropriate comparator(s) 
identified?
9.2.2
Comments:
5.4 There is only one dosage of Spiolto and exposure duration in observational 
studies is uncertain
Section 6: Outcome definition and 
measurement
Yes
No
N/A
Section 
Number
6.1
Does the protocol specify the primary 
and secondary (if applicable) outcome(s) 
to be investigated?
9.3.2
6.2
Does the protocol describe how the 
outcomes are defined and measured? 
9.3.2
6.3
Does the protocol address the validity 
of outcome measurement? (e.g. precision, 
accuracy, sensitivity, specificity, positive 
predictive value, use of validation sub-study)

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Section 6: Outcome definition and 
measurement
Yes
No
N/A
Section 
Number
6.4
Does the protocol describe specific 
outcomes relevant for Health 
Technology Assessment? (e.g. HRQoL, 
QALYs, DALYS, health care services utilization, 
burden of disease or treatment, compliance, 
disease management)
Comments:
The Outcome and Analysis sections will be complemented with SEAP.
Section 7: Bias
Yes
No
N/A
Section 
Number
7.1
Does the protocol address ways to 
measure confounding? (e.g. 
confounding by indication)
7.2
Does the protocol address selection 
bias? (e.g. healthy user/adherer bias)
7.3
Does the protocol address information 
bias? (e.g. misclassification of exposure and 
outcomes, time-related bias)
Comments:
Section 8: Effect measure modification
Yes
No
N/A
Section 
Number
8.1
Does the protocol address effect 
modifiers? (e.g. collection of data on known 
effect modifiers, sub-group analyses, anticipated 
direction of effect) 
Comments:

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Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1
Does the protocol describe the data 
source(s) used in the study for the 
ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-
face interview)
9.4
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics)
9.4
9.1.3 Covariates and other characteristics?
9.4
9.2
Does the protocol describe the 
information available from the data 
source(s) on:
9.2.1 Exposure? (e.g. date of dispensing, drug 
quantity, dose, number of days of supply prescription, 
daily dosage,  prescriber)
9.3.1
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event)
9.3.2
9.2.3 Covariates and other characteristics? 
(e.g. age, sex, clinical and drug use history, co-
morbidity, co-medications, lifestyle)
9.3.3
9.3
Is a coding system described for: 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, 
Anatomical Therapeutic Chemical (ATC) Classification 
System)
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD), Medical Dictionary for Regulatory 
Activities (MedDRA))
9.3.3 Covariates and other characteristics?
9.4
Is a linkage method between data 
sources described? (e.g. based on a unique 
identifier or other)
9.4
Comments:
9.3 Details will be described in SEAP.

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Section 10: Analysis plan
Yes
No
N/A
Section 
Number
10.1 Are the statistical methods and the 
reason for their choice described? 
9.7
10.2 Is study size and/or statistical precision 
estimated?
9.5
10.3 Are descriptive analyses included?
9.7.1
10.4 Are stratified analyses included?
9.7.2
10.5 Does the plan describe methods for 
analytic control of confounding?
10.6 Does the plan describe methods for 
analytic control of outcome 
misclassification?
10.7 Does the plan describe methods for 
handling missing data?
10.8 Are relevant sensitivity analyses 
described?
9.7.2
Comments:
Section 11: Data management and quality 
control
Yes
No
N/A
Section 
Number
11.1 Does the protocol provide information on 
data storage? (e.g. software and IT 
environment, database maintenance and anti-fraud 
protection, archiving)
11.2 Are methods of quality assurance 
described?
9.8
11.3 Is there a system in place for 
independent review of study results? 

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Comments:
11.1 Details will be described in DMRP.
Section 12: Limitations
Yes
No
N/A
Section  
Number
12.1 Does the protocol discuss the impact on 
the study results of:
12.1.1 Selection bias?
9.9
12.1.2 Information bias?
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods).
12.2 Does the protocol discuss study 
feasibility? (e.g. study size, anticipated exposure 
uptake, duration of follow-up in a cohort study, 
patient recruitment, precision of the estimates)
9.5
Comments:
Section 13: Ethical/data protection issues
Yes
No
N/A
Section  
Number
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been 
described?
9.10.1
13.2 Has any outcome of an ethical review 
procedure been addressed?
13.3 Have data protection requirements been 
described?
Comments:
Section 14: Amendments and deviations
Yes
No
N/A
Section 
Number
14.1 Does the protocol include a section to 
document amendments and deviations? 
5
Comments:

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ANNEX 3. ADDITIONAL INFORMATION
None

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ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES
The NIS Protocol must be sent for review to the following individuals prior to approval.
Reviewer
NIS involving BI 
product(s)
NIS not involving BI product(s)
Global 
NIS
Local NIS
NIS Lead
X
X
X
Global TM Epi
X
X
X
Global TMM / TMMA / TM 
Market Access
X
X
Global Project Statistician
X
X
Global TM RA
X
Global PVWG Chair
X
GPV SC
X
X
X
Global CTIS representative
X
Local Medical Director
X (if local study)
X
Local Head MAcc / HEOR 
Director
X (if local study)
X
Global TA Head Epi*
X
X
Global TA Head Clinical 
Development / Medical 
Affairs / Market Access*
X
X
Global TA Head PV RM*
X
RWE CoE
X
X
PSTAT / PSTAT-MA
(for NISnd only)
X
X
X
NIS DM
X
X
X
Local Head 
MA/Clinical 
Development
X (does not apply 
to NISed without 
chart abstraction)
* After review by Global TM for function

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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Study Title: Safety profile of Tiotropium + Olodaterol used as maintenance treatment in 
COPD patients in Taiwan: a non-interventional study based on the Taiwan National 
Health Insurance (NHI) data
Study Number: 1237-0109
Protocol Version: 1.0
I herewith certify that I agree to the content of the study protocol and to all documents 
referenced in the study protocol.
Note: Please insert respective signatories with regard to the SOP.
Position: 
      
Name/Date:                                           
Signature:
Position: 
      
Name/Date:                                            
Signature:
Position: 
Name/Date:
Signature:
Position: 
Name/Date:
Signature:
Position: 
Name/Date:
Signature:
Position: 
Name/Date:
Signature:
Position: 
Name/Date:
Signature: