Effectiveness of Maintenance Treatment With Tiotropium + Olodaterol in Comparison to Inhaled Corticosteroids + Long-acting β2 Agonists 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

ABCD
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
 
Non-Interventional Study (NIS) Protocol
 
Document Number:
c38660249-01
BI Study Number:
1237-0110
BI Investigational
Product(s):
Spiolto Respimat
Title:
Effectiveness of Maintenance Treatment with Tiotropium + Olodaterol 
in Comparison to Inhaled Corticosteroids + Long-acting β2 agonists in 
COPD patients in Taiwan: a non-interventional study based on the 
Taiwan National Health Insurance (NHI) data.
Brief lay title:
Effectiveness of Tiotropium + Olodaterol versus ICS+LABA among 
COPD patients in Taiwan
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
Not applicable
PASS:
No
EU PAS register 
number:
Study not registered
Active substance:
Tiotropium + Olodaterol (R03AL06)
Medicinal product:
Spiolto Respimat
Product reference:
BC26735443
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Boehringer Ingelheim International GmbH
Joint PASS:
No
Research question and 
objectives:
To compare the risk of exacerbations between initiators of Tiotropium 
/ Olodaterol (Tio/Olo) and inhaled corticolsteroids / long-acting β2-
agonists (ICS/LABA) in a real world setting
Author:

BOEHRINGER INGELHEIM Group of Companies
NIS Protocol 
BI Study Number: 1237-0110
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Marketing authorisation 
holder(s):
Boehringer Ingelheim International GmbH
MAH contact person:
Not applicable
EU-QPPV:
Not applicable
Signature of EU-QPPV:
Not applicable
Date:
23 May 2022
Page 1 of 48
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.............................................................................................5
4.
ABSTRACT....................................................................................................................7
5.
AMENDMENTS AND UPDATES..............................................................................19
6.
MILESTONES..............................................................................................................20
7.
RATIONALE AND BACKGROUND.........................................................................21
8.
RESEARCH QUESTION AND OBJECTIVES ..........................................................22
9.
RESEARCH METHODS .............................................................................................23
9.1
STUDY DESIGN.....................................................................................................23
9.2
SETTING.................................................................................................................23
9.2.1
Study sites ........................................................................................................23
9.2.2
Study population ..............................................................................................23
9.2.3
Study visits .......................................................................................................24
9.2.4
Study discontinuation.......................................................................................24
9.3
VARIABLES ...........................................................................................................24
9.3.1
Exposures .........................................................................................................24
9.3.2
Outcomes..........................................................................................................24
9.3.2.1
Primary outcomes......................................................................................24
9.3.2.2
Secondary outcomes..................................................................................25
9.3.3
Covariates.........................................................................................................25
9.4
DATA SOURCES....................................................................................................28
9.5
STUDY SIZE...........................................................................................................29
9.6
DATA MANAGEMENT.........................................................................................29
9.7
DATA ANALYSIS..................................................................................................29
9.7.1
Main analysis....................................................................................................29
9.7.3
Safety Analysis.................................................................................................31
9.8
QUALITY CONTROL............................................................................................31
9.9
LIMITATIONS OF THE RESEARCH METHODS...............................................32
9.10
OTHER ASPECTS ..................................................................................................32
9.10.1
Data quality assurance......................................................................................32

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BI Study Number: 1237-0110
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9.10.2
Study records....................................................................................................32
9.10.2.1
Source documents .....................................................................................32
9.10.2.2
Direct access to source data and documents .............................................33
10.
PROTECTION OF HUMAN SUBJECTS ...................................................................34
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...............................................................................................................34
10.2
STATEMENT OF CONFIDENTIALITY...............................................................34
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS................................................................................................................35
11.1
DEFINITIONS OF ADVERSE EVENTS...............................................................35
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING ...........................................................................................................35
11.3
REPORTING TO HEALTH AUTHORITIES.........................................................35
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ..36
13.
REFERENCES .............................................................................................................37
13.1
PUBLISHED REFERENCES..................................................................................37
13.2
UNPUBLISHED REFERENCES............................................................................37
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.......................................................38
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .......................................39
ANNEX 3. ADDITIONAL INFORMATION.......................................................................46
ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES............................................47

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NIS Protocol 
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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
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
BI NIS Lead (Scientific)
BI NIS Lead (Operation)

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4.
ABSTRACT
COPD is a leading cause of morbidity and mortality throughout the world. Long-acting 
bronchodilator medications, which include long-acting β2-agonists (LABAs) and the long-
acting muscarinic antagonists (LAMAs) such as tiotropium, are the central maintenance 
therapy to the management of COPD, with inhaled corticosteroids (ICSs) added with 
increasing severity. The up-to-date GOLD guideline recommends to initiate ICS/LABA in 
patients with high blood eosinophils level and frequent exacerbation history[P21-01394]. 
However, ICS containing therapy has been widely used inappropriately in real world practice.
The role of ICS in COPD has been debated for decades and studies have been conducted to 
investigate the effect of ICS-containing therapy in patients with COPD. INSPIRE
[P07-11820] study indicated that ICS/LABA and tiotropium showed similar effects on the 
reduction of exacerbations, while the risk of pneumonia was higher in the ICS/LABA group. 
And the FLAME [P16-05628] study showed LAMA/LABA was superior to ICS/LABA in 
terms of exacerbation prevention, while in some newly published data focusing on FDC triple 
therapy showing reversed results. .
With more and more fixed dose combination medications, i.e. LAMA/LABA, 
ICS/LABA/LAMA, approved and prescribed in recent years, it is of clinical interests to 
understand the effectiveness and safety profile of these therapies in real world settings. 
The aim of this real world study is to assess effectiveness and safety profile between 
tiotropium/olodaterol (Tio/Olo) and ICS/LABA. The primary outcome of the study will be 
risk of moderate or severe COPD exacerbations. Other outcomes include time to 
ICS/LABA/LAMA escalation, rate of escalation to triple therapy, pneumonia and rescue 
medication use.

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BI Study Number: 1237-0110
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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat
Name of active ingredient:
Tiotropium + Olodaterol 
{R03AL06}
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
23 May 2022
1237-0110
1.0
NA
Title of study:
Effectiveness of Maintenance Treatment with Tiotropium + Olodaterol in 
Comparison to Inhaled Corticosteroids + Long-acting β2 agonists in COPD 
patients in Taiwan: a non-interventional study based on the Taiwan National 
Health Insurance (NHI) data
Rationale and 
background:
COPD is a leading cause of morbidity and mortality throughout the 
world. Long-acting bronchodilator medications, which include long-
acting β2-agonists (LABAs) and the long-acting muscarinic antagonists 
(LAMAs) such as tiotropium, are the central maintenance therapy to the 
management of COPD, with inhaled corticosteroids (ICSs) added with 
increasing severity. The up-to-date GOLD guideline recommends to 
initiate ICS/LABA in patients with high blood eosinophils level and 
frequent exacerbation history[P21-01394]. However, ICS containing 
therapy has been widely used inappropriately in real world practice.
The role of ICS in COPD has been debated for decades and studies have 
been conducted to investigate the effect of ICS-containing therapy in 
patients with COPD. INSPIRE [P07-11820] study indicated that 
ICS/LABA and tiotropium showed similar effects on the reduction of 
exacerbations, while the risk of pneumonia was higher in the ICS/LABA 
group. And the FLAME [P16-05628] study showed LAMA/LABA was 
superior to ICS/LABA in terms of exacerbation prevention, while in 
some newly published data focusing on FDC triple therapy showing 
reversed results. .
With more and more fixed dose combination medications, i.e. 
LAMA/LABA, ICS/LABA/LAMA, approved and prescribed in recent 
years, it is of clinical interests to understand the effectiveness and safety 
profile of these therapies in real world settings. 
The aim of this real world study is to assess effectiveness and safety profile 
between tiotropium/olodaterol (Tio/Olo) and ICS/LABA. The primary 
outcome of the study will be time to the first moderate or severe COPD 
exacerbations. Other outcomes include time to ICS/LABA/LAMA 

BOEHRINGER INGELHEIM Group of Companies
NIS Protocol 
BI Study Number: 1237-0110
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001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat
Name of active ingredient:
Tiotropium + Olodaterol 
{R03AL06}
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
23 May 2022
1237-0110
1.0
NA
escalation, rate of escalation to triple therapy, pneumonia and rescue 
medication use.
Research question 
and objectives:
Primary objective:
•
To compare time to the first moderate or severe COPD exacerbations 
between initiators of Tiotropium / Olodaterol (Tio/Olo) and inhaled 
corticolsteroids / long-acting β2-agonists (ICS/LABA) after entry 
between 1st January 2014 and 31st December 2019 
Secondary objectives:
•
To compare time to escalation to triple therapy between initiators of 
Tio/Olo and ICS/LABA;
•
To compare the rate of escalation to triple therapy between initiators 
of Tio/Olo and ICS/LABA;
•
To compare the time to first hospitalization for community-acquired 
pneumonia between initiators of Tio/Olo and ICS/LABA;
•
To compare the number of prescriptions of rescue medication between 
initiators of Tio/Olo and ICS/LABA
•
To compare the annualized rate of moderate or severe COPD 
exacerbation
The study period of between 1st January 2014 and 31st December 2019 
apply to secondary objectives above
Study design:
This study will be a non-interventional cohort study based on existing data 
(NISed).

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BI Study Number: 1237-0110
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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat
Name of active ingredient:
Tiotropium + Olodaterol 
{R03AL06}
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
23 May 2022
1237-0110
1.0
NA
Population:
Inclusion criteria:
1.
At least one prescription for Tio/Olo combined inhaler or for 
LABA/ICS combined inhaler 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, ICS/LABA, or ICS/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, or  ICS/LABA during the study period.
Outcomes:
Primary outcome:
•
Time to the first moderate or severe COPD exacerbations after 
entry
Secondary outcomes: 
•
Time to triple therapy escalation after entry
•
Incidence rate of triple therapy initiation;

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BI Study Number: 1237-0110
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001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat
Name of active ingredient:
Tiotropium + Olodaterol 
{R03AL06}
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
23 May 2022
1237-0110
1.0
NA
•
Time to the first hospitalization for community-acquired 
pneumonia;
•
Annualized rate of prescriptions of rescue medications (calculated 
as: annualized rate=number of prescriptions/total patient year at 
risk=number of prescriptions per patient year);
•
Annualized rate of moderate or severe COPD exacerbation 
(calculated as: annualized rate=number of moderate or severe 
COPD exacerbations/total patient year at risk=number of
exacerbations per patient year)
Covariates:
Demographic characteristics and cohort entry information:
•
Sex
•
Age
•
Calendar year of cohort entry
•
Season of index date (winter, spring, summer, fall)
Additional, the following clinical characteristics will be 
measured during the 1 year pre-index baseline period: 
Specific previous COPD treatments

LAMA monotherapy

LABA monotherapy

ICS monotherapy

LAMA/ICS combination therapy

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001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat
Name of active ingredient:
Tiotropium + Olodaterol 
{R03AL06}
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
23 May 2022
1237-0110
1.0
NA
Use of other respiratory drugs

Mucolytics

Theophylline

Short-acting beta-agonists

Short-acting muscarinic antagonists
•
Number of 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)
•
Number of hospitalizations caused by exacerbation of  
COPD in 12 months prior to the index date:

0;

1;

2+;
•
Number of all-cause hospitalizations in 12 months prior to 
index date:

0;

1;

2+;

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Proprietary confidential information © 2022 Boehringer Ingelheim International GmbH or one or more of its affiliated
001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat
Name of active ingredient:
Tiotropium + Olodaterol 
{R03AL06}
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
23 May 2022
1237-0110
1.0
NA
•
Comorbidities:

Cardiovascular disease

Cerebrovascular disease

Diabetes

Chronic kidney disease

Pneumonia

Cancer

Cirrhosis
•
Charlson Comorbidity Index (CCI)
•
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
•
COPD severity

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat
Name of active ingredient:
Tiotropium + Olodaterol 
{R03AL06}
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
23 May 2022
1237-0110
1.0
NA
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

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001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat
Name of active ingredient:
Tiotropium + Olodaterol 
{R03AL06}
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
23 May 2022
1237-0110
1.0
NA
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 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

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001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat
Name of active ingredient:
Tiotropium + Olodaterol 
{R03AL06}
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
23 May 2022
1237-0110
1.0
NA
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:
Based on the result of study by Wedzicha JA, et al, (where at least 25% of 
the patients in the Tio/Olo group have a  first moderate or severe 
exacerbation at 127 days [95% CI, 107 to 149] and in ICS/LABA group at 
87 days [95% CI, 81 to 103] (HR = 0.78, [95% CI 0.70 to 0.86])), we 
assume that at least 25% of patients in the ICS/LABA experienced a first
moderate or severe COPD exacerbation at 103 days and the HR of  Tio/Olo 
to LABA/ICS is 0.9.  For a study duration of 6 years, a total of 4978 
patients (2489 patients each arm) are needed to detect the difference 
between the two arms with 2-sided alpha of 0.05 and 90% power..
Data analysis:
All variables, including patient characteristics, baseline measures, and 
outcomes, will be analysed descriptively.
All analyses will be presented for each exposure group (Tio+Olo vs 
LABA/ICS) overall. We will first describe formation of the study cohort. 
Patient characteristics at baseline in patients treated with Tio+Olo and 
patients treated with LABA/ICS will be described separately using standard 
descriptive statistics after propensity score matching. Absolute standardized 
differences (ASDs) will be used to compare the characteristics between the 
two groups after propensity score matching, in which a >0.1 ASD indicates a 
meaningful difference. 

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat
Name of active ingredient:
Tiotropium + Olodaterol 
{R03AL06}
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
23 May 2022
1237-0110
1.0
NA
For the analysis of the primary outcome, Cox proportional hazard regression 
model will be used to compare the outcome of interest between the two 
treatment groups, while accounting for the potential baseline differences 
between them. Other known predictors would also be included in the model 
as covariates. It will provide an estimate of the hazard ratio (HR) of time to 
the first moderate or severe COPD exacerbation associated with Tio+Olo 
use relative to LABA/ICS use, along with 95% confidence intervals (CI). 
The analysis will be on-treatment.
The analysis of the secondary objectives related to time to triple therapy 
escalation, time to first hospitalization for community-acquired pneumonia, 
will use a Cox proportional hazard regression model with an as-treated 
approach, similar to that of the primary analysis. The estimate of the hazard 
ratio (HR) of time to triple therapy escalation, hospitalization for 
community-acquired pneumonia associated with Tio+Olo use relative to 
LABA/ICS use, along with 95% confidence intervals (CI) will be provided.
Incidence rate of triple therapy initiation (first event per patient), annualized 
rate of moderate or severe COPD exacerbations, and annualized rate of 
prescriptions of rescue medications will be calculated by cohort. Incidence 
rate ratio (IRR) will be calculated. Incidence differences and their 95% 
confidence intervals will also be derived.
The incidence rate ratio (IRR) for the triple therapy initiation in the Tio+Olo 
- exposed group relative to that in the comparator group, along with 95% 
confidence intervals will be derived using negative binomial model.
For annualized rate of moderate or severe COPD exacerbation and 
annualized rate of prescriptions of rescue medications, ratio of Tio+Olo –
exposed group relative to LABA/ICS group, along with 95% confidence 
intervals will be derived using negative binomial model.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Spiolto Respimat
Name of active ingredient:
Tiotropium + Olodaterol 
{R03AL06}
Protocol date:
Study
number:
Version/Revision:
Version/Revision date:
23 May 2022
1237-0110
1.0
NA
Milestones:
IRB/IEC approval: 22-Oct-2020
Feasibility assessment: 2020. Q3
EU PAS Registration: 01-Jun-2022
Full analysis:
•
Data Access: 15-Jun-2022
•
Complete data analysis: 30-Aug-2022
Final report of study results: 15-Oct-2022
Publications timeline:
•
Abstract: 2023 ATS.

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5.
AMENDMENTS AND UPDATES
None

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6.
MILESTONES
Milestone
Planned Date
IRB/IEC approval
Oct 2020 (completed)
Feasibility assessment
Oct 2020 (completed)
EU PAS Registration
01/Jun/2022
Full analysis
Data Access
15/Jun/2022
Complete data analysis
30/Aug/2022
Final report of study results
15/Oct/2022

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7.
RATIONALE AND BACKGROUND
COPD is a leading cause of morbidity and mortality throughout the world. Long-acting 
bronchodilator medications, which include long-acting β2-agonists (LABAs) and the long-
acting muscarinic antagonists (LAMAs) such as tiotropium, are the central maintenance 
therapy to the management of COPD, with inhaled corticosteroids (ICSs) added with 
increasing severity. The up-to-date GOLD guideline recommends to initiate ICS/LABA in 
patients with high blood eosinophils level and frequent exacerbation history[P21-01394]. 
However, ICS containing therapy has been widely used inappropriately in real world practice.
The role of ICS in COPD has been debated for decades and studies have been conducted to 
investigate the effect of ICS-containing therapy in patients with COPD. INSPIRE 
[P07-11820] study indicated that ICS/LABA and tiotropium showed similar effects on the 
reduction of exacerbations, while the risk of pneumonia was higher in the ICS/LABA group. 
And the FLAME [P16-05628] study showed LAMA/LABA was superior to ICS/LABA in 
terms of exacerbation prevention, while in some newly published data focusing on FDC triple 
therapy showing reversed results. 
With more and more fixed dose combination medications, i.e. LAMA/LABA, 
ICS/LABA/LAMA, approved and prescribed in recent years, it is of clinical interests to 
understand the effectiveness and safety profile of these therapies in real world settings. 
The aim of this real world study is to assess effectiveness and safety profile between 
tiotropium/olodaterol (Tio/Olo) and ICS/LABA. The primary outcome of the study will be 
time to  first moderate or severe COPD exacerbations. Other outcomes include time to 
ICS/LABA/LAMA escalation, rate of escalation to triple therapy, pneumonia and rescue 
medication use.  

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8.
RESEARCH QUESTION AND OBJECTIVES
Primary objective:
•
To compare time to the first moderate or severe COPD exacerbations between 
initiators of Tio/Olo and ICS/LABA in a real world setting; 
Secondary objectives:
•
To compare time to escalation to triple therapy between initiators of Tio/Olo and 
ICS/LABA;
•
To compare the rate of escalation to triple therapy between initiators of Tio/Olo and 
ICS/LABA;
•
To compare the time to first hospitalization for community-acquired pneumonia 
between initiators of Tio/Olo and ICS/LABA;
•
To compare the number of prescriptions of rescue medication between initiators of 
Tio/Olo and ICS/LABA;
•
To compare the annualized rate of moderate or severe COPD exacerbation between 
initiators of Tio/Olo and ICS/LABA..

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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 first 1) moderate or severe COPD 
exacerbation; 2) disenrollment; 3) the end of the study period; 4) death; 5) discontinuation of 
the index drug use as a lapse of 1.5 months without subsequent prescription (except for 
switching from the index ICS/LABA to a different ICS/LABA); 6) adding ICS mono on top 
of Tio/Olo, or adding LAMA momo on top of the index ICS/LABA
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:
1. 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 Tiotropium/Olodaterol, or ICS/LABA 
during the study period.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
-
Outcome type: Primary
-
Outcome Name:Time to the first moderate or severe COPD exacerbations after 
index date 
-
Time Frame: 2014~2019 
-
Safety Issue (Yes/No): No

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9.3.2.2
Secondary outcomes
-
Outcome type: Secondary
-
Outcome Name: Time to triple therapy escalation after index date
-
Time Frame: 2014~2019 
-
Safety Issue (Yes/No): No
-
Outcome type: Secondary
-
Outcome Name:  Incidence rate of triple therapy initiation (first event per patient)
-
Time Frame: 2014~2019 
-
Safety Issue (Yes/No): No
-
Outcome type: Secondary
-
Outcome Name: Time to the first hospitalization for community-acquired 
pneumonia after entry 
-
Time Frame: 2014~2019 
-
Safety Issue (Yes/No): No
-
Outcome type: Secondary
-
Outcome Name: Annualized rate of prescriptions of rescue medications after the 
index date
-
Calculation: annualized rate=number of prescriptions/total patient year at 
risk=number of prescriptions per patient year
-
Time Frame: 2014~2019 
-
Safety Issue (Yes/No): No
-
Outcome type: Secondary
-
Outcome Name: Annualized rate of moderate or severe COPD exacerbation after 
the index date
-
Calculation: annualized rate=number of moderate or severe COPD 
exacerbations/total patient year at risk=number of exacerbations per patient year
-
Time Frame: 2014~2019 
-
Safety Issue (Yes/No): No
9.3.3
Covariates
Demographic characteristics and cohort entry information:
!
Sex

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!
Age
!
Calendar year of cohort entry
!
Season of index date (winter, spring, summer, fall)
Additional, the following clinical characteristics will be measured during the 1 year pre-index 
baseline period: 
Previous COPD treatments
 LAMA monotherapy
 LABA monotherapy
 ICS monotherapy
 LAMA/ICS combination therapy
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 the index date:
 0;
 1;
 2+;
•
all-cause hospitalizations in 12 months prior to index date:
 0;
 1;
 2+;
•
Comorbidities:
 Cardiovascular disease
 Cerebrovascular disease
 Diabetes
 Chronic kidney disease
 Pneumonia
 Cancer
 Cirrhosis

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•
Charlson Comorbidity Index (CCI)
•
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
•
COPD severity 
The definition of the severity of COPD  in this study was developed based on the information 
in previous studies, GOLD recommendations and clinical practice in Taiwan, see below. 
Patients who fulfil criteria for more than one category will be classified as being in the most 
severe category.
Criteria of COPD severity:
 Mild: 
Naïve to COPD treatment, or at least one dispensing of the following categories of 
medications either alone or in combination: 1) SABA or SAMA or SABA+SAMA, 2) 
LAMA or LABA monotherapy, 3) theophylline or mucolytics, in the 12 months 
before the index date;
 Moderate: 
At least one dispensing of LAMA + LABA in the 12 months before the index date;
 Severe: 
Occurrence of at least one of the following events in the 12 months before the index 
date:
•
Hospitalisation for COPD
•
Recorded diagnosis of pneumonia
•
Second course of antibiotics for respiratory tract infections
•
Second course of systemic corticosteroids for the treatment of COPD 
exacerbation
•
Two diagnoses of COPD exacerbation without hospitalisation
 Very severe:
Occurrence of at least one of the following events in the 12 months before the index 
date unless other time period is specified:
•
Dispensed oxygen therapy
•
Dispensed nebuliser therapy

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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 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 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 

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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
Based on the result of study by Wedzicha JA, et al, [P16-05628] (where at least 25% of the 
patients in the Tio/Olo group have a  first moderate or severe exacerbation at 127 days [95% 
CI, 107 to 149] and in ICS/LABA group at 87 days [95% CI, 81 to 103] (HR = 0.78, [95% CI 
0.70 to 0.86])), we assume that at least 25% of patients in the ICS/LABA experienced a first 
moderate or severe COPD exacerbation at 103 days and the HR of  Tio/Olo to LABA/ICS is 
0.9.  For a study duration of 6 years, a total of 4978 patients (2489 patients each arm) are 
needed to detect the difference between the two arms with 2-sided alpha of 0.05 and 90% 
power
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 
analyzed 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.
All analyses will be presented for each treatment group (Tio+Olo vs LABA/ICS) overall. We 
will first describe formation of the study cohort. Propensity score matching will be used to 
balance the baseline characteristics of patients in the two treatment groups. The covariates 
used to calculate the propensity score would be specified in the SEAP. All the analyses will 
be performed on patients after propensity score matching. Patient characteristics at baseline 
in patients treated with Tio+Olo and patients treated with LABA/ICS will be described 
separately using standard descriptive statistics after propensity score matching. Absolute 
standardized differences (ASDs) will be used to compare the characteristics between the two 

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groups after propensity score matching, in which a >0.1 ASD indicates a meaningful 
difference. 
For the analysis of the primary outcome, individuals will be followed up from the index date 
until the first moderate or severe COPD exacerbation. The data after the earliest date of the 
following  would be censored: 1) disenrollment; 2) the end of the study period; 3) death; 4) 
discontinuation of the index drug (except for switching from the index ICS/LABA to a 
different ICS/LABA); 5) escalation to triple therapies (ICS/LAMA/LABA free or fix dose 
combination). Cox proportional hazard regression model will be used to compare the  time to 
event between the two  treatment groups, while accounting for the potential baseline 
differences between them. Other known predictors will also be included in the model as 
covariates. It will provide an estimate of the hazard ratio (HR) of time to the first moderate or 
severe COPD exacerbation associated with Tio+Olo use relative to LABA/ICS use, along 
with 95% confidence intervals (CI). The analysis will be on-treatment.
The analysis of the secondary objectives related to time to triple therapy escalation, time to 
first hospitalization for community-acquired pneumonia, will use a Cox proportional hazard 
regression model with an as-treated approach, similar to that of the primary analysis. The 
estimate of hazard ratio (HR) of time to triple therapy escalation and first hospitalization for 
community-acquired pneumonia associated with Tio+Olo use relative to LABA/ICS use, 
along with 95% confidence intervals (CI) will be provided. For the analysis of these time-to-
event outcomes, patients will be followed up until until the earliest of the date of the follows, 
whichever happened first 1) outcome event of interest; 2) disenrollment; 3) the end of the 
study period; 4) death; 5) discontinuation of the index drug (except for switching from the 
index ICS/LABA to a different ICS/LABA).
For incidence rate of triple therapy initiation (first event per patient), annualized rate of 
moderate or severe COPD exacerbations, and annualized number of prescriptions of rescue 
medications will be calculated by cohort. 
For continuous and categorical variables, we will use standard descriptive statistics to 
describe. For incidence rates, it will be calculated for each cohort as follows:
Incidence rate among the Tio+Olo cohort = (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)
Incidence rate among the comparison cohort = (total number of patients in the comparator 
LABA/ICS cohort experiencing an event of interest for the first time during the given time 
period) / (total person-time at risk from current use of comparator LABA/ICS during the 
given period)
The incidence rate ratio (IRR) and incidence difference for the outcome in the Tio+Olo -
exposed group relative to that in the comparator group will be derived as follows:
Incidence rate ratio = incidence rate from the Tio+Olo cohort divided by the incidence rate 
from the matched comparator cohort.

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Incidence difference = incidence rate from the Tio+Olo cohort – incidence rate from the 
matched comparator cohort
The IRRs will be calculated. Incidence differences and their 95% confidence intervals will 
also be derived.
For annualized rates, it will be calculated for each cohort as follows:
Annualized rate among the Tio+Olo cohort = (total number of events in the Tio+Olo cohort 
during the given time period) / (total person-time at risk from current use of Tio+Olo during 
the given period)
Annualized rate among the comparison cohort = (total number of events in the comparator 
LABA/ICS cohort during the given time period) / (total person-time at risk from current use 
of comparator LABA/ICS during the given period)
The incidence rate ratio (IRR) for the triple therapy initiation in the Tio+Olo - exposed group 
relative to that in the comparator group, along with 95% confidence intervals will be derived 
using negative binomial model.
For annualized rate of moderate or severe COPD exacerbations and annualized number of 
prescriptions of rescue medications, the ratio of Tio+Olo – exposed group relative to 
LABA/ICS group, along with 95% confidence intervals will be derived using negative 
binomial model.
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 propotol, 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). The statistical 

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9.10.2.2
Direct access to source data and documents
Not applicable.
Data are 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.  

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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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BI Study Number: 1237-0110
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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P21-01394   Global initiative for chronic obstructive lung disease. Global strategy for 
the diagnosis, management, and prevention of chronic obstructive pulmonary disease 
(2021 REPORT) . https://goldcopd.org/goldreports/.
P07-11820   Wedzicha JA  et al. The prevention of COPD exacerbations by 
salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care 
Med.2008;177:19-26.
P16-05628   Wedzicha J A, et al. Indacaterol–Glycopyrronium versus
Salmeterol–Fluticasone for COPD. N Engl J Med, 2016, 2016(374): 2222-2234
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
No document # Taiwan National Health Insurance, column_note_in_TW_NHI_20210824. 24 
Aug 2021

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BI Study Number: 1237-0110
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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Number
Document 
Reference Number
Date
Title
None

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BI Study Number: 1237-0110
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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Study title:
Effectiveness of Maintenance Treatment with Tiotropium + Olodaterol in 
Comparison to Inhaled Corticosteroids + Long-acting β2 agonists 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): 1237-0110
Section 1: Milestones
Yes
No
N/A
Section 
Number
1.1
Does the protocol specify timelines 
for 
1.1.1 Start of data collection1
1.1.2 End of data collection2
1.1.3 Progress report(s)
1.1.4 Interim report(s)
1.1.5 Registration in the EU PAS 
Register®
1.1.6 Final report of study results.
6
Comments:
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 generalised)
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)
11
Comments:
Section 4: Source and study 
populations
Ye
s
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
9.2.2
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
Comments:

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Section 5: Exposure definition and 
measurement
Yes
No
N/A
Section 
Number
5.1
Does the protocol describe how the 
study exposure is defined and 
measured? (e.g. operational details for 
defining and categorising exposure, 
measurement of dose and duration of drug 
exposure)
9.3.1
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 categorised according to 
time windows? 
5.4
Is intensity of exposure addressed? 
(e.g. dose, duration)
5.5
Is exposure categorised 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?
9.1
Comments:
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)
6.4
Does the protocol describe specific 
outcomes relevant for Health 
Technology Assessment? (e.g. HRQoL, 
QALYs, DALYS, health care services utilisation, 
burden of disease or treatment, compliance, 
disease management)
Comments:
Specifics will be described in SEAP.

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Section 7: Bias
Yes
No
N/A
Section 
Number
7.1
Does the protocol address ways to 
measure confounding? (e.g. 
confounding by indication)
9.7.1
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)
9.9
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:
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)
9.4
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event)
9.4
9.2.3 Covariates and other characteristics? 
(e.g. age, sex, clinical and drug use history, co-
morbidity, co-medications, lifestyle)
9.4
9.3
Is a coding system described for: 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, 
Anatomical Therapeutic Chemical (ATC) 
Classification System)

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Section 9: Data sources
Yes
No
N/A
Section 
Number
9.3.2 Outcomes? (e.g. International Classification 
of Diseases (ICD), Medical Dictionary for Regulatory 
Activities (MedDRA))
9.4
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:
Specifics will be described in SEAP.
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?
9.7.1
10.6 Does the plan describe methods for 
analytic control of outcome 
misclassification?
10.7 Does the plan describe methods for 
handling missing data?
 
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? 
Comments:

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BI Study Number: 1237-0110
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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?
9.9
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such 
biases, validation sub-study, use of validation and 
external data, analytical methods).
9.9
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:
Section 15: Plans for communication of 
study results
Yes
No
N/A
Section 
Number
15.1 Are plans described for 
communicating study results (e.g. to 
regulatory authorities)? 
12
15.2 Are plans described for disseminating 
study results externally, including 
publication?
12

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BI Study Number: 1237-0110
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ANNEX 3. ADDITIONAL INFORMATION
None

BOEHRINGER INGELHEIM Group of Companies
NIS Protocol 
BI Study Number: 1237-0110
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001-MCS-90-118 RD-23 (2.0) / Saved on: 02 Jul 2020
Study Title: Effectiveness of Maintenance Treatment with Tiotropium + Olodaterol 
in Comparison to Inhaled Corticosteroids + Long-acting β2 agonists in COPD 
patients in Taiwan: a non-interventional study based on the Taiwan National Health 
Insurance (NHI) data.
Study Number: 1237-0110
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.
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