Taiwan Outcomes and Real-world Treatment Options for Chronic Obstructive Pulmonary Disease
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

 
Protocol version: V1.0 
Date: 25 November 2019                                                                                                                           001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015 
TITLE PAGE 
Non-interventional Study Protocol 
Document Number: 
TBD 
BI Study Number: 
1237-0086 
BI Investigational 
Product(s): 
Tiotropium/olodaterol (Spiolto®) 
Title: 
Taiwan Outcomes and Real-world Treatment Options for Chronic 
Obstructive Pulmonary Disease (TOReTO) 
Brief lay title 
A study in Taiwan based on medical records that looks at the 
occurrence of flare-ups in patients with chronic obstructive 
pulmonary disease (COPD) who started LABA/LAMA or 
LAMA treatment 
Protocol version 
identifier: 
V1.0 
Date of last version of 
protocol: 
25 November 2019 
PASS: 
No 
EU PAS register 
number: 
TBD 
Active substance: 
R03AL06-olodaterol and tiotropium bromide 
Medicinal product: 
tiotropium/olodaterol 
Product reference: 
EMEA/H/C/003821 (EMA agency product number) 
FDA reference ID: 3643917 
Procedure number: 
Not applicable 
Marketing authorisation 
holder(s): 
This study is initiated, managed, and financed by: 
 
 
 
Joint PASS: 
No 
Research question and 
objectives: 
The primary objective is to understand the occurrence of COPD 
exacerbations in patients treated with LABA/LAMA in the 
routine clinical practice in Taiwan. 
The secondary objectives are to realize the clinical characteristics 
and prescription patterns for the COPD population in Taiwan. 
Country(-ies) of study: 
Taiwan 

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Protocol version: V1.0 
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Author: 
 
Title: 
 
 
Name: 
 
Tel: 
 
Direct Line: 
 
Fax:
 
 
Marketing authorisation 
holder(s): 
 
Title: 
 
 
Name: 
 
Tel: 
 
Direct Line: 
 
Fax: 
 
Address: 
 
 
 
In case of PASS, add: 
MAH contact person: 
Not applicable 
In case of PASS, add: 
<EU-QPPV:> 
Not applicable 
In case of PASS, add: 
<Signature of EU-
QPPV:> 
Not applicable 
Date: 
25 November 2019 
 
Page 2 of 41 
 
Proprietary confidential information 
©  2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission 
 

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Protocol version: V1.0 
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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ....................................................................................... 3 
2. 
LIST OF ABBREVIATIONS ................................................................................ 5 
3. 
RESPONSIBLE PARTIES .................................................................................... 7 
4. 
ABSTRACT ........................................................................................................... 8 
5. 
AMENDMENTS AND UPDATES ..................................................................... 12 
6. 
MILESTONES ..................................................................................................... 13 
7. 
RATIONALE AND BACKGROUND ................................................................ 14 
8. 
RESEARCH QUESTION AND OBJECTIVES ................................................. 15 
9. 
RESEARCH METHODS .................................................................................... 16 
9.1 
STUDY DESIGN ............................................................................................ 16 
9.2 
SETTING ........................................................................................................ 16 
9.2.1 
Study sites ............................................................................................... 16 
9.2.2 
Study population ..................................................................................... 16 
9.2.3 
Study visits .............................................................................................. 17 
9.2.4 
Study discontinuation .............................................................................. 19 
9.3 
VARIABLES .................................................................................................. 19 
9.3.1 
Exposures ................................................................................................ 19 
9.3.2 
Outcomes ................................................................................................. 19 
9.3.2.1 
Primary outcomes ............................................................................. 19 
9.3.2.2 
Secondary outcomes ......................................................................... 19 
9.3.3 
Covariates ................................................................................................ 20 
9.3.3.1 
Eligibility assessments ..................................................................... 20 
9.3.3.2 
Demographics and other characteristics ........................................... 20 
9.3.3.3 
Acute exacerbation of COPD ........................................................... 22 
9.3.3.4 
COPD assessment test (CAT) .......................................................... 22 
9.3.3.5 
modified Medical Research Council dyspnea scale (mMRC) ......... 23 
9.3.3.6 
Spirometry results ............................................................................ 23 
9.3.3.7 
Treatments ........................................................................................ 23 
9.4 
DATA SOURCES ........................................................................................... 24 
9.5 
STUDY SIZE .................................................................................................. 24 
9.6 
DATA MANAGEMENT ................................................................................ 25 
9.7 
DATA ANALYSIS ......................................................................................... 25 

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9.7.1 
Main analysis ........................................................................................... 26 
9.7.3 
Handling of the missing data ................................................................... 26 
9.8 
QUALITY CONTROL ................................................................................... 27 
9.9 
LIMITATIONS OF THE RESEARCH METHODS ...................................... 27 
9.10 
OTHER ASPECTS ......................................................................................... 27 
9.10.1 
Data quality assurance ............................................................................. 28 
9.10.2 
Study records ........................................................................................... 28 
9.10.2.1 
Source documents ............................................................................ 28 
9.10.2.2 
Direct access to source data and documents .................................... 29 
10. 
PROTECTION OF HUMAN SUBJECTS .......................................................... 30 
10.1 
Study approval, patient information, and informed consent ........................... 30 
10.2 
Statement of confidentiality ............................................................................ 30 
11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ....................................................................................................... 32 
11.1 
Definitions of adverse events .......................................................................... 32 
11.2 
Adverse event and serious adverse event collection and reporting................. 33 
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 ................................................................... 38 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 39 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 40 
ANNEX 3. ADDITIONAL INFORMATION .............................................................. 41 
 
 

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2. 
LIST OD ABBREVIATIONS 
ACOS 
Asthma-COPD Overlap Syndrome 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
BI 
Boehringer Ingelheim 
BMI 
Body Mass Index 
CA 
Competent Authority 
CAT 
COPD Assessment Test 
CI 
Confidence Interval 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
e.g. 
Exempli Gratia 
etc. 
ET Cetera 
DVP 
Data Validation Plan 
EMA 
European Medicines Agency 
ENCePP  European Network of Centres for Pharmacoepidemiology and Pharmacovigilance 
FDA 
Food and Drug Administration 
FDC 
Fixed-dose Combination 
FEV1 
Forced Expiratory Volume in one second 
FVC 
Forced Volume Vital Capacity 
GCP 
Good Clinical Practice 
GEP 
Good Epidemiological Practice 
GERD 
GastroEsophageal Reflux Disease 
GI 
GastroIntestinal 
GPP 
Good Pharmacoepidemiology Practice 
GVP 
Good Pharmacovigilance Practices 
GOLD 
the Global Initiative for Chronic Obstructive Lung Disease 
ICD 
The International Classification of Diseases 
ICH 
The International Conference on Harmonisation 
ICS 
Inhaled Corticosteroids 
IEC 
Independent Ethics Committee 
IPPV 
Intermittent Positive Pressure Ventilation 
IRB 
Institutional Review Board 
LABA 
Long-Acting Beta-Agonist 
LAMA 
Long-Acting Muscarinic Antagonist 
MAH 
Marketing Authorisation Holder 
mMRC 
modified Medical Research Council dyspnea scale 
NIS 
Non-Interventional Study 
NIPPV 
NonInvasive Positive Pressure Ventilator 
Olo 
Olodaterol 
PASS 
Post-Authorization Safety Study 
SABA 
Short-Acting Beta-Agonist 
SADR 
Serious Adverse Drug Reaction 
SAMA 
Short-Acting Muscarinic Antagonist 

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Protocol version: V1.0 
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SOP 
Standard Operating Procedure 
Tio 
Tiotropium 
WHO 
World Health Organization 

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3. 
RESPONSIBLE PARTIES 
Title 
Name 
Boehringer Ingelheim, Division Medicine/Medical Affairs 
 
 
Associate Medical Advisor 
Boehringer Ingelheim, Local Pharmacovigilence Officer 
 
 
 

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4. 
ABSTRACT 
 
Name of company: 
 
 
Boehringer Ingelheim 
Name of finished medicinal product:  
Spiolto® (tiotropium/olodaterol) 
 
Name of active ingredient: 
tiotropium/olodaterol 
(ATC code: R03AL06; long-acting 
bronchodilators; a muscarinic receptor 
antagonist for tiotropium and a β 
adrenoreceptor agonist for olodaterol) 
 
Protocol date: 
Study number: 
Version/Revision: 
Version/Revision date: 
18 June 2019 
1237-0086 
1.0 
25 November 2019 
Title of study: 
Taiwan Outcomes and Real-world Treatment Options for Chronic 
Obstructive Pulmonary Disease 
Rationale and 
background: 
Recently, more and more randomized controlled trials (RCT) 
demonstrated effectiveness of dual bronchodilators for the treatment of 
chronic obstructive pulmonary disease (COPD). DYNAGITO trial1 has 
provided further evidences for tiotropium + olodaterol (Tio + Olo) 
compared with tiotropium in reducing moderate/severe exacerbations. 
In the real-world setting in Taiwan, the medication environment and 
electronic medical charts are well-established in medical centers. Hence, 
retrospective analysis is fully possible. Boehringer Ingelheim (BI) 
Taiwan and clinical practitioners’ common goal are to adopt optimal 
treatment for COPD patients diagnosed per GOLD guideline. 
So far, we can refer to some head to head studies examining the impact 
on lung function of various LABA/LAMA combinations; however, 
there is no study observing real world outcomes on prevention/risk 
reduction of acute exacerbations in Taiwan. The extent of outcomes 
from Tio + Olo (Spiolto®), other LABA/LAMA fixed-dose 
combinations [FDC]/free combos, or LAMA treatment of benefit for 
COPD patients in reducing acute exacerbation, is of great interest to 
explore. 
Research question 
and objectives: 
The primary objective is to understand the occurrence of COPD 
exacerbations in patients treated with LABA/LAMA or LAMA in the 
routine clinical practice in Taiwan. 
The secondary objectives are to realize the clinical characteristics and 
prescription patterns for the COPD population in Taiwan. 
Study design: 
This is a retrospective, multi-center, cohort study to collect the data on 
COPD patients who were administered with LABA/LAMA (FDC or 
free combo) or LAMA treatment for 3 months at least prior to 30 June 
2018. For LABA/LAMA therapy, new initiation or switching from other 
therapy (i.e., single/dual/triple) are both acceptable; for LAMA 

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treatment, only new initiation will be acceptable. The data abstracted 
from eligible patients will be recorded only when they are available in 
the medical chart and will be categorized into the cohort A (patients 
treated with Tio + Olo), B (patients treated with other LABA/LAMA 
therapy), and C (LAMA therapy). 
The follow-up period for each patient will be from the index date* until 
the date of death or 1 year after the index date, whichever occurs first. 
Patients will be censored at the time from one LAMA/LABA or LAMA 
switched to another LAMA/LABA or ICS. 
*Index date: It is defined as the date of COPD patients in the cohort A 
and B stating using LABA/LAMA therapy regardless of new initiation 
or switching from other single/dual/triple treatment, or the date of the 
patients in the cohort C starting using LAMA treatment. 
Population: 
This study plans to review the medical chart from approximately 1,800 
COPD patients receiving LABA/LAMA or LAMA treatment for 3 
months at least prior to June 30 2018 in Taiwan. 
Inclusion criteria 
Patients who fulfil ALL the following criteria are included. 
1. 
Patients who diagnosed with COPD who were prescribed with 
LABA/LAMA (FDC or free combo) as a new initiation or 
switching from other therapy (i.e., single/dual/triple), or newly 
receiving LAMA treatment for 3 months at least prior to 30 June 
2018 
2. 
Male or female patients ≥ 40 years of age 
Exclusion criteria 
Patients who meet the following criterion are not included. 
1. 
Patients with documented diagnosis of bronchial asthma, asthma-
COPD overlap syndrome (ACOS), bronchiectasis, cystic fibrosis, 
or lung cancer 
Variables: 
Variables 
• 
Patient demographics (date of birth, gender, race, body mass index 
[BMI], family history, occupation, etc.) 
• 
Diagnosis of COPD (date of diagnosis, disease severity, etc.) 
• 
Smoking status 
• 
Spirometry data (e.g., FEV1, FVC) 
• 
COPD assessments (e.g., CAT, mMRC) 
• 
Acute exacerbations from 1 year before the index date until 1 year 
after the index date or the date of death (onset/stop date, etc.) 
• 
Hospitalizations 
due 
to 
COPD 
exacerbation 
(e.g., 
admission/discharge date, treatments) 
• 
Laboratory data (e.g., eosinophil counts) 

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• 
Pharmacological/non-pharmacological treatments from 6 months 
before the index date to 1 year after the index date or the date of 
death, especially for the following: 
- 
Treatment related to COPD (start/stop dates, dosage, 
frequency, etc.) 
- 
Rescue treatments for COPD (antibiotics, oral corticosteroid, 
ventilator support, etc.) 
- 
Oxygen therapies 
- 
Surgeries for COPD therapy or improvement of lung function 
• 
Time/reasons for treatment switching (e.g., single/dual/triple 
therapy to LABA/LAMA prior to the index date, Tio + Olo to other 
therapies, single/dual escalating to dual/triple therapy) 
• 
Comorbidities (cardiovascular, cerebrovascular, respiratory, 
hepatic, 
renal, 
gastrointestinal, 
metabolic, 
infectious 
comorbidities, etc.) 
 
Primary outcomes 
• 
Time to the first moderate or severe COPD exacerbation 
 
Secondary outcomes 
• 
Annualized rate of mild/moderate/severe exacerbation 
• 
Time/reason (e.g., severe airflow limitation, diagnosis of asthma, 
worsening exacerbation) from LABA/LAMA escalating to 
LABA/LAMA/ICS or from LAMA to dual therapy 
• 
Percentage of patients receiving LABA/LAMA switched to triple 
therapy or LAMA switched to dual therapy 
• 
Change in pulmonary function after LABA/LAMA or LAMA 
initiation 
• 
Use of rescue medications 
Data sources: 
Source data are collected from medical charts in 12 medical hospitals in 
Taiwan. The case report form (CRF) will be designed for the data 
collection. 
Study size: 
Approximately 1,800 eligible COPD patients are planned to be enrolled 
from 12 medical hospitals in Taiwan. 
Data analysis: 
A Data Validation Plan (DVP) will be prepared to describe the processes 
for data validation. 
The data abstracted from the medical chart will be described with 
number, mean, standard deviation (SD), range, and 95% confidence 
intervals (95% CI) for continuous variables, and frequencies and 
percentages for categorical variables. 

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The propensity score matching approach* will be used to balance the 
baseline characteristics between the study cohorts (Tio + Olo vs. other 
LABA/LAMA vs. LAMA therapy). 
These data will be compared descriptively between patients receiving 
different regimens (Tio + Olo vs. other LABA/LAMA vs. LAMA 
therapy). If the propensity score matching is done, the difference before 
and after matching will be considered both. 
The annualized rate of exacerbation with various severities will be 
calculated for each study group (episodes/patient-year), and the 
differences between the three cohorts will be compared by rate ratio. 
Time to the first moderate or severe COPD exacerbation or escalating 
to dual or triple therapy will be compared between different cohorts 
using Kaplan-Meier curves with the incidence and time to events, and 
statistical significance will be assessed using log-rank tests. 
Chi-square test or Fisher’s exact test will be applied for categorical 
variables such as reasons for switching/escalating therapies, frequency, 
and percentage, etc. 
*NOTE: Variables may include but not limited to age, gender, disease 
duration before index date, smoking status, body mass index, COPD 
assessment score (e.g., CAT and mMRC), spirometry data (e.g., FEV1), 
oxygen therapy, comorbidities, disease severity, previous exacerbation, 
previous treatments, or eosinophil counts, where appropriate. 
Milestones: 
Planned the start of data collection: July 2019 
Planned the end of data collection: November 2019 
Planned final study report: the end of January 2020 

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5. 
AMENDMENTS AND UPDATES 
Number 
Date 
Section of  
study protocol 
Amendment 
or update 
Reason 
1 
25 November 
2019 
1. 
Abstract 
2. 
Section 9.2.2 
Amendment 
1. 
Revised typos from 
LABA/LABA to 
LABA/LAMA 
 

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6. 
MILESTONES 
Milestone 
Planned Date 
IRB/IEC approval 
31 July 2019 
Start of data collection 
01 August 2019 
End of data collection 
30 November 2019 
Registration in the EU PAS register 31 July 2019 
Final report of study results: 
31 January 2020 
 

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7. 
RATIONALE AND BACKGROUND 
Chronic obstructive pulmonary disease (COPD) is a common, worldwide, and irreversible 
obstructive airway disease due to chronic inflammation in alveoli or airway. Generally, COPD 
manifests in males over 40 years and gradually progresses their health status even under the 
treatments. However, the steady increase prevalence in females or young patients is also found 
based on previous studies,2,3 which implies that those already known risk factors (i.e., smoking, 
exposure to biomass fuel or chemical particles) should be emphasized. According to the report 
of World Health Organization (WHO),4 COPD is the third leading cause of death begetting 1.7 
million of death in 2016; meanwhile, it is the fifth cause of burden of disease in 2010 around 
the world.5 The global prevalence of COPD cannot be estimated precisely because of the 
different approaches applied for calculation.6 Averagely, the estimated global prevalence of 
COPD is 11.7% and the highest is observed in the America region with 15.2% compared to 
Europe and China with 7.4% and 6.5%, respectively.7,8 In Taiwan, COPD is the seventh leading 
cause of death with the estimated prevalence of 6.1%.9,10 
The general diagnosis of COPD includes reviewing patients’ medical history, evaluating the 
lung function by spirometry, and emphysema using computed tomography (CT). 
Exacerbation/hospitalization due to exacerbation occurring ≥ 2 times/year is a predictor for a 
poor prognosis and increase in mortality.11,12 Hence, how to prevent the exacerbation is at issue 
for the COPD management. For this purpose, pharmacological/non-pharmacological therapies 
are recommended based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 
guideline (version 2017)6 for the prevention of COPD exacerbation and reduction of the 
symptoms. Long-acting bronchodilators are suitable for the maintenance therapies, including 
long-acting beta-agonists (LABA) alone, long-acting muscarinic antagonists (LAMA) alone, 
and the dual therapy (fixed-dose combination [FDC] or free combos). 
A few studies show LABA/LAMA therapy, especially for tiotropium (Tio) plus olodaterol 
(Olo), is more effective on prevention of COPD exacerbation and improvement of the quality 
of life and lung function than monotherapy or placebo,1,13-15 along with the comparison to other 
dual therapies.16-18 In Taiwan, Tio plus Olo FDC therapy (Spiolto®) is on the market since 2016, 
but the clinical data reflecting the real-world setting on COPD patients treated with Tio plus 
Olo vis-à-vis those with other LABA/LAMA or LAMA therapy are limited. Therefore, a 
retrospective, cohort study is planned to collect the clinical outcome on the prevention of acute 
exacerbation between different therapies for COPD in Taiwan. 
 

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8. 
RESEARCH QUESTION AND OBJECTIVES 
The primary objective is to understand the occurrence of COPD exacerbations in patients 
treated with LABA/LAMA or LAMA in the routine clinical practice in Taiwan. 
The secondary objectives are to realize the clinical characteristics and prescription patterns for 
the COPD population in Taiwan. 

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9. 
RESEARCH METHODS 
9.1 
STUDY DESIGN 
It is a retrospective, multi-center, cohort study to collect the data on COPD patients who were 
administered with LABA/LAMA (FDC or free combo) or LAMA therapy for 3 months at least 
prior to 30 June 2018. The patients using LABA/LAMA therapy will be enrolled regardless of 
new initiation or switched from other single/dual/triple treatment, whereas those using LAMA 
treatment will only be acceptable when LAMA is newly initiated. This study aims to estimate 
the occurrence of COPD exacerbation in the COPD population under the real-world practice 
in Taiwan. Additionally, the study also assesses outcomes of clinical characteristics and 
prescription patterns for patients using LABA/LAMA or LAMA. After Institutional Review 
Board’s (IRB) permission, it will be carried out in around 12 medical centers in Taiwan and 
plans to collect the clinical data abstracted from the medical charts of approximately 1,800 
eligible patients. The eligible patients will be separated into three cohorts based on the 
prescription for COPD on the index date. Cohort A includes the patients treated with Tio + Olo, 
cohort B is the patients treated with other LABA/LAMA therapy, and cohort C is the patients 
receiving LAMA treatment. No investigational or interventional treatment will be provided in 
the retrospective study. 
The retrospective study will review medical charts of COPD patients with LABA/LAMA or 
LAMA therapy until death or 1 year after the index date, whichever occurs first. The data 
collection will be conducted after eligibility assessment. Medical records will be reviewed and 
relevant information will be abstracted for various details such as patient demographics, 
diagnosis of COPD, smoking status, records of exacerbations and hospitalization, examinations 
of lung function and laboratory, treatments related to COPD or comorbidities, reasons for 
treatment switching, and comorbidities. 
 
9.2 
SETTING 
This study plans to retrospectively collect the data abstracted from the electronic medical charts 
of eligible patients from around 12 medical hospitals in Taiwan. 
 
9.2.1 
Study sites 
Selected sites include around 12 medical hospitals with the highest level in Taiwan from 
Northern to Southern area. Further, these hospitals have adequate patient pool and sufficient 
clinical data for collection. 
 
9.2.2 
Study population 
The data will be retrospectively abstracted from the medical chart after eligibility assessment. 
Eligible patients will be categorized into the cohort A (patients treated with Tio + Olo), B 
(patients treated with other LABA/LAMA therapy), and C (patients treated with LAMA 
therapy). 

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Inclusion criteria 
Patients who fulfil ALL the following criteria are included. 
1. 
Patients who diagnosed with COPD who were prescribed with LABA/LAMA (FDC or 
free combo) as a new initiation or switching from other therapy (i.e., single/dual/triple), 
or newly receiving LAMA treatment for 3 months at least prior to 30 June 2018 
2. 
Male or female patients ≥ 40 years of age 
 
Exclusion criteria 
Patients who meet the following criterion are not included. 
1. 
Patients with documented diagnosis of bronchial asthma, asthma-COPD overlap 
syndrome (ACOS), bronchiectasis, cystic fibrosis, or lung cancer 
 
9.2.3 
Study visits 
The abstracted data will be recorded on the case report form (CRF). Table 1 shows the 
collected data at different retrospective period of the medical chart. 
Table 1 Data collection schedule 
Time points 
 
Variables 
Eligibility 
assessment 
Data collection retrospectively 
Before the  
index date 
Index date# 
1-year follow-up 
period† 
Eligibility assessments 
X 
 
 
 
Demographics1 
 
 
X* 
 
Diagnosis of COPD2 
 
 
X* 
 
Smoking status3 
 
 
X* 
 
Comorbidity4, $ 
 
X◊ 
X 
X 
COPD assessments‡ 
 
 
 
 
CAT5 
 
X∆ 
X 
X 
mMRC6 
 
X∆ 
X 
X 
Examinations‡ 
 
 
 
 
Spirometry data7 
 
X∆ 
X 
X 
Eosinophils 
 
X∆ 
X 
X 
Records‡ 
 
 
 
 
Acute exacerbations8 
 
X& 
X 
X 
Hospital admissions9 
 
X& 
X 
X 
Treatments 
 
 
 
 

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Time points 
 
Variables 
Eligibility 
assessment 
Data collection retrospectively 
Before the  
index date 
Index date# 
1-year follow-up 
period† 
Related to COPD10, $ 
 
X11, ◊ 
X 
X 
Related to comorbidities12, $ 
 
X◊ 
X 
X 
Rescue treatments13, ‡ 
 
X◊ 
X 
X 
Oxygen therapy14, $ 
 
X◊ 
X 
X 
Others15, $ 
 
X◊ 
X 
X 
#Not later than 30 June 2018; defined as the date of COPD patients in the cohort A and B stating using 
LABA/LAMA therapy regardless of new initiation or switching from other single/dual/triple treatment, or the 
date of the patients in the cohort C starting using LAMA treatment 
†Not later than 1 year after the index date 
*The data nearest to the index date will be collected. 
◊The data 6 months before the index date will be documented. 
$The data will be collected every 6 months (allowed window: ± 1 month). 
‡All available data on the medical chart will be recorded. 
∆The data nearest to the index date will be collected as the Baseline. 
&The data/events ever since patients started receiving LABA/LAMA or LAMA therapy will be collected 
(maximum: trace back to 1 year before the index date). 
1. 
Date of birth, gender, race, BMI, occupation, and family history 
2. 
Date of diagnosis and disease severity (GOLD grade: GOLD 1, 2, 3, 4; GOLD group: A, B, C. or D) 
3. 
Former, current smoker, or non-smoker 
4. 
Cardiovascular (e.g., ischemic heart disease, heart failure, coronary artery disease, myocardial infarction), 
cerebrovascular (e.g., stroke), respiratory (e.g., pulmonary hypertension), hepatic (e.g., hepatitis), renal 
(e.g., chronic kidney disease, kidney failure), gastrointestinal (e.g., GERD, GI bleeding, gastric disease), 
metabolic (e.g., diabetes mellitus [T1 or T2], hypertension, obesity, hyperlipidemia), infectious (e.g., 
pneumonia, respiratory tract infection, influenza, tuberculosis, viral infection), osteoporosis, anxiety, and 
depression. 
5. 
Score between 0 – 40 points 
6. 
Score between 0 – 4 points 
7. 
FEV1 and FVC, etc. 
8. 
The definition of an acute exacerbation is that a complex of lower respiratory events/symptoms (worsening 
or new onset) related to the underlying COPD, with a duration of 3 days or more, requiring a prescription 
of antibiotics and/or systemic steroids and/or hospitalization (ICD-9: 491.21; ICD-10: J44.1). Onset/stop 
date, severity (mild, moderate, severe), and leading to hospitalization/acute respiratory failure (ICD-9-
518.81 or ICD-10-J96.00/J96.01/ J96.02) or not will be recorded. 
9. 
Hospitalizations caused by COPD exacerbation (ICD-9: 491.21; ICD-10: J44.1) will be collected only. 
The information includes admission/discharge date, treatments for COPD, and reasons for switching 
medications. 
10. 
Including SABA (fenoterol, salbutamol, terbutaline), SAMA (ipratropium bromide), LABA (indacaterol, 
olodaterol), LAMA (aclidinium bromide, glycopyrronium, tiotropium, umeclidinium), LABA + LAMA 
(FDC; tiotropium/olodaterol, indacaterol/glycopyrronium, vilanterol/umeclidinium), LABA + ICS 
(formoterol/beclomethasone, formoterol/budesonide, salmeterol/fluticasone, vilanterol/fluticasone), triple 
therapies (free combo or vilanterol/umeclidinium/fluticasone [FDC]), or others (theophylline, roflumilast, 
mucolytics, etc.). Prescription date, doses, frequency, and reasons for switching medications will be 
recorded. 

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Time points 
 
Variables 
Eligibility 
assessment 
Data collection retrospectively 
Before the  
index date 
Index date# 
1-year follow-up 
period† 
11. 
If a patient receiving SABA, SAMA, LABA/ICS or a triple therapy before LABA/LAMA treatment on the 
index date, the relevant information on the medications, doses, frequency, the route of administration, the 
reasons for switching medications should be recorded. 
12. 
Prescription date, doses, and frequency will be recorded. 
13. 
Therapies for the emergency/hospitalization regarding COPD (ICD-9: 491.21; ICD-10: J44.1) will be 
collected, including but not limited to short-acting bronchodilators, antibiotics, oral corticosteroid (e.g., 
prednisone or prednisolone), ventilator support, or oxygen therapy. Prescription date, doses, frequency, and 
the route of administration will be recorded. 
14. 
NIPPV or IPPV for those not for rescue use 
15. 
Including but not limited to surgeries for COPD or improvement of lung function. 
 
9.2.4 
Study discontinuation 
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular study 
site at any time for the following reasons: 
• 
Violation of Good Clinical Practice (GCP), the study protocol, or the contract by a study 
site or investigator, disturbing the appropriate conduct of the study 
The investigator/the study site will be reimbursed for reasonable expenses incurred in case of 
study termination (except in case of the third reason). 
 
9.3 
VARIABLES 
9.3.1 
Exposures 
Not applicable. 
 
9.3.2 
Outcomes 
9.3.2.1 
Primary outcomes 
• 
Time to the first moderate or severe COPD exacerbation 
 
9.3.2.2 
Secondary outcomes 
• 
Annualized rate of mild/moderate/severe exacerbation 
• 
Time/reason (e.g., severe airflow limitation, diagnosis of asthma, worsening exacerbation) 
from LABA/LAMA escalating to LABA/LAMA/ICS or from LAMA to dual therapy 

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• 
Percentage of patients receiving LABA/LAMA switched to triple therapy or LAMA 
switched to dual therapy 
• 
Change in pulmonary function after LABA/LAMA or LAMA initiation 
• 
Use of rescue medications 
 
 
9.3.3 
Covariates 
9.3.3.1 
Eligibility assessments 
The eligibility should be checked by investigators before the data collection (see Section 9.2.2 
in detail). The following assessments are conducted to determine the eligibility for each patient: 
1. 
Review the medical chart to confirm if a subject with COPD were prescribed with 
LABA/LAMA or LAMA therapy for 3 months at least (not later than 30 June 2018). 
Additionally, a subject must be ≥ 40 years of age. 
2. 
Check the medical chart to exclude the patient with bronchial asthma, ACOS, 
bronchiectasis, cystic fibrosis, or lung cancer 
 
9.3.3.2 
Demographics and other characteristics 
1. 
Demographics: date of birth, gender, race, BMI, occupation, and family history 
• 
Family history includes asthma, COPD, bronchiectasis, and lung cancer 
2. 
Smoking status: former, current smoker, or non-smoker 
3. 
COPD-related history and comorbidities 
• 
COPD-related history: 
The data to be documented include date of diagnosis (ICD-9-496 or ICD-10-J44.9), 
disease severity on index date of starting LABA/LAMA or LAMA therapy (GOLD 
grade: GOLD 1, 2, 3, 4; GOLD group: A, B, C, or D), results of COPD assessments 
(CAT and mMRC, see the definitions in the Section 9.3.3.4 and 9.3.3.5), spirometry 
results (FEV1 and FVC, see Section 9.3.3.6), and acute exacerbations (see Section 
9.3.3.3). 
According to the COPD guideline (version 2017),6 patients will be graded and 
grouped by disease severity based on the results of COPD assessments and 
spirometry. Detailed criteria are presented in Figure 1. 

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•  
• 
Comorbidities of interest: 
Comorbidities regarding any medical findings from 6 months before the index date* 
until death or 1 year after the index date should be collected as below. 
- 
Cardiovascular disease: ischemic heart disease, heart failure, coronary artery 
disease, myocardial infarction 
- 
Cerebrovascular disease: stroke 
- 
Respiratory disease: pulmonary hypertension 
- 
Hepatic disease: hepatitis 
- 
Renal disease: chronic kidney disease, kidney failure 
- 
Gastrointestinal disease: gastroesophageal reflux disease (GERD), GI bleeding, 
gastric disease 
- 
Metabolic disease: diabetes mellitus [T1 or T2], hypertension, obesity, 
hyperlipidemia 
- 
Infectious disease: pneumonia, respiratory tract infection, influenza, 
tuberculosis, viral infection 
- 
Osteoporosis 
- 
Anxiety 
- 
Depression 
*Index date: It is defined as the date of COPD patients in the cohort A and B stating using 
LABA/LAMA therapy regardless of new initiation or switching from other 
single/dual/triple treatment, or the date of the patients in the cohort C starting using 
LAMA treatment. 
4. 
Hospitalization records: 
These records from 1 year before the index date until death or 1 year after the index date 
should be collected. 
Figure 1 Disease severity of COPD 

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The hospitalization caused by COPD exacerbation (ICD-9: 491.21; ICD-10: J44.1) should 
be documented on the CRF, including admission/discharge date, treatments (doses, 
frequency, and the route of administration), and reasons for switching medications. Other 
hospitalizations unrelated to COPD exacerbation will not be recorded. 
5. 
Laboratory data: eosinophils 
The data nearest to the index date will be collected as the Baseline and will continue 
recording until death or 1 year after the index date. 
Blood eosinophil counts are used for a standard of applying ICS treatment for patients 
with ≥ 2% eosinophil counts.6 Additionally, higher blood eosinophils may incur greater 
exacerbations in patients treated with LABA only (without ICS).19,20 Eosinophils counts 
and assessment date will be recorded. 
 
9.3.3.3 
Acute exacerbation of COPD 
The data from 1 year before the index date until death or 1 year after the index date should be 
collected. 
Acute exacerbation is defined as a complex of lower respiratory events/symptoms (worsening 
or new onset) related to the underlying COPD, with a duration of 3 days or more, requiring a 
prescription of antibiotics and/or systemic steroids and/or hospitalization (should all be 
accompanied by code of ICD-9-491.21 or ICD-10-J44.1). Within the retrospective period, the 
onset/stop date of COPD exacerbation, severity* (mild, moderate, severe), and its outcome 
(leading 
to 
hospitalization/acute 
respiratory 
failure 
[ICD-9-518.81 
or 
ICD-10-
J96.00/J96.01/J96.02] or not) will be recorded. In terms of the exacerbation-related therapies, 
they will be recorded onto the page of “Rescue treatments” in the CRF. 
*Mild exacerbation is a patient with worsening but self-managed symptoms. 
Moderate exacerbation is a patient receiving an exacerbation-related prescription such as oral 
corticosteroid (prednisone or prednisolone) and/or antibiotic, but not requiring hospitalization. 
Severe exacerbation is a patient requiring hospitalization or emergency room visit due to COPD 
(ICD-9-491.21 or ICD-10-J44.1). 
 
9.3.3.4 
COPD assessment test (CAT) 
The data nearest to the index date will be collected as the Baseline and will continue recording 
until death or 1 year after the index date. 
The COPD assessment test (CAT) is a simple, 8-item, health status instrument which provides 
a simple method for assessing the impact of COPD on the patient’s health and the quality of 
life. The total CAT score ranging from 0 - 40 is calculated by summing the points for each 
variable. A decrease in CAT score represents an improvement in health status, whereas an 
increase in CAT score represents a worsening in health status.21 The most reliable estimate of 
the minimum significant difference in the CAT score is 2 points.22 
 

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9.3.3.5 
modified Medical Research Council dyspnea scale (mMRC) 
The data nearest to the index date will be collected as the Baseline and will continue recording 
until death or 1 year after the index date. 
mMRC is a 4-item questionnaire for measuring the severity of dyspnea of patients, and the 
score is correlated with health status23 and mortality24,25 for patients with respiratory disease. 
If mMRC scale of the patient is > 2, it means the patient may suffer from dyspnea. 
 
9.3.3.6 
Spirometry results 
The data nearest to the index date will be collected as the Baseline and will continue recording 
until death or 1 year after the index date. 
Spirometry is the most common tool to evaluate the lung function of patients with respiratory 
disease. Among the results of spirometry, FEV1 and the ration of FEV1/FVC are well-known 
for assisting in the diagnosis, determining disease severity, and following up the 
prognosis.6,26,27 In general, patients may be suspected to have COPD based on the criteria 
including post-bronchodilator FEV1 < 80% predicted and FEV1/FVC ratio < 70% in 
accordance with GOLD guideline (version 2017).6 
 
9.3.3.7 
Treatments 
Treatments for COPD will be recorded in the CRF within the retrospective duration, including 
medications related to COPD, rescue treatments, and oxygen therapies, etc.; of which, 
prescription date, doses, frequency, the route of administration, and reasons for switching 
medications will be recorded. Above information (except for rescue treatments) will be 
recorded every 6 months from 6 months before the index date until death or 1 year after the 
index date, whichever occurs first. 
In addition, pharmacological therapies for comorbidities will also be documented and 
information will be recorded every 6 months from 6 months before the index date until death 
or 1 year after the index date, whichever occurs first. 
• 
Related to COPD: 
Medications of interest 
- 
SABA: fenoterol, salbutamol, and terbutaline 
- 
SAMA: ipratropium bromide 
- 
LABA: indacaterol and olodaterol 
- 
LAMA: aclidinium bromide, glycopyrronium, and tiotropium, umeclidinium 
- 
LABA 
+ 
LAMA: 
tiotropium/olodaterol, 
indacaterol/glycopyrronium, 
and 
vilanterol/umeclidinium (FDC) 
- 
LABA 
+ 
ICS: 
formoterol/beclomethasone, 
formoterol/budesonide, 
salmeterol/fluticasone, and vilanterol/fluticasone 

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- 
Triple therapies: free combo or vilanterol/umeclidinium/fluticasone (FDC) 
- 
Others: theophylline, roflumilast, and mucolytics, etc. 
Rescue treatments 
Therapies for the emergency or hospitalization regarding COPD will be collected, 
including but not limited to the following list: 
- 
Short-acting bronchodilators: SABA (fenoterol, salbutamol, or terbutaline) or 
SAMA (ipratropium bromide) 
- 
Antibiotics, only record those for respiratory infections 
- 
Oral corticosteroid: prednisone or prednisolone 
- 
Ventilator support: noninvasive (nasal/facial mask) or invasive (orotracheal tube or 
tracheostomy), or oxygen therapies 
Others 
Non-pharmacological therapies, including but not limited to the following: 
- 
Oxygen therapy: collecting the therapy for maintenance such as noninvasive positive 
pressure ventilators (NIPPV) or intermittent positive pressure ventilation (IPPV) 
- 
Surgery, especially relating to COPD or improving the lung function 
• 
Related to comorbidities 
Pharmacological therapies for comorbidities of interest (see Section 9.3.3.2) will be 
collected. 
 
9.4 
DATA SOURCES 
No additional diagnostic or monitoring procedures will be applied to the patients because of a 
retrospective study, and this study plans to collect the data onto the designed CRF as only those 
are available in the medical records. The data source includes medical records in ~ 12 hospitals 
in Taiwan, where pulmonologists licensed with specialty care for respiratory diseases (COPD 
included) and critical care medicine. 
Each patient is identified by a unique subject/initial number, which is only used for study 
purposes. 
 
9.5 
STUDY SIZE 
Based on the projected market share and per physician’s clinical experience, data from 
approximately 1,800 patients will be collected. 
Among these patients, using Tio + Olo FDC versus other LABA/LAMA therapy (FDC or free 
combo) is assumed the ratio of 1:2 (~ 300 Tio + Olo, ~ 800 other LABA/LAMA therapy). If 
we assume the same annualized event rates as in the Taiwanese subgroup analysis report of 
DYNAGITO1 (i.e. 0.78 per patient-year for Tio + Olo and 0.90 per patient-year for other 

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therapies), expecting the 95% CI for incidence rate ratio to be 0.87 (0.768, 0.978), with good 
precision. The following Table 2 also shows that with smaller sample size, the precision is 
reduced (wider 95% CI). 
Table 2 Sample size estimation 
Tio + Olo 
Other 
Incidence rate ratio (95% CI) 
True Incidence 
rate 
Sample size 
True Incidence 
rate 
Sample size 
0.78 
300 
0.90 
800 
0.87 (0.768, 0.978) 
0.78 
300 
0.90 
300 
0.87 (0.751, 1.000) 
0.90 
300 
0.97 
800 
0.93 (0.829, 1.039) 
0.90 
300 
0.97 
300 
0.93 (0.810, 1.062) 
0.90 
200 
0.97 
200 
0.93 (0.786, 1.094) 
0.90 
200 
0.97 
100 
0.93 (0.734, 1.173) 
In this table, it is assumed that all patients have on average ~ 2 patient-year exposure. 
 
9.6 
DATA MANAGEMENT 
The data abstracted from eligible patients in this study will be recorded on the CRF or other 
applicable forms. The designated personnel will capture, check, store, and analyze the data. 
The designated personnel will follow Boehringer Ingelheim standard operating procedures 
(SOPs) and their own internal SOPs. 
A data validation plan (DVP) will be created to describe the process for data validation. 
Data will be transferred to Boehringer Ingelheim after the closure of the study. 
 
9.7 
DATA ANALYSIS 
Statistical analyses will be conducted by the designated personnel. The main analysis 
population will consist of all eligible patients (i.e., all patients fulfilling all inclusion criteria 
and no exclusion criterion). 
Descriptive analyses will be performed to summarize patient baseline characteristics, the 
observation period, the time to exacerbation/or to escalating to triple therapy, and the rates of 
exacerbation, etc. Continuous variables include number, mean, median, standard deviation 
(SD), range (minimum and maximum value), and 95% confidence intervals (CI). Categorical 
variables are frequency and percentage. 
Statistical analysis of all data will be performed using the latest version of SAS® statistical 
software (SAS Institute, Cary, NC, USA) or other commercially available standard statistical 
software. 
All information already collected as part of the study will be retained for further analyses; 
however, no extra efforts will be made to obtain or record additional information regarding the 
patient. In general, data imputation will not be permitted for any analyses in this study. 

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9.7.1 
Main analysis 
The propensity score matching approach* will be used to balance the baseline characteristics 
between the study cohorts. These data will be compared descriptively between patients 
receiving different regimens (Tio + Olo vs. other LABA/LAMA vs. LAMA). If the propensity 
score matching is done, the difference before and after matching will be considered both. 
For the primary outcome 
Time to the first moderate or severe COPD exacerbation will be compared between different 
cohorts using Kaplan-Meier curves with the incidence and time to events, and statistical 
significance will be assessed using log-rank tests. 
Time to first acute exacerbation starts from the index date to the date of the first acute 
exacerbation recorded on the CRF. Patients with exacerbation free at the time of escalating to 
ICS or no documented with exacerbations will be censored. 
For secondary outcomes 
• 
Time to escalating to dual/triple therapy will also be analysed using Kaplan-Meier curves 
and log-rank tests. 
• 
The annualized rate of exacerbation with various severity will be calculated for each study 
group (episodes/patient-year), and the differences between the three cohorts will be 
compared by rate ratio. 
• 
Results of lung function (i.e., spirometry data) and COPD assessments (i.e., CAT and 
mMRC) will be evaluated by the change from baseline. Pair t-test or other applicable 
statistical methods will be used for assessing the intra-group difference under a 
significance level of 0.05. 
• 
Chi-square test or Fisher’s exact test will be applied for categorical variables such as 
reasons for switching/escalating therapies, frequency, and percentage, etc. 
*NOTE: Variables may include but not limited to age, gender, disease duration before index 
date, smoking status, body mass index, COPD assessment score (e.g., CAT and mMRC), 
spirometry data (e.g., FEV1), oxygen therapy, comorbidities, disease severity, previous 
exacerbation, previous treatments, or eosinophil counts, where appropriate. 
 
 
9.7.3 
Handling of the missing data 
No imputation will be allowed in the retrospective study to reflect the real-world data. 
 

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9.8 
QUALITY CONTROL 
Before the study launch, participating physicians will be trained on the protocol and study 
conduct procedures by Boehringer Ingelheim (or designee). 
In keeping with the non-interventional design employed in this study, site interaction (e.g., 
direct contact between site study staff or patients) is minimized if needed. 
During the study, the occurrence of any protocol violations will be determined. After these 
actions have been completed and the clinical database has been declared to be complete and 
accurate, it will be locked. Quality control will be conducted to ensure data accuracy, 
completeness, and reliability. All information will be kept confidential. 
Boehringer Ingelheim or designated personnel will assure database quality processes are 
followed including the review of the data entered into the CRFs by investigational staffs for 
completeness and accuracy, and in accordance with the data validation plan. 
 
9.9 
LIMITATIONS OF THE RESEARCH METHODS 
Data collection 
A retrospective study is a suitable design to obtain instantly enormous information on the use 
of medications and their outcomes under the clinical practice. However, data integrity may be 
limited by data availability in the medical chart. The lack of data of interest may be one of the 
limitations. Considering the characteristics of COPD, the data regarding relevant assessments 
(CAT, mMRC, or spirometry) and medications for COPD are common tools to manage the 
disease progression. Sponsor, designated personnel, and sites will do their best to collect the 
available data of interest. 
Unbalanced patients’ characteristics 
This study is a non-randomized retrospective study, which means the characteristics of enrolled 
patients may be imbalanced and influential to study endpoints. Hence, this study plans to apply 
propensity score matching for the study cohorts to balance the baseline characteristics. 
Significant difference between patients using different regimens is easier to be observed after 
the baseline matching. 
Patient pool 
The sample size of COPD patients using tiotropium/olodaterol (Spiolto®) may be less because 
this product is late on the market in Taiwan on April 18, 2016. To screen more possible patients, 
the entry criteria are non-restrictive and will permit data collection from a broad patient 
population. 
 
9.10 
OTHER ASPECTS 
No other aspect of the research method is not covered in the previous sections. 
 

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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 all 
medical records and the investigator’s study-related files and correspondence of this study. 
 
9.10.2 
Study records 
Case Report Forms (CRFs) for individual patients will be provided by the sponsor. 
• 
The principal investigator will sign and date the indicated places on the CRFs. These 
signatures will indicate that the principal investigator inspected or reviewed the data on 
the CRF, the data queries, and the site notifications, and agrees with the content. 
 
9.10.2.1 
Source documents 
Source documents are original documents, data, and records from which the subject’s CRF 
data are obtained from the medical chart mainly. 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRFs that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study; also current 
medical records must be available. 
For CRFs, the following data need to be derived from source documents: 
• 
Patient identification (gender, date of birth, etc.) 
• 
Patient participation in the study (substance, study number, patient number) 
• 
Comorbidity 
• 
Pharmacological and non-pharmacological history (prescription date, reasons, etc.) 
• 
Hospitalization records (start/discharge date, etc.) 
• 
Acute exacerbation records 
• 
COPD assessments (CAT, mMRC, etc.) 
The investigator should maintain a list of appropriately qualified persons to whom he/she has 
delegated trial duties. All persons authorized to make entries and/or corrections on the CRFs 
will be included on the Authority Form. 
No information in source documents about the identity of the patients will be disclosed. No 
study document should be destroyed without prior written agreement between Boehringer 
Ingelheim and the investigator. Should the investigator wish to assign the study records to 
another party or move them to another location, he/she must notify Boehringer Ingelheim in 
advance. 

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9.10.2.2 
Direct access to source data and documents 
The investigator/institution will permit study-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes and copies of laboratory and medical test results 
must be available at all times for review by the sponsor’s clinical study monitor, auditor and 
inspection by health authorities (e.g., US Food and Drug Administration [FDA]). The auditor 
may review all CRFs. The accuracy of the data will be verified by reviewing the documents 
described in the Section 9.10.2.1. 
 

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10. 
PROTECTION OF HUMAN SUBJECTS 
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for Good 
Clinical Practice (GCP), Good Epidemiological Practice (GEP), Guidelines for Good 
Pharmacoepidemiology Practice (GPP), and relevant BI Standard Operating Procedures 
(SOPs). 
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches of 
the protocol/ICH GCP. 
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. 
 
10.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT 
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and Competent Authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments. 
Prior to the start of data collection in the study, written informed consent must be obtained 
from each patient (or the patient’s legally accepted representative) if requested by IRBs or the 
local regulatory organization. Each signature must be personally dated by each signatory and 
the informed consent and any additional patient-information form retained by the investigator 
as part of the study records. A signed copy of the informed consent and any additional patient 
information must be given to each patient or the patient’s legally accepted representative. 
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of disclosure 
must also be explained to the patient. 
The patient must be informed that his/her medical records may be examined by Quality 
Medicine auditors appointed by Boehringer Ingelheim, by appropriate IRB IEC members, and 
by inspectors from regulatory authorities. 
 
10.2 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this study 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. 
No subject names will be supplied to Boehringer Ingelheim or other responsible parties. Only 
the subject number and subject initials will be recorded on the CRF, and if the subject’s name 
appears on any other document (e.g., medical chart), it must be obliterated before a copy of 
the document is supplied to Boehringer Ingelheim or other responsible parties. Study findings 
stored on a computer will be stored in accordance with local data protection laws. 

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The investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. 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. All personal information made 
available for inspection will be handled in strictest confidence and in accordance with local 
data protection laws. 
 

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11. 
MANAGEMENT 
AND 
REPORTING 
OF 
ADVERSE 
EVENTS/ADVERSE REACTIONS 
11.1 
DEFINITIONS OF ADVERSE EVENTS 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavourable 
and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
 
Adverse reaction 
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorization or from 
occupational exposure. Conditions of use outside the marketing authorization include off-label 
use, overdose, misuse, abuse and medication errors. 
 
Serious adverse event 
A serious adverse event is defined as any AE which 
- results in death, 
- is life-threatening, 
- requires in-patient hospitalization, or 
- prolongation of existing hospitalization, 
- results in persistent or significant disability or incapacity, or 
- is a congenital anomaly/birth defect 
 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe. 
 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction. 
 
Adverse Event of Special Interest (AESI) 
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this study, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 

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No AESIs have been defined for this study. 
 
11.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING 
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
 
Collection of AEs 
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorization. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined. Only ADRs and AEs with fatal outcomes will be collected on the CRF due 
to the retrospective study design. ADR is defined as that there is an actual causal relationship 
with Spiolto® on the medical chart. 
 
The following must be collected by the investigator in the (e)CRF from signing the informed 
consent onwards until the end of the study:  
 
- all ADRs (serious and non-serious),  
- all AEs with fatal outcome,   
 
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.  
 
Causal relationship of adverse event 
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse reaction, 
in contrast to an adverse event, is characterized by the fact that a causal relationship between a 
medicinal product and an occurrence is suspected.  
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history.  
 
Arguments that may suggest a reasonable causal relationship could be: 
• 
The event is consistent with the known pharmacology of the drug  
• 
The event is known to be caused by or attributed to the drug class. 
• 
A plausible time to onset of the event relative to the time of drug exposure. 
• 
Evidence that the event is reproducible when the drug is re-introduced 
• 
No medically sound alternative etiologies that could explain the event (e.g., 
preexisting or concomitant diseases, or co-medications). 
• 
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g., Stevens-Johnson syndrome). 
• 
An indication of dose-response (i.e., greater effect size if the dose is increased, smaller 
effect size if dose is diminished). 
 

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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be: 
• 
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned) 
• 
Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives). 
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger. 
• 
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned). 
• 
Disappearance of the event even though the study drug treatment continues or remains 
unchanged. 
 
Intensity of adverse event 
The intensity of the AE should be judged based on the following: 
Mild: 
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe: 
Incapacitating or causing inability to work or to perform usual activities 
 
Pregnancy: 
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the study, 
after having taken BI drug taken for the disease in scope of the study, the investigator must 
report any drug exposure during pregnancy, which occurred in a female subject or in a partner 
to a male subject to the Sponsor by means of Part A of the Pregnancy Monitoring Form. The 
outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported by means of Part B of the Pregnancy Monitoring Form. 
 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 
 
Expedited Reporting of AEs and Drug Exposure During Pregnancy 
The following must be reported by the investigator on the NIS AE form from signing the 
informed consent onwards until the end of the study:  
 
Type of Report 
Timeline 
All SADRs associated with the Spiolto® 
immediately within 24 hours 
All AEs with fatal outcome in patients 
exposed to Spiolto® 
immediately within 24 hours 
All non-serious ADRs associated with the 
Spiolto® 
7 calendar days 
All pregnancy monitoring forms 
7 calendar days 
 

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The same timelines apply if follow-up information becomes available for the respective events. 
In specific occasions the Investigator could inform the Sponsor upfront via telephone. This 
does not replace the requirement to complete and fax the NIS AE form. 
 
Information required 
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate (e)CRF pages and the NIS AE form. 
 
Reporting of related Adverse Events associated with any other BI drug 
The investigator is encouraged to report all adverse events related to any BI drug other than the 
Spiolto® according to the local regulatory requirements for spontaneous AE reporting at the 
investigator’s discretion by using the locally established routes and AE report forms. The term 
AE includes drug exposure during pregnancy, and, regardless of whether an AE occurred or 
not, any abuse, off-label use, misuse, medication error, occupational exposure, lack of effect, 
and unexpected benefit. 
 
 
11.3 
REPORTING TO HEALTH AUTHORITIES 
Adverse event reporting to regulatory agencies will be done by the MAH according to local 
and international regulatory requirements. 
 

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12. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
The rights of the investigator and of the sponsor with regard to publication of the results of this 
study are described in the investigator contract. As a general rule, no study results should be 
published prior to finalization of the study report. 

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13. 
REFERENCES 
13.1 
PUBLISHED REFERENCES 
[1] 
Calverley PMA, Anzueto AR, Carter K, et al. Tiotropium and olodaterol in the 
prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a 
double-blind, randomised, parallel-group, active-controlled trial. The Lancet 
Respiratory Medicine. 2018;6 (5): 337-344. 
[2] 
Svanes C, Sunyer J, Plana E, et al. Early life origins of chronic obstructive pulmonary 
disease. Thorax. 2010;65 (1): 14-20. 
[3] 
Landis SH, Muellerova H, Mannino DM, et al. Continuing to Confront COPD 
International Patient Survey: methods, COPD prevalence, and disease burden in 2012-
2013. Int J Chron Obstruct Pulmon Dis. 2014;9 597-611. 
[4] 
The top 10 causes of death. 2018. Available at: http://www.who.int/news-room/fact-
sheets/detail/the-top-10-causes-of-death. Accessed 23-Nov, 2018. 
[5] 
Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 
sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global 
Burden of Disease Study 2010. Lancet. 2012;380 (9859): 2163-2196. 
[6] 
GOLD 2017  Global Strategy for the Diagnosis, Management and Prevention of COPD. 
2017. 
Available 
at: 
http://goldcopd.org/gold-2017-global-strategy-diagnosis-
management-prevention-copd/. Accessed 23-Nov, 2018. 
[7] 
Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systematic review and 
meta-analysis. Eur Respir J. 2006;28 (3): 523-532. 
[8] 
Adeloye D, Chua S, Lee C, et al. Global and regional estimates of COPD prevalence: 
Systematic review and meta-analysis. J Glob Health. 2015;5 (2): 020415. 
[9] 
Cheng S-L, Chan M-C, Wang C-C, et al. COPD in Taiwan: a National Epidemiology 
Survey. Int J Chron Obstruct Pulmon Dis. 2015;10 2459-2467. 
[10] 
Taiwan’s 
Leading 
Causes 
of 
Death 
in 
2016. 
2017. 
Available 
at: 
https://www.mohw.gov.tw/cp-3425-33347-2.html. Accessed 23-Nov, 2018. 
[11] 
Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and 
prevention. Lancet. 2007;370 (9589): 786-796. 
[12] 
Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic 
obstructive pulmonary disease. N Engl J Med. 2010;363 (12): 1128-1138. 
[13] 
Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose 
combination versus mono-components in COPD (GOLD 2-4). Eur Respir J. 2015;45 
(4): 969-979. 
[14] 
Singh D, Ferguson GT, Bolitschek J, et al. Tiotropium + olodaterol shows clinically 
meaningful improvements in quality of life. Respir Med. 2015;109 (10): 1312-1319. 
[15] 
Beeh KM, Westerman J, Kirsten AM, et al. The 24-h lung-function profile of once-
daily tiotropium and olodaterol fixed-dose combination in chronic obstructive 
pulmonary disease. Pulm Pharmacol Ther. 2015;32 53-59. 
[16] 
Beeh KM, Derom E, Echave-Sustaeta J, et al. The lung function profile of once-daily 
tiotropium and olodaterol via Respimat((R)) is superior to that of twice-daily salmeterol 
and fluticasone propionate via Accuhaler((R)) (ENERGITO((R)) study). Int J Chron 
Obstruct Pulmon Dis. 2016;11 193-205. 
[17] 
Derom E, Brusselle GG, Joos GF. Efficacy of tiotropium-olodaterol fixed-dose 
combination in COPD. Int J Chron Obstruct Pulmon Dis. 2016;11 3163-3177. 

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Date: 25 November 2019                                                                                                                            001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015 
[18] 
Tebboth A, Ternouth A, Gonzalez-Rojas N. UK-specific cost-effectiveness of 
tiotropium + olodaterol fixed-dose combination versus other LAMA + LABA 
combinations in patients with COPD. Clinicoecon Outcomes Res. 2016;8 667-674. 
[19] 
Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. Blood eosinophil counts, 
exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol 
in patients with chronic obstructive pulmonary disease: a secondary analysis of data 
from two parallel randomised controlled trials. Lancet Respir Med. 2015;3 (6): 435-
442. 
[20] 
Siddiqui SH, Guasconi A, Vestbo J, et al. Blood Eosinophils: A Biomarker of Response 
to Extrafine Beclomethasone/Formoterol in Chronic Obstructive Pulmonary Disease. 
Am J Respir Crit Care Med. 2015;192 (4): 523-525. 
[21] 
Jones PW, Harding G, Berry P, et al. Development and first validation of the COPD 
Assessment Test. Eur Respir J. 2009;34 (3): 648-654. 
[22] 
Kon SS, Canavan JL, Jones SE, et al. Minimum clinically important difference for the 
COPD Assessment Test: a prospective analysis. Lancet Respir Med. 2014;2 (3): 195-
203. 
[23] 
Bestall JC, Paul EA, Garrod R, et al. Usefulness of the Medical Research Council 
(MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive 
pulmonary disease. Thorax. 1999;54 (7): 581-586. 
[24] 
Sundh J, Janson C, Lisspers K, Stallberg B, Montgomery S. The Dyspnoea, Obstruction, 
Smoking, Exacerbation (DOSE) index is predictive of mortality in COPD. Prim Care 
Respir J. 2012;21 (3): 295-301. 
[25] 
Nishimura K, Izumi T, Tsukino M, Oga T. Dyspnea is a better predictor of 5-year 
survival than airway obstruction in patients with COPD. Chest. 2002;121 (5): 1434-
1440. 
[26] 
Barnes PJ, Burney PGJ, Silverman EK, et al. Chronic obstructive pulmonary disease. 
Nature Reviews Disease Primers. 2015;1 15076. 
[27] 
Anthonisen NR, Wright EC, Hodgkin JE. Prognosis in chronic obstructive pulmonary 
disease. Am Rev Respir Dis. 1986;133 (1): 14-20. 
 
13.2 
UNPUBLISHED REFERENCES 
None. 
 

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
None. 
 

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
Please refer to the attachment. 

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ANNEX 3. ADDITIONAL INFORMATION 
None.