Post-marketing Surveillance of Ofev Capsules in Chronic Fibrosing Interstitial Lung Diseases With a Progressive Phenotype in Japan
Conditions: Lung Diseases, Interstitial
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
pTITLE PAGE
Non-interventional Study Protocol
TITLE PAGE
Document Number:
c29889733-04
BI Study Number:
1199.402
BI Investigational
Product(s):
Nintedanib
Title:
Post-marketing Surveillance of Ofev Capsules in Chronic 
fibrosing Interstitial Lung Diseases with a progressive phenotype 
in Japan
Brief lay title
PMS of Ofev Capsules in PF-ILD
Protocol version 
identifier:
Version 4.0
Date of last version of 
protocol:
1 April, 2024
PASS:
Yes
EU PAS register 
number:
EUPAS36605
Active substance:
Nintedanib
Medicinal product:
  Ofev Capsules
300 mg daily (150 mg b.i.d) or 200 mg (100 mg b.i.d)
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Joint PASS:
No
Research question and 
objectives:
The primary objective is to evaluate the incidence of adverse drug 
reactions (focus on hepatic function disorders) of Ofev
Capsules under the real world setting in patients with PF-ILD
Country(-ies) of study:
Japan
Author:

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Marketing authorisation 
holder(s):
.
In case of PASS, add:
MAH contact person:
In case of PASS, add:
<EU-QPPV:>
In case of PASS, add:
<Signature of EU-
QPPV:>
e-signature is on BIRDS.
Date:
1 APR 2024
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© 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 11
6.
MILESTONES..................................................................................................... 12
7.
RATIONALE AND BACKGROUND................................................................ 13
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 16
9.
RESEARCH METHODS .................................................................................... 17
9.1
STUDY DESIGN............................................................................................ 17
9.2
SETTING........................................................................................................ 17
9.2.1
Study sites ............................................................................................... 17
9.2.2
Study population ..................................................................................... 17
9.2.2.1
Inclusion/ exclusion criteria ............................................................. 17
9.2.2.2
Registration period........................................................................... 17
9.2.2.3
Patient registration method .............................................................. 17
9.2.3
Study visits .............................................................................................. 18
9.2.4
Study discontinuation.............................................................................. 18
9.3
VARIABLES .................................................................................................. 18
9.3.1
Exposures ................................................................................................ 18
9.3.2
Outcomes................................................................................................. 18
9.3.2.1
Primary outcomes............................................................................. 18
9.3.2.2
Secondary outcomes......................................................................... 19
9.3.3
Survey items............................................................................................ 19
9.4
DATA SOURCES........................................................................................... 20
9.5
STUDY SIZE.................................................................................................. 21
9.6
DATA MANAGEMENT................................................................................ 21
9.7
DATA ANALYSIS......................................................................................... 21
9.7.1
Main analysis........................................................................................... 22
9.8
QUALITY CONTROL................................................................................... 23

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9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 23
9.10
OTHER ASPECTS ......................................................................................... 23
9.10.1
Data quality assurance............................................................................. 23
9.10.2
Completion of study................................................................................ 23
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 24
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 24
10.2
STATEMENT OF CONFIDENTIALITY...................................................... 24
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 25
11.1
STUDY RECORDS........................................................................................ 25
11.1.1
Source documents ................................................................................... 25
11.1.2
Direct access to source data and documents ........................................... 25
11.2
DEFINITIONS OF ADVERSE EVENTS...................................................... 25
11.3
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 26
11.4
REPORTING TO HEALTH AUTHORITIES................................................ 28
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 29
13.
REFERENCES .................................................................................................... 30
13.1
PUBLISHED REFERENCES......................................................................... 30

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2.
LIST OF ABBREVIATIONS
ACA
Anti-Centromere Antibodies
ADR(s)
Adverse Drug Reaction(s)
AE(s)
Adverse Event(s)
AESI
Adverse Event of Special Interest
ALP
Alkaline phosphatase 
ALT
Alanine aminotransferase
ANA
Antinuclear antibodies
ANCA
Anti-neutrophil cytoplasmic antibody
aPTT
Activated partial thromboplastin time
ARS
Amino acyl-tRNA synthetases
AST
Aspartate aminotransferase
ATA
Anti-topoisomerase antibodies
BI
Boehringer Ingelheim
BNP
Brain natriuretic peptide
CCP
Cyclic Citrullinated Peptid
CI
Confidence Interval
CRF
Case Report Form
CRP
C-reactive protein
CTP
Clinical Trial Protocol
DLco
Carbon Monoxide diffusion capacity
eCRF
Electronic Case Report Form
EDC
ENCePP
Electronic Data Capture
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity
GGT
Gamma-glutamyltransferase
GPSP
Good Post-marketing Study Practice
Hb
Hemoglobin
Hct
Hematocrit
HRCT
High-Resolution Computed Tomography
ILD
Interstitial Lung Disease
INR
International Normalised Ratio
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
KL-6
Krebs von den Lungen-6
LDH
Lactase Dehydrogenase
MAH
Marketing Authorisation Holder
MedDRA
Medical Dictionary for Drug Regulatory Activities
MHLW
Ministry of Health Labour and Welfare
MPO
Myeloperoxidase
NIS
Non-Interventional Study
NSIP
Non-specific Interstitial Pneumonia
ONIS
Observational Non-Interventional Study
PASS
Post-Authorization Safety Study

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PF-ILD
Chronic fibrosing Interstitial Lung Diseases with a progressive 
phenotype
PMD
Pharmaceutical and Medical Device 
PMDA
Pharmaceuticals and Medical Devices Agency
PMS
Post Marketing Surveillance
PR3
Serine Proteinase3
PT
Prothrombin Time
RBC
Red Blood cell Count
RF
Rheumatoid Factor
RMP
Risk Management Plan
SAE
Serious Adverse Event
SOP
Standard Operating Procedure
SP-D
Surfactant Protein D
SS
Sjögren's syndrome
SSc
Systemic Sclerosis
TSAP
Trial Statistical Analysis Plan
UIP
Usual Interstitial Pneumonia
ULN
Upper Limit of Normal
WBC
White Blood cell Count

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3.
RESPONSIBLE PARTIES
Contact details and the list of all investigators will be kept in a stand-alone document. This
document will be managed in the Post Marketing Surveillance (PMS) tracking system which
manages the contracts with site and investigators name.

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev capsules
Name of active ingredient:
List pharmacotherapeutic
Nintedanib
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
13 March, 2020
1199.402
Version 4.0
1 April, 2024
Title of study:
Post-marketing Surveillance of Ofev Capsules in Progressive Fibrosing 
Interstitial Lung Disease in Japan
Rationale and 
background:
This PMS plan is proposed as additional pharmacovigilance plan of 
the Japanese RMP.
In Japan, post-approval execution of PMS is requested by the Japanese 
Pharmaceuticals and Medical Devices Act (J-PMD Act) in order to 
accumulate safety and effectiveness data for re-examination.
Re-examination period is defined by J-PMD Act. Five years and ten 
months after approval for new indication of orphan drugs, results of 
PMS need to be submitted as a part of re-examination dossier to the 
Japanese regulatory authority, the Ministry of Health, Labour and 
Welfare (MHLW).
Collected data from PMS will be included in the Japanese periodic
safety reports and submitted to PMDA on designated dates until the
end of re-examination period.
The INBUILD (1199.247) trial was completed and INBUILD-ON 
(1199.248) trial is conducted as Phase III trials that evaluated the 
efficacy and safety of nintedanib in patients with PF-ILD. IPF patients 
were excluded in these trials.
As the number of Japanese patients treated with nintednib in 
INBUILD trial was few (52, total: 332), confirmation of the safety 
profile of nintedanib treatment for PF-ILD patients in the real world 
clinical setting is required.
Research question 
and objectives:
To evaluate the incidence of adverse drug reactions (focus on hepatic 
function disorders including liver enzyme elevation) of Ofev Capsules 
under the real world setting in patients with PF-ILD.
Study design:
Non-interventional cohort study with new data collection (NISnd)
Patients newly initiated Ofev Capsules will be enrolled and followed
up to 104 weeks (2 years) or until discontinuation of administration.

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev capsules
Name of active ingredient:
List pharmacotherapeutic
Nintedanib
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
13 March, 2020
1199.402
Version 4.0
1 April, 2024
Population:
Inclusion criteria
- Patients in Japan with PF-ILD who are prescribed with Ofev 
Capsules and have never been treated with Ofev Capsules before 
enrolment will be included.
Exclusion criteria
-
Diagnosis of IPF
-
Patients with PF-ILD due to systemic scleroderma as the 
underlying disease
Variables:
  Outcomes:
Primary outcome:
Incidence of adverse drug reactions (ADRs) by overall, each 
individual (especially focus on the safety specification on J-RMP: 
hepatic function disorders)
Secondary outcome:
None

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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev capsules
Name of active ingredient:
List pharmacotherapeutic
Nintedanib
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
13 March, 2020
1199.402
Version 4.0
1 April, 2024
Others: characteristics associated with ADRs
Demographics, baseline characteristics, labs and vitals as baseline, 
concomitant therapy and medications etc.
Data sources:
Patients’ data will be collected by electronic Case Report Form on 
Electronic Data Capture system
Study size:
Approximately 400 (for enrolment)
Data analysis:
Analyses are descriptive in nature, incidence rates and corresponding 
confidence intervals will be given for all ADRs in terms of Ofev for 
PF-ILD.
Milestones:
Planned start of data collection:  1 OCT 2020
Planned end of data collection:  31 DEC 2024
Study Report planned to be archived in 4Q 2025

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5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study 
protocol
Amendment or 
update
Reason
2.0
03 June, 2020
Study 
population
Amendment
Indication 
wording was 
changed
4.0
1 April, 2024
9.6 DATA 
MANAGE
MENT
Amendment 
(non-substantial)
Contract 2 of 9.6 
DATA 
MANAGEMENT 
was changed from 
1.Apr.2024. This 
amendment is 
non-substantial 
and categorized 
as unnecessary to 
submit to PMDA.

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
1 October 2020
End of data collection
31 December 2024
Registration in the EU PAS 
register
EUPAS36605
Final report of study results:
4Q 2025

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7.
RATIONALE AND BACKGROUND
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, quality of life 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 Chronic fibrosing Interstitial 
Lung Diseases with a progressive phenotype (PF-ILD).
Based on expert consensus, the main fibrosing ILDs in which progressive behavior 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 interstitial 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. And, the efficacy of 
Nintedanib for PF-ILD was shown at INBUILD trial.
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. Because of the similarity in both the underlying pathophysiology
and clinical course of PF-ILD and IPF, it became clear that nintedanib elicit similar effects in 
PF-ILD as it demonstrated in IPF shown in the INBUILD trial. These clinical results confirm 
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).
The primary endpoint of the INBUILD trial was met in both co-primary populations. 
Treatment with nintedanib significantly reduced the annual rate of decline in FVC [mL/year] 
over 52 weeks compared with placebo in the overall population and in patients with HRCT 
with UIP-like fibrotic pattern. The results were shown to be robust and were consistent in the 
complementary population of patients with other HRCT fibrotic patterns.
Analyses of time-to-event endpoints indicated reductions in clinically meaningful outcome 
events and provided supportive evidence for a slowing of disease progression by nintedanib. 
The treatment benefit of nintedanib on lung function was accompanied by improvements in 
patient-reported outcomes such as dyspnoea and cough.
The observed safety profile of nintedanib in patients with progressive fibrosing ILD 

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comprised risks that were manageable or occurred at a low frequency. The most frequently 
reported AEs were gastrointestinal disorders, in particular diarrhoea, nausea, and vomiting. 
Common AEs were mostly mild or moderate in intensity. In addition, treatment with 
nintedanib was associated with elevations in liver enzymes. The large majority of liver 
enzyme elevations normalised upon treatment interruption, dose reduction, treatment
discontinuation, or spontaneously with continued treatment. There were no new or 
unexpected safety concerns identified in the INBUILD trial.
The safety profile of nintedanib has been investigated comprehensively in IPF and stablished 
in this indication in > 80 000 patient-years exposure postmarketing as of May 2019. The risks 
of treatment with nintedanib are primarily related to the gastrointestinal tract (diarrhoea, 
nausea, vomiting, abdominal pain, pancreatitis) and increases in liver enzymes and bilirubin, 
including drug-induced liver injury (DILI). Based on data from clinical trials and post-
marketing and supported by population pharmacokinetic models, patients with low body 
weight (<65 kg), Asian, and female patients have a higher risk of liver enzyme elevations 
with nintedanib treatment. Risks of nintedanib treatment also include hypertension, bleeding, 
thrombocytopenia, gastrointestinal perforation, thrombo-embolism, decreased appetite, 
decreased weight, rash, pruritus, alopecia and headache.
The INBUILD trial is a randomized, placebo-controlled Phase III trial that evaluated the 
efficacy and safety of nintedanib in patients with PF-ILD.
As the number of Japanese patients treated with nintedanib in INBUILD trial was few (52, 
total 332), confirmation of the safety profile of nintedanib treatment for PF-ILD patients in 
the real world clinical setting is required.
This “PMS with 400 patients for enrolment” that will take into consideration the following 
points.

The safety profile in Ofev was similar in ‘PF-ILD patients’ to that in IPF in the clinical 
trials. The incidence of hepatic enzyme elevation was higher in Japanese population than 
overall population in the INBUILD trial for PF-ILD other than IPF.

Real world data in patients with IPF has already been collected over 3 years through post-
marketing experience after 2015 in 1199.202 (the ongoing all case survey of PMS in IPF). 
The total number of patients registered in 1199.202 was over 5,000. PF-ILD patients may 
have different concomitant diseases and medications with IPF patients in 1199.202.

As the IPF is also a progressive fibrosing ILD, the safety data collected in 1199.202 
would be supportive for PF-ILD, however the number of patient with PF-ILD other than 
IPF is limited. Therefore, the PMS in patients with PF-ILD other than IPF will be 
required in order to accumulate the safety data under the real world setting in Japanese 
PF-ILD patients to assess the safety profile, especially hepatic function disorders 
including liver enzyme elevation.
In Japan, Ofev Capsules for PF-ILD indication has received marketing approval on May
2020 (Plan).
This PMS plan is proposed as additional pharmacovigilance plan of the Japanese RMP.

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In Japan, post-approval execution of PMS is requested by the Japanese Pharmaceuticals and 
Medical Devices Act (J-PMD Act) in order to accumulate safety and effectiveness data for 
re-examination. 
Re-examination period is defined by J-PMD Act. Five years and ten months after approval 
for additional indication on orphan drugs, results of PMS need to be submitted as a part of re-
examination dossier to the Japanese regulatory authority, the Ministry of Health, Labour and 
Welfare (MHLW). 
Collected data from PMS will be included in the Japanese periodic safety reports and 
submitted to PMDA on designated dates until the end of re-examination period.

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8.
RESEARCH QUESTION AND OBJECTIVES
The primary objective is to evaluate the incidence of adverse drug reactions (focus on hepatic 
function disorders) of Ofev Capsules under the real world setting in patients with PF-ILD.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a non-interventional study based on newly collected data of patients under routine 
care to confirm safety of Ofev Capsules in the real-world setting in Japanese patients with 
PF-ILD.
9.2
SETTING
9.2.1
Study sites
Sites throughout entire country will be equally listed according the size of the hospitals or 
general clinics at which Ofev Capsules are available for prescription.
Planned number of sites: Approximately 100 Sites
A medical representative will explain the objective and design of this study to investigators at 
each study site and conclude a written contract with the head of the study site (e.g., hospital 
director). 
9.2.2
Study population
As this is a non-interventional study, treatment with Ofev for PF-ILD at the contracted site is 
for participation. No limitations are set up on background factors and their concomitant drugs 
in use of actual medical practice.
9.2.2.1
Inclusion/ exclusion criteria
Inclusion criteria
- Patients in Japan with PF-ILD who are prescribed with Ofev Capsules and have never been 
treated with Ofev Capsules before enrolment will be included.
Exclusion criteria
- Diagnosis of IPF
- Patients with PF-ILD due to systemic scleroderma as the underlying disease
9.2.2.2
Registration period
From October 2020 to September 2022
9.2.2.3
Patient registration method
The registration method will be a continuous investigation system. Patients who begin 
treatment with Ofev Capsules after the conclusion of the contract will be registered by 
entering necessary information in the Electronic Data Capture (EDC) system within 14 days 
whenever possible from the day of treatment initiation (inclusive).

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Patient registration will be stopped when the overall target number of patients for the study is 
reached. After the end of the registration period, investigators use a signed form to confirm 
that patients have been registered continuously at the site. A log of all patients included in the 
study will be maintained at the site.
9.2.3
Study visits
The study will consist of a baseline visit and further visits in a 104-week follow-up for 
patients who have initiated Ofev Capsules treatment. See ANNEX 2 for more details.
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:
1. Failure to meet expected enrolment goals overall or at a particular study site
2. Emergence of any effectiveness/safety information that could significantly affect 
continuation of the study or any other administrative reasons.
3. Violation of Good Post-marketing Study Practice (GPSP) , the study protocol, or the 
contract by a study site or investigator, disturbing the appropriate conduct of the study
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason).
9.3
VARIABLES
9.3.1
Exposures
Exposure to Ofev Capsules is estimated as time from the day Ofev Capsules is initiated until 
the day the drug is last administrated on a patient-level (or the final contact with the patient 
during the regular observation period).
Patients newly initiating Ofev Capsules will be followed up to 104 weeks.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
The primary outcome of this study is the incidence of adverse drug reactions (ADRs).
ADRs definition and reporting is described in section 11.
There is no primary outcome for effectiveness as the primary objective of a PMS is 
evaluating safety.

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9.3.2.2
Secondary outcomes
None
9.3.3
Survey items
- Demographics
•
Gender (Pregnancy status, only for female)
•
Age (Year of birth)
•
Height (cm)
•
Weight (Kg)
•
Systolic/Diastolic blood pressure (mmHg) and pulse rate (bpm) in the sitting 
position
•
Smoking status
•
Reason for Ofev prescription
•
Underlying diagnosis (Idiopathic nonspecific interstitial pneumonia, Unclassifiable 
idiopathic interstitial pneumonia, Hypersensitivity pneumonitis, Rheumatoid 
Arthritis associated ILD, Mixed connective tissue disease, Exposure-related ILD, 
Sarcoidosis, Other ILD)
•
Child-Pugh classification (with any hepatic concomitant disease)
•
Serum creatinine (Creatinine clearance according to Cockcroft and Gault).
•
Immunological test (Rheumatoid Factor, Anti-cyclic citrullinated peptid antibody, 

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Antinuclear antibodies, Anti Sjögren's syndrome-A antibody, Anti-amino acyl-tRNA 
synthetases antibody, MPO-ANCA, PR3-ANCA, other)
•
Time [years] since PF-ILD diagnosis (PF-ILD First diagnosis)
•
Criteria for assessment of progression (images, symptoms, respiratory function 
examination)
•
Chest HRCT criteria (UIP-like*, Others)
•
ILD symptoms (Dyspnea, Cough)
•
Criteria for PF-ILD**
*: The HRCT criteria for UIP pattern as the Phase III IPF trials for Nintedanib is used. UIP-like pattern
includes A, B and C, or criteria A and C, or criteria B and C as described below: 
A. Definite honeycomb lung destruction with basal and peripheral predominance 
B. Presence of reticular abnormality AND traction bronchiectasis consistent with fibrosis with basal and 
peripheral predominance 
C. Atypical features are ABSENT, specifically: nodules and consolidation. Ground glass opacity, if 
present, is less extensive than reticular opacity pattern 
**: The patients who fulfil at least one of the following criteria for PF-ILD within 24 months of the 
screening visit
- clinically significant decline in FVC % predicted (%pred) based on ≥10% relative
Decline
- marginal decline in FVC %pred based on ≥5 – <10% relative decline in FVC combined with worsening 
of respiratory symptoms
- marginal decline in FVC %pred based on ≥5 – <10% relative decline in FVC
combined with increasing extent of fibrotic changes on chest imaging
- worsening of respiratory symptoms as well as increasing extent of fibrotic changes on chest imaging
- Treatment states of Ofev (start date, reason for use, dosage and administration status)
- Medical history/Concomitant diagnosis
- Previous/Concomitant medications for PF-ILD and except for PF-ILD
- Concomitant therapy
- Pulmonary function test (FVC, FVC percent predicted, FEV1, FEV1 percent predicted, 
DLco percent predicted, SpO2 at rest)
- Laboratory tests:
Collect data which is needed for case. AST/ALT are collected from all cases as possible.
•
Hematological (RBC, Hb, Hct, Platelet count, WBC, differential count of 
leukocytes)
•
Liver function (AST, ALT, γ-GTP, ALP, Total bilirubin)
•
Other biochemical (CRP, CK, LDH, BNP, SP-D, KL-6)
•
Coagulation (PT, PT-INR, aPTT)
•
Others
See ANNEX 2 and ANNEX 3 for more details.
9.4
DATA SOURCES
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via the
EDC system.

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In EDC system, three casebooks will be set:
- Book 1 includes baseline, 4 and 12 weeks. 
- Book 2 includes 24, 36 and 52 weeks.
- Book 3 includes 72, 84, 96 and 104 weeks.
The data are to be transmitted immediately after being entered into EDC at 12 weeks (Book 
1), 52 weeks (Book 2) and 104 weeks (Book 3) after the start of treatment or at 
discontinuation.
For any adverse events, the data should be immediately entered into EDC and transmitted. 
9.5
STUDY SIZE
As mentioned below, 354 patients will be needed as safety analysis set in the study. There 
may be cases that some patients are not eligible for analyses (see Section 9.7). Therefore 
planned number of registration will be approximately 400 patients.
The incidence of hepatic enzyme elevation tends to be higher in Japanese patients than in 
other ethnic groups. Hepatic functional disorder (AE) including hepatic enzyme elevation is 
an important factor for evaluating risk-benefit balance.
It is used as reference event for the sample size evaluation in PMS studies in Japan. The 
proportion of overall patients with maximum ALT and/or AST ≥ 5 Upper Limit of Normal 
was 3.8% (2/52) in Japanese nintedanib group of INBUILD trial.
If the true proportion of patients with hepatic enzymes elevation is assumed to be 2-fold (i.e., 
7.6%), the sample size of 354 is required to have 90% power for rejecting the null hypothesis 
of incidence = 3.8% by using one sample chi-square test with a 0.05 two-sided significance 
level.
9.6
DATA MANAGEMENT
Patients’ data will be gathered by EDC system provided by external vendor below.
Contract 1
Contract 2
Company Name
Outsourced work
EDC system setting
Patient registration
Clinical Data Management
Document management of 
contract with site.
9.7
DATA ANALYSIS
This is a non-interventional study to collect data on patients under routine medical practice on 
safety of Ofev Capsules treatment. Analyses are descriptive in nature, including confidence 
intervals. Subgroup analyses will be performed if sample size allows.

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Per local regulation, any patient who meets one of the following criteria is treated as 
ineligible for all analyses:
•
No visit after registration.
•
No required registration procedure was followed.
•
No valid site contract was available.
9.7.1
Main analysis
In general, safety analyses will be descriptive in nature, and will be based on BI standards, 
and will focus on any ADRs, serious AEs, AEs leading to death, AEs leading to treatment 
discontinuation, acute ILD exacerbations and liver enzyme elevations (AST and/or ALT ≥3x 
to <5x ULN, ≥5x ULN).
AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be based on the concept of treatment emergent AEs. To this 
end, all AEs occurring between first intake of Ofev Capsules prescribed at baseline visit and 
within 28 days (inclusive) after the last intake will be considered ‘treatment emergent’. An 
AE is considered to be an ADR if either the physician who has reported the AE or the 
sponsor assesses its causal relationship as ‘related’.
The frequency and incidence of AEs/ADRs will be tabulated by system organ class and 
preferred term for overall and for subgroups based on the important baseline characteristics 
(see section 9.3.3).
No imputation is planned for missing AE data except for missing onset dates which will be 
handled according to BI standard.

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9.8
QUALITY CONTROL
All processes are conducted according to GPSP Standard Operating Procedures (SOP) 
. Appropriate records and documents are stored based on the GPSP 
SOPs and these processes are checked by internal self-check.
9.9
LIMITATIONS OF THE RESEARCH METHODS
The general scientific objective of this non-interventional study is to obtain an incidence of 
adverse drug reactions in the population under study.
Due to the design which uses a single cohort in this observational safety study, a potential 
limitation is the absence of comparator group arising from the study sites for comparing the 
data to be obtained with active treatments. However, baseline data from a registry are 
expected to be available for use as a comparison group if feasible.
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
This PMS study is to be conducted in accordance with both the in-house SOP and working 
instructions which are in compliance with GPSP.
9.10.2
Completion of study
Completion of the PMS will be notified to PMDA when the re-examination document and 
periodic safety reports are applied to in accordance with J-PMD Act and GPSP.

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10.
PROTECTION OF HUMAN SUBJECTS
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
There is no regulation or requirement for ensuring the well-being and rights of participants in 
a non-interventional observational study. 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the patient’s treating physician.
The review by IRB is not mandatory for conducting PMS in Japanese GPSP. The sponsor 
will enter into a contract with a representative (e.g., head of hospital) in accordance with 
GPSP. Written informed consent prior to patient participation in the trial is not a regulatory or 
legal requirement in accordance with GPSP.
10.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this PMS is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Data generated as a result of the PMS needs to be available for inspection on request by the 
regulatory authorities.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Procedures for the collection, management and reporting of individual cases of adverse 
events/adverse reactions (see 
  for collection requirements) 
and of any new information that might influence the evaluation of the benefit-risk balance of 
the product while the study is being conducted. 
11.1
STUDY RECORDS
eCRFs for individual patients will be provided by the sponsor via remote data capture. 
11.1.1
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 study site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the study; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
11.1.2
Direct access to source data and documents
Direct access to source data and documents for PMS study by 
is not allowed in Japan.
11.2
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavorable 
and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorization or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which

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-
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 hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
An AE which possibly leads to disability will be reported as an SAE. Every new occurrence 
of cancer or an exacerbation of an existing cancer will be reported as a SAE regardless of the 
duration between discontinuation of the drug and the occurrence of the cancer.
No AESIs have been defined for this study.
11.3
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorization. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined.
The following must be collected by the investigator in the eCRF. When any adverse events 
occur, the data should be immediately entered into eCRF and transmitted.
-
all adverse events (AEs) (serious and non-serious), 
-
all AEs with fatal outcome, 
All ADRs including those persisting after study completion must be followed up until they 
are resolved, have been sufficiently characterized, or no further information can be obtained.

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The investigator carefully assesses whether an AE constitutes an ADR using the information 
below.
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g.
situations where other drugs or underlying diseases appear to provide a more likely
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities

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Pregnancy:
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
study, after having taken Ofev capsules, the investigator must report any drug exposure 
during pregnancy, which occurred in a female subject or in a partner to a male subject to the 
Sponsor by means of Part A of the Pregnancy Monitoring Form. The outcome of the 
pregnancy associated with the drug exposure during pregnancy must be followed up and 
reported by means of Part B of the Pregnancy Monitoring Form. 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 
Focused safety specification on J-RMP:
Hepatic function disorders (important identified risks)
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate eCRF pages.
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 capsules 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.
11.4
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local
and international regulatory requirements.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The progress reports and final reports will be submitted to PMDA in Japan Periodic safety 
report. And also the final report for this PMS is included in re-examination documents.
This study is planned for the publication based on the Study report.
The rights of the physician and of the sponsor with regard to publication of the results of this 
PMS study are described in the contract. As a general rule, no PMS study results should be 
published prior to finalization of the Study Report.
In addition, further interim analysis might be performed for the scientific presentations and 
publications for the purposes of promoting appropriate use of Ofev Capsules.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
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)
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)
P14-07514
Richeldi L, et al, INPULSIS Trial Investigators. Efficacy and safety of 
nintedanib in idiopathic pulmonary fibrosis. New England Journal of Medicine, 
published on May 18, 2014, doi: 10.1056/NEJMoa1402584 N Engl J Med 
2014. 370(22):2071-2082
R96-0690
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16(1):31-41.

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APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29889733
4.0
1199-0402-non-interventional-study-protocol
Post-marketing Surveillance of Ofev Capsules in Chronic fibrosing Interstitial Lung
Diseases with a progressive phenotype  in Japan
Approval-Clinical Trial Leader
09 Apr 2024 01:38 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c29889733
4.0