A Regulatory Required Non-interventional Study to Monitor the Safety and Effectiveness of Ofev(Nintedanib 150mg/100mg BID) in Korean Patients
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

 
ABCD 
001-MCS-90-118_RD-01 (7 0) / Saved on: 09 Nov 2015
Non-interventional Study Protocol
Document Number: 
c37684029-02 
BI Study Number: 
1199-0417
BI Investigational 
Product(s):
Ofev® 
(Nintedanib) 
Title:
A regulatory required non-interventional study to monitor the 
safety and effectiveness of Ofev(Nintedanib 150mg/100mg 
BID) in Korean patients 
Brief lay title
Ofev rPMS in Korean patients 
Protocol version 
identifier: 
2.1
Date of last version of 
protocol: 
Not applicable
PASS:
Yes
EU PAS register number: 
EUPAS41912 
Active substance: 
Nintedanib 
Medicinal product:
Ofev, soft-gelatin capsules 150mg, 100mg
Product reference:
Not Applicable 
Procedure number:
Not Applicable 
Marketing authorisation 
holder(s):
Joint PASS:
Not Applicable 
Research question and 
objectives:
To monitor the safety profile and effectiveness of Ofev in 
Korean patients in a routine clinical practice setting
Country(-ies) of study:
South Korea 
Author: 
NIS specialist
Phone:
  Fax: 

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PMarketing authorisation 
holder(s):
MAH contact person:
EU-QPPV: 
Signature of EU-QPPV:
The signature of the EU-QPPV is provided electronically 
Date: 
10 May 2022 
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE .................................................................................................................. 1 
1. 
TABLE OF CONTENTS ....................................................................................... 3 
2. 
LIST OF ABBREVIATIONS ................................................................................ 7 
3. 
RESPONSIBLE PARTIES .................................................................................... 9 
4. 
ABSTRACT ......................................................................................................... 10 
4.1 
FLOW CHART ............................................................................................... 12 
5. 
AMENDMENTS AND UPDATES ..................................................................... 13 
6. 
MILESTONES ..................................................................................................... 16 
7. 
RATIONALE AND BACKGROUND ................................................................ 17 
7.1 
RATIONALE .................................................................................................. 17 
7.2 
BACKGROUND ............................................................................................ 17 
7.2.1 
Idiopathic pulmonary fibrosis(IPF) ......................................................... 17 
7.2.2 
Systemic Sclerosis associated Interstitial Lung Disease(SSc-ILD) ........ 18 
7.2.3 
Chronic fibrosing ILD with a progressive phenotype ............................. 19 
7.3 
DRUG PROFILE ............................................................................................ 19 
8. 
RESEARCH QUESTION AND OBJECTIVES ................................................. 21 
8.1 
PRIMARY OBJECTIVE ................................................................................ 21 
8.2 
SECONDARY OBJECTIVE .......................................................................... 21 
9. 
RESEARCH METHODS .................................................................................... 22 
9.1 
STUDY DESIGN ............................................................................................ 22 
9.1.1 
Method of assigning patients to treatment groups .................................. 22 
9.1.2 
Dosage and Administration ..................................................................... 22 
9.1.3 
Concomitant therapy, Restrictions, and Rescue ...................................... 22 
9.1.3.1 
Rescue medication, emergency procedures, and additional treatments22 
9.2 
SETTING ........................................................................................................ 23 
9.2.1 
Study sites ............................................................................................... 23 
9.2.2 
Study population ..................................................................................... 23 
9.2.2.1 
Main diagnosis for study entry ......................................................... 23 
9.2.2.2 
Inclusion criteria: ............................................................................. 23 
9.2.2.3 
Exclusion criteria: ............................................................................ 23 
9.2.2.4 
Subjects of special investigation ...................................................... 23 
9.2.3 
Study visits .............................................................................................. 24 

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9.2.3.1 
Screening and run-in periods ........................................................... 24 
9.2.3.2 
Visit 1; Baseline Visit ...................................................................... 24 
9.2.3.3 
Visit 2; 12 weeks from Visit 1 ......................................................... 24 
9.2.3.4 
Visit 3; 24 weeks from Visit 1 ......................................................... 25 
9.2.3.5 
End of study and follow-up period ................................................... 25 
9.2.4 
Study discontinuation .............................................................................. 25 
9.3 
VARIABLES .................................................................................................. 26 
9.3.1 
Safety ....................................................................................................... 26 
9.3.1.1 
Outcome(s) of safety ........................................................................ 26 
9.3.2 
Effectiveness ........................................................................................... 26 
9.3.2.1 
Outcome(s) of effectiveness ............................................................. 26 
9.3.2.2 
Assessment of Effectiveness ............................................................ 26 
9.3.3 
Items of Investigation .............................................................................. 27 
9.3.3.1 
Demographic data ............................................................................ 27 
9.3.3.2 
Medical history ................................................................................. 27 
9.3.3.3 
Vital sign .......................................................................................... 27 
9.3.3.4 
Pulmonary function test ................................................................... 27 
9.3.3.5 
Liver Function Test .......................................................................... 28 
9.3.3.6 
Concomitant medication .................................................................. 28 
9.3.3.7 
Drug administration status ............................................................... 28 
9.3.3.8 
Information on the site ..................................................................... 28 
9.3.3.9 
Result or laboratory tests(if applicable) ........................................... 28 
9.3.3.10 
Overall evaluation ............................................................................ 29 
9.3.3.11 
Main points of study and details of study method ........................... 29 
9.3.4 
Outcomes of Subjects Evaluation ........................................................... 29 
9.3.4.1 
Subject evaluation items .................................................................. 29 
9.4 
DATA SOURCES ........................................................................................... 30 
9.5 
STUDY SIZE .................................................................................................. 30 
9.6 
DATA MANAGEMENT ................................................................................ 31 
9.7 
DATA ANALYSIS ......................................................................................... 31 
9.7.1 
Analysis of Safety ................................................................................... 31 
9.7.2 
Analysis of Effectiveness ........................................................................ 32 
9.7.2.1 
Main outcome analyses .................................................................... 32 
9.7.2.2 
Other outcomes analyses .................................................................. 32 
9.7.3 
Interim analyses ....................................................................................... 32 

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9.7.4 
Handling of missing data ......................................................................... 32 
9.8 
QUALITY CONTROL ................................................................................... 32 
9.9 
LIMITATIONS OF THE RESEARCH METHODS ...................................... 33 
9.9.1 
Loss to follow-up .................................................................................... 33 
9.9.2 
Channelling bias ...................................................................................... 33 
9.9.3 
Confounding ............................................................................................ 33 
9.10 
OTHER ASPECTS ......................................................................................... 33 
9.10.1 
Study approval, patient information, and data release consent ............... 34 
9.10.2 
Data quality assurance ............................................................................. 34 
9.10.3 
Study records ........................................................................................... 34 
9.10.3.1 
Source documents ............................................................................ 34 
9.10.3.2 
Direct access to source data and documents .................................... 35 
9.10.3.3 
Storage of records ............................................................................ 35 
10. 
PROTECTION OF HUMAN SUBJECTS .......................................................... 36 
10.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 36 
10.2 
STATEMENT OF CONFIDENTIALITY ...................................................... 36 
11. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ....................................................................................................... 38 
11.1 
DEFINITIONS OF ADVERSE EVENTS ...................................................... 38 
11.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 39 
11.3 
REPORTING TO HEALTH AUTHORITIES AND IEC/IRB ....................... 42 
12. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
 ............................................................................................................................. 43 
12.1 
STATEMENT OF CONFIDENTIALITY ...................................................... 43 
12.2 
PUBLICATION POLICY ............................................................................... 43 
13. 
REFERENCES .................................................................................................... 44 
13.1 
PUBLISHED REFERENCES ......................................................................... 44 
13.2 
UNPUBLISHED REFERENCES ................................................................... 47 
14. 
APPENDICES ..................................................................................................... 48 
14.1 
ELECTRONIC CASE REPORT FORM ........................................................ 48 
14.2 
SAE/NON-SERIOUS ADVERSE REACTION REPORT ............................ 48 
14.3 
PREGNANCY MONITORING FORM ......................................................... 48 
14.4 
OFEV® PRESCRIPTION INFORMATION FOR KOREA ........................... 48 
15. 
ANNEXES ........................................................................................................... 49 

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15.1 
LIST OF STAND-ALONE DOCUMENTS ................................................... 49 
15.2 
ENCEPP CHECKLIST FOR STUDY PROTOCOLS ................................... 49 
15.3 
ADDITIONAL INFORMATION ................................................................... 49 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .............................................. 50 
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 51 
ANNEX 3. ADDITIONAL INFORMATION .............................................................. 56 

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AE
Adverse Event
AESI
Adverse Event of Special interest
CA
Competent Authority
CCDS
Company Core Data Sheet
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DLco
Pulmonary diffusion capacity of carbon monoxide
DMP
Data Management Plan
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
EU
European Union
EU PAS
European Union Post-Authorization Safety
FDA
Food and Drug Administration
FGFR
Fibroblast Growth Factor Receptor
Flt-e
Fms-like Tyrosine-protein Kinase
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
Ȗ-GTP
*DPPDȖ-Glutamyl Transpeptidase
GVP
Good Pharmacovigilance Practices
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
ISF
Investigator Site File
KIMS
Korea Index of Medical Specialties
Lck
lymphocyte-specific tyrosine-protein kinase
LPVM
Local PV Manager
Lyn
tyrosine-protein kinase Lyn
MAH
Marketing Authorisation Holder
MedDRA
Medical Dictionary for Drug Regulatory Activities

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MFDS
The Ministry of Food and Drug Safety
NCE
New Chemical Entity
NIS
Non-Interventional Study
NSADR
Non Serious Adverse Drug Reaction
OPU
Operative Unit
PASS
Post-Authorization Safety Study
PDGF
Platelet-derived Growth Factor
PDGFR
Platelet-derived Growth Factor Receptor
PF-ILD
Progressive Fibrosing Interstitial Lung Disease
SAE
Serious Adverse Event
SADR
Serious Adverse Drug Reaction
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
SpO2
O2 Saturation
Src
proto-oncogene tyrosine-protein kinase
SSc-ILD
Systemic sclerosis associated interstitial lung disease
SUSAR
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TMF
Trial Master File
TMM
Team Member Medicine
UIP
Usual Interstitial Pneumonia
VEGF
Vascular Endothelial Growth Factor

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

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4.
ABSTRACT
Name of company:
Name of finished medicinal 
product:  
Ofev
Name of active ingredient:
Nintedanib 
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
30 June 2020
1199-0417
2.0
02 December 2021
Title of study:
A regulatory requirement non-interventional study to monitor the 
safety and effectiveness of Ofev(Nintedanib, 150mg/100mg, BID) in 
Korean patients
Rationale and 
background:
According to the local regulations, when a new chemical entity (NCE) 
is registered, a regulatory non-interventional study (NIS) should be 
conducted. Such NIS can provide supplementary data to monitor the 
safety of NCEs in a real-world situation and complement information 
from clinical trials. Indeed, even if the safety profile of Ofev has been 
confirmed in clinical trials setting, there is a possibility in the real-
world setting that Ofev is administered to more heterogeneous 
patients than the ones included in the trials. 
Research question 
and objectives:
The objectives of this study are to monitor the safety and effectiveness 
of Ofev in Korean patients in a routine clinical practice setting.
Study design:
Non-interventional, multi-center and single national study based on 
newly collected data.  
Population:
Diagnosis:
y
Patients diagnosed with Idiopathic Pulmonary Fibrosis 
y
(or) patients diagnosed with Systemic Sclerosis associated 
Interstitial Lung Disease
y
(or) patients diagnosed with chronic fibrosing ILD with a 
progressive phenotype
Inclusion criteria:
y
Patients who have been started on Ofev in accordance with the 
approved label in Korea 
y
Patients who have signed on the data release consent form
Exclusion criteria:
y
Patients for whom Ofev is contraindicated according local 
label of Ofev
i.
Patients with known hypersensitivity to Ofev, peanut 
or soya, or to any of the excipients 
ii.
Women who are pregnant or nursing 
iii.
Patients with moderate(Child pugh B) and 
severe(Child Pugh c) hepatic impairment 

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Name of company:
Name of finished medicinal 
product:  
Ofev
Name of active ingredient:
Nintedanib 
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
30 June 2020
1199-0417
2.0
02 December 2021
Variables:
Outcome(s) of Safety
All reported adverse events in patients who have take at least one dose 
of Ofev will be noted.  
Outcome(s) of Effectiveness:
Primary objective
1) Change from baseline in FVC(FVC(mL) after 12, 24 weeks of 
treatment. 
Secondary objective 
1) Change from baseline in % Predicted FVC after 12, 24 weeks 
of treatment.
2) Change from baseline in overall evaluation of Ofev after 12, 24 
weeks of treatment.
Data sources:
Field study with new data collection
Study size:
Single arm (N=59 approximately)
Data analysis:
In this non-interventional study, all statistical analyses will be 
descriptive. Data of characteristics and other status of patients will be 
described and proportions including the confidence intervals will be 
provided. 
Milestones:
Study duration: 6 years
MFDS sets Ofev re-examination period from 21 Oct 2016 to 20 Oct 
2022. Interim report planned biannually for the initial two years and 
annually thereafter by Jan 2023.

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4.1
FLOW CHART
Data points 
Baseline
Follow-up 1
Follow-up 2
Visit Number
1
2
3
Week/s
1
12
24
Data release consent
X 
Diagnosis 
X 
Inclusion / exclusion criteria 
X 
Demographics 
X 
Family history
X 
Surgical lung biopsy 
XA
Comorbidities
X 
X 
X 
Vital Sign
XA
XA
XA
Pulmonary function test
-
FVC
-
% predicted FVC
XA
XA
XA
Chest HRCT evaluation
XA
Remaining liver function test classifies 
according to the grade
XA
Concomitant medications
X 
X 
X 
Ofev administration status
X 
X 
X 
Liver function test 
X 
X 
X 
Overall evaluation
XA
XA
Laboratory test 
XA
XA
XA
Adverse events
X 
X 
Study completion 
X 
X 
A: If applicable

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5.
AMENDMENTS AND UPDATES

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Num
ber
Date
Section of 
study protocol
Amendment or update
Reason 
1
07 Dec 2021 
Title page 
Version No. 
EUPAS number updated 
Author’s contact information 
Update MAH contact person
Minor update of 
information
2
07 Dec 2021 
4. Abstract 
Study size: 
Single arm(N=58 
approximately) 
Recalculate the 
sample size
3
07 Dec 2021 
9.5 study size 
Study size is changed to 58 
from 3,000. 
Recalculate the 
sample size
4
07 Dec 2021 
9.9.2
Channelling 
bias 
Delete ‘To assess the extent 
of preferential prescribing of 
Ofev and the potential for 
channelling bias, a 
comparator group maybe 
helpful.’ 
This study has 
no comparator 
group. 
5
07 Dec 2021 
11.2 Adverse 
Event and 
Serious Adverse 
Event collection 
and reporting 
All SAEs and AESIs must be 
reported with details of 
relevant non-serious AEs, 
within 24 hours of occurrence 
via Electronic Data Capture 
System to the Local PV 
Manager(LPVM) of
using the NIS AE report 
form(Attachment 2).
Was changed to:
All SAEs and AESIs must be 
reported with details of 
relevant non-serious AEs, 
within 24 hours of occurrence 
via Fax to the Local PV 
Manager(LPVM) of 
using the NIS AE report 
form(Attachment 2).
The method of 
reporting AE is 
changed. 
6
05 May 2022
4. Abstract 
Study size: 
Single arm(N=59
approximately)
Correction of a 
typographical 
error in the 
sample size
7
05 May 2022
9.2.2 Study 
population 
Study population: 59  
Correction of a 
typographical 
error in the 
sample size

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Num
ber
Date
Section of 
study protocol
Amendment or update
Reason 
7
05 May 2022
9.5 Study size 
Study size: 59 
Correction of a 
typographical 
error in the 
sample size

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6.
MILESTONES 
Milestone
Planned Date
Start of data collection
21 Oct 2016 (HA’s approval date) 
End of data collection 
20 Oct 2022 
Interim report 1-1 
20 June 2017 
Interim report 1-2 
20 Dec 2017 
Interim report 2-1 
20 June 2018 
Interim report 2-2 
20 Dec 2018 
Third-year report
20 Dec 2019 
Fourth-year report 
20 Dec 2020 
Fifth-year report 
20 Dec 2021 
Registration in the EU PAS 
register
07 July 2021 
Final report of study results: 
20 Jan 2023 

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7.
RATIONALE AND BACKGROUND
7.1
RATIONALE
According to the local regulations, when a new chemical entity (NCE) is registered, a 
regulatory non-interventional study (NIS) should be conducted. Such NIS can provide 
supplementary data to monitor the safety of NCEs in a real-world situation. Indeed, even if 
the safe profile of Ofev has been confirmed in clinical trials setting, there is a possibility in 
the real-world setting that Ofev is administered to more heterogeneous patients than the ones 
included in the trials.
This is a non-interventional, multi-centre single national study. It will provide additional 
safety information of Ofev(nintedanib) in Korean patients in a routine clinical practice 
setting.
7.2
BACKGROUND
7.2.1
Idiopathic pulmonary fibrosis(IPF) 
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 
limited to the lungs. It is characterized by progressive worsening of dyspnea and lung 
function and is associated with a poor prognosis. [P11-07084] 
The number of incident and prevalent IPF cases varies greatly in published studies (range, 
0.5-27.9 cases per 100,000). Some studies reported differences in the epidemiology of IPF 
between Asian and Western countries. For example, a large population based study from 
Taiwan found lower IPF incidence and prevalence (0.5-6.4 per 100,000 and 0.5-1.4 per 
100,000, respectively) in Asian than in Western countries. [R13-2612] Another study from 
Japan showed that the estimate of overall IPF prevalence was 2.95 per 100,000, which is also 
lower than that reported in Western countries. [R11-5085] Based on the new 
ATS/ERS/JRS/ALAT statement published in 2011, the incidence rate of IPF in Korea was 
1.7/100,000. [1] 
IPF is characterized by alveolar epithelial cell injury and subsequent dysregulated repair, 
characterised by excessive deposition of extracellular matrix and loss of normal parenchymal 
architecture and lung function. In IPF fibroblasts exhibit unregulated proliferation and 
differentiate into myofibroblasts. The latter is considered the hallmark cell in the 
development and establishment of lung fibrosis [P12-03241]. Several growth factors are 
implicated in the proliferation, migration and transdifferentiation of the fibroblast and 
myofibroblast pool in IPF [c01805141-16].
Platelet-derived growth factor (PDGF) is implicated in the development of pulmonary 
fibrosis [R06-0898, R12-3729]. PDGF is a potent mitogen for fibroblasts [P04-12378] and 
appears to play an essential role in the expansion of myofibroblasts by stimulating 
proliferation, migration and survival. Elevated levels of PDGF have consistently been 
observed in the fibrotic lesions of various organs [R12-3729]. Tyrosine kinase inhibitors that 

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inhibit PDGF receptor (PDGF/R) have been shown to reduce pulmonary fibrosis in various 
animal models [R06-0113, R12-3733, R12-3754, R12-3731, R12-3734].
The precise role of vascular endothelial growth factor (VEGF) in IPF is controversial [R07- 
0010] and remains to be further explored. A tendency of a decreased survival rate in IPF 
patients with high concentrations of VEGF in the serum was reported. In addition, the serum 
VEGF level appears to predict deterioration of vital capacity in IPF patients [R13-2758].
Experimental evidence in rats suggests that inhibition of VEGF receptors may reduce fibrosis 
[R06-0596].
Nintedanib is associated with gastrointestinal side effects, including nausea, vomiting, 
abdominal discomfort, and diarrhoea. Diarrhoea was the most frequent side effect. In the 
phase 3 trials, diarrhoea was reported in 62.4 % versus 18.4 % of patients treated with 
nintedanib and placebo, respectively. In most patients diarrhoea was of mild to moderate 
intensity (respectively 56.8% and 37.7% of nintedanib-patients with diarrhoea) and occurred 
within the first 3 months of treatment. Nausea and vomiting were also frequently reported 
adverse events. In most patients with nausea and vomiting, the event was of mild to moderate 
intensity. In the phase 3 trials, 7.4% of patients in the nintedanib group discontinued 
treatment due a gastrointestinal AE. Diarrhoea led to discontinuation of nintedanib in 4.4% of 
the patients [c01805141-16]. Administration of Ofev Capsules was associated with liver 
enzyme (ALT, AST, ALP, and Ȗ-GTP) and bilirubin elevations which were reversible upon 
dose reduction, treatment interruption or withdrawal [c03498541-01]. 
7.2.2
Systemic Sclerosis associated Interstitial Lung Disease(SSc-ILD)
Systemic Sclerosis (SSc) is a devastating disease of unknown etiology. The pathogenesis of 
SSc is characterized by systemic (multi-organ) immunological, vascular and fibrotic 
abnormalities. It is a rare disorder, an orphan disease, with prevalence rate of approximately 
50 to 300 in US, 20 to 50 in Asia and 100 to 200 per million in Europe (R14-4918, R14-
4927).
Patients suffer from multiple organ fibrosis, leading to chronic disability and premature 
death. Aside from skin, the lung is most often involved, but the disease may also manifest as 
proliferative and obliterative vascular abnormalities, kidney disease, oesophageal and 
gastrointestinal involvement (hypomotility), cardiac disorders, and muscle disease. SSc 
related mortality is mainly driven by interstitial lung disease and pulmonary arterial 
hypertension. Median survival is 5–8 years in SSc associated Interstitial Lung Disease 
(ILD)(P14-07919).
Based on pre-clinical and clinical evidence of antifibrotic activity of nintedanib in Idiopathic 
Pulmonary Fibrosis (IPF) and preclinical evidence of potential effects in SSc, along with an 
acceptable safety profile as demonstrated in clinical trials with nintedanib in IPF, 
investigation in a patient population with active SSc-ILD accompanied by varying degrees of 
skin and other organ fibrosis is medically rational. Nintedanib may offer a long term 
antifibrotic maintenance treatment option for SSc, a medical indication with high unmet 
medical need.

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7.2.3
Chronic fibrosing ILD with a progressive phenotype
ILDs, also referred to as diffuse parenchymal lung diseases (DPLD), encompasses a large 
group of over 200 pulmonary disorders. The clinical assessment of a patient with ILD 
requires a multidisciplinary approach: medical history including occupational, environmental, 
medication, smoking and family history, vital sign, laboratory investigation, lung function 
testing together with chest imaging studies and histologic/Bronchial Alveolar Lavage 
examinations are necessary to establish the diagnosis. Achieving a correct diagnosis is a 
dynamic process requiring close communication between clinician, radiologist and 
pathologist (R13-4145).
Based on clinical experience, there is a group of patients who, independent from the ILD 
classification, at some point in time, develop a progressive fibrosing phenotype. In this group 
of patients, the natural history appears to follow a course similar to IPF with worsening of 
respiratory symptoms, lung function, QoL and functional status, as well as early mortality 
despite treatment with currently available non-approved immunomodulatory therapies. The 
proposed terminology for describing this group is progressive fibrosing interstitial lung 
disease (PF-ILD).
Based on expert consensus, the main fibrosing ILDs in which progressive behaviour is 
present include: 
•
Idiopathic Interstitial Pneumonias (IIPs): mainly IPF, idiopathic non-specific 
interstitial pneumonia (iNSIP) and unclassifiable IIP
•
Chronic fibrosing hypersensitivity pneumonitis (CHP) 
•
Autoimmune ILDs: connective tissue disease- ILD (CTD-ILD) (mainly RA-ILD and 
SSc-ILD) and idiopathic pneumonia with autoimmune features 
•
Environmental/occupational fibrosing lung disease 
The scientific working hypothesis is that the response to lung injury in these ILDs includes 
the development of fibrosis which becomes progressive, self-sustaining and independent of 
the original clinical association or trigger. It is postulated that, at this stage, targeted 
antifibrotic therapy is required to slow the progression of the disease. 
Based on the similarity in both, the biologic and clinical behaviours i.e. self-sustaining 
fibrosis and progressive decline in lung function and early mortality, it is considered justified 
to group patients with PF- ILDs together regardless of their original ILD diagnosis. 
Nintedanib is a kinase inhibitor indicated for the treatment of IPF, which has been shown to 
slow the progression of IPF. Based on the similarity in both the underlying pathophysiology 
and clinical course of PF-ILD and IPF, it is anticipated that nintedanib will elicit similar 
effects in PF-ILD as it demonstrated in IPF. This assumption is supported by the pre-clinical 
data indicating that nintedanib impacts fundamental processes of lung fibrosis and that the 
anti-fibrotic activity of nintedanib is independent of the cause of the fibrosing lung 
disease(P14-02860, P14-17410, P15-02392, P15-06100).
Robust data of PF-ILD incidence/prevalence in Korea are currently not available.
7.3
DRUG PROFILE
Ofev is a small molecule tyrosine kinase inhibitor including the receptors platelet-derived 
JURZWKIDFWRUUHFHSWRU3'*)5ĮDQGȕILEUREODVWJURZWKIDFWRUUHFHSWRU)*)5-3, and 
VEGFR 1-3. Ofev binds competitively to the adenosine triphosphate (ATP) binding pocket of 

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these receptors and blocks the intracellular signalling. In addition Ofev inhibits Flt-3 (Fms-
like tyrosine-protein kinase), Lck (lymphocyte-specific tyrosine-protein kinase), Lyn 
(tyrosine-protein kinase lyn) and Src (proto-oncogene tyrosine-protein kinase src) kinases. 
Ofev inhibits the activation of FGFR and PDGFR signalling cascades which are critically 
involved in proliferation, migration and differentiation of lung fibroblasts/myofibroblasts, the 
hallmark cells in the pathology of idiopathic pulmonary fibrosis. The potential impact of 
VEGFR inhibition by Ofev and the anti-angiogenic activity of Ofev on IPF pathology are 
currently not fully elucidated. In preclinical disease models of lung fibrosis Ofev exerts 
potent anti-fibrotic and anti-inflammatory activity. Ofev inhibits proliferation, migration and 
fibroblast to myofibroblast transformation of human lung fibroblasts from patients with IPF 
[R15-2110]. 
For a more detailed description of the drug profile refer to the local prescribing information 
of Ofev.

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8.
RESEARCH QUESTION AND OBJECTIVES
8.1
PRIMARY OBJECTIVE
The primary objective is to monitor the safety profile of Ofev in Korean patient in a routine 
clinical setting. 
8.2
SECONDARY OBJECTIVE
The secondary objective is to monitor the effectiveness of Ofev by evaluating the change 
from baseline after 12 and/or 24 weeks in the FVC(mL), % predicted FVC and overall 
evaluation of Korean patients. 

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9.
RESEARCH METHODS
This NIS is a non-interventional, multi-centre national observational study. The study 
duration will be confirmed after discussion with the regulatory authority. However, active 
enrolment is to be initiated in Jun 2020 after finalizing the re-imbursement agreement with 
the authority. Before initiation of the study, any newly reported adverse events collected from 
other sources such as spontaneous cases, literature cases etc will be closely monitored. The 
last patient follow up is to be determined later. 
This study will be carried out by enrolling patients in a consecutive manner into the study 
requiring completion of case report forms(CRFs) from the subject who was initially 
administered the drug following the study start date to the requested number of subjects 
without omission. Prior to initiation of the study, written contract shall be concluded, and this 
contract shall be concluded with the head of the site or the investigator with his/her consent.  
Patients will be managed according to the local practice guidelines. The choice of treatment 
will be solely at the discretion of the participating physician. Ofev will be administered 
according to the approved label in Korea. Hence there are no additional risks to patients by 
participating in this NIS.
9.1
STUDY DESIGN
This is a NIS based on single arm with Ofev. 
Ofev will be prescribed according to the local label and at the discretion of the treating 
physician. Since this is a non-interventional study, the drug will not be supplied by the 
sponsor. Furthermore, the sponsor will not cover the expenses related to other medications 
taken by the patient, interventions, procedures, or diagnostic test.
9.1.1
Method of assigning patients to treatment groups 
The choice of treatment is fully at the discretion of the physician and the patient. There is no 
treatment assignment by a third party.  
9.1.2
Dosage and Administration  
The starting dose is based on the current authorized label in Korea. 
9.1.3
Concomitant therapy, Restrictions, and Rescue 
The protocol will allow additional drugs considered necessary for the patient’s welfare to be 
prescribed at the discretion of the treating physician. It is required, however, to record the 
details of all concomitant medication administered to the patient during the course of 
treatment in eCRF. This includes concomitant therapies started one month prior to Ofev 
initiation until the patient completes the final follow-up visit. 
9.1.3.1
Rescue medication, emergency procedures, and additional treatments 
Please refer to the current local label.

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9.2
SETTING
Enrolled patients will have a follow up after 12 and 24 weeks of treatment period.
9.2.1
Study sites
Approximately 60 sites by as many as 60 or more NIS physicians will participate. To 
minimize the selection bias at the site level, the goal is to have participating centers reflect a 
balance between general hospitals which has own IRB for study. The treating physicians will 
mainly be internists.
9.2.2
Study population
A total of 59 patients will be enrolled at approximately 60 sites by as many as 60 or more 
NIS physicians. To minimize the selection bias, consecutive patients from each site who meet 
inclusion criteria will be enrolled in this study. 
9.2.2.1
Main diagnosis for study entry 
y
Patients diagnosed with idiopathic pulmonary fibrosis 
y
(or) Patients diagnosed with systemic sclerosis associated interstitial lung disease
y
(or) patients diagnosed with chronic fibrosing ILD with a progressive phenotype
9.2.2.2
Inclusion criteria:
y
Patients who have been started on Ofev in accordance with the approved label in 
Korea
y
Patients who have signed on the data release consent form 
9.2.2.3
Exclusion criteria:
y
Patients for whom Ofev is contraindicated according local label of Ofev
i.
Patients with known hypersensitivity to Ofev, peanut or soya, or to any of the 
excipients
ii.
Women who are pregnant or nursing 
iii.
Patients with moderate(Child pugh B) and severe(Child Pugh c) hepatic 
impairment
9.2.2.4
Subjects of special investigation 
The patient who have signed on the data release consent form, subjects of special 
investigation(Pediatric (Younger than 18 years), Geriatric(Older than 65 years), Pregnant 
Women, Lactating Women, renal impairment, hepatic impairment and other special 
population) among the patients who conducted investigation for safety assessment after the 
administration of Ofev can be further investigation into cases collected from this study may 
be taken into account according to the outcome of retrospective analysis. 

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9.2.3
Study visits
9.2.3.1
Screening and run-in periods 
This section is not applicable as this is a non-interventional study. 
9.2.3.2
Visit 1; Baseline Visit 
Upon patient enrolment, the following will be recorded on the patient’s eCRF. 
y
Visit date
y
Data release consent form : Date patient was data release consent
y
Diagnosis : date of the diagnosis and diagnosed disease 
y
Inclusion / Exclusion criteria
y
Demographic data : year of birth(age), gender, pregnancy, previous allergy, height, 
weight, smoking status, alcohol habit, occupation or exposure status 
y
Family history
y
Medical history: history of concomitant disease since 6 months prior to the baseline 
visit.
y
Vital sign: blood pressure, pulse rate, body temperature(if applicable) 
y
Liver Function: AST, ALT and total bilirubin
y
Child Pugh Score Class(if necessary) 
y
Pulmonary function: FVC(mL), % predicted FVC(if applicable)
y
Date of Chest HRCT (if applicable)
y
Chest HRCT evaluation: UIP pattern, possible UIP pattern, inconsistent UIP pattern, 
emphysema or not available(if applicable) 
y
Date of surgical lung biopsy(if applicable) 
y
Result of lung biopsy: UIP pattern, probable UIP pattern, possible UIP pattern, 
inconsistent with UIP or not available(if applicable)
y
Concomitant medications: record all medications that have been taken at least once 
since one month(30 days) prior to the baseline visit. 
y
Dose of Ofev given 
y
Laboratory test(if necessary)
At visit 1, the patient will be requested to contact the treating physician in the event of any 
adverse events noted after initiating Ofev treatment.
9.2.3.3
Visit 2; 12 weeks from Visit 1 
After 12 weeks from Visit 1, the patients will return for follow-up. The followings will be 
noted and recorded in the eCRF. 
y
Visit date
y
Vital sign : blood pressure, pulse rate, body temperature(if applicable) 
y
Liver Function : AST, ALT and total bilirubin 
y
Any change of Ofev given 
y
Pulmonary function : FVC(mL), % predicted FVC(if applicable) 

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y
Concomitant medications including new medications taken since last visit : any 
change in the concomitant medications (dose and dosing intervals) 
y
Any changes in laboratory tests if there is any lab result which was clinically 
significant compared to data before Ofev therapy(This data is collected on the basis 
of medical need, i.e. independent of the NIS)  
y
Any adverse events noted 
y
Study completion status(if necessary) 
y
Overall evaluation(if necessary)
y
Laboratory test(if necessary)
y
NIS physician’s electronic signature for data integrity(if necessary)
9.2.3.4
Visit 3; 24 weeks from Visit 1 
After 24 weeks from Visit 1, the patients will return for follow-up. The followings will be 
noted and recorded in the eCRF. 
y
Visit date
y
Vital sign: blood pressure, pulse rate, temperature(if applicable) 
y
Liver Function : AST, ALT and total bilirubin 
y
Any change of Ofev given 
y
Pulmonary function : FVC(mL), % predicted FVC(if applicable) 
y
Concomitant medications including new medications taken since last visit : any 
change in the concomitant medications(dose and dosing intervals) 
y
Any changes in laboratory tests if there is any lab result which was clinically 
significant compared to data before Ofev therapy(This data is collected on the basis 
of medical need, i.e. independent of the NIS)  
y
Any adverse events noted 
y
Study completion status(if necessary) 
y
Overall evaluation(if necessary)
y
Laboratory test(if necessary)
y
NIS physician’s electronic signature for data integrity
9.2.3.5
End of study and follow-up period 
Patients with adverse events noted at the final follow-up visit or upon premature 
discontinuation of Ofev will be monitored further until the resolution of those adverse events. 
Alternatively, those patients will be followed up until the NIS physician and sponsor agree 
that no further follow-up is necessary.
9.2.4
Study discontinuation
 reserves the right to discontinue the study overall or at a 
particular study site at any time for the following reasons: 

Emergence of any effectiveness/safety information that could significantly affect 
continuation of the study 

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
Violation of applicable local regulations, the NIS protocol, or the contract by a study 
site or participating physician, disturbing the appropriate conduct of the study. 
9.3
VARIABLES
9.3.1
Safety
9.3.1.1
Outcome(s) of safety
All reported adverse events in patients who take at least one dose of Ofev will be noted. 
Outcomes pertaining to safety will include:
•
Adverse events
•
Unexpected adverse events
•
Serious adverse events
•
Drug-related adverse events
•
Adverse events leading to discontinuation 
•
Adverse events by intensity, outcome of the events, causality. 
9.3.2
Effectiveness
9.3.2.1
Outcome(s) of effectiveness
9.3.2.1.1
Main outcome 
•
Change from baseline in FVC(mL) after 12, 24 weeks of treatment
9.3.2.1.2
Other outcomes 
•
Change from baseline in % predicted FVC after 12, 24 weeks of treatment. 
•
Overall evaluation(Improved, unchanged, aggravated or unassessable) by 
investigator based on overall clinical assessment including change from baseline in 
effectiveness assessment(FVC(mL), % predicted FVC) after 12, 24 weeks of 
treatment. ‘Improved’ is assessed as “Effective”, ‘Unchanged, Aggravated’ are 
assessed as “Invalid”. 
9.3.2.2
Assessment of Effectiveness
FVC(Forced Vital Capacity) :
FVC should be collected within 1 year prior to baseline and after 12 weeks and/or 24 weeks 
of treatment.
% predicted FVC: 
% predicted FVC should be collected within 1 year prior to baseline and after 12 weeks 
and/or 24 weeks of treatment. 
Overall evaluation:
Overall evaluation should be collected after 12 weeks or 24 weeks of treatment. 

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9.3.3
Items of Investigation 
9.3.3.1
Demographic data
For demographic evaluation, following background information of subjects shall be recorded: 
y
Subject data release consent signed date  
y
Subject study number  
y
Gender
y
Pregnancy
y
Height 
y
Weight
y
Year of birth (age)
y
Smoking status 
y
Alcohol habit 
y
Previous allergy 
y
Occupation or exposure status and period 
y
Child Pugh Score Class 
y
Family history of IPF, SSc-ILD or PF-ILD
y
Chest HRCT evaluation: Date, UIP pattern, Possible UIP pattern, inconsistent UIP 
pattern, Emphysema 
y
Result of lung Biopsy: Date, UIP pattern, probable UIP pattern, Possible UIP pattern, 
Inconsistent with UIP
9.3.3.2
Medical history
The medical history to be collected prior to administration of this drug includes: 
y
Check hepatic or renal impairment
y
Name of diagnosis 
y
Severity(Mild, Moderate or Severe) 
y
Date of diagnosis or surgery 
y
End date or continuation 
9.3.3.3
Vital sign
The vital sign that is to be collected includes:
y
Systolic blood pressure 
y
Diastolic blood pressure 
y
Pulse rate
y
Body temperature 
9.3.3.4
Pulmonary function test 
The pulmonary function test that is to be collected includes: 

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y
Forced vital capacity(FVC, ml)
y
Forced vital capacity(FVC % predicted)
9.3.3.5
Liver Function Test 
The liver function test that is to be collected includes:
y
alanine aminotransferase(ALT)
y
aspartate aminotransferase(AST)
y
Total bilirubin
9.3.3.6
Concomitant medication
Information on concomitant medication that is to be collected includes: 
y
Brand name or product name 
y
Generic name
y
Route of medication
y
Daily dose  
y
Unit
y
Purpose of administration 
y
Indication  
y
Start date
y
Date of discontinuation or continuation  
9.3.3.7
Drug administration status
Information on the drug administration status includes: 
y
Dose(Once daily treatment)
y
Unit
y
Start date
y
Date of discontinuation or continuation 
9.3.3.8
Information on the site 
Information on the site includes: 
y
Hospital name 
y
Department 
y
Physician name 
y
Date of site initiation
9.3.3.9
Result or laboratory tests(if applicable)
Information on the result of laboratory tests includes:
Any adverse events obtained from a laboratory test that is conducted as required, which 
contains abnormal clinically significant lab result, must be reported. 

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y
Name of lab test
y
Range of normal(Unit, Maximum and minimum data) 
y
Result of lab test before treatment
y
Result of lab test after treatment
9.3.3.10
Overall evaluation
Information on the overall evaluation includes: 
y
Improved: If determined as there is any effect of maintaining or improving 
symptoms. 
y
Unchanged: If symptoms have not been changed compared with before 
administration, and not determined as there is any effect of maintaining symptoms. 
y
Aggravated: If symptoms are worse than before administration. 
y
Unassessable: If it cannot be determined. 
9.3.3.11
Main points of study and details of study method 
If a particular trend or change associated with safety is found from spontaneous adverse event 
report during this study, special investigation into the relevant item shall be planned and 
implemented. Also, the situations of occurrence of any unexpected adverse drug reactions or 
adverse events whose causal relationship with the drug has not been established and 
frequency is extremely low, which have not appeared in the course of development of the 
drug during the study period, shall be intensively observed and investigated. 
9.3.4
Outcomes of Subjects Evaluation 
9.3.4.1
Subject evaluation items
9.3.4.1.1
Number of cases who accepted the study 
This number means the planned number of cases as specified in the contract concluded with 
the investigator (physician) prior to initiation of the study. 
9.3.4.1.2
Number of cases subject who collected eCRF
This number means the number of cases who signed the data release consent form to 
participate in the study as subject, and have record of taking Ofev once at least.
9.3.4.1.3
Number of dropouts 
These cases include those who signed the data release consent form to participate in this 
study as subject but did not meet any of the inclusion criteria, do not have any prescription 
record of Ofev, have prescription record but have not been followed up by the physician 
following prescription, and started administration prior to the signed date. 

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9.3.4.1.4
Number of cases subject to safety evaluation
These cases include those who signed the data release consent form to participate in this 
study as subject, took Ofev once at least, and were followed up by the physician once or 
more.
9.3.4.1.5
Number of cases subject to effectiveness evaluation
These cases include those who signed the data release consent form to participate in this 
study as subject, visited as per the study schedule, took Ofev once at least, the cases included 
in safety evaluation, and were evaluated for the effectiveness including overall evaluation(if 
the case assessed as ‘unassessable’ will be excluded).
9.3.4.1.6
Number of cases subject of special investigation 
The patient who have signed on the data release consent form, subjects of special 
investigation(Pediatric, Geriatric, Pregnant Women, Lactating Women, renal impairment, 
hepatic impairment and other special population) among the patients who conducted 
investigation for safety assessment after the administration of Ofev can be further 
investigation into cases collected from this study may be taken into account according to the 
outcome of retrospective analysis.
9.4
DATA SOURCES
Patients will be enrolled in a consecutive manner into the study. The investigator will 
prospectively collect data in the case report form(CRF) for each included patient who will 
have been newly treated with Ofev, at baseline and at follow-up visits at 12 and/or 24 weeks.  
9.5
STUDY SIZE
Since IPF, SSc-ILD and PF-ILD is chronic disease it might be restrictive to collect safety and 
effectiveness data in short-term (12weeks) period, all patients will be enrolled for long-term 
(24weeks) surveillance for maintaining approved indication. Thus all patients will be enrolled 
for long-term(24weeks) surveillance, basically.
Total 59 cases with IPF or SSc-ILD or PF-ILD will be included in the safety analysis. 
The proportion of overall patients with ALT and/or AST ˻ 3 Upper Limit of Normal was 
5.1% in nintedanib group on the pooled data of trials 1199-0032 and 1199-0034. 
With a sample size of 59, ADR with an incidence of 5.1% can be detected in at least one 
patient with a probability of 95% by rule of three statistics method.
Considering total surveillance size of 59 cases, at least 20%(12 cases approximately) of total 
would be enrolled for long-term(24weeks) surveillance, even considering follow up loss in 
real world clinical practice.

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9.6
DATA MANAGEMENT
Patients’ data will be collected by eCRF. The data management procedures to ensure the 
quality of the data are described in detail in the data management plan (DMP) available in 
TMF. Data management and statistics will be outsourced to a qualified contract research 
organization (CRO). 
9.7
DATA ANALYSIS
The safety evaluation will be performed on the “safety set” that will include all patients who 
have received treatment of Ofev at least one time except those who are found to have, invalid 
registration, or invalid contract with the site. The effectiveness evaluation will be performed 
on the “effectiveness set”, a subset of the safety set, which will include all patients in the 
“safety set” except those who have no available effectiveness data.
In this NIS, all statistical analyses will be descriptive. Demographic baseline data analysis 
will be based on mean, standard deviation, min value, max value, median and IQR for 
continuous variables, and on absolute and relative frequency for categorical variables 
(including 95% CI). Details will be provided in the statistical analysis plan(SAP).
9.7.1
Analysis of Safety 
-
Number of subjects and cases of AEs will be reported and incidence rate with 95% CI 
will be calculated.
-
Provide cases and percentage of AEs classification and system organ class(SOC).
-
Adverse events by subgroup based on demographic data will be analysed by Chi-
square test or Fisher’s exact test.
-
Logistic regression analysis maybe implemented to assume and estimate any factors 
that may affect analysed AEs incidence rate, and medical opinion is stated based on 
the contents that show statistically significant results(p-value).
Adverse Events (AEs) will be coded according to the latest version of Medical Dictionary for 
Drug Regulatory Affairs (MedDRA) coding system. Concomitant therapies will be coded 
according to the latest version of KIMS(Korea Index of Medical Specialties) coding system. 
The study database will not be locked until coding is complete. 
Safety analyses will be based on all patients treated, i.e. all patients who received at least one 
dose of Ofev. However, if data for patients who have been treated with Ofev beyond the 
scope of approved label are collected, separate safety analyses will be performed. Safety 
analyses will be performed by subgroup based on demographics and baseline characteristics.
In case of the adverse events that matched from the important safety review under the Risk 
Management Plan(RMP), or when a in sufficient information patient groups (in case of 
contraindicated case, i.e. pregnant women, nursing mothers, etc.) are recruited, measures 
shall be taken in accordance by the approved local label. Adverse events in the case and lack 
information will be sub-analyzed separately.
Patients lost to follow up will be characterized compared to the remaining patients and reason 
and time point of loss to follow up will be evaluated. 

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9.7.2
Analysis of Effectiveness
9.7.2.1
Main outcome analyses
A descriptive analysis of outcome is planned. For patients treated with Ofev, the change of 
FVC(mL) from baseline after 12, 24 weeks will be calculated with paired t-test. Effectiveness 
analysis will be performed based on demographics and baseline characteristics.
9.7.2.2
Other outcomes analyses
A descriptive analysis of effectiveness outcomes is planned. For % predicted of FVC, 
descriptive statistics will be calculated with paired t-test after 12, 24 weeks of Ofev treatment.
For overall evaluation, descriptive analysis will be calculated for assessed one of the 
items(improved, unchanged, worsen or unassessable) by investigator with medical opinion of 
each individual components and the changes from data before first administration. 
Effectiveness analysis will be performed by subgroup based on demographics and baseline 
characteristics.
Logistic regression analysis is implemented to assume and estimate any factors that may 
affect effectiveness check. Consequently, medical opinion is stated based on the contents that 
show statistically significant results(p-value). 
9.7.3
Interim analyses
In accordance with local regulation for NIS, interim analyses are planned biannually for the 
initial two years and annually thereafter.
9.7.4
Handling of missing data 
As this is non-interventional study, there are no required investigations and diagnostic 
procedure (e.g. lab, ultrasound). 
Maximum attempt will be made to ensure the completeness of data collection. All available 
data will be used in the data analysis. Missing or incomplete AE dates are imputed according 
to BI standard.
9.8
QUALITY CONTROL
All entries in the eCRF and the existing coding will be stored in a database. The structure of 
the database is based on the division into sections and entry fields defined in the eCRF. To 
improve and ensure data quality, data checks will be performed automatically in the eCRF 
directly on electronic entry at the study site. 
Plausible value ranges for numerical data entries and logical data and list entries will be filed 
in the eCRF. The tests for consistency and completeness based on this will be performed 
during entry in the eCRF. The validity of the recorded data will therefore be ensured by the 
validations incorporated in the documentation system, which highlight incorrect or 
implausible entries to the data entry clerk/doctor. 
All changes after initial data entry will be documented in an audit trail.
An additional inspection/quality assurance check of the data collected within this NIS can be 
performed in case of any deviation.

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9.9
LIMITATIONS OF THE RESEARCH METHODS
9.9.1
Loss to follow-up
All efforts will be made to minimize loss to follow up, particularly in the tracking of lost 
patients. To the extent possible, occurrence of adverse event, at minimum, for patients lost to 
follow up will be obtained. Also, patients lost to follow up will be characterized compared to 
the patients who had the complete follow-up, and reason and time point of loss to follow up 
will be evaluated.
9.9.2
Channelling bias
Channeling bias can occur due to preferential prescribing in relation to different risks for the 
events of interest: e.g., if Ofev would be more often prescribed to higher risk patients 
compared to other treatments, higher incidences of outcome events will then expected in the 
Ofev group. 
However this will not be assessed since there is no comparator group. 
9.9.3
Confounding
As in any observational study, confounding may affect the estimation of association between 
drug exposure and outcome of interest. Major known confounders will be captured in this 
study, however residual (unmeasured) confounding may remain. 
9.10
OTHER ASPECTS
The International Conference on Harmonization/Harmonized Tripartite Guideline for Good 
Clinical Practice (ICH/GCP) does not often apply to NIS as most elements are relevant for 
controlled clinical trials. However, in this NIS, all attempts will be made to adhere, as close 
as possible, to the standards of ICH/GCP.  
The protocol of this regulatory required NIS will be submitted to the Ministry of Food And 
Drug Safety (MFDS) for notification. It is not a local requirement in Korea to obtain 
Institutional Review Board (IRB) approval for the conduct of regulatory required NIS. 
However, the protocol of this NIS will be submitted to IRBs whenever required or requested 
by these institutions. This study will be conducted in accordance with the Standards for Re-
examination of New Medicines notified by MFDS, Korean Pharmaceutical Affairs Code 
(KPAC), Enforcement Regulation of KPAC and other applicable local laws and industry 
code (including but not limited to the Regulations on Fair Competition in the Trade of 
Medicines of KPMA and KRPIA).  
 will submit periodic reports during re-examination period, and 
the final report to MFDS upon study completion. The periodic report for the final year will be 
substituted with the final report. When required, the interim reports and the final report will 
be submitted to the IRBs as well.

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9.10.1
Study approval, patient information, and data release consent 
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and Competent Authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments. 
Prior to patient participation in the study, written data release consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to the regulatory and 
legal requirements of the participating country. Each signature must be personally dated by 
each signatory and the data release consent retained by the investigator as part of the study 
records. A signed copy of the data release consent and any additional patient information 
must be given to each patient or the patient’s legally accepted representative.
The patient must be informed that his/her personal study-related data will be used by BI in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the patient.
The patient must be informed that his / her medical records may be examined by NIS 
specialist or Clinical Quality Assurance auditors appointed by BI, by appropriate IRB / IEC 
members, and by inspectors from regulatory authorities 
9.10.2
Data quality assurance 
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s study-related files and 
correspondence, and the data release consent documentation of this non-interventional study. 
9.10.3
Study records
All of the clinical data will be captured via a web-based EDC (Electronic Data Capture) 
System. The site staff will enter and edit the data via a secure network, with secure access 
features (username, password and secure identification – an electronic password system). A 
complete electronic audit trail will be maintained. The treating physician will approve the 
data using an electronic signature. 
Patients will not be identified on the eCRF by name. Appropriate code identification (i.e., 
patient number) will be used. The treating physician will make a separate confidential record 
of these details (patient identification code list) to permit identification of all patients enrolled 
in this study in case follow-up is required. Likewise, any supporting documentation will be 
redacted of any patient identifying information, and the patient ID number clearly written on 
the documents.  
9.10.3.1
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.

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Data reported on the eCRFs must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study; current medical records must also be available.
For the eCRF, the following data need to be derived from source documents: 
x
Patient identification (gender, date of birth) 
x
Patient participation in the study (study number, patient number, date patient was data 
release consent)
x
Dates of Patient’s visits, including dispensing of study medication
x
Medical history (including study indication and concomitant diseases, if applicable) 
x
Medication history 
x
Adverse events and outcome events (onset date (mandatory), and end date (if available)) 
x
Serious adverse events (onset date (mandatory), and end date (if available)) 
x
Concomitant therapy (start date, changes) 
x
Laboratory results (if applicable)
x
Completion of Patient’s Participation in the study
9.10.3.2
Direct access to source data and documents
The Investigator / institution will permit study-related monitoring, audits, IRB review and 
regulatory inspection, providing direct access to all related source data / documents. eCRF 
and all source documents must be available at all times for review by the Sponsor’s NIS 
specialist, auditor and inspection by health authorities (e.g. MFDS). The NIS specialist and 
auditor may review all eCRF, and written data release consents. The accuracy of the data will 
be verified by reviewing the documents described in section 9.10.3.1.
9.10.3.3
Storage of records 
The NIS physician and the site are jointly responsible for maintaining essential study 
documents for 3 years after completion of the study (defined as termination date of re-
examination period) by the Pharmaceutical Affairs Law and shall take measures to prevent 
accidental or premature destruction of these documents.

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

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sponsor’s representatives, by the IRB / IEC and the regulatory authorities <for EU>, i.e. the 
CA.

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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
Adverse Drug Reaction(ADR) refers to any harmful, unintended reaction to the medicinal 
product of any dose at which a causal relationship with the medicinal product cannot be ruled 
out. 
Serious adverse event
A serious adverse event(SAE) is defined as any AE which 
-
results in death,  
-
is life-threatening,  
-
requires in-patient hospitalization, or
-
prolongation of existing hospitalisation,  
-
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 judgement 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 hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation 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.  

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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 characterised 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).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be: 
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger. 
•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned). 
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged. 
The causal relationship must be provided by the Investigator for all potential study drugs, i.e. 
the BI study drug and for all other study drugs. 
The reason for the decision on causal relationship needs to be provided in the (e)CRF and on 
the SAE form (if applicable).
Related
a.
Certain : An event occurring in a plausible time relationship to drug administration 
and that cannot be explained by concurrent disease or other drugs or chemicals. The 
response to withdrawal of the drug (dechallenge) should be clinically plausible. The 

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event must be definitive pharmacologically or phenomenologically, using a 
satisfactory rechallenge procedure if necessary. 
b.
Probable/Likely : An event with a reasonable time sequence to administration of the 
drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and 
which follows a  clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition.
c.
Possible : An event with a reasonable time sequence to administration of the drug, 
but which could also be explained by concurrent disease or other drugs or chemicals. 
Information on drug withdrawal may be lacking or unclear. 
d.
Conditional/Unclassifiable: Case of requiring more data or reviewing the additional 
data for the appropriate assessment
e.
Unassessable/ Unclassifiable: Case that it cannot be judged and complemented or 
confirmed due to the insufficient or contradictory information 
Not related
Unlikely : An event with a temporal relationship to drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or underlying disease provide 
plausible explanations. 
Intensity of 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 Ofev, the investigator must report any drug exposure during 
pregnancy, which occurred in a female subject or in a partner to a male subject to the 
Sponsor’s LPVM by means of Part A of the Pregnancy Monitoring Form. The outcome of the 
pregnancy associated with the drug exposure during pregnancy must be followed up and 
reported by means of Part B of the Pregnancy Monitoring Form.  
In the absence of an AE, the Pregnancy Monitoring Form is to be completed. If there is an 
AE associated with the pregnancy then the AE has to be reported on the AE page of the eCRF 
and/or the NIS AE form in addition following the timeline.
Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS AE form or Pregnancy 
Monitoring Form(as applicable) from signing the data release consent onwards until the end 
of the study:  
Type of Report
Timeline

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All Serious Adverse Events(SAEs)
immediately within 24 hours
All Adverse Event of Special Interest(AESIs)
immediately within 24 hours
All non-serious adverse events 
7 calendar days 
all Drug Exposure During Pregnancy 
7 calendar days 
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor upfront via telephone. 
This does not replace the requirement to complete the AE page of the eCRF and/or 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. 
For each AE, the investigator will provide the onset, end, intensity, outcome, seriousness and 
action taken with Ofev. The investigator will determine the relationship of Ofev to all AEs as 
defined in the ‘Adverse Event Reporting’ section of the physician binder. 
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 Ofev 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 AND IEC/IRB
Adverse event reporting to regulatory agencies and IEC/IRB 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
12.1
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study will be considered 
confidential and disclosure to third parties will be prohibited with the exceptions noted 
below. Patient confidentiality will be ensured by using patient identification code numbers. 
Treatment data will be made available to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated from the 
study will be made available for inspection on request by the participating physicians, the 
sponsor and/or its representatives and/or designees, by the IRBs/IECs and the regulatory 
authorities.
12.2
PUBLICATION POLICY
Boehringer Ingelheim, to the best of their ability will support the process of free exchange of 
relevant scientific information. Any publication of the result of this NIS study must be 
consistent with the Boehringer Ingelheim publication policy. 

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P11-07084
Raghu G, et al, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary 
Fibrosis: An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary 
fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir 
Crit Care Med 183 (6), 788 - 824 (2011) 
R13-2612 
Lai CC, Wang CY, Lu HM, Chen L, Teng NC, Yan YH, Wang JY, Chang YT, 
Chao TT, Lin HI, Chen CR, Yu CJ, Wang JD: Idiopathic pulmonary fibrosis in
Taiwan - a population-based study. Respir Med 106, 1566 - 1574 (2012) 
R11-5085 
Ohno S, Nakaya T, Bando M, Sugiyama Y: Idiopathic pulmonary fibrosis – 
results from a Japanese nationwide epidemiological survey using individual 
clinical records. Respirology 13 (6), 926 - 928 (2008)
1
Gjonbrataj, J.1; Choi, W-I.2; Bahn, Y. E.3; Rho, B. H.3; Lee, J. J.4; Lee, C. W.:
Incidence of idiopathic pulmonary fibrosis in Korea based on the 2011 
ATS/ERS/JRS/ALAT statement. The International Journal of Tuberculosis and 
Lung Disease, Volume 19, Number 6, 1 June 2015, pp. 742-746(5)
P12-03241
King TE, Pardo A, Selman M: Idiopathic pulmonary fibrosis. Lancet 378 (9807), 
1949 - 1961 (2011) 
R06-0898 
Selman M, Pardo A: The epithelial/fibroblastic pathway in the pathogenesis of 
idiopathic pulmonary fibrosis: tying loose ends. Am J Respir Cell Mol Biol 29, 
S93 - S97 (2003)
R12-3729 
Bonner JC: Regulation of PDGF and its receptors in fibrotic diseases. Cytokine 
Growth Factor Rev 15, 255 - 273 (2004)
P04-12378
Thannickal VJ, Flaherty KR, Martinez FJ, Lynch JP: Idiopathic pulmonary 
fibrosis: emerging concepts on pharmacotherapy. Expert Opin Pharmacother 5 
(8), 1671 - 1686 (2004)
P14-02860 
Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Anti-fibrotic and anti-
inflammatory activity of the tyrosine kinase inhibitor, nintedanib, in
experimental models of lung fibrosis. J Pharmacol Exp Ther 349, 209 – 220 
(2014) 
P14-17410 
Hostettler KE, Zhong J, Papakonstantinou E, Karakiulakis G, Tamm M, Seidel P, 
Sun Q, Mandal J, Lardinois D, Lambers C, Roth M. Anti-fibrotic effects of 
nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary 
fibrosis. Respir Res (Lond) 15, 157 (2014)
P15-02392 
Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, Kolb M. 
Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. 
Eur Respir J 45 (5), 1434 - 1445 (2015) 

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P15-06100 
Huang J, Beyer C, Palumbo-Zerr K, Zhang Y, Ramming A, Distler A, Gelse K, 
Distler O, Schett G, Wollin L, Distler JHW. Nintedanib inhibits fibroblast 
activation and ameliorates fibrosis in preclinical models of systemic sclerosis. 
Ann Rheum Dis 75 (5), 883 - 890 (2016)
R06-0113
Rice AB, Moomaw CR, Morgan DL, Bonner JC: Specific inhibitors of platelet-
derived growth factor or epidermal growth factor receptor tyrosine kinase reduce 
pulmonary fibrosis in rats. Am J Pathol 155 (1), 213 - 221 (1999) 
R12-3733 
Aono Y, Nishioka Y, Inayama M, Ugai M, Kishi J, Uehara H, Izumi K, Sone S 
Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in 
mice. Am J Respir Crit Care Med 171, 1279 - 1285 (2005)
R12-3754 
Vuorinen K, Gao F, Oury TD, Kinnula VL, Myllarniemi M: Imatinib mesylate 
inhibits fibrogenesis in asbestos-induced interstitial pneumonia. Exp Lung Res 
33, 357 - 373 (2007)
R12-3731 
Li M, Abdollahi A, Groene HJ, Lipson KE, Belka C, Huber PE: Late treatment 
with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse 
model. Radiat Oncol 4, 66 (2009)
R12-3734 
Abdollahi A, Li M, Ping G, Plathow C, Domhan S, Kiessling F, Lee LB, 
McMahon G, Groene HJ, Lipson KE, Huber PE: Inhibition of platelet-derived 
growth factor signaling attenuates pulmonary fibrosis. J Exp Med 201 (6), 925 - 
935 (2005)
R07-0010
Renzoni EA: Neovascularization in idiopathic pulmonary fibrosis: too much or 
too little? Am J Respir Crit Care Med 169, 1179 - 1180 (2004)
R13-2758
Ando M, Miyazaki E, Ito T, Hiroshige S, Nureki S, Ueno T, Takenaka R, 
Fukami T, Kumamoto T: Significance of serum vascular endothelial growth 
factor level in patients with idiopathic pulmonary fibrosis. Lung 188 (3), 247 - 
252 (2010) 
R13-4145 
Travis WD, et al, ATS/ERS Committee on Idiopathic Interstitial Pneumonias. An official 
American Thoracic Society/European Respiratory Society statement: update of the 
international multidisciplinary classification of the idiopathic interstitial pneumonias. Am 
J Respir Crit Care Med 188 (6), 733 - 748 (2013)
R06-0596 
Hamada N, Kuwano K, Yamada M, Hagimoto N, Hiasa K, Egashira K, 
Nakashima N, Maeyama T, Yoshimi M, Nakanishi Y: Anti-vascular endothelial 
growth factor gene therapy attenuates lung injury and fibrosis in mice. J
Immunol 175, 1224 - 1231 (2005)
R15-2110
Ofev 100 mg, 150 mg soft capsules (summary of product characteristics, 
manufacturer responsible for batch release, conditions or restrictions regarding 
supply and use, other conditions and requirements of the marketing 
authorisation, conditions or restrictions with regard to the safe and effective use 
of the medicinal product, labelling and package leaflet, first published: 
13/02/2015). 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-

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_Product_Information/ human/003821/WC500182474.pdf (access date: 4 May 
2015) (2015)
R14-4918
Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, 
survival, risk factors, malignancy, and environmental triggers. Curr Opin 
Rheumatol 2012. 24(2):165-170. 
R14-4927 
Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med 2009. 
360(19):1989-2003.
P14-07919 
Herzog EL, Mathur A, Tager AM, Feghali-Bostwick C, Schneider F, 
Varga J. Interstitial lung disease associated with systemic sclerosis and 
idiopathic pulmonary fibrosis: how similar and distinct Arthritis and 
Rheumatology, Accepted Article, Accepted: May 08, 2014, doi: 
10.1002/art.38702 Arthritis Rheumatol 2014. 66(8):1967-1978. 

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13.2
UNPUBLISHED REFERENCES
c01805141-16 
nintedanib Investigator’s Brochure 
c03498541-01 
. 1199.202_Non-interventional Study Protocol: The 
special drug use-results survey (All-Case Surveillance) of Ofev® Capsules in
patients with Idiopathic Pulmonary Fibrosis (IPF) in Japan

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

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15.
ANNEXES
15.1
LIST OF STAND-ALONE DOCUMENTS
See Annex 1. 
15.2
ENCEPP CHECKLIST FOR STUDY PROTOCOLS
See Annex 2. 
15.3
ADDITIONAL INFORMATION
See Annex 3. 

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

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Doc.Ref. EMA/540136/2009 
ENCePP Checklist for Study Protocols (Revision 2, amended) 
Adopted by the ENCePP Steering Group on 14/01/2013
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) welcomes innovative 
designs and new methods of research. This Checklist has been developed by ENCePP to stimulate consideration of 
important principles when designing and writing a pharmacoepidemiological or pharmacovigilance study protocol. The 
Checklist is intended to promote the quality of such studies, not their uniformity. 
For each question of the Checklist, the investigator should indicate whether or not it has been addressed in the study 
protocol. This Checklist should be included as an Annex by marketing authorisation holders when submitting the protocol of 
a non-interventional post-authorisation safety study (PASS) to a regulatory authority (see the Guidance on the format and 
content of the protocol of non-interventional post-authorisation safety studies).  
Study title:
A regulatory required non-interventional study to monitor the safety and effectiveness of 
Ofev(Nintedanib 150mg/ 100mg BID) in Korean patients
Study reference number:
1199.XX
Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
1.1 Does the protocol specify timelines for 
1.1.1 Start of data collection
1.1.2 End of data collection
1.1.3 Study progress report(s) 
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
1.1.6 Final report of study results.
13
13
13
13
13
13
Comments:
     
Section 2: Research question
Yes
No
N/A
Page 
Number(s)
2.1
Does the formulation of the research question and objectives 
clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address an important 
public health concern, a risk identified in the risk management plan, an 
emerging safety issue)
2.1.2 The objective(s) of the study?
14
16
2.1.3 The target population? (i.e. population or subgroup to whom the 
study results are intended to be generalised)
2.1.4 Which formal hypothesis(-es) is (are) to be tested? 
18

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Section 2: Research question
Yes
No
N/A
Page 
Number(s)
2.1.5 If applicable, that there is no a priori hypothesis?
Comments:
     
Section 3: Study design
Yes
No
N/A
Page 
Number(s)
3.1
Is the study design described? (e.g. cohort, case-control, randomised
controlled trial, new or alternative design) 
17
3.2
Does the protocol specify the primary and secondary (if 
applicable) endpoint(s) to be investigated?
16
3.3
Does the protocol describe the measure(s) of effect? (e.g. 
relative risk, odds ratio, deaths per 1000 person-years, absolute risk, excess 
risk, incidence rate ratio, hazard ratio, number needed to harm (NNH) per 
year)
21
Comments:
     
Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1
Is the source population described?
18
4.2
Is the planned study population defined in terms of:
4.2.1 Study time period?
4.2.2 Age and sex?
4.2.3 Country of origin?
4.2.4 Disease/indication? 
4.2.5 Co-morbidity?
4.2.6 Seasonality?
17
18
18
18
4.3
Does the protocol define how the study population will be 
sampled from the source population? (e.g. event or 
inclusion/exclusion criteria)  
18
Comments:
     
Section 5: Exposure definition and measurement
Yes
No
N/A
Page 
Number(s)
5.1
Does the protocol describe how exposure is defined and 
measured? (e.g. operational details for defining and categorising exposure)  
5.2
Does the protocol discuss the validity of exposure 
measurement? (e.g. precision, accuracy, prospective ascertainment, 
exposure information recorded before the outcome occurred, use of 
validation sub-study)
5.3
Is exposure classified according to time windows? (e.g. current 
user, former user, non-use)

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Section 5: Exposure definition and measurement
Yes
No
N/A
Page 
Number(s)
5.4
Is exposure classified based on biological mechanism of 
action and taking into account the pharmacokinetics and 
pharmacodynamics of the drug?
5.5
Does the protocol specify whether a dose-dependent or 
duration-dependent response is measured?
Comments:
     
Section 6: Endpoint definition and measurement
Yes
No
N/A
Page 
Number(s)
6.1
Does the protocol describe how the endpoints are defined and 
measured? 
21
6.2
Does the protocol discuss the validity of endpoint 
measurement? (e.g. precision, accuracy, sensitivity, specificity, positive 
predictive value, prospective or retrospective ascertainment, use of validation 
sub-study)
21
Comments:
     
Section 7: Confounders and effect modifiers
Yes
No
N/A
Page 
Number(s)
7.1
Does the protocol address known confounders? (e.g. collection of 
data on known confounders, methods of controlling for known confounders)
7.2
Does the protocol address known effect modifiers? (e.g. 
collection of data on known effect modifiers, anticipated direction of effect)
Comments:
     
Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.1
Does the protocol describe the data source(s) used in the study 
for the ascertainment of:
8.1.1 Exposure? (e.g. pharmacy dispensing, general practice prescribing, 
claims data, self-report, face-to-face interview, etc.)  
8.1.2 Endpoints? (e.g. clinical records, laboratory markers or values, 
claims data, self-report, patient interview including scales and questionnaires, 
vital statistics, etc.)
8.1.3 Covariates? 
22
22
8.2
Does the protocol describe the information available from the 
data source(s) on:
8.2.1 Exposure? (e.g. date of dispensing, drug quantity, dose,  number of 
days of supply prescription, daily dosage,  prescriber)  
8.2.2 Endpoints? (e.g. date of occurrence, multiple event, severity 
measures related to event)  
8.2.3 Covariates? (e.g. age, sex, clinical and drug use history, co-
morbidity, co-medications, life style, etc.)
23
23
8.3
Is a coding system described for:
8.3.1 Diseases? (e.g. International Classification of Diseases (ICD)-10)
18

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Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.3.2 Endpoints? (e.g. Medical Dictionary for Regulatory Activities 
(MedDRA) for adverse events)
8.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical Therapeutic 
Chemical (ATC)Classification System)
25
25
8.4
Is the linkage method between data sources described? (e.g.
based on a unique identifier or other)  
Comments:
     
Section 9: Study size and power
Yes
No
N/A
Page 
Number(s)
9.1 Is sample size and/or statistical power calculated? 
Comments:
     
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1
Does the plan include measurement of excess risks?
27
10.2
Is the choice of statistical techniques described? 
27
10.3
Are descriptive analyses included?
27 ~ 28
10.4
Are stratified analyses included? 
28
10.5
Does the plan describe methods for adjusting for 
confounding?
29
10.6
Does the plan describe methods addressing effect 
modification?
29
Comments:
     
Section 11: Data management and quality control
Yes
No
N/A
Page 
Number(s)
11.1
Is information provided on the management of missing 
data?
26
11.2
Does the protocol provide information on data storage? (e.g. 
software and IT environment, database maintenance and anti-fraud 
protection, archiving)
29
11.3
Are methods of quality assurance described?
28
11.4 
Does the protocol describe possible quality issues related to 
the data source(s)?
28
11.5
Is there a system in place for independent review of study 
results? 
Comments:
     

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Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
12.1
Does the protocol discuss:
12.1.1 Selection biases?
12.1.2 Information biases?
(e.g. anticipated direction and magnitude of such biases, validation sub-
study, use of validation and external data, analytical methods)
25
25
12.2
Does the protocol discuss study feasibility? (e.g. sample size, 
anticipated exposure, duration of follow-up in a cohort study, patient 
recruitment)
23
12.3 Does the protocol address other limitations? 
25
Comments:
     
Section 13: Ethical issues
Yes
No
N/A
Page 
Number(s)
13.1
Have requirements of Ethics Committee/Institutional 
Review Board approval been described?
28
13.2
Has any outcome of an ethical review procedure been 
addressed?
28
13.3
Have data protection requirements been described?
28
Comments:
     
Section 14: Amendments and deviations
Yes
No
N/A
Page 
Number(s)
14.1
Does the protocol include a section to document future 
amendments and deviations? 
Comments:
     
Section 15: Plans for communication of study results
Yes
No
N/A
Page 
Number(s)
15.1
Are plans described for communicating study results (e.g. to 
regulatory authorities)? 
33
15.2
Are plans described for disseminating study results 
externally, including publication?
36
Comments:
     
Name of the main author of the protocol: 
Date: 21/Feb/2020
              
Signature

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ANNEX 3. ADDITIONAL INFORMATION
None 

 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
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Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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