Non-Interventional Study (NIS) Collecting Experiences For IPF in Taiwan
Conditions: Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

 
 
Protocol version 5.0 
Date: 10 April 2017 
 
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015 
TITLE PAGE 
Non-interventional Study Protocol 
Document Number: 
c16462309-02 
BI Study Number: 
1199-0303 
BI Investigational 
Product(s): 
Nintedanib (OFEV®) 
Title: 
Non-Interventional study (NIS) Collecting Experiences For IPF 
in Taiwan 
Brief lay title 
NICEFIT 
Protocol version 
identifier: 
V5.0 
Date of last version of 
protocol: 
10 April 2017 
PASS: 
No 
EU PAS register 
number: 
TBD 
Active substance: 
L01XE31-Nintedanib 
Medicinal product: 
Nintedanib 
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 characterize the IPF population in 
Taiwan with regard to their clinical course under clinical practice 
conditions in Taiwan.  
The secondary objectives are to understand the clinical 
characteristics and quality of life of IPF population in Taiwan. 

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Country(-ies) of study: 
Taiwan 
Author: 
Boehringer Ingelheim 
Title: 
 of Medical Affairs 
Name: 
 
Tel: 
 
Direct Line: 
 
Fax:
 
 
Marketing authorisation 
holder(s): 
Title: 
 of Medical Affairs 
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: 
10 April 2017 
 
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Proprietary confidential information 
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission
 

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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ....................................................................................... 3 
2. 
LIST OF ABBREVIATIONS ................................................................................ 5 
3. 
RESPONSIBLE PARTIES .................................................................................... 7 
4. 
ABSTRACT ........................................................................................................... 8 
5. 
AMENDMENTS AND UPDATES ..................................................................... 13 
6. 
MILESTONES ..................................................................................................... 14 
7. 
RATIONALE AND BACKGROUND ................................................................ 15 
8. 
RESEARCH QUESTION AND OBJECTIVES ................................................. 16 
9. 
RESEARCH METHODS .................................................................................... 17 
9.1 
STUDY DESIGN ............................................................................................ 17 
9.2 
SETTING ........................................................................................................ 17 
9.2.1 
Study sites ............................................................................................... 17 
9.2.2 
Study population ..................................................................................... 17 
9.2.3 
Study visits .............................................................................................. 18 
9.2.4 
Study discontinuation .............................................................................. 23 
9.3 
VARIABLES .................................................................................................. 23 
9.3.1 
Exposures ................................................................................................ 23 
9.3.2 
Outcomes ................................................................................................. 23 
9.3.2.1 
Primary outcomes ............................................................................. 23 
9.3.2.2 
Secondary outcomes ......................................................................... 23 
9.3.3 
Covariates ................................................................................................ 24 
9.3.3.1 
Baseline characteristics and general information ............................. 24 
9.3.3.2 
IPF symptoms ................................................................................... 25 
9.3.3.3 
Acute exacerbation of IPF ................................................................ 25 
9.3.3.4 
Six-minute walk test (6MWT) ......................................................... 26 
9.3.3.5 
St. George's Respiratory Questionnaire (SGRQ) ............................. 26 
9.3.3.6 
COPD Assessment Test (CAT) ........................................................ 26 
9.3.3.7 
Mortality ........................................................................................... 27 
9.3.3.8 
Serological tests ............................................................................... 27 
9.3.3.9 
Biomarker tests ................................................................................. 28 
9.3.3.10 
Gene polymorphism test .................................................................. 28 

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9.3.4 
Study completion ..................................................................................... 28 
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 ........................................................................................... 30 
9.7.3 
Safety analysis ......................................................................................... 31 
9.7.4 
Handling of missing data ......................................................................... 31 
9.8 
QUALITY CONTROL ................................................................................... 31 
9.9 
LIMITATIONS OF THE RESEARCH METHODS ...................................... 32 
9.10 
OTHER ASPECTS ......................................................................................... 33 
9.10.1 
Data quality assurance ............................................................................. 33 
9.10.2 
Study records ........................................................................................... 33 
9.10.2.1 
Source documents ............................................................................ 33 
9.10.2.2 
Direct access to source data and documents .................................... 34 
10. 
PROTECTION OF HUMAN SUBJECTS .......................................................... 35 
10.1 
Study approval, patient information, and informed consent ........................... 35 
10.2 
Statement of confidentiality ............................................................................ 36 
11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ....................................................................................................... 37 
11.1 
Definitions of adverse events .......................................................................... 37 
11.2 
Adverse event and serious adverse event collection and reporting................. 38 
11.3 
Reporting to health Authorities ....................................................................... 41 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
 ............................................................................................................................. 42 
13. 
REFERENCES .................................................................................................... 43 
13.1 
PUBLISHED REFERENCES ......................................................................... 43 
13.2 
UNPUBLISHED REFERENCES ................................................................... 44 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 45 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 46 
ANNEX 3. ADDITIONAL INFORMATION .............................................................. 47 

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2. 
LIST OF ABBREVIATIONS 
Ab 
Antibody 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALAT 
Latin American Thoracic Association 
ATS 
American Thoracic Society 
BMI 
Body Mass Index 
CA 
Competent Authority 
c-ANCA 
Cytoplasmic Anti-Neutrophil Cytoplasmic Antibodies 
CAT 
COPD Assessment Test 
CAD 
Coronary Artery Disease 
CCDS 
Company Core Data Sheet 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CK 
Creatine Kinase 
CML 
Clinical Monitor Local 
COPD 
Chronic Obstructive Pulmonary Disease 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTP 
Clinical Trial Protocol 
DLCO 
Diffusing capacity of the Lungs for Carbon monoxide 
DVT 
Deep Vein Thrombosis 
eGFR 
Estimated Glomerular Filtration Rate 
ENCePP  
European Network of Centers for Pharmacoepidemiology and 
Pharmacovigilance  
ERS 
European Respiratory Society 
FDA 
Food and Drug Administration 
FGF 
Fibroblast Growth Factor 
FPF 
Familial Pulmonary Fibrosis 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GEP 
Good Epidemiological Practice 
GI 
Gastrointestinal 
GPP 
Good Pharmacoepidemiology Practice 
GVP 
Good Pharmacovigilance Practices 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HRCT 
High-Resolution Computed Tomography 
IB 
Investigator’s Brochure 
IC 
Inspiratory Capacity 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 

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ILD 
Interstitial Lung Disease 
IPF 
Idiopathic Pulmonary Fibrosis 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
JRS 
Japanese Respiratory Society 
MAH 
Marketing Authorisation Holder 
MDT 
Multidisciplinary Team 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
NIS 
Non-Interventional Study 
p-ANCA 
Perinuclear Anti-Neutrophil Cytoplasmic Antibody 
PASS 
Post-Authorization Safety Study 
PDGF 
Platelet Derived Growth Factor 
PH 
Pulmonary Hypertension 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis Software 
SGRQ 
St George's Respiratory Questionnaire 
SOP 
Standard Operation Procedure 
SpO2 
Oxygen Saturation 
TB 
Tuberculosis 
TIA 
Transient Ischaemic Attack 
TLC 
Total Lung Capacity 
UIP 
Usual Interstitial Pneumonia 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell 
6MWT 
Six-Minutes Walking Test 
 

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3. 
RESPONSIBLE PARTIES 
Title 
Name 
Boehringer Ingelheim, Division Medicine/Medical Affairs 
 of Medical Affairs 
Associate Medical Advisor 
 Medical Science Liaison 
Boehringer Ingelheim, Local Pharmacovigilence Officer 
 
  Data 
/Biostatistician 
 
  Clinical Research 
 

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4. 
ABSTRACT 
Name of company: 
 
 
Boehringer Ingelheim 
Name of finished medicinal 
product:  
OFEV® (Nintedanib) 
 
Name of active ingredient: 
Nintedanib (ATC code: L01XE31, 
antineoplastic agents, protein kinase 
inhibitors) 
 
Protocol date: 
Study 
number: 
Version/Revision: 
Version/Revision 
date: 
08 February 2017 
1199-0303 
5.0 
10 April 2017 
Title of study: 
Non-Interventional study (NIS) Collecting Experiences For IPF in 
Taiwan 
Rationale and 
background: 
The prevalence and incidence of IPF from 1997 to 2007 in Taiwan is 
0.7-6.4 cases/100,000 and 0.6-1.4/100,000 respectively (Ref 8, C.-C. 
Lai et al. Respiratory Medicine, 2012. 106: p. 1566-1574), which is 
relatively low compared to western countries (Ref 5, Raghu, G., et al. 
Am J Respir Crit Care Med, 2006. 174: p. 810-816.). The median 
survival in Taiwan is only 0.9 year after IPF diagnosis (Ref 8, C.-C. 
Lai et al. Respiratory Medicine, 2012. 106: p. 1566-1574). 
There are two anti-fibrotic drugs conditionally recommended by the 
update of the IPF international consensus statement in 2015 (American 
Journal of Respiratory and Critical Care Medicine Volume 192 
Number 2 | July 15 2015): nintedanib and pirfenidone. Nintedanib 
(OFEV®) has been on the market in Taiwan since September 2015 and 
pirfenidone (Pirespa®) is on market in the first half of 2016. 
Data on characteristics and management of IPF patients are still scarce 
in Taiwan. An IPF non-interventional study would help to gain a better 
understanding of the epidemiology of the disease and how it is 
currently managed. 
Research question 
and objectives: 
The primary objective is to characterize the IPF population in Taiwan 
with regard to their clinical course under clinical practice conditions in 
Taiwan.  
The secondary objectives are to understand the clinical characteristics 
and quality of life of IPF population in Taiwan. 
Study design: 
This is a non-interventional multi-center study based on newly 
collected data on idiopathic pulmonary fibrosis (IPF) patients in 
clinical practice in Taiwan. 
IPF patients will be enrolled in a consecutive manner and data will be 
collected in accordance with real-world clinical practice (baseline [the 

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date of study enrolment], the first month, and approximately every 3 
months afterward). Visits will be in accordance with clinical needs 
judged by physicians. 
The enrolment period for the study will be one year and each patient 
will be followed-up for 2 years. 

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Population: 
Patients newly diagnosed with IPF less than 6 months before the 
patient’s baseline (inclusion) visit will be consecutively enrolled 
and included in the study. 
 
Inclusion criteria 
Patients can be included if ALL the following criteria are met: 
1. Newly diagnosed with IPF within 6 months based upon 
recent ATS/ERS/JRS/ALAT IPF guideline (Ref 1, 
Raghu G, et al. 2011). 
 
Exclusion of other known causes of ILD (e.g. 
domestic 
and 
occupational 
environmental 
exposures, connective tissue disease, and drug 
toxicity). 
 
Assessment of IPF based on HRCT or HRCT and 
surgical lung biopsy, if available. 
2. Patient  20 years of age 
3. Written informed consent prior to participation 
4. Patients with further follow-up possible with participating 
physician during planned study period 
5. Ability to read and write in the local language 
 
Exclusion criteria 
Patients should not be included if ANY of the following criteria 
is met: 
1. Lung transplantation expected within next 6 months. 
2. Inclusion in ongoing clinical trials. 
 
Variables: 
Variables 
 
Patient demographics (age, gender, race, etc.) 
 
IPF baseline characteristics: diagnostic procedure (HRCT, 
surgical lung biopsy, multidisciplinary team [MDT] 
diagnosis, UIP pattern, etc.) 
 
Symptoms examination (e.g. cough, dyspnea, fatigue, etc.) 
 
Smoking history 
 
Pulmonary function test (FVC, DLCO, SpO2, TLC, IC) 
 
6 minutes walking test (6MWT) 
 
SGRQ 
 
CAT 
 
Acute exacerbations 
 
Comorbidities (cardio and cerebrovascular, respiratory, 

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renal comorbidities, etc.) and relevant data (STOP-Bang 
Scoring Model, Berlin questionnaire, and echocardiography 
data) 
 
Concomitant medications for comorbidities 
 
Anti-fibrotic drug treatment: start/stop dates and dosage 
 
Adverse drug reaction (ADR) 
 
Serological test: Hct, Hb, platelets, RBC, WBC, 
neutrophils, 
lymphocytes, 
monocytes, 
eosinophils, 
basophils, CRP, CK, rheumatoid factor, antinuclear Ab, 
anti-Jo1 Ab, Sjogrens SS-A or SS-B Ab, seleroderma-70 
Ab, C-ANCA, and p-ANCA, etc.. 
 
Biomarkers of IPF progression: PDGF, VEGF, FGF, etc.. 
 
Gene polymorphism testing: MUC5B, etc.. 
 
Primary outcomes 
 
Annual percentage of decline from baseline in FVC 
 
Annual decline from baseline in DLco 
 
Annual decline from baseline in resting and exercise SpO2 
 
Annual percentage of decline from baseline in TLC 
 
Annual percentage of decline from baseline in IC 
Secondary outcomes 
 
Time to first acute exacerbation of IPF after enrolment 
 
Annual change from baseline in SGRQ 
 
Annual change from baseline in CAT 
 
Annual change from baseline in 6MWT 
 
Mortality (with cause of death) and time to death 

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Data sources: 
Source data are collected from medical charts at 10 medical centers, 
the expert centers where IPF patients are mainly managed in Taiwan. 
Case report form will be designed for data collection. 
Study size: 
Approximately 100 patients are planned to be enrolled. Since most 
outcomes are continuous, this number should be sufficient in order to 
get insights into Taiwanese IPF patients. 
Data analysis: 
A Data Management Plan (DMP) and Statistical Analysis Plan (SAP) 
will be prepared to describe all processes, variables, and specifications 
for data collection, cleaning, validation, and analyses.  
The study is essentially descriptive. All patients who have signed the 
informed consent and fulfilled study criteria will be included in the 
main analysis. The variables included in the study objectives will be 
analyzed with measures of central tendency (mean and median), 
variability/dispersion (standard deviation and interquartile ranges), 
distributions of absolute and relative frequencies, and 95% confidence 
intervals, as appropriate. Mortality will be analyzed by Kaplan-Meier 
estimates. 
For analysis of primary and secondary outcomes (spirometry tests, 
SGRQ, CAT, and 6MWT), imputation will be permitted, if deemed 
appropriate and on a case-by-case basis, depending on the extent and 
distribution of missing values, and will be described in the SAP. 
Milestones: 
Planned start of data collection: Q2 2017 
Planned end of data collection: Q2 2020 
Planned final study report: Q4 2020 
 

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5. 
AMENDMENTS AND UPDATES 
None. 
 
 

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6. 
MILESTONES 
Milestone 
Planned Date 
IRB/IEC approval 
Q2 2017 
Start of data collection 
Q2 2017 
End of data collection 
Q2 2020 
Final report of study results:
Q4 2020 
 

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7. 
RATIONALE AND BACKGROUND 
Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive, 
fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and 
is limited to the lungs. 1  Possible risk factors may include infectious agents, gastro-
oesophageal reflux, smoking, exposure to wood dusts, and genetic factors. The true 
incidence and prevalence of IPF are unknown. Data from a recent British Lung Foundation 
(BLF) report2 suggest that in the UK the incidence rate is increasing with age from 12 per 
100,000 person-years is rising with age to as high as 72 per 100,000 person-years for those 
over the age of 70. The prevalence rate is estimated to be 50 per 100,000 persons with the 
highest rates in Northern Ireland, North West England, Scotland, and Wales. 3  The 
prevalence and incidence of IPF from 1997 to 2007 in Taiwan is 0.7-6.4 cases/100,000 and 
0.6-1.4/100,000 respectively,4 which is relatively low compared to western countries.5 
IPF carries a prognosis that is worse than that of many cancers. The reported median 
survival in IPF is 3 years from diagnosis.6 Only 20% of IPF patients are reported to survive 
to 5 years post-diagnosis.7 However, the median survival in Taiwan is even worse, with only 
0.9 year of median survival after IPF diagnosis.8  
IPF is believed to arise from an aberrant proliferation of fibrous tissue.9 There are two anti-
fibrotic drugs conditionally recommended in the update of treatment recommendations of 
the IPF international consensus statement in 2015 (American Journal of Respiratory and 
Critical Care Medicine Volume 192 Number 2 | July 15 2015): Nintedanib and pirfenidone. 
Nintedanib (OFEV®) is on the market in Taiwan since September 2015 and pirfenidone 
(Pirespa®) is on market in the first half of 2016. 
Currently, substantial efforts are being made to investigate the efficacy and safety of these 
new drugs for IPF in controlled clinical trials. However, observational data on the 
characteristics of patients with IPF outside clinical studies, their management under clinical 
practice conditions, and their long-term outcomes are scarce in Taiwan. A better 
understanding of the epidemiology of the disease is needed since in order to improve future 
management of IPF. Due to the lack of evidence concerning characteristics and management 
of IPF patients in Taiwan, this non-interventional study is carried out to prospectively and 
comprehensively assess the characteristics, diagnostic and treatment patterns, quality of life, 
and long-term outcomes of patients with IPF under clinical practice conditions in Taiwan.  

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8. 
RESEARCH QUESTION AND OBJECTIVES 
The primary objective is to characterize the IPF population in Taiwan with regard to their 
clinical course under clinical practice conditions in Taiwan.   
The secondary objectives are to understand the clinical characteristics and quality of life of 
IPF population in Taiwan. 

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9. 
RESEARCH METHODS 
9.1 
STUDY DESIGN 
This is a non-interventional, multi-center study to collect data from patients with idiopathic 
pulmonary fibrosis (IPF) in clinical practice in Taiwan. The study will be carried out at 10 
medical centers, the expert centers where IPF patients are mainly managed in Taiwan. A 
total of 100 IPF patients are planned to be included. Only patients who meet all study 
criteria will be enrolled. 
The study duration consists of a 1-year enrolment period and a 2-year follow-up period. IPF 
patients will be enrolled in a consecutive manner. The observation period was from study 
inclusion until death, lung transplantation, end of data collection at 2-years, or loss to 
follow-up. Data collection will be started at the initial screening assessment based on the 
medical records, and prospectively thereafter if patients are eligible for inclusion. 
The study will not interfere with the management of patients by their physician. Visits will 
be in accordance with clinical needs judged by physicians. All the data will be collected in 
line with real-world clinical practice (baseline [study enrolment], the first month, and every 
3 months afterward). 
 
9.2 
SETTING 
It is planned that data of approximately 100 patients from 10 sites in Taiwan will be 
collected.  
 
9.2.1 
Study sites 
Selected sites include around 10 major medical centers in Taiwan, from Northern to Southern 
area, with physicians and facilities that reflect the locally clinical practice. The site selection 
criteria will help to ensure that the patients recruited into this study will represent the IPF 
population treated in Taiwan. The included centers are the highest level of Taiwanese 
hospitals. IPF patients may be diagnosed in local hospitals as well; however, medical center 
has the largest patient pool for enrolment. 
 
9.2.2 
Study population 
Inclusion criteria 
Patients can be included if ALL the following criteria are met: 
1. Newly diagnosed IPF within 6 months based upon recent ATS/ERS/JRS/ALAT IPF 
guideline (Ref 1, Raghu G, et al. 2011) 

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Exclusion of other known causes of ILD (e.g. domestic and occupational 
environmental exposures, connective tissue disease, and drug toxicity) which needs 
serological test. 
 
Assessment of IPF based on HRCT or HRCT and surgical lung biopsy, if available. 
2. Patient  20 years of age 
3. Written informed consent prior to participation 
4. Patients with further follow-up possible with participating physician during planned 
study period 
5. Ability to read and write in the local language 
 
Exclusion criteria 
Patients should not be included if ANY of the following criteria is met: 
1. Lung transplantation expected within next 6 months. 
2. Inclusion in ongoing clinical trials 
 
Withdrawal criteria 
Every patient has the right to discontinue study participation at any time, and every patient 
may be discontinued from the study for any reason beneficial to his/her well-being. If a 
patient ends the study earlier, the physician must record the discontinuation/withdrawal 
reason on the CRF. A patient may discontinue the study participation due to any one of the 
following reasons: 
1. Withdrawal of consent 
2. Lost to follow-up 
3. Administrative problems 
4. Lung transplantation 
5. Death 
 
9.2.3 
Study visits 
The collection of patient data should be managed during routine clinical practice visits, 
which is approximately every 3 month in Taiwan Information on pre-specified variables of 
interest will be collected at inclusion (baseline visit) and captured at pre-defined intervals 
during the follow-up period (e.g. at 3, 6 months (time window: ± 1 month) and then every 6 
months (time window: ± 2 month) intervals until finalization of the study).  
Data will be collected and recorded on the CRF at baseline and follow-up visits according to 
Table 1 Data Collection Schedule, if available. 
 
Baseline visit (Visit 1) 

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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
 
Protocol version 5.0 
Date: 10 April 2017 
 
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015 
No data collection for study purposes must be performed unless the patient has consented to 
participate in the study. Once the patient has signed the informed consent form, the patient is 
considered to be enrolled in the study and patient details should be recorded on the 
enrolment log.  
The following procedures will be performed at the baseline visit, and data will be collected 
from the medical chart and recorded on the CRF, if available: 
 
Sign informed consent form. A copy of the consent should be given to the patient. 
 
Review of inclusion and exclusion criteria, and record date of inclusion 
 
Collection 
of 
demographic 
data: 
Age, 
gender, 
race, 
education 
level, 
environmental/occupation exposures, height, weight, and BMI 
 
Collection of IPF-related characteristics: High-resolution computed tomography 
(HRCT), surgical lung biopsy, multidisciplinary team (MDT) diagnosis, and UIP 
pattern 
 
Record of IPF symptoms at baseline 
 
Record of smoking status 
 
Collection of comorbidities and its related concomitant medications that prescribed 
within 6 months prior to enrolment with IPF diagnosis. 
- 
Collect STOP-Bang Scoring Model results to evaluate if patients have comorbidity of 
obstructive sleep apnea 
- 
Collect Berlin questionnaire results for patients with comorbidity of obstructive sleep 
apnea 
- 
Collect echocardiography results for patients with comorbidity of PH 
 
Record of anti-fibrotic drugs used currently and within 6 months before enrollment 
with IPF diagnosis (i.e., nintedanib and pirfenidone) 
 
Collect spirometry results that closest to the baseline 
 
Collect 6MWT results that closest to the baseline 
 
Collect St. George's Respiratory Questionnaire (SGRQ) results that closest to the 
baseline 
 
Collect COPD Assessment Test (CAT) results that closest to the baseline 
 
Record of acute exacerbation happening at baseline 
 
Conduct safety reporting for OFEV® relevant ADR (serious, non-serious), fatal AEs, 
and pregnancies; and record them on corresponding ADR forms and CRF pages 
 
Collect data of serological tests that closest to the baseline 
 
Collect data of biomarker tests 
 
Collect data of gene polymorphism test 
 
Complete the screening log for all patients that do not qualify for screening visit* 
*Information to be collected on screening failures 

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Protocol version 5.0 
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The screening log entry with demographic information and the primary reason for not 
continuing or ineligibility must be completed for all screened patients that do not qualify for 
Baseline Visit (Visit 1). CRF pages of screening criteria and demographics (birth, gender, 
race, education level, environmental/occupation exposures, height, weight, and BMI); and 
the study screening log will be collected for these patients. The subject number of these 
ineligible patients should be kept, and the following enrolments will be numbered in 
sequence. 
Remark: Since this is a non-interventional study, all the tests collected at baseline will be 
performed as judged appropriate by the treating physician, and the results of interest will be 
recorded only if they are available. This study does not require additional tests or 
examinations to be performed. 
 
First month of follow-up period (Visit 2, Week 4) 
The first time of data collection during the follow-up period will be scheduled for the first 
month (4 weeks after the baseline visit) with an allowed window of ± 14 days. The 
following assessments will be documented: 
 
Record of IPF symptoms 
 
Record of current anti-fibrotic drugs used for IPF (i.e., nintedanib and pirfenidone) and 
reasons and date for dose change or discontinuation 
 
spirometry results 
 
6MWT results 
 
St. George's Respiratory Questionnaire (SGRQ) results 
 
COPD Assessment Test (CAT) results 
 
Record of any acute exacerbations since the baseline visit 
 
Conduct safety reporting for OFEV® relevant ADR (serious, non-serious), fatal AEs, 
and pregnancies; and record them on corresponding ADR forms and CRF pages 
Remark: Since this is a non-interventional, observational study, all the tests collected will 
be performed as judged appropriate by the treating physician, however for test marked as 
mandatory variables it will be at least assessed if the test has been performed and if yes the 
results of interest will be recorded. This study does not require additional tests or 
examinations to be performed. 
 
Subsequent follow-up period (Visit 3 ~ 10, Week 16 ~ 100) 
During the following observational period until the end of study observation (Week 100), 
data collection will be performed every 12 weeks (3 months) with an allowed window of ± 1 
month. The following assessments will be documented: 
 
Record of IPF symptoms 
 
Record of current anti-fibrotic drugs used for IPF (i.e., nintedanib and pirfenidone) and 
reasons and date for dose change or discontinuation 

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Protocol version 5.0 
Date: 10 April 2017 
 
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015 
 
Collect spirometry results 
 
Collect 6MWT results (only at Week 52 and 100) 
 
Collect St. George's Respiratory Questionnaire (SGRQ) results 
 
Collect COPD Assessment Test (CAT) results 
 
Collect Berlin questionnaire results for patients with comorbidity of obstructive sleep 
apnea (only at Week 28, 52, 76, and 100) 
 
Collect echocardiography results for patients with comorbidity of PH (only at Week 28, 
52, 76, and 100) 
 
Record of any acute exacerbations since the preceding visit 
 
Conduct safety reporting for OFEV® relevant ADR (serious, non-serious), fatal AEs, 
and pregnancies; and record them on corresponding ADR forms and CRF pages 
 
Collect data of serological tests (only at Week 16, 52, 76, and 100) 
 
Collect data of biomarker tests (only at Week 52 and 100) 
Remark: Since this is a non-interventional, observational study, all the tests collected will 
be performed as judged appropriate by the treating physician, however for test marked as 
mandatory variables it will be at least assessed if the test has been performed and if yes the 
results of interest will be recorded. This study does not require additional tests or 
examinations to be performed. 
 
Table 1 is the recommended data collection schedule that most likely mirrors the patterns of 
routine clinical care of most IPF patients. The sign “X” indicates when the data will be 
collected if available. 
 
Table 1 Data Collection Schedule 
Week#
Visit 
Variables 
Baseline
Wk 4
Wk 16
Wk 28
Wk 40
Wk 52
Wk 64
Wk 76
Wk 88
Wk 100
1
2
3
4
5
6
7
8
9
10
3-month interval
Allowed window 
 
± 14 
days 
± 1 month 
Informed consent
X
Inclusion/exclusion
X
Demographics1 
X
IPF characteristics 
(diagnosis)*, 2 
X 
 
 
 
 
 
 
 
 
 
IPF symptoms3 
X
X
X
X
X
X
X
X
X
X
Smoking status 
X
Comorbidities 
X
- 
STOP-Bang 
Scoring Model4
X& 
 
 
 
 
 
 
 
 
 

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Protocol version 5.0 
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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015 
Week#
Visit 
Variables 
Baseline
Wk 4
Wk 16
Wk 28
Wk 40
Wk 52
Wk 64
Wk 76
Wk 88
Wk 100
1
2
3
4
5
6
7
8
9
10
3-month interval
Allowed window 
 
± 14 
days 
± 1 month 
- 
Berlin 
Questionnaire- 
obstructive 
sleep apnea4 
X& 
 
 
X 
 
X 
 
X 
 
X 
- 
Echocardiograp
hy data-PH 
X& 
 
 
X 
 
X 
 
X 
 
X 
Concomitant 
medications5 
X 
X 
X 
X 
x 
x 
X 
X 
X 
X 
Record of anti-
fibrotic drugs* 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lung function*, 7
X&
X
X
X
X
X
X
X
X
X
6MWT*
X&
X
X
SGRQ*
X&
X
X
X
X
X
X
X
X
X
CAT*
X&
X
X
X
X
X
X
X
X
X
Acute exacerbation
X
X
X
X
X
X
X
X
X
X
Safety reporting8
Serological tests*, 9
X&
X
X
X
X
Biomarkers*, 10 
X
X
X
Gene test*, 11 
X
*Data will be collected, if applicable. All examinations and managements will be based on the discretion of the physician and 
regular practice. 
#Data collection time points will follow visit schedule in clinical practice. 
&Since this is an observational study, examinations and tests will be performed as judged appropriately by the treating 
physician according to local medical standards, and the results of interest that closest to the baseline will be registered only if 
those are available prior to baseline visit. 
1. Age, gender, race, education level, environmental/occupation exposures, height, weight, and BMI. 
2. HRCT, surgical lung biopsy, multidisciplinary team (MDT) diagnosis, and UIP pattern. 
3. Cough, dyspnea, fatigue, weight loss, dizziness, chest pain, anxiety, aching muscles and joints, clubbed fingers, require 
oxygen therapy (device), or others (according to physicians’ judgment and should be specified on the CRF) 
4. STOP-Bang Scoring Model data will be collected to assess if patients have obstructive sleep apnea, and Berlin 
questionnaire results will only be collected from those with suspected/confirmed obstructive sleep apnea according to 
STOP-Bang Scoring Model. 
5. Concomitant medications used for treating comorbidities within 6 months prior to enrolment will be collected. 
6. Anti-fibrotic drugs (i.e., nintedanib and pirfenidone) used within 6 months before baseline will be recorded. 
7. Spirometry data include FVC, DLCO, SpO2, TLC, IC, etc. 
8. OFEV relevant ADR (serious and non-serious), fatal AEs, and pregnancies. 
9. Hct, Hb, platelets, RBC, WBC, neutrophils, lymphocytes, monocytes, eosinophils, basophils, CRP, CK, rheumatoid factor, 
antinuclear Ab, anti-Jo1 Ab, Sjogrens SS-A or SS-B Ab, seleroderma-70 Ab, c-ANCA, and p-ANCA, etc.. 
10. PDGF, VEGF, FGF, etc.. 
11. MUC5B, etc..
 

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Protocol version 5.0 
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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015 
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: 
1. Failure to meet expected enrolment goals overall or at a particular study site 
2. Emergence of any efficacy/safety information that could significantly affect the 
continuation of the study, or any other administrative reasons. 
3. Violation of Good Clinical Practice (GCP), Good Epidemiological Practice (GEP), or 
Good Pharmacoepidemiology Practice (GPP) (as applicable), 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 
Currently, 2 anti-fibrotic drugs, namely nintedanib and pirfenidone, have been approved for 
treating IPF patients. The use of nintedanib and pirfenidone will be according to the 
Summary of Product characteristics and physician’s discretion. Prescription of nintedanib 
and pirfenidone will be collected and recorded on CRF during the observational period, 
including start/end date, dose, and the reason for dose adjustment or interruption. 
 
9.3.2 
Outcomes 
9.3.2.1 
Primary outcomes 
Key study outcomes are to characterize lung function profile of IPF patients in clinical 
practice: 
 
Annual percentage of decline from baseline in FVC 
 
Annual decline from baseline in DLco 
 
Annual decline from baseline in resting and exercise SpO2 
 
Annual percentage of decline from baseline in TLC 
 
Annual percentage of decline from baseline in IC 
 
9.3.2.2 
Secondary outcomes 
 
Time to first acute exacerbation of IPF after enrolment 
 
Annual change from baseline in SGRQ 

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Protocol version 5.0 
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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015 
 
Annual change from baseline in CAT 
 
Annual change from baseline in 6MWT 
 
Mortality (with cause of death) and time to death 
 
 
9.3.3 
Covariates 
Details of handling covariates will be given in the statistical analysis plan (SAP), if any 
covariates of interest are detected. 
 
9.3.3.1 
Baseline characteristics and general information 
 
Demographics: Age, gender, race, education level, environmental/occupation 
exposures, height, weight, and BMI. 
 
Smoking status (current smokers, ex-smokers, or non-smokers) 
 
Medical history: IPF characteristics regarding diagnosis and comorbidities with related 
concomitant medications 
- 
IPF characteristics regarding diagnosis:  
The procedures used for IPF diagnosis and the results will be documented at 
enrolment. Data to be collected include performing date, performed method or 
examination (HRCT, surgical lung biopsy, multidisciplinary team [MDT] 
diagnosis), and diagnosis results (UIP pattern). 
- 
Comorbidities of interest:  
Comorbidities are any medical findings, whether they are present before the start of 
the study (no retrospective time limit is set) or being an ongoing condition, related 
data should be collected. For any comorbidity, the status (past or active) should be 
documented at enrolment. For certain comorbidities the definition are described in 
the Appendix. Comorbidities included but not limited to diseases listed below are 
considered to be relevant to IPF: 
i. 
Cardio and cerebrovascular comorbidities: Arterial hypertension, coronary 
artery disease (CAD), myocardial infarction (MI), congestive heart failure 
(CHF), stroke, transient ischemic attack (TIA), peripheral artery disease, 
atrial fibrillation, deep venous thrombosis, pulmonary embolism, pulmonary 
hypertension (PH)#, Anemia, other thromboembolic events, hemorrhage 
ii. 
Respiratory comorbidities: chronic obstructive pulmonary disease (COPD), 
emphysema (radiologic), asthma, pneumonia, obstructive sleep apnea 

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001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015 
(according to STOP-Bang Scoring Model at baseline)*, respiratory failure, 
acute exacerbation of IPF 
iii. 
Renal comorbidities: chronic renal failure 
iv. 
Hepatic comorbidities: chronic hepatic failure, cirrhosis 
v. 
Gastrointestinal comorbidities: gastroesophageal reflux disease (GERD), 
gastric ulcer, GI perforation, inflammatory bowel disease (e.g. Crohn’s 
disease, ulcerative colitis), GI cancer, diverticulitis 
vi. 
Metabolic comorbidities: T2/T1 diabetes mellitus, hyperlipidemia 
vii. 
Neoplasms: lung, liver, stomach, colorectal, breast and esophageal, prostate 
and cervix cancer 
#Results of echocardiography will be collected for patients with PH (data collection 
points: Baseline, Week 28, 52, 76, and 100). 
*Data of Berlin questionnaire for obstructive sleep apnea (only collect from 
patients with suspected/confirmed obstructive sleep apnea according to STOP-Bang 
Scoring Model) will be collected, including date of assessment and score (data 
collection points: Baseline, Week 28, 52, 76, and 100).  
- 
Comorbidities related concomitant medications: 
Concomitant medications used for treating comorbidities within 6 months prior to 
enrolment will be collected. Data of interest include start/stop date or ongoing, dose, 
unit, and frequency. 
 
9.3.3.2 
IPF symptoms 
Clinical presentations included but not limited to symptoms below are considered to be 
relevant to IPF. The investigator should assess if patients have the following symptoms and 
record them on the CRF, at baseline and during each follow-up visits. 
 
Cough, dyspnea, fatigue, weight loss, dizziness, chest pain, anxiety, aching muscles 
and joints, clubbed fingers, require oxygen therapy (device), or others (according to 
physicians’ judgment and should be specified on the CRF) 
 
9.3.3.3 
Acute exacerbation of IPF 
Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of a 
unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria were 
defined as events meeting ALL of the following criteria:10  
 
Unexplained worsening or development of dyspnea within the previous 30 days 
 
New diffuse pulmonary infiltrates visualized on chest radiography, HRCT, or both, or 
the development of parenchymal abnormalities with no pneumothorax or pleural 
effusion (new ground-glass opacities) since the preceding visit 

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Exclusion of any known causes of acute worsening, including infection, left heart failure, 
pulmonary embolism, and any identifiable cause of acute lung injury, in accordance with the 
routine clinical practice and microbiologic studies. 
Date of acute exacerbation and corresponding clinical presentations should be recorded on 
the CRF. 
 
9.3.3.4 
Six-minute walk test (6MWT) 
Measurement of exercise capacity is an integral element in the assessment of patients with 
cardiopulmonary disease. 6MWT provides information regarding functional capacity, 
response to therapy, and prognosis. 
It will be assessed if the test was performed and if yes results of 6MWT will be collected at 
baseline, Week 25, and Week 100. Data of interest include the date of assessment, distance 
(meter), resting SpO2 (%), and exercise saturation (SpO2 %). 
 
9.3.3.5 
St. George's Respiratory Questionnaire (SGRQ) 
The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in 
patients with diseases of airways obstruction. The questionnaire is divided into 3 subscales 
measuring symptoms (8 items), activity limitation (16 items), and social and emotional 
impact of disease (26 items). Each item is accorded a weight determined by the degree of 
distress accorded to each symptom or state described. For each subscale and for the overall 
questionnaire, scores range from 0 (no effect on quality of life) to a maximum score of 100 
(maximum perceived distress); thus, a higher score means a poorer quality of life.11 A 
minimum change in score of 4 units was established as clinically relevant after patient and 
clinician testing.12 
Results of SGRQ will be collected at baseline and every follow-up visit, if available. Data of 
interest include the date of assessment and SGRQ score. 
 
9.3.3.6 
COPD Assessment Test (CAT) 
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 
quality of life. The total CAT score (range of zero to 40) was calculated for each individual 
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.13 The most reliable estimate of the minimum important difference of the CAT 
is 2 points.14 
Since both COPD and IPF are pulmonary diseases regarding airways obstruction, CAT is 
used as one of the outcome assessments in this observational study. Results of CAT will be 

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collected at baseline and every follow-up visit, if available. Data of interest include the date 
of assessment and CAT score. 
 
9.3.3.7 
Mortality 
For assessment of mortality, the following data will be collected if death occurs: 
a. Date of death 
b. Cause of death 
a) Related to IPF 
i. 
Respiratory failure: 
Is the consequence of lung failure leading to impaired gas exchange; that is, 
hypoxemia and/or hypercapnia 
ii. 
Acute exacerbation of IPF (see definition in Section 9.3.3.3) 
iii. 
Other related to IPF (please specify) 
b) Comorbid condition (please specify): 
i. 
Coronary heart disease 
ii. 
Cerebrovascular disease 
iii. 
Pneumonia/respiratory infection 
iv. 
Pulmonary embolism 
v. 
Pulmonary hypertension or Pulmonary arterial hypertension/right heart 
failure 
vi. 
Lung cancer 
c) Other cause (please specify) 
d) Unknown 
 
9.3.3.8 
Serological tests 
Since this is an observational study, serological tests will be assessed as judged 
appropriately by the treating physician according to local medical standards, and the results 
of interest, including date and results of serological tests with and clinical judgments 
(normal, abnormal with/without clinical significance) will be collected only if those are 
available from the medical chart. Results of biomarker tests will be collected at baseline, 
Week 16, Week 52, Week 76, and Week 100 for the following tests: 
 
Hematocrit (Hct), hemoglobin (Hb), platelets, RBC, WBC, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, C-reactive protein (CRP), creatine kinase (CK), 
rheumatoid factor, antinuclear antibody, anti-Jo1 antibody, Sjogrens SS-A or SS-B 

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antibody, seleroderma-70 antibody, cytoplasmic anti-neutrophil cytoplasmic antibody 
(c-ANCA), and perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA), etc.. 
 
9.3.3.9 
Biomarker tests 
Since this is an observational study, biomarker tests will be assessed as judged appropriately 
by the treating physician according to local medical standards, and the results of interest, 
including date and results of biomarker tests, will be collected only if those are available 
from the medical chart. Results of biomarker tests will be collected at baseline, Week 52, 
and Week 100 for the following biomarkers: 
 
PDGF, VEGF, FGF, etc.. 
 
9.3.3.10 
Gene polymorphism test 
Candidate genes help to clarify pivotal aspects in the diagnosis, prognosis, and therapies in 
IPF. Since this is an observational study, gene tests will be assessed as judged appropriately 
by the treating physician according to local medical standards, and the results of interest, 
including date and results of gene tests, will be collected only if those are available from the 
medical chart. Results of gene tests will be collected at baseline for the following genes: 
 
Gene is associated with IPF in previous publication: MUC5B,15 etc.. 
 
9.3.4 
Study completion 
The study will be considered completed for an individual patient when he/she completes 100 
weeks of study participation unless reasons for early termination are met (see Section 9.2.2). 
The whole study will be completed after estimated 100 patients are enrolled and complete 
the data collection. Patients who are prematurely withdrawn from the study will not be 
replaced by an equal number of newly enrolled patients.  
A complete end of study visit must be performed for any patient discontinuing study 
participation. If a patient discontinues the study prematurely, another follow-up assessment 
should be performed if possible (unless the reason for discontinuation is erroneous 
enrolment of the patient into the study at baseline). All relevant information, including date, 
vital status, and the reason for discontinuation, must be recorded on the appropriate page of 
CRF of the next planned visit. 
 
9.4 
DATA SOURCES 
As this is a non-interventional study, no diagnostic or monitoring procedures additional to 
the standard of care and routine practice will be applied to the patients. All the assessment 

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will be performed by the investigator if they are deemed necessary for the medical treatment 
procedure. 
This non-interventional study will collect the data onto the designed paper case report form 
(CRF) if available by the investigators or delegated site staffs. Data source includes 
questionnaires, hospital discharge files, abstracts of primary clinical records, electronic 
medical records, clinical databases, administrative records such as eligibility files, 
prescription drug files, biological measurements, exposure/work history record reviews, etc. 
during the routine clinical practice.  
Each patient is identified by a unique central patient identification code, which is only used 
for study purposes. 
 
9.5 
STUDY SIZE 
Approximately 100 patients are planned to be enrolled based on the recruitment timeframe 
and patient pool in 10 medical centers, the expert centers where patients are mainly 
managed in Taiwan. Since most outcomes are continuous, this number should be sufficient 
in order to get insights into Taiwanese IPF patients. 
 
9.6 
DATA MANAGEMENT 
The data from enrolling patients in this study will be recorded on a CRF or other applicable 
forms. The designated CRO will capture, check, store and analyze the data. The designated 
CRO will follow Boehringer Ingelheim standard operating procedures (SOPs) and their own 
internal SOPs. 
A data management plan (DMP) will be created to describe all functions, processes, and 
specifications for data collection, cleaning, and validation. 
Data will be transferred to Boehringer Ingelheim after the closure of the study. 
 
9.7 
DATA ANALYSIS 
Analyses will be performed by a designated CRO. The main analysis population will consist 
of all eligible patients (i.e. all patients who have signed the informed consent and fulfilled 
all inclusion criteria and no exclusion criteria). 
Analytic specifications, including tables and listings, will be detailed in the statistical 
analysis plan (SAP) that is separate from the full study protocol and will be updated over 
time as necessary. A change to the data analysis methods described in the study protocol 
will require an amendment only if it changes a principal feature of the study objective. 
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
Descriptive analyses will be performed to gain an understanding of the characteristics of the 
sample studied. Summary statistics of continuous variables will include number, mean, 

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standard deviation, minimum, Q1 (lower quartile), median, Q2 (upper quartile), maximum 
value, and 95% confidence intervals, as appropriate. 
Tabulations of categorical variables will present all possible categories and display the 
absolute and relative frequencies. Estimates will be presented with 95% confidence intervals.  
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. 
For analysis of primary and secondary outcomes (spirometry tests, SGRQ, CAT, and 
6MWT), imputation will be permitted, if deemed appropriate and on a case-by-case basis, 
depending on the extent and distribution of missing values, and will be described in the SAP. 
All information already collected as part of the study will be retained for analysis; however, 
no further efforts will be made to obtain or record additional information regarding the 
patient. 
 
9.7.1 
Main analysis 
The analysis for primary and secondary outcomes, including results of spirometry tests, 
SGRQ, CAT, and 6MWT will conducted on the basis of continuous variables, with number, 
mean (for annual change/decline from baseline, one mean annual change over the whole 
study period [0-2 years as maximum] will be presented), standard deviation, minimum, Q1 
(lower quartile), median, Q2 (upper quartile), maximum value, and 95% confidence 
intervals included. Wilcoxon Signed Ranked test or t-test, whichever is applicable, will be 
used to test the change from baseline under a significant level of 0.05. 
Time to first acute exacerbation and mortality will be analyzed by Kaplan-Meier estimates, 
with incidence and time to event included. Time to first acute exacerbation starts from the 
date of enrolment to the date of first acute exacerbation recorded on the CRF. Patients with 
exacerbation free at the time of the last contact will be censored. The time of event data will 
be analyzed using Kaplan-Meier curves. The median, range, and 95% CI for median time 
and will be reported. Time to death is calculated from the date of enrolment to the date of 
death from any cause. Patients with no documented death will be censored at the last time 
they were known to be alive at the time of the last contact. The time of event data (overall 
survival, censored at 100 weeks) will be analyzed by Kaplan-Meier survival method. The 
median, range and 95% CI for median survival time and survival curve will be reported. 
 
 

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9.7.3 
Safety analysis 
The assessment of safety will be based mainly on the frequency of adverse events, which 
includes all serious adverse events. All adverse events will be summarized with the coding 
term, severity, and relationship to study drug by frequency tables with the counts and 
percentage. In addition, serious adverse events will be listed with event narration. Medical 
history/current medical conditions and adverse events will be coded using the latest version 
of Medical dictionary for regulatory activities (MedDRA) terminology. 
 
9.7.4 
Handling of missing data 
Imputation will be permitted for analyses of primary and secondary outcomes, if deemed 
appropriate and on a case-by-case basis, depending on the extent and distribution of missing 
values, and will be described in the SAP. In the analyses of the time-to-event endpoints, 
missing or incomplete data are managed by standard survival analysis techniques. It is not 
planned to impute missing values for safety analysis (ADR, fetal AE, and pregnancy). 
All information already collected as part of the study will be retained for analysis; however, 
no further efforts will be made to obtain or record additional information regarding the 
patient. 
 
9.8 
QUALITY CONTROL 
Before the study launch, participating physicians will be trained on the protocol, safety 
reporting (as described in Section 11) 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 and representatives of the call center or the 
Study Coordinating Center) is minimized. 
Fifty percent source data verification is planned in this study based on IPF diagnosis 
definition. The details of source data verification plan and rules will be described in the 
monitoring visit plan (MVP). At any time during the course of the study, the site study staff 
may contact designated personnel for clarification of study conduct. All information will be 
kept confidential. 
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. 
To ensure the data accuracy, completeness, and reliability, quality control will be the 
ongoing, concurrent review of data collection forms for completion and logic. The research 
staffs will preserve documented data from all sources on CRF, including lab test results, 
chart records, treatment conditions, physical examination, concomitant medication, and any 
safety information. 

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Boehringer Ingelheim or designated CRO 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 non-interventional study is the most suitable design for obtaining information about the 
use of medicines in everyday therapeutic practice and thus for clarifying prospectively 
questions in everyday therapeutic practice. In addition, the observational design intends to 
collect available data that are recorded on medical charts. The lack of data of interest may be 
one of the limitations. 
Missing data will be handled for primary and secondary outcomes as appropriate on a case-
by-case basis, depending on the extent and distribution of missing values (see Section 9.7.4). 
All efforts will be made to minimize missing data and loss to follow-up in patients who are 
enrolled. For instance, before start of data collection, a study initiation visit will be 
performed for each medical center, where investigators and site staffs will be trained for 
study implementation, data collection, and safety reporting, etc. Investigator and site staff 
should escalate issues that can potentially jeopardize study outcomes to sponsor or CRO 
upon awareness. Sponsor, CRO, and site should work closely to manage any risks. 
Selection bias 
The entry criteria are non-restrictive and will permit the enrolment of a broad patient 
population. The choice of treatment is at the discretion of the investigator. Selection bias 
could occur at both the site (physician) level and the patient level. To minimize the site level 
selection bias, the goal is to have participating centers (i.e., medical center of Taiwan) that 
are representative for managing IPF patients in Taiwan and have access to all available 
treatment options for IPF that are approved for use in Taiwan.  
Selection bias at the patient level could occur if sites preferentially enroll specific patients 
into the study. To minimize selection bias at the patient level, consecutive enrolment is 
performed. 
Small sample size 
The limitations created by a small sample size can have profound effects on the outcome 
and worth of a study. A small sample size may increase the data variability and have 
extremely detrimental effects. Therefore, when looking into the study outcome, study 
statisticians will determine whether the small sample size limitations will have a negative 
impact on study's results before getting underway; and if it does, study statisticians will not 
perform stratified analyses. Also, study results will be elaborated carefully because a small 
sample size may deviate the true results of the real-world population. 
 

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9.10 
OTHER ASPECTS 
No other aspect of the research method is not covered in the previous sections. 
 
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, the investigator’s study-related files and correspondence, and the informed 
consent documentation of this study. 
 
9.10.2 
Study records 
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via paper. 
All paper CRFs should be typed or filled out with a black ball-point pen and must be legible.  
 
Corrections to paper forms will be made by a single line stroke through the error and 
insertion of the correction above or beside the error. The change must be initialed and 
dated by the investigator or a member of the study staff authorized by the investigator 
on the Authority Form. No erasers, correction fluid, or tape may be used. 
 
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. These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and 
correspondence. Case report form entries may be considered source data if the CRF is the 
site of the original recording (i.e., there is no other written or electronic record of data). 
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 paper CRFs, the following data need to be derived from source documents: 
 
Patient identification (gender, date of birth, etc.) 

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Patient participation in the study (substance, study number, patient number, date patient 
was informed) 
 
Dates of patient’s visits, including prescription of study medication 
 
Medical history (including concomitant diseases and concomitant, if applicable) 
 
Adverse drug reactions and outcome events (onset date [mandatory], and end date [if 
available]) 
 
Serious adverse events (SAEs) (onset date (mandatory), and end date (if available)) 
 
Originals or copies of laboratory results or examinations (in validated electronic format, 
if available) 
 
Conclusion of Patient’s Participation in the study 
The physician must keep the original informed consent form signed by the patient (a signed 
copy is given to the patient). 
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 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. 
 
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, 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 Clinical Research Associate (CRA)/Clinical Monitor Local (CML) and the auditor may 
review all CRFs and written informed consents. The accuracy of the data will be verified by 
reviewing the documents described in Section 9.10.2.19.10.2.1. 
 

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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) (to the extent applicable to the NIS setting and required by 
local regulations), Good Epidemiological Practice (GEP), Guidelines for Good 
Pharmacoepidemiology Practice (GPP), and relevant BI Standard Operating Procedures 
(SOPs). Standard medical care (prophylactic, diagnostic and therapeutic procedures) 
remains in the responsibility of the treating physician of the patient. 
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/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. 
Insurance Cover: The requirements for insurance depend on local law and legislations. If 
required, the terms and conditions of the insurance cover are made available to the 
investigator and the patients, and the documentation must be archived in the Investigator 
Site File (ISF). 
 
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 to the implementation of changes introduced by amendments. 
Prior to patient participation in the study, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. 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. Eligible patients may only be included in 
the study after providing written (witnessed, where required by law or regulation), IRB/EC-
approved informed consent, or, if incapable of doing so, after such consent has been 
provided by a legally acceptable representative of the patient. In cases where the patient’s 
representative gives consent, the patient should be informed about the study to the extent 
possible given his/her understanding. If the patient is capable of doing so, he/she should 
assent by personally signing and dating the written informed consent document or a separate 

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assent form. Informed consent must be obtained before any data are collected. The process 
of obtaining informed consent should be documented in the patient source documents. 
The patient must be informed that his/her medical records may be examined by authorized 
monitors (CML/CRA) or 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., laboratory report), 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.  
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 unfavorable and unintended sign (e.g. an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
 
Adverse reaction 
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. The 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 the 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 

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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 Adverse Event of Special Interest (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. 
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. 
The following must be collected by the investigator in the paper CRF from signing the 
informed consent onwards until the end of the study:  
 
All adverse drug reaction (ADRs) (serious and non-serious),  
 
All AEs with fatal outcome,   
 
All ADRs including those persisting after study completion must be followed up until they 
are resolved, have been sufficiently characterized, or no further information can be obtained. 
The investigator should carefully assess 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 the pattern of reaction, temporal relationship, de-challenge or re-challenge, 
and confounding factors such as concomitant medication, concomitant diseases, and 
relevant history.  

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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 the dose is diminished). 
 
Arguments that may suggest that there is no reasonable possibility of a causal 
relationship could be: 
 
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned) 
 
Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives). 
 
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger. 
 
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned). 
 
Disappearance of the event even though the study drug treatment continues or remains 
unchanged. 
 
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: 

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In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
study, after having taken OFEV® 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 paper AE form from signing 
the informed consent onwards until the end of the study:  
 
Type of Report 
Timeline 
All serious ADRs associated with  OFEV® 
immediately within 24 hours 
All AEs with fatal outcome in patients 
exposed to OFEV® 
immediately within 24 hours 
All non-serious ADRs associated with 
OFEV® 
7 calendar days 
All pregnancy monitoring forms 
7 calendar days 
 
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions, the Investigator could inform the Sponsor upfront via 
telephone. This does not replace the requirement to complete and fax the NIS AE form. 
 
Information required 
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate paper 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 
OFEV® taken for the disease in the scope of the study 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. 

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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 
Upon study completion and finalization of the study report, the results of this non-
interventional study will be submitted for publication. The rights of the investigator and of 
the sponsor with regard to publication of the study design or results of this study are 
described in the investigator contract. 

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13. 
REFERENCES 
13.1 
PUBLISHED REFERENCES 
                                                 
1  Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: 
idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. 
Am J Respir Crit Care Med 2011; 183: 788–824. 
2
British 
Lung 
Foundation, 
The 
Battle 
for 
Breath 
(2016), 
available 
at: 
https://www.blf.org.uk/what-we-do/our-research/thebattle-for-breath-2016 
3  British Lung Foundation, Idiopathic pulmonary fibrosis statistics, available at: 
https://statistics.blf.org.uk/pulmonary-fibrosis 
4 Karina Raimundo, Eunice Chang, Michael S. Broder, Kimberly Alexander, James Zazzali, 
Jeffrey J. Swigris. Clinical and economic burden of idiopathic pulmonary fibrosis: a 
retrospective cohort study. BMC Pulm Med. 2016; 16: 2. 
5 Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of 
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006 Oct 1;174(7):810-816. 
6  Bjoraker JA, Ryu JH, Edwin MK, et al. (1998) Prognostic significance of histopathologic 
subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 157(1): 199-203 
7 Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic 
pulmonary fibrosis. Am J Respir Crit Care Med. 2011 Feb 15;183(4):431-440. 
8 Lai CC, Wang CY, Lu HM, et al. Idiopathic pulmonary fibrosis in Taiwan – A population-
based study. Respir Med. 2012 Nov;106(11):1566-1574. 
9 King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 2011; 378:1949-61. 
10 Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary 
fibrosis. Am J Respir Crit Care Med 2007;176:636-643. 
11 Ferrer M, Villasante C, Alonso J, et al. Interpretation of quality of life scores from the St 
George's Respiratory Questionnaire. Eur Respir J 2002;19:405–413. 
12 Jones PW. St George's Respiratory Questionnaire: MCID. COPD 2005;2:75–79. 
13 Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and 
first validation of the COPD Assessment Test. Eur Respir J 2009; 34: 648–654. 
14 Kon SS, Canavan JL, Jones SE, et al. Minimum clinically important difference for the 
COPD Assessment Test: a prospective analysis. Lancet Respir Med. 2014 Mar;2(3):195-
203. 
15 Peljto AL, Zhang Y, Fingerlin TE, et al. Association between the MUC5B promoter 
polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA. 2013 
Jun 5;309(21):2232-2239. 

 
 
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13.2 
UNPUBLISHED REFERENCES 
None. 
 

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
Number 
Document Reference 
Number 
Date 
Title 
1 
NA 
11 May 2004 
St. George's Respiratory 
Questionnaire (SGRQ) 
2 
NA 
2009 
COPD Assessment Test 
(CAT) 
3 
NA 
TBD 
Berlin Questionnaire 
4 
NA 
TBD 
STOP-Bang Scoring Model 
 
 

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BI Study Number 1199-0303 
c16462309-02
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
 
Protocol version 5.0 
Date: 10 April 2017 
 
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
As attached. 

Boehringer Ingelheim 
Page 47 of 47
Non-interventional Study Protocol 
BI Study Number 1199-0303 
c16462309-02
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
 
Protocol version 5.0 
Date: 10 April 2017 
 
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015 
ANNEX 3. ADDITIONAL INFORMATION 
None.