Prospective Observational Investigation of Possible Correlations Between Change in FVC and Change in Cough or Dyspnea Scores Using the Living With Pulmonary Fibrosis Questionnaire (L-PF) Between Baseline and After Approximately 52 Weeks of Nintedanib Treatment in Patients Suffering From Chronic Fibrosing ILD With a Progressive Phenotype
Conditions: Lung Diseases, Interstitial
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
TITLE PAGE
Non-Interventional Study (NIS) Protocol 
TITLE PAGE
Document Number:
c34369089-02
BI Study Number:
1199-0449
BI Investigational
Product(s):
Nintedanib (Ofev®)
Title:
Prospective observational investigation of possible correlations 
between change in FVC and change in cough or dyspnea scores using 
the living with pulmonary fibrosis questionnaire (L-PF) between 
baseline and after approximately 52 weeks of nintedanib treatment in 
patients suffering from chronic fibrosing ILD with a progressive 
phenotype.
Brief lay title:
INREAL – Nintedanib for changes in dyspnea and cough in patients 
suffering from chronic fibrosing interstitial lung disease with a 
progressive phenotype in everyday clinical practice: a real-world 
evaluation
Protocol version 
identifier:
2.0
Date of last version of 
protocol:
8 February 2021
PASS:
No
EU PAS register 
number:
EUPAS38272
Active substance:
Nintedanib
Medicinal product:
Nintedanib
Product reference:
EMEA/H/C/003821
Procedure number:
n.a.
Marketing authorisation 
holder(s):
Joint PASS:
No
Research question and 
objectives:
Primary objective:
The primary objective of this study is to investigate the correlation 
between changes from baseline at 52 weeks in FVC [% pred.] and 
changes from baseline at 52 weeks in dyspnea score [points] or cough 
score [points] as measured with the L-PF questionnaire over 52 weeks 

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Non-interventional Study Protocol
BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
of nintedanib treatment in patients suffering from chronic fibrosing 
ILD with a progressive phenotype (excluding IPF):

Correlation between change from baseline to week 52 in FVC 
[% pred.] and change from baseline to week 52 in dyspnea 
symptom score

Correlation between change from baseline to week 52 in FVC 
[% pred.] and change from baseline to week 52 in cough 
symptom score
Secondary objectives

Correlation between change from baseline to week 52 in FVC 
[mL] and change from baseline to week 52 in dyspnea symptom 
score

Correlation between change from baseline to week 52 in FVC 
[mL] and change from baseline to week 52 in cough symptom 
score

Absolute change from baseline in L-PF cough symptom score at 
week 52

Absolute change from baseline in L-PF dyspnea symptom score 
at week 52
Primary and secondary objectives will be analyzed for the treated set.
Country(-ies) of study:
Germany
Author:
Marketing authorisation 
holder(s):
Date:
8 February 2021
Page 1 of 54
Proprietary confidential information
© 2021 Boehringer Ingelheim Group of companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

Boehringer Ingelheim
                          
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Non-interventional Study Protocol
BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 6
4.
ABSTRACT........................................................................................................... 7
5.
AMENDMENTS AND UPDATES..................................................................... 18
6.
MILESTONES..................................................................................................... 19
7.
RATIONALE AND BACKGROUND................................................................ 19
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 22
9.
RESEARCH METHODS .................................................................................... 23
9.1
STUDY DESIGN............................................................................................ 23
9.2
SETTING........................................................................................................ 24
9.2.1
Study sites ............................................................................................... 25
9.2.2
Study population ..................................................................................... 25
9.2.3
Study visits .............................................................................................. 26
9.2.4
Study discontinuation.............................................................................. 30
9.3
VARIABLES .................................................................................................. 30
9.3.1
Exposures ................................................................................................ 31
9.3.2
Objectives and Outcomes........................................................................ 32
9.3.2.1
Primary outcomes............................................................................. 33
9.3.2.2
Secondary outcomes......................................................................... 33
9.3.3
Covariates................................................................................................ 34
9.4
DATA SOURCES........................................................................................... 34
9.5
STUDY SIZE.................................................................................................. 35
9.6
DATA MANAGEMENT................................................................................ 36
9.6.1
Data Entry / EDC .................................................................................... 37
9.6.2
Source Documents................................................................................... 37
9.6.3
File Retention and Archiving.................................................................. 38
9.7
DATA ANALYSIS......................................................................................... 38
9.7.1
Main analysis........................................................................................... 38
9.7.3
Safety Analysis........................................................................................ 39

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BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
9.8
QUALITY CONTROL................................................................................... 40
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 40
9.9.1
Data quality assurance............................................................................. 41
9.9.2
Study records........................................................................................... 41
9.9.2.1
Source documents ............................................................................ 41
9.9.2.2
Direct access to source data and documents .................................... 41
9.9.3
Completion of study................................................................................ 41
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 42
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED
CONSENT ...................................................................................................... 42
10.2
STATEMENT OF CONFIDENTIALITY...................................................... 42
10.3
BENEFIT-RISK ASSESSMENT ................................................................... 43
10.4
INFLUENCE OF COVID- 19 PANDEMIC ON THE STUDY 
PARTICIPANTS ............................................................................................ 44
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 45
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 45
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION
AND REPORTING......................................................................................... 47
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 49
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY
RESULTS............................................................................................................ 50
13.
REFERENCES .................................................................................................... 50
13.1
PUBLISHED REFERENCES......................................................................... 50
13.2
UNPUBLISHED REFERENCES................................................................... 50
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 51
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 52
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 53
ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES................................... 54

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Non-interventional Study Protocol
BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
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
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
eCRF
Electronic Case Report Form
ENCePP 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
GVP
Good Pharmacovigilance Practices
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
MAH
Marketing Authorization Holder
MedDRA
Medical Dictionary for Regulatory Activities
NIS
Non-Interventional Study
PASS
Post-Authorization Safety Study
SAE
Serious Adverse Event

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BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
3.
RESPONSIBLE PARTIES
Function
Name
Contact details
NIS 
phone:
Principle Investigator
(Wissenschaftlicher 
Leiter)
CRO
Statisticians
(oversight)
The study will be fully funded by Boehringer Ingelheim Pharma GmbH & Co. KG.

Boehringer Ingelheim
                          
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BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev®
Name of active ingredient:
L01XE31 Nintedanib
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
15-Dec-2020
1199-0449
2.0
8-Feb-2021
Title of 
study:
Prospective observational investigation of possible correlations between change in 
FVC and change in cough or dyspnea scores using the living with pulmonary fibrosis 
questionnaire (L-PF) between baseline and after approximately 52 weeks of nintedanib 
treatment in patients suffering from chronic fibrosing ILD with a progressive 
phenotype.
INREAL – Nintedanib for changes in dyspnea and cough in chronic PF-ILD patients 
in everyday clinical practice: a real-world evaluation
Rationale 
and 
background:
The term interstitial lung disease (ILD) encompasses a large group of > 200 
parenchymal pulmonary disorders, of which the majority are classified as rare. The most 
widely studied and most common ILD is Idiopathic Pulmonary Fibrosis (IPF). It is 
characterized by progressive fibrosis, lung scarring and a radiological pattern known as 
usual interstitial pneumonia (UIP). Several other ILDs (such as hypersensitivity 
pneumonitis (HP), rheumatoid arthritis-associated ILD (RA-ILD) and Systemic 
Sclerosis-ILD (SSc-ILD)) may present a progressive fibrosing phenotype as well. 
Given their overlapping clinical, radiological and pathological presentations, a
terminology to describe these patients may be “chronic fibrosing ILD with a progressive 
phenotype”.
Figure 1 Classification of Interstitial Lung Disease (from 1).

Boehringer Ingelheim
                          
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Non-interventional Study Protocol
BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev®
Name of active ingredient:
L01XE31 Nintedanib
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
15-Dec-2020
1199-0449
2.0
8-Feb-2021
Progressive fibrosis of the lung parenchyma is self-sustaining and causes progressive 
deterioration in lung function, respiratory symptoms such as dyspnea. It therefore 
increases the risk of early death2. Cough and quality of life are also part of the 
progressive deterioration. 
Scientific evidence shows from both the TOMORROW and the INPULSIS-1 and -2 
trials that nintedanib is effective and its’ side effects are manageable for the treatment 
of IPF in patients with different degrees of lung function impairment3,4,5. The available 
real-world data confirmed the safety and efficacy profiles of nintedanib in IPF that were 
established in clinical trials6.
Furthermore, nintedanib was shown to significantly slow the annual rate of decline in 
the forced vital capacity (FVC) in patients with progressive fibrosing ILD7. In the 
INBUILD trial, which included ILD patients with a variety of underlying interstitial 
lung diseases, the magnitude of this benefit was similar to that previously described in 
the IPF population5. The treatment effect was consistent for patients with a UIP-like 
pattern as well as other patterns on HRCT, and also consistent across pre-defined 
subgroups of ILD diagnoses.
Insights from INBUILD further support the initial hypothesis that common traits in 
fibrotic mechanisms explain the clinical similarity of IPF and other fibrosing ILDs. In 
SENSCIS, patients suffering from SSc-ILD and treated with nintedanib were shown to 
have a reduced annual rate of decline in FVC vs patients in the placebo arm; though no 
clinical benefit of nintedanib was observed for other manifestations of systemic 
sclerosis8.
To our knowledge, the effects of an antifibrotic therapy with nintedanib on the patient-
reported outcomes (PRO) dyspnea or cough has only been investigated scarcely, 
especially in a real-world cohort. 
This may partly be due to a lack of well-established, simple to use patient 
questionnaire that focuses on such symptoms. The living with pulmonary fibrosis 
questionnaire (L-PF) was used in the INBUILD trial. The complete L-PF 
questionnaire is a 44 item questionnaire with two modules: 1) symptoms (23 items) 
and 2) impacts (21 items). In this NIS, we will use the whole questionnaire. Its 
symptom part consists of three subdomains a) dyspnea b) cough c) fatigue (together 23 
items). Each question is answered by the patient indicating one tick-box answer per 
question. Only one statement can be chosen. L-PF symptoms domain scores range 
from 0 to 100; the higher the score, the greater the impairment. An improved 
understanding of the patients’ situation will benefit from further investigation of this 
instrument generated in a real-world setting.

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Non-interventional Study Protocol
BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev®
Name of active ingredient:
L01XE31 Nintedanib
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
15-Dec-2020
1199-0449
2.0
8-Feb-2021
Results from INBUILD show that differences in the change of the score for cough and 
dyspnea from baseline to 52 weeks were statistically significant in favor of nintedanib, 
comparing treatment arm with placebo1.. Those differences were small. A meaningful 
threshold (“MCID”) has not been established for the L-PF questionnaire so far.
By applying the L-PF questionnaire and capturing the FVC, we want to further 
investigate whether there are correlations between change of FVC (∆FVC: 52 weeks 
vs baseline) and change in cough or dyspnea score (∆cough, ∆dyspnea: 52 weeks vs 
baseline) respectively, in this real-world patient population as well.  Data from a real-
world patient population may strengthen the data basis on this issue.
We are planning to include patients with chronic fibrosing ILD with a progressive 
phenotype excluding IPF patients. Regarding their specific form of chronic fibrosing 
ILD with a progressive phenotype, patients will be enrolled based on their phenotype 
and not on predetermined ILDs. – The study will include a pre-specified analysis of 
outcomes according to specific diagnoses, as the L-PF questionnaire was specifically 
developed for and validated in patients with chronic fibrosing ILD with a progressive 
phenotype, except IPF1. Furthermore, we plan to investigate a possible change in 
dyspnea and cough scores under nintedanib treatment, to answer the question whether 
nintedanib has a direct effect on PROs in a real-world patient population. 
All patients will receive nintedanib according to standard of care, i. e. there will be no 
untreated comparison group in this study. Given the natural course of the disease, this 
poses a limitation in that results from the treated group will be difficult to interpret 
meaningfully in the absence of a reference group to demonstrate how the study 
outcomes appear in the absence of treatment in the real world setting.
In conclusion, this prospective, non-interventional study (NIS) aims to assess a 
possible correlation between the reduction of FVC decline and symptomatic burden 
under nintedanib treatment for 52 weeks in 100 patients with chronic fibrosing ILD 
with a progressive phenotype, measured as a possible change in dyspnea and cough 
scores from baseline using the L-PF questionnaire in a real-world patient population.

Boehringer Ingelheim
                          
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Non-interventional Study Protocol
BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev®
Name of active ingredient:
L01XE31 Nintedanib
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
15-Dec-2020
1199-0449
2.0
8-Feb-2021
Research 
question and 
objectives:
The primary objective of this observational study is to investigate changes in dyspnea 
or cough as measured with the L-PF questionnaire over 52 weeks of nintedanib 
treatment in patients suffering from chronic fibrosing ILD with a progressive 
phenotype (excluding IPF), including a snapshot-analysis before last patient in, to 
evaluate a possible correlation between changes in FVC and L-PF (dyspnea and 
cough).
This is the first RWE study in patients suffering from chronic fibrosing ILD with a 
progressive phenotype in Germany being treated with nintedanib. In addition, the 
German healthcare system is currently strongly supporting all necessary activities to 
fight the global Covid-19 pandemic with possible effects on the conduct of this study. 
In order to be able to identify and counteract possible restrictions due to these 
circumstances, a descriptive snapshot analysis is planned at the time of Last Patient In 
(LPI) in this study.
With regard to the current COVID-19 pandemic, it was considered that all patients to 
be included into this NIS suffer from a severe medical condition and are in need of 
treatment according to their treating physician’s assessment. The patients will be 
treated in usual care, no additional visits or examinations are demanded or required 
other than in clinical routine. So there is no additional risk for the patients in the 
COVID-19 pandemic caused by the study apart from their inherent risk as patients 
with a serious systemic disease affecting the lung.
The study hypothesis is that in a one year observational study a correlation can be 
found between changes in lung function measured by FVC and the changes in the 
scores for dyspnea and cough of the L-PF questionnaire in ILD patients.
Study 
design:
Observational study according to §4, section 23 and §67, section 6 German Medicines 
Act (NIS) based on newly collected data.

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Non-interventional Study Protocol
BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev®
Name of active ingredient:
L01XE31 Nintedanib
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
15-Dec-2020
1199-0449
2.0
8-Feb-2021
Population:
Patients to be recruited within this study have to have a physician diagnosed chronic  
fibrosing ILD with a progressive phenotype (except IPF), for which nintedanib is an 
indicated treatment.
Before visit 1, patients must not have been treated with either nintedanib or 
pirfenidone, i. e., all patients are considered treatment naïve with regard to these 
antifibrotic treatments. 

Only patients, for whom their treating physician has made the clinical decision 
to start nintedanib treatment (but not actually started treatment) independently 
of this study, are eligible to enter the study. 

During the study, all patients are treated with nintedanib. For each individual 
patient, a treatment observation period of 52 weeks is aimed for. Handling of 
patient data with shorter observation period is going to be described in the SAP.
Inclusion criteria

Adults ≥ 18 years at Visit 1

Subjects must be contractually capable and mentally able to understand and 
follow the instructions of the study personnel

Physician’s diagnosis of chronic fibrosing ILD with a progressive phenotype, 
except IPF

Treatment with nintedanib in INREAL will be the first and only prescription 
of any antifibrotic treatment for each individual patient within this 
observational study after a physician’s decision being made for this treatment 
option earlier

Outpatients not currently hospitalized with a life expectancy > 12 months per 
investigator’s assessment

Written informed consent prior to study participation

Current FVC measurement (taken within the last 3 months) available in the 
patient file

Women of childbearing potential must take appropriate precautions against 
getting pregnant during the intake of nintedanib.

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BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev®
Name of active ingredient:
L01XE31 Nintedanib
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
15-Dec-2020
1199-0449
2.0
8-Feb-2021
Exclusion criteria

Patients with contraindications according to SmPC 

Prior use of antifibrotic treatment

Pregnant or lactating females

Lack of informed consent 

Any physician diagnosed exacerbation of ILD in the patient’s history, 
irrespective of time since event

Current diagnosis of lung cancer

Respiratory failure (pH < 7,35 and/or respiratory rate > 30/min) in the patient’s 
history

Participation in a parallel interventional clinical trial
Patients being spouse or lateral relatives to the second degree or economically 
dependent from the investigator

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BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev®
Name of active ingredient:
L01XE31 Nintedanib
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
15-Dec-2020
1199-0449
2.0
8-Feb-2021
Variables:
Parameter
Visit 1;
baseline 
visit
Visit 2;
(optional) 
ca. week 
13
Visit 3;
mid of 
observa-
tion; ca. 
week 26* 
Visit 4;
(optional) 
ca. week 
39
Visit 5;
end of 
observa-
tion; ca. 
week 52
Visit 6
FU ca. 
week 52**
Informed Consent
X
Inclusion / Exclusion 
Criteria
X
Patient demographics 
(age, gender, height, and 
weight)
X
Smoking history
X
History of ILD, including 
ILD entity and HRCT 
pattern (where available 
in patient documentation)
X
current DLCO measures 
(where available in 
patient documentation)
X
X
X
X
X
Concomitant diseases / 
Comorbidities
X
X
X
X
X
Past ILD therapies (6 
weeks before visit 1)
X
Current ILD related or 
other relevant 
concomitant medication
X
X
X
X
X
FVC (mL and % pred.; if 
available in patient data)
X
X
X
X
X
X
Severity of disease as per 
the treating physician’s 
estimation (if available in 
patient data)
X
X
X
X
X
X
L-PF questionnaire, 
completed by patient
X
X
X
X
X
X
Safety: Adverse Drug 
Reactions (serious and 
non-serious), fatal AEs, 
pregnancy
X
X
X
X
X
X

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BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev®
Name of active ingredient:
L01XE31 Nintedanib
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
15-Dec-2020
1199-0449
2.0
8-Feb-2021
Parameter
Visit 1;
baseline 
visit
Visit 2;
(optional) 
ca. week 
13
Visit 3;
mid of 
observa-
tion; ca. 
week 26* 
Visit 4;
(optional) 
ca. week 
39
Visit 5;
end of 
observa-
tion; ca. 
week 52
Visit 6
FU ca. 
week 52**
Rationale for treatment 
discontinuation (if 
applicable)
X
X
X
X
Further treatment options 
yes/no (as applicable
X
X
X
X
X
Intention to continue or 
discontinue treatment 
with nintedanib after the 
study (yes/no)
X
X
X
X
Survival data
X
* after 26 weeks of observation for each individual patient
** if available and/or patients is willing to perform, phone contact acceptable
In addition to the mandatory visits, i.e. Visit 1 (baseline), Visit 3 (mid of observation; 
26 weeks after baseline) and Visit 5 (end of observation) and Visit 6 (Follow-up 52 
weeks after baseline), optional study visits will be enabled between V1 and V3 (V2) as 
well as between V3 and V5 (V4), each occurring about midway between V1 and V3 or 
V3 and V5, respectively. Therefore, patients will be seen by their study investigator at 
least every 6 months and up to every quarter of the observational period.
When optional visits are conducted, then the same parameters as in Visit 3 should be 
documented.
Each visit should take place not earlier than six weeks before and no later than six 
weeks after the planned visit date and thus reflect patients’ and physicians’ real-world 
experience.
Survival data are to be collected 52 weeks after inclusion for all patients - including 
those patients who drop out. Patients who discontinue the study before week 52 for 
any reason should be contacted for survival status and follow-up data at week 52 (visit 
6). For all other patients, visit 5 and visit 6 are completed in the same visit.

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BI Study Number 1199-0449                                                                         c34369089-02       
001-MCS-90-118_RD-23 (2.0) / Saved on: 02 Jul 2020
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev®
Name of active ingredient:
L01XE31 Nintedanib
Protocol 
date:
Study number:
Version/Revision:
Version/Revision date:
15-Dec-2020
1199-0449
2.0
8-Feb-2021
Data 
sources:
In this NIS, information about the effect of a treatment with nintedanib on differences 
in cough and dyspnea scores, measured via the L-PF questionnaire, will be collected 
and this information will be assessed in relation to FVC from these patients’ medical 
files in patients with chronic fibrosing ILD with a progressive phenotype from 100 
patients in about 20 study centers throughout Germany by specialized physicians 
(pulmonologists, rheumatologists) experienced in the treatment of ILD patients.
Study size:
In the INBUILD trial, patient groups on placebo vs nintedanib therapy differed in both 
their loss of FVC and dyspnea and cough symptom scores in the L-PF questionnaire 
(Fig. 2; see below).
Fig. 2 Changes in dyspnea (left) and cough (right), respectively, seen in INBUILD
FVC, dyspnea and cough symptom scores from INBUILD (see Tab. 1 below) 
were applied to estimate sample sizes.
Correlation between change from baseline FVC (both FVC in mL and FVC as 
% predicted) and change from both L-PF dyspnea symptom score and cough symptom
score for the treated set at 52 weeks of treatment were ≈ -0.3 for the Pearson 
correlation coefficient in the nintedanib arm (see Tab. 2 below)11.

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BI Study Number 1199-0449                                                                         c34369089-02       
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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev®
Name of active ingredient:
L01XE31 Nintedanib
Protocol date:
Study 
number:
Version/Revision:
Version/Revision date:
15-Dec-2020
1199-0449
2.0
8-Feb-2021
Data analysis:
Tab. 2 Pearson correlation for change from baseline to week 52 between FVC and L-PF 
symptoms scores in the nintedanib arm (Values were similar for the total population.)
Currently, a meaningful threshold (“MCID”) for neither the cough nor the dyspnea 
domain of the L-PF has been published. However, should that information become 
available during the study, study results will be discussed in relation to the 
meaningful threshold (“MCID”) values.
Given a correlation ρ between change from baseline to week 52 in FVC [% pred.] and 
change from baseline to week 52 in dyspnea symptom score as well between change 
from baseline to week 52 in FVC [% pred.] and change from baseline to week 52 in 
cough symptom score of approximately -0.3, then 84 patient data sets would be 
required for evaluation. Assuming an estimated drop-out rate of approx. 15 % 100 
patients will have to be recruited for this study. With this patient number (N = 84) and 
the assumption of a Pearson correlation of -0.3, the overall type I error is protected at 
the two-sided 0.05 level with a power of 80 %.
Lower
Upper
L-PF symptoms dyspnoe score and …
FVC in ml
-0.35
-0.45
-0.23
FVC (% predicted)
-0.37
-0.47
-0.26
L-PF symptoms cough score and …
FVC in ml
-0.26
-0.37
-0.14
FVC (% predicted)
-0.26
-0.37
-0.14
95% Confidence interval
Pearson correlation (change from baseline at 
week 52) between FVC and L-PF symptoms 
Coefficient

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BI Study Number 1199-0449                                                                         c34369089-02       
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Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Ofev®
Name of active ingredient:
L01XE31 Nintedanib
Protocol 
date:
15-Dec-2020
Study number:
1199-0449
Version/Revision:
2.0
Version/Revision date:
8-Feb-2021
Therefore 100 patients are planned to be recruited for this NIS by about 20 specialists, 
experienced in treating ILD patients, (e. g., pulmonologists and rheumatologists) 
throughout Germany. Each investigator will include ca. 5 consecutive patients for whom 
he/she had decided for a treatment with nintedanib before actual recruitment of the 
patient. The treatment decision will have to have taken place before actual recruitment of 
the patient.
Due to the observational nature of the study, all analyses are exploratory. 
No weighting will be applied to either of the co-primary endpoints.

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BI Study Number 1199-0449                                                                         c34369089-02       
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5.
AMENDMENTS AND UPDATES
V 1.0 dated 11 December 2020
V 2.0 dated 8 February 2021

Changes as recommended by the ethics committee Medizinische Fakultät Heidelberg 
in chapter 9.2.3 Study visits

Changes as recommended by the ethics committee Medizinische Fakultät Heidelberg 
in chapter 10 Protection of human subjects

Two additional further outcomes added in chapter 9.3.2.3 Further Outcomes as 
recommended by TSTAT.

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BI Study Number 1199-0449                                                                         c34369089-02       
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6.
MILESTONES
Milestone
Planned Date
IRB/IEC approval
Feb 2021
Start of data collection
Feb 2021
End of data collection
Feb 2023
Final report of study results:
Oct 2023
7.
RATIONALE AND BACKGROUND
The term interstitial lung disease (ILD) encompasses a large group of > 200 parenchymal 
pulmonary disorders, of which the majority are classified as rare. The most widely studied 
and most common ILD is Idiopathic Pulmonary Fibrosis (IPF). It is characterized by 
progressive fibrosis, lung scarring and a radiological pattern known as usual interstitial 
pneumonia (UIP). Several other ILDs (such as hypersensitivity pneumonitis (HP), 
rheumatoid arthritis-associated ILD (RA-ILD) and Systemic Sclerosis-ILD (SSc-ILD)) may 
present a progressive fibrosing phenotype as well. 
Given their overlapping clinical, radiological and pathological presentations, a terminology to 
describe these patients may be “chronic fibrosing ILD with a progressive phenotype”.
Figure 7:1 Classification of Interstitial Lung Disease (from 1).

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BI Study Number 1199-0449                                                                         c34369089-02       
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Progressive fibrosis of the lung parenchyma is self-sustaining and causes progressive 
deterioration in lung function, respiratory symptoms such as dyspnea. It therefore increases 
the risk of early death[2]. Cough and quality of life are also part of the progressive 
deterioration. 
Scientific evidence shows from both the TOMORROW and the INPULSIS-1 and -2 trials 
that nintedanib is effective and it’s side effects are manageable for the treatment of IPF in 
patients with different degrees of lung function impairment[3][4][5]. The available real-world 
data confirmed the safety and efficacy profiles of nintedanib in IPF that were established in 
clinical trials[6].
Furthermore, nintedanib was shown to significantly slow the annual rate of decline in the 
forced vital capacity (FVC) in patients with progressive fibrosing ILD[7]. In the INBUILD 
trial, which included ILD patients with a variety of underlying interstitial lung diseases, the 
magnitude of this benefit was similar to that previously described in the IPF population[5]. 
The treatment effect was consistent for patients with a UIP-like pattern as well as other 
patterns on HRCT, and also consistent across pre-defined subgroups of ILD diagnoses.
Insights from INBUILD further support the initial hypothesis that common traits in fibrotic 
mechanisms explain the clinical similarity of IPF and other fibrosing ILDs. In SENSCIS, 
patients suffering from SSc-ILD and treated with nintedanib were shown to have a reduced 
annual rate of decline in FVC vs patients in the placebo arm; though no clinical benefit of 
nintedanib was observed for other manifestations of systemic sclerosis[9].
To our knowledge, the effects of an antifibrotic therapy with nintedanib on the patient-
reported outcomes (PRO) dyspnea or cough has only been investigated scarcely, especially in 
a real-world cohort. 
This may partly be due to a lack of well-established, patient questionnaire that focuses on 
such symptoms. The living with pulmonary fibrosis questionnaire (L-PF) was used in the 
INBUILD trial. The complete L-PF questionnaire is a 44 item questionnaire with two 
modules: 1) symptoms (23 items) and 2) impacts (21 items). In this NIS, we will use the 
whole L-PF questionnaire. Its symptom part consists of three subdomains a) dyspnea b) 
cough c) fatigue (together 23 items). Each question is answered by the patient indicating one 
tick-box answer per question. Only one statement can be chosen.  L-PF symptoms domain 
scores range from 0 to 100; the higher the score, the greater the impairment. An improved 
understanding of the patients’ situation will benefit from further investigation of this 
instrument in a real-world setting.
Results from INBUILD show that differences in the change of the score for cough and 
dyspnea from baseline to 52 weeks were statistically significant in favor of nintedanib, 
comparing treatment arm with placebo[12]. Those differences were small. The meaningful 
threshold (“MCID”) has not been established for the L-PF questionnaire so far.
By applying the L-PF questionnaire and capturing the FVC, we want to further investigate 
whether there are correlations between change of FVC (∆FVC: 52 weeks vs baseline) and 
change in cough or dyspnea score (∆cough, ∆dyspnea: 52 weeks vs baseline) respectively, in 
this real-world patient population as well.  Data from a real-world patient population may 
strengthen the data basis on this issue.

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BI Study Number 1199-0449                                                                         c34369089-02       
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We are planning to include patients with chronic fibrosing ILD with a progressive phenotype
excluding IPF patients. Regarding their specific form of chronic fibrosing ILD with a 
progressive phenotype, patients will be enrolled based on their phenotype and not on 
predetermined ILDs. – The study will include a pre-specified analysis of outcomes according 
to specific diagnoses, as the L-PF questionnaire was specifically developed for and validated 
in patients with chronic fibrosing ILD with a progressive phenotype, except IPF1. 
Furthermore, we plan to investigate a possible change in dyspnea and cough scores under 
nintedanib treatment, to answer the question whether nintedanib has a direct effect on PROs 
in a real-world patient population. 
All patients will receive nintedanib according to standard of care; i. e. there will be no 
untreated comparison group in this study. Given the natural course of the disease, this poses a 
limitation in that results from the treated group will be difficult to interpret meaningfully in 
the absence of a reference group to demonstrate how the study outcomes appear in the 
absence of treatment in the real world setting. However, data from this study will 
complement the data from INBUILD and INBUILD-ON, which can in turn provide context 
to this study.
In conclusion, this prospective, non-interventional study (NIS) aims to assess a possible 
correlation between the reduction of FVC decline and symptomatic burden under nintedanib 
treatment for 52 weeks in 100 patients with chronic fibrosing ILD with a progressive 
phenotype, measured as a possible change in dyspnea and cough scores from baseline using 
the L-PF questionnaire in a real-world patient population.

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BI Study Number 1199-0449                                                                         c34369089-02       
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8.
RESEARCH QUESTION AND OBJECTIVES
Primary objective
The primary objective of this observational study is to investigate the correlation between 
changes from baseline at 52 weeks in FVC [% pred.] and changes from baseline at 52 weeks 
in dyspnea score [points] or cough score [points] as measured with the L-PF questionnaire 
over 52 weeks of nintedanib treatment in patients suffering from chronic fibrosing ILD with a 
progressive phenotype (excluding IPF):

Correlation between change from baseline to week 52 in FVC [% pred.] and change 
from baseline to week 52 in dyspnea symptom score

Correlation between change from baseline to week 52 in FVC [% pred.] and change 
from baseline to week 52 in cough symptom score
Secondary objectives

Correlation between change from baseline to week 52 in FVC [mL] and change from 
baseline to week 52 in dyspnea symptom score

Correlation between change from baseline to week 52 in FVC [mL] and change from 
baseline to week 52 in cough symptom score

Absolute change from baseline in L-PF cough symptom score at week 52

Absolute change from baseline in L-PF dyspnea symptom score at week 52
Primary and secondary objectives will be analyzed for the treated set.
Additional objectives
Further outcomes will be described in Section 9.3.2.2 of the protocol.
Collection of serious and non-serious adverse drug reactions and fatal adverse effects during 
the whole NIS (52 weeks) and reporting according to relevant SOP.
This is the first RWE study in patients suffering from chronic fibrosing ILD with a 
progressive phenotype in Germany being treated with nintedanib. In addition, the German 
healthcare system is currently strongly supporting all necessary activities to fight the global 
Covid-19 pandemic with possible effects on the conduct of this study. In order to be able to 
identify and counteract possible restrictions due to these circumstances, a descriptive 
snapshot analysis is planned at the time of Last Patient In (LPI) in this study.

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BI Study Number 1199-0449                                                                         c34369089-02       
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9.
RESEARCH METHODS
9.1
STUDY DESIGN
Single-arm, open-label observational cohort study according to §4, section 23 and §67, 
section 6 German Medicines Act (NIS): All included chronic fibrosing ILD with a 
progressive phenotype patients will receive treatment with nintedanib for approximately 52 
weeks. NIS based on newly collected data.
Primarily, this study aims to observe the course of FVC, dyspnea- and cough scores in the L-
PF questionnaire over 52 weeks of nintedanib treatment in patients suffering from chronic 
fibrosing ILD with a progressive phenotype (but not IPF) and investigate possible 
correlations between

Correlation between change from baseline to week 52 in FVC [% pred.] and 
change from baseline to week 52 in dyspnea symptom score; safety issue: no

Correlation between change from baseline to week 52 in FVC [% pred.] and 
change from baseline to week 52 in cough symptom score; safety issue: no
from each individual patient’s difference between baseline and after 52 weeks of treatment 
with nintedanib. Secondary objectives are change in L-PF cough and dyspnea symptom 
scores over time.

Correlation between change from baseline to week 52 in FVC [mL] and change from 
baseline to week 52 in dyspnea symptom score; safety issue: no

Correlation between change from baseline to week 52 in FVC [mL] and change from 
baseline to week 52 in cough symptom score; safety issue: no

Absolute change from baseline in L-PF cough symptom score at week 52

Absolute change from baseline in L-PF dyspnea symptom score at week 52
In Germany, more than 99.9 % of citizens are health insured and usually treatment expenses 
for approved drugs are covered by the health insurance. Therefore, patients receive treatment, 
except those unwilling to be treated. Those patients are very rare and not suitable as a control 
group. As Nintedanib is the first treatment approved in Germany in this indication, a 
comparator arm is not feasible. As treatment is available, a NIS with a placebo group will not 
get ethical approval in Germany. 
Patients recruited for this non interventional study will be treatment-naïve for prior 
antifibrotic treatment. This will allow to collect clinical baseline data before starting any 
therapy. After 52 weeks, we will be able to compare these baseline data with the data 
collected while on nintedanib treatment at the study visits for up to 52 weeks. However, it 
should be mentioned that due to the natural course of the disease, FVC is expected to decline 
during the study for the population. As an untreated or placebo group is not planned for due 

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BI Study Number 1199-0449                                                                         c34369089-02       
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to ethical reasons, this limitation needs to be considered. However, efficacy and safety of 
nintedanib have been well established in the RCT INBUILD, also in comparison to placebo. 
Among others the following will be analyzed:

comparison of patient data at baseline (patients have no prior antifibrotic treatment) vs 
data after 52 weeks of nintedanib treatment.

comparison of the correlation ∆FVC and ∆cough/∆dyspnea in the first 26 weeks with 
vs correlation ∆FVC and ∆cough/∆dyspnea in the last 26 weeks.
This approach will allow for comparison between patients untreated and patients after up to 
52 weeks of nintedanib treatment as well as during the first and second half year of treatment.
9.2
SETTING
In this NIS, data on the effect of a nintedanib in chronic fibrosing ILD with progressive 
phenotype in about 100 patients will be collected in routine clinical practice by ca. 20 
specialists, experienced in treating ILD patients, (e. g. pulmonologists and rheumatologists) 
throughout Germany. Each investigator will include ca. 5 consecutive patients for whom the 
physician had decided on a nintedanib treatment before. 
Per definition, non-interventional studies do not include any randomization. In this study, 
there will be no procedure outside routine clinical practice. Patients will be recruited for this 
study only after a physician’s therapeutic decision to treat the individual patient with 
nintedanib. 
For ethical and/or medical reasons, patients with contraindications (CI) to nintedanib 
according to SmPC, including pregnant or lactating women, current cancer patients, patients 
not willing to consent and patients being spouse or lateral relatives to the second degree or 
economically dependent from the investigator will be excluded. 
All calculations for this study, including statistics and patient numbers, are based on the 
randomized clinical trial INBUILD. In order to be able to duplicate the most crucial design 
features, in this study nintedanib will solely be tested as a first and only antifibrotic treatment 
in PF-ILD patients, as it was in INBUILD. Therefore, in accordance with INBUILD trial 
design, patients must not have used or use any antifibrotic before or during this observational 
study apart from nintedanib.
This study is planned to observe patients for 12 months. Therefore, patients with a life 
expectancy of 12 months or less should not be included. As acute exacerbations severely 
impact life expectancy, patients with acute ILD exacerbations should not be included in the 
study12.
Patients must not participate in a parallel interventional clinical trial for not to interfere with 
the study aims and outcomes.

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BI Study Number 1199-0449                                                                         c34369089-02       
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The impact of excluding those patients seems low, as the number is expected to be minimal 
and patients with contraindications in any case would not be treated with nintedanib.
9.2.1
Study sites
Data collection of approximately 100 patients from approximately 20 recruiting sites, 
experienced in treating ILD patients, (e. g., pulmonologists and rheumatologists) throughout
Germany is planned. Site selection will be performed to reflect routine care for chronic 
fibrosing ILD patients with a progressive phenotype in Germany in order to secure 
representativeness of this specific ILD population. 
9.2.2
Study population
Indication
Patients to be recruited within this study have to have a physician diagnosed chronic fibrosing 
ILD with a progressive phenotype (except IPF), for which nintedanib is an indicated 
treatment.
Before visit 1, patients must not have been treated with either nintedanib or pirfenidone, i. e., 
all patients are considered treatment naïve with regard to these antifibrotic treatments. 

Only patients, for whom their treating physician has made the clinical decisions to 
start nintedanib treatment (but not actually started treatment) independently of this 
study, are eligible to enter the study. 

During the study, all patients are treated with nintedanib according to standard of 
care. For each individual patient, a treatment observation period of 52 weeks is aimed 
for. Handling of patient data with shorter observation period is going to be described 
in the SAP.
Inclusion criteria

Adults ≥ 18 years at Visit 1

Subjects must be contractually capable and mentally able to understand and follow the 
instructions of the study personnel

Physician’s diagnosis of chronic fibrosing ILD with a progressive phenotype, except 
IPF

Treatment with nintedanib in INREAL will be the first and only prescription of any 
antifibrotic treatment for each individual patient within this observational study after a 
physician’s decision being made for this treatment option earlier

Outpatients not currently hospitalized with a life expectancy > 12 months per 
investigator’s assessment

Written informed consent prior to study participation

Current FVC measurement (taken within the last 3 months) available in the patient 
file

Women of childbearing potential must take appropriate precautions against getting 
pregnant during the intake of nintedanib.

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BI Study Number 1199-0449                                                                         c34369089-02       
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Exclusion criteria

Patients with contraindications acc. to SmPC 

Prior use of any antifibrotic treatment

Lack of informed consent 

Pregnant or lactating females

Any physician diagnosed exacerbation of ILD in the patient’s history file, irrespective 
of time since event

Current diagnosis of lung cancer

Respiratory failure (pH < 7,35 and/ or respiratory rate > 30/min) in the patient’s 
history

Participation in a parallel interventional clinical trial

Patients being spouse or lateral relatives to the second degree or economically 
dependent from the investigator 
Recently, an ILD incidence rate of 20–30 per 100,000 person-years was suggested for 
populations across Europe13.
Suitable patients shall be included consecutively at the sites. Patient selection and proposition 
of study participation by the investigator will be conducted independently from the treatment 
decision and after the treatment decision has been agreed between the treating physician and 
the patient. 
If the patient is interested in study participation, the treating physician will explain the study 
details including the nature and importance of the study and its impact on health and potential 
risks, both orally and in writing. The patient will have ample time to read the information, ask 
questions and consider study participation before giving written informed consent.
For more details see sections 9.2.3 (Study Visits) and 10.1. (STUDY APPROVAL, 
PATIENT INFORMATION AND INFORMED CONSENT).
A subject screening log will be kept at the site or in the study electronic portal, recording 
basic information (e.g. initials, gender, date of birth, reason for not enrolling the patient etc.) 
on all patients who were invited to participate in the study, with information on the eligibility 
(or reasons for non-eligibility) and date of signed informed consent, if applicable. In the case 
of refusal, reasons for refusal should be given. In addition, a log of all patients included into 
the study (i.e. having given informed consent) will be maintained in the main study file at the 
study site. 
9.2.3
Study visits
In this NIS, data on the effect of a treatment with nintedanib on differences in cough and 
dyspnea scores, measured via the L-PF questionnaire, will be collected and this information 
will be assessed in relation to FVC from these patients’ medical files in patients with chronic 
fibrosing ILD with a progressive phenotype.

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BI Study Number 1199-0449                                                                         c34369089-02       
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Four visits are mandatory within this study:
V1 –
baseline visit
V3 –
mid-observation period
planned visit date: 26 weeks after V1
must not take place earlier than week 20 or later than week 32 after V1
V5 –
end of observation
planned visit date: 52 weeks after V1, must not take place earlier than week 46 or later than 
week 58 after V1
V6 –
Follow-up 52 weeks after start of treatment
Each of these visit should take place not earlier than six weeks before and not later than six 
weeks after the planned visit date (V1 + 26 weeks; V1 + 52 weeks) and thus reflect patients’ 
and physicians’ real-world experience.
In addition to Visits 1, 3 and 5 described here, optional study visits will be enabled between 
V1 and V3 as well as between V3 and V5, each occurring about midway between V1 and V2 
or V2 and V3, respectively. Optional visits should take place 
optional Visit V2:  planned visit date week 13 after V1
if applicable, V2 must not take place earlier than week 7 or later than week 20 after 
V1
optional visit V4:  planned visit date week 39 after V1
if applicable V4 must not take place earlier than week 33 or later than week 45 after 
V1
When optional visits are conducted, then the same parameters as in Visit 3 should be 
documented.
Therefore, patients will be seen by their investigator at least every 6 months and up to every 
quarter of the observational period.
The baseline visit will take the patients ca. one hour including filling out the questionnaires, 
visits 2 to 6 will take about 30 minutes each. All data documented during those visits, 
including the questionnaires, record examinations and information necessary during the 
course of the disease and nintedanib treatment. 
If possible, patients who discontinue the study before week 52 for any reason should be 
contacted for survival status and follow-up data at week 52, as available (Visit 6). A phone 
contact with the patient / relatives / family doctor is acceptable for V6.
So, the time needed by the patient for the whole study depends on the number of visits 
performed. The duration of each visit depends on the amount of data to be collected and the 
possible questions to be discussed between investigator and participant. For baseline, we 

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BI Study Number 1199-0449                                                                         c34369089-02       
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presume about one hour, for the following visits about 30 minutes including filling out the 
questionnaire. 
All details on the data collected and tasks performed at each visit are shown in table 9.2.3: 1.
Table 9.2.3: 1 Flow Chart
Parameter
Visit 1;
baseline 
visit
Visit 2;
(optional) 
ca. week 
13
Visit 3;
mid of 
observa-
tion; ca. 
week 26* 
Visit 4;
(optional) 
ca. week 
39
Visit 5;
end of 
observa-
tion; ca. 
week 52
Visit 6
FU ca. 
week 52**
Informed Consent
X
Inclusion / Exclusion 
Criteria
X
Patient demographics 
(age, gender, height, 
and weight)
X
Smoking history
X
History of ILD, 
including ILD entity 
and HRCT pattern
(where available in 
patient documentation)
X
current DLCO 
measures (where 
available in patient 
documentation)
X
X
X
X
X
Concomitant diseases / 
Comorbidities
X
X
X
X
X
Past ILD therapies (6 
weeks before visit 1)
X
Current ILD related or 
other relevant 
concomitant 
medication
X
X
X
X
X
FVC (mL and % pred.; 
if available in patient 
data)
X
X
X
X
X
X
Severity of disease as 
per the treating 
physician’s estimation 
(if available in patient 
data)
X
X
X
X
X
X
L-PF questionnaire, 
completed by patient
X
X
X
X
X
X

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BI Study Number 1199-0449                                                                         c34369089-02       
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Table 9.2.3: 1 (cont´d)
Flow Chart
Parameter
Visit 1;
baseline 
visit
Visit 2;
(optional) 
ca. week 
13
Visit 3;
mid of 
observa-
tion; ca. 
week 26* 
Visit 4;
(optional)
ca. week 
39
Visit 5;
end of 
observa-
tion; ca. 
week 52
Visit 6
FU ca. 
week 52**
Safety: Adverse Drug 
Reactions (serious and 
non-serious), fatal AEs, 
pregnancy
X
X
X
X
X
X
Rationale for treatment 
discontinuation (if 
applicable)
X
X
X
X
Further treatment 
options yes/no (as 
applicable
X
X
X
X
X
Intention to continue or 
discontinue treatment 
with nintedanib after 
the study (yes/no)
X
X
X
X
Survival data
X
* after 26 weeks of observation for each individual patient
** if available and/or patients willing to perform, phone contact acceptable
In addition to the mandatory visits, i.e. Visit 1 (baseline), Visit 3 (mid of observation; 26 
weeks after baseline) and Visit 5 (end of observation) and Visit 6 (Follow-up 52 weeks after 
baseline), optional study visits will be enabled between V1 and V3 (V2) as well as between 
V3 and V5 (V4), each occurring about midway between V1 and V3 or V3 and V5, 
respectively. Therefore, patients will be seen by their study investigator at least every 6 
months and up to every quarter of the observational period.
When optional visits are conducted, then the same parameters as in Visit 3 should be 
documented.
Each visit should take place not earlier than six weeks before and no later than six weeks 
after the planned visit date and thus reflect patients’ and physicians’ real-world experience.
If possible, patients who discontinue the study before week 52 for any reason should be 
contacted for survival status and follow-up data to week 52 (visit 6).
For all other patients, visit 5 and visit 6 are completed in the same visit.

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BI Study Number 1199-0449                                                                         c34369089-02       
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9.2.4
Study discontinuation
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular study site
2. Emergence of any effectiveness/safety information that could significantly affect 
continuation of the study
3. Violation of Good Pharmacoepidemiology Practice (GPP), the study protocol, or the 
contract by a study site, investigator or research collaborator, disturbing the appropriate 
conduct of the study
The investigator/the study site/research collaborator will be reimbursed for reasonable 
expenses incurred in case of study/site termination (except in case of the third reason).
The patients have the right to stop study participation any time and for any reason, without 
any drawback on their further treatment. Study participation may be stopped for a given 
patient in case of individual safety issues.
9.3
VARIABLES
The following parameters will be collected and assessed at visits 1 to 5, as applicable:

Patient demographics (age, gender, height, weight)

Smoking history, current status (current smokers, former smokers, and never 
smokers) and pack-years

History of ILD, including ILD entity and HRCT pattern (where available in patient 
documentation)

current DLCO measures (where available in patient documentation)

Concomitant diseases 

Previous ILD therapies in the 6 weeks before visit 1

Current ILD related or other relevant concomitant medication

FVC (mL and % pred.; if available in patient data)

Severity of disease as per the treating physician’s estimation (if available in patient 
data)

L-PF questionnaire, completed by patient

Safety: ADRs (serious and non-serious), fatal AEs, pregnancies during the study

Rationale for treatment discontinuation (if applicable)

Intention to continue or discontinue treatment with nintedanib (Ofev®) after the study 
(yes/no) 

Further treatment options yes/no, as applicable

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BI Study Number 1199-0449                                                                         c34369089-02       
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9.3.1
Exposures
The active ingredient of Ofev® is nintedanib. During this study, it is planned to observe for 
each patient a treatment period with nintedanib of approximately 52 weeks.
The recommended daily dose of nintedanib (Ofev®) is 150 mg twice daily administered 
approximately 12 hours apart. The 100 mg twice daily dose is only recommended to be used 
in patients who do not tolerate the 150 mg twice daily dose.
The treating physician ensures that the treatment follows all specific requirements described 
in the SmPC as e.g. contraindications including pregnancy, monitoring, discontinuation, dose 
reduction etc.
The Summaries of Product Characteristics on Ofev® is contained in the NIS ISF in the 
“Summary of Product Characteristics” section.
Note: The recommended doses stated in the Summary of Product Characteristics should not 
be exceeded.
Other adequate therapy will be applied according to label as described in the respective 
SmPCs.
The study aims to observe for each patient a treatment period with nintedanib of 
approximately 52 weeks (including a mid-of-observation evaluation and 2 further optional 
intermediate visits). As there is no untreated comparator group, each patient included in the 
study is planned to be continually exposed to nintedanib as a standard of care for the whole 
observational period of 52 weeks at the indicated dosage of 150 mg daily. As this is a real-
world observational study, patients will be instructed on the correct drug application by their 
treating physician. In case of dose reductions deemed necessary by the treating physicians, 
these may be applied according the SmPC. All cases of dose reduction or dose interruption 
will have to be documented and reasons given in the eCRF.
A dose interruption of nintedanib for more than 12 weeks and/or initiation of another 
antifibrotic therapy during the observation phase of the study will result in exclusion of the 
concerned patients’ data from efficacy analysis. 
Handling of missing data will be described in the SAP.
Exposure variables will be cough score and symptoms score as measured via L-PF 
questionnaire. 
The complete L-PF questionnaire will be collected by the site in an eCRF. Each question is 
answered by the patient indicating one tick-box answer per question. Only one statement can 
be chosen. The higher the score the greater the impairment.
Ofev® (Nintedanib) is authorized in Germany for the treatment of adult patients suffering 
from chronic fibrosing ILD with a progressive phenotype as Ofev®. Each patient in need and 
meeting the criteria defined in the SmPC may get an Ofev® prescription by the treating 
physician. Statutory health insurances in Germany cover Ofev® prescription costs. 

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BI Study Number 1199-0449                                                                         c34369089-02       
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Furthermore, Ofev® is also indicated to treat adults with idiopathic pulmonary fibrosis (IPF), 
systemic sclerosis associated interstitial lung disease (SSc-ILD), and other chronic fibrosing 
interstitial lung diseases which are progressive.
This study aims to continually observe adult patients suffering from chronic fibrosing ILD 
with a progressive phenotype who are newly treated with nintedanib without any previous 
antifibrotic therapy, i. e. neither pirfenidone nor nintedanib, for 52 weeks. Neither switchers 
nor past or current users of nintedanib (or pirfenidone) are to be included. Based on the 
INBUILD study, this study is planned in a parallel way. It is assumed that PROs will be 
determinable best in new users. All calculations for this study, including statistics and patient 
numbers, are based on the randomized clinical trial INBUILD. In order to be able to duplicate 
the most crucial design features, in this study nintedanib will solely be tested as a first and 
only antifibrotic treatment in PF-ILD patients, as it was in INBUILD. Therefore, in 
accordance with INBUILD trial design, patients must not have used or use any other 
antifibrotic before or during this observational study, except nintedanib during the study.
9.3.2
Objectives and Outcomes
The primary objective of this study is to investigate the correlation between changes from 
baseline to 52 weeks in FVC [% pred.] and changes from baseline to 52 weeks in dyspnea
score [points] or cough score [points] as measured with the L-PF questionnaire over 52 weeks 
of nintedanib treatment in patients suffering from chronic fibrosing ILD with a progressive 
phenotype (excluding IPF):

Correlation between change from baseline to week 52 in FVC [% pred.] and change 
from baseline to week 52 in dyspnea symptom score

Correlation between change from baseline to week 52 in FVC [% pred.] and change 
from baseline to week 52 in cough symptom score
from each individual patient’s difference between baseline and after 52 weeks of treatment 
with nintedanib. As such, comparisons will be made within treated population alone. 
The questionnaire will be completed by the patient during each visit and will reflect the 
actual symptoms and the patient’s status at that day, as described by the patient. 
There will be no true comparison group of untreated patients in this study for a complete 
interpretation of findings since all patients in this study will receive nintedanib after their 
treating physician had decided for this therapeutic option for the respective individual patient. 
Therefore, an untreated patient population will not exist. Further, the within-group 
comparison among treated patients before and after nintedanib initiation may not be ideal due 
to the process of progression itself during the follow up period which may limit the 
comparability of the two time-points. 

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BI Study Number 1199-0449                                                                         c34369089-02       
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9.3.2.1
Primary outcomes

Correlation between change from baseline to week 52 in FVC [% pred.] and change 
from baseline to week 52 in dyspnea symptom score

Correlation between change from baseline to week 52 in FVC [% pred.] and change 
from baseline to week 52 in cough symptom score
The primary outcomes do not touch any safety question.
9.3.2.2
Secondary outcomes

Correlation between change from baseline to week 52 in FVC [mL] and change from 
baseline to week 52 in dyspnea symptom score; safety issue: no

Correlation between change from baseline to week 52 in FVC [mL] and change from 
baseline to week 52 in cough symptom score; safety issue: no

Absolute change from baseline in L-PF cough symptom score [points] at week 52; 
safety issue: no

Absolute change from baseline in L-PF dyspnea symptom score [points] at week 52; 
safety issue: no
Primary and secondary outcomes will be analyzed for the Treated Set. 
The secondary outcomes do not touch any safety question.

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BI Study Number 1199-0449                                                                         c34369089-02       
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9.3.3
Covariates
Covariates for adjustment will include patient demographics and disease characteristics. 
These will be discussed in the SAP.
9.4
DATA SOURCES
Medical records collected through routine clinical care will be used to assess the 
inclusion/exclusion criteria of patients as well as for patient demographics, smoking history, 
collection of previous ILD medication, concomitant diseases, and concomitant medication, as 
well as for the health data of the patient during the course of the observation.
The LPF questionnaire will be provided as paper version to the patient to be filled out in 
writing at visits V1 to V5, as applicable.
All patients will be enrolled consecutively.

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BI Study Number 1199-0449                                                                         c34369089-02       
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9.5
STUDY SIZE
In the INBUILD trial, patient groups on placebo vs nintedanib therapy differed in both their 
loss of FVC and dyspnea and cough symptom scores in the L-PF questionnaire (Figure 9.5:1; 
see below).
Figure 9.5:1 Changes from baseline to week 52 in L-PF symptoms dyspnea (left) and cough 
(right), domain scores respectively, seen in INBUILD

FVC, dyspnea and cough symptom scores from INBUILD (see Table 9.5:1 below) were 
applied to estimate sample sizes.
Correlations between the change from baseline to week 52 in FVC (both FVC in mL and 
FVC as % predicted) and the change from baseline to week 52 in both L-PF dyspnea 
symptom score and cough symptom score measured by Pearson’s correlation coefficient were 
≈ -0.3 in the Nintedanib arm of the treated set (see Table 9.5:1 below).14

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BI Study Number 1199-0449                                                                         c34369089-02       
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Table 9.5:1
Pearson correlation between the change from baseline to week 52 in 
FVC and the change from baseline to week 52 in L-PF symptoms 
scores in the Nintedanib arm (results were similar for the total 
population.)
Currently, a meaningful threshold (“MCID”) has been published for neither the cough nor the 
dyspnea domain of the L-PF. However, should that information become available during the 
study, study results will be discussed in relation to meaningful thresholds (“MCID”) values.
Given a correlation ρ between change from baseline to week 52 in FVC [% pred.] and change 
from baseline to week 52 in dyspnea symptom score as well as change from baseline to week 
52 in FVC [% pred.] and change from baseline to week 52 in cough symptom score of 
approximately -0.3, then 84 patient data sets would be required for evaluation. Assuming an 
estimated drop-out rate of approx. 15 % 100 patients will have to be recruited for this study. 
With this patient number (N = 84) and the assumption of a Pearson correlation of -0.3, the 
overall type I error is protected at the two-sided 0.05 level with a power of 80 %.
Therefore 100 patients are planned to be recruited for this NIS by about 20 specialists, 
experienced in treating ILD patients, (e. g., pulmonologists and rheumatologists) throughout 
Germany. Each investigator will include ca. 5 consecutive patients for whom the physician
had decided for a treatment with nintedanib before actual recruitment of the patient. The 
treatment decision will have to have taken place before actual recruitment of the patient.
Due to the observational nature of the study, all analyses are exploratory. No weighting will 
be applied to either of the co-primary endpoints. All analyses in this observational study are 
exploratory. No weighting will be applied to either of the co-primary endpoints. 
9.6
DATA MANAGEMENT
The data management plan is summarized below. Full details of the data management plan 
are documented in a separate NIS-Data Management and Review Plan (NIS-DMRP).
The NIS-DMRP will describe all functions, processes, and specifications for data collection, 
cleaning and validation. The electronic Case Report Forms (eCRFs) will include 
programmable edits to obtain immediate feedback if data are missing (also negative answers, 
unknown), out of range, illogical or potentially erroneous. These rules may encompass simple 
checks such as range validation or presence/absence of data. Concurrent manual data review 
may be performed based on parameters dictated by the DMP. Ad hoc queries to the sites may 
Lower
Upper
L-PF symptoms dyspnoe score and …
FVC in ml
-0.35
-0.45
-0.23
FVC (% predicted)
-0.37
-0.47
-0.26
L-PF symptoms cough score and …
FVC in ml
-0.26
-0.37
-0.14
FVC (% predicted)
-0.26
-0.37
-0.14
95% Confidence interval
Pearson correlation (change from baseline at 
week 52) between FVC and L-PF symptoms 
Coefficient

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BI Study Number 1199-0449                                                                         c34369089-02       
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be generated and followed up for resolution. A source data quality audit may be initiated to 
ensure that the data in the database is accurate. Source data verification (SDV) will be 
performed at each recruiting site and further at sites identified by a risk-based approach as 
needed.
The database will be housed in a physically and logically secure computer system maintained 
in accordance with a written security policy. The system will meet the standards of the 
International Committee on Harmonization guideline E6R1 regarding electronic study data 
handling and the safety requirements of the FDA (US Food & Drug Administration) 
concerning systems for the data acquisition of clinical studies in accordance with "Title 21 
Code of Federal Regulations (21 CFR Part 11): Electronic Records; Electronic Signatures. 
Patient confidentiality will be strictly maintained.
9.6.1
Data Entry / EDC
Data entry into the eCRF including the data of the patient questionnaires follows the 
instructions in the EDC system user manual and is further supported by help and hint texts. 
Support documents will also be provided within the online system documents, which give 
explanations to basic functions and field types in the eCRF.
With data entry into the EDC system, all changes and user information will be saved in an 
audit trail.
The data review and validation steps for a project are defined in the data validation plan 
(DVP).
The DVP includes all definitions of electronic checks and the defined manual checks, which 
will be performed directly in the EDC system or can be based on listings.
Electronic edit checks (eChecks) are performed automatically and directly when entering data 
into the eCRF. Missing or implausible data entries or are indicated to the user immediately.
Manual Checks are applied to verify the entered data validity and plausibility.
Queries can result from various sources:

Manual Checks by data management

Manual Checks by pharmacovigilance 

Source data verification during on-site monitoring
9.6.2 Source Documents
The source documents are contained in the patient’s medical record. The filled-in patient 
questionnaires are regarded source data and must be kept in the study site file. Data collected 
on the eCRFs must be traceable to these source documents in the patient’s medical records as 
far as this is routine documentation. All original source documentation is expected to be 
stored at the site for the longest possible time required by local applicable regulations. The 
site will be instructed to notify the Sponsor before any destruction of medical records of 
study participants.

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BI Study Number 1199-0449                                                                         c34369089-02       
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9.6.3 File Retention and Archiving
The study database and all study-specific documents received by 
 will be transferred 
to BI regularly during and after the study period. Archiving will be performed by BI Pharma 
in accordance with BI SOPs.
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the 
investigator agrees to keep records, including the identity of participating patients, copies of 
all CRFs, SAE forms, source documents and adequate documentation of relevant 
correspondence (e.g., letters, meeting minutes, telephone calls reports). The records should be 
retained by the investigator according to local regulations, or as specified in the study 
contract, whichever is longer.
Each site will receive a study site file at study initiation that contains all documents necessary 
for the conduct of the study and is updated throughout the study. This file must be available 
for review in the event the site is selected for monitoring, audits, or inspections and must be 
safely archived for at least thirty years after the completing participation in the study. In the 
event that archiving of the file is no longer possible at the site, the site will be instructed to 
notify the Sponsor.
9.7
DATA ANALYSIS
The statistical analysis plan for the study is summarized below. Full details of the statistical 
analysis will be documented in the SAP, which will be finalized before the end of data 
collection.
All patients who have received at least one dose of nintedanib will be included in the treated 
set. All analyses will be performed on the treated set. 
9.7.1
Main analysis
For the analysis of the primary outcomes

Correlation between change from baseline to week 52 in FVC [% pred.] and change 
from baseline to week 52 in dyspnea symptom score

Correlation between change from baseline to week 52 in FVC [% pred.] and change 
from baseline to week 52 in cough symptom score
Pearson measures of correlation along with 95% two-sided confidence intervals and the two-
sided p-values will be provided. 
For the secondary outcomes

Correlation between change from baseline to week 52 in FVC [mL] and change from 
baseline to week 52 in dyspnea symptom score

Correlation between change from baseline to week 52 in FVC [mL] and change from 
baseline to week 52 in cough symptom score
Pearson measures of correlation along with 95% two-sided confidence intervals and the two-
sided p-values will be provided.

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BI Study Number 1199-0449                                                                         c34369089-02       
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The secondary outcomes

absolute change from baseline in L-PF symptoms dyspnoea domain score between 
week 52 and baseline

absolute change from baseline in L-PF symptoms cough domain score between week 
52 and baseline
will be analyzed using a restricted maximum likelihood (REML) based repeated measures 
approach. Analyses will include the fixed, categorical effect of visit, as well as the 
continuous, fixed covariates of baseline and baseline-by-visit interaction. An unstructured 
(co)variance structure will be used to model the within-patient measurements.
9.7.3
Safety Analysis
All adverse drug reactions (ADRs) (serious and non-serious) and all AEs with fatal outcome 
as collected per study protocol will be included and summarised in the final study report. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Kaplan-Meier plots will be produced for the time to premature treatment discontinuation, for
the time to first dose reduction and for the time to first treatment interruption.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent
adverse events. To this end, all adverse events occurring between start of treatment and end
of the residual effect period will be considered ‘treatment-emergent’. The residual effect
period is defined as the 28 days after the date of the last dose of study medication. Adverse
events that start before first drug intake and deteriorate under treatment will also be
considered ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system
organ class and preferred term after coding according to the current version of MedDRA.

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BI Study Number 1199-0449                                                                         c34369089-02       
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9.8
QUALITY CONTROL
The quality control, review, and monitoring plan are summarized below. The NIS-DMRP
details the data management plans, including quality review measures, site monitoring plans, 
and site qualification/training plan.
All participating sites will receive a comprehensive study site file with all information on the 
NIS. Site staff will be further trained by a mandatory webinar. Training will be documented 
in the study site file.
To improve and secure data quality, automatic data checks upon data entry will be done 
within the eCRF. In the eCRF, plausible ranges of values for numeric data entries as well as 
logical data entries and listings will be provided for each entry field. Based on this, checks on 
completeness and plausibility will be performed upon data entry in the eCRF.
Validity of data entry thus is ensured by integrated validation checks performed by the
system, indicating missing or implausible entries to the document list or investigator. All 
corrections will be visible from the systems audit trail.
To provide further quality assurance of the documented patient observations, source data 
validation will take place at each recruiting site and involve an on-site review of the 
documented data for completeness and consistency by a monitoring visit. An additional 
check/ review of the quality assurance of this NIS can be performed. Depending on site 
recruitment and data status in the eCRF, monitoring visits will be planned following a pre-
defined risk analysis with risk-based approach. Details will be specified in the study 
monitoring plan. In case of decreasing compliance (i.e. of missing data, data discrepancies, 
protocol violations, etc.) a for-cause audit or risk-based monitoring visits will be performed.
At study end, the database and all relevant programs as e.g. statistical programming will be 
transferred to BDS to be archived in the appropriate DMS.
9.9
LIMITATIONS OF THE RESEARCH METHODS
This study aims to continually observe adult patients suffering from chronic fibrosing ILD 
with a progressive phenotype who are newly treated with nintedanib without any previous 
antifibrotic therapy, i. e. neither pirfenidone nor nintedanib, for 52 weeks.
A NIS appears the most suitable instrument for obtaining information about the use of 
medicines in everyday therapeutic practice and thus for investigating prospectively questions 
in everyday therapeutic practice.
Consecutive enrolment will be employed to minimize selection bias. The entry criteria are 
non-restrictive which will permit the enrolment of a broad patient population. The choice of 
treatment is at the discretion of the investigator.
Selection bias could occur at the site level and the patient level. To minimize the site level 
selection bias, the goal is to have participating centers with access to all available and 
approved treatment options in that country for the targeted patient population. To minimize 
selection bias at the patient level, consecutive enrolment is performed. Information bias will 

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BI Study Number 1199-0449                                                                         c34369089-02       
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be minimized by the use of standard eCRF, questionnaire and physicians’ training on the 
study protocol. Furthermore, baseline characteristics will be compared with INBUILD data to 
explore possible bias.
9.9.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by regulatory authorities. The quality assurance auditor will have 
access to all medical records, the investigator’s study-related files and correspondence, and 
the informed consent documentation of this study.
9.9.2
Study records
Electronic Case Report Forms (eCRFs) for individual patients will be provided by the 
sponsor, via remote data capture. 
9.9.2.1
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.
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.
9.9.2.2
Direct access to source data and documents
The investigator/institution will permit study-related monitoring, audits, and regulatory 
inspection, providing direct access to all related source data/documents. CRFs/eCRFs and all 
source documents, including progress notes and copies of laboratory and medical test results 
must be available at all times for review by the sponsor’s clinical study monitor, auditor and 
inspection by health authorities (e.g. US Food and Drug Administration (FDA)). BI study 
staff and auditor may review all CRFs/eCRFs, and written informed consents. The accuracy 
of the data will be verified by reviewing the documents described in Section 9.9.2.1.
9.9.3
Completion of study
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the study (last patient/patient out, unless specified differently in Section 9.2) or 
early termination of the study. 

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BI Study Number 1199-0449                                                                         c34369089-02       
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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 the current version, Guidelines for Good Pharmacoepidemiology 
Practice (GPP), and the relevant BI Standard Operating Procedures (SOPs). Standard medical 
care (prophylactic, diagnostic and therapeutic procedures) remains 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.
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This NIS will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC: Ethikkommission der Medizinischen Fakultät Heidelberg) 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 informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) per GPP and according to the 
regulatory and legal requirements of the participating country. 
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patients’ study participation is voluntary and the patients have the right to stop study 
participation any time and for any reason, without any drawback on their further treatment. 
If patients withdraw, they will decide if their study data are to be deleted or may be further 
used for the analysis of the study. If the patients agree, survival data after 52 weeks will be 
collected also from patients who withdraw from study participation. 
These decisions may be revised by the patient during the course of the study and the deletion 
of the study data may be requested. 
Once the data are anonymized and analysed, data deletion upon patient wish is not possible 
any more.
10.2
STATEMENT OF CONFIDENTIALITY
Federal and local legal requirements concerning confidential medical communication as 
patient names and other confidential information and concerning data protection (DSGVO, 
BDSG, LDSG) as well as medical professional privilege will be followed.

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BI Study Number 1199-0449                                                                         c34369089-02       
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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. The medical and personal patient 
data may be inspected by dedicated study site staff and by dedicated monitors (CRAs) for 
quality assurance reasons. All this personnel is obligated to confidentiality.
Data generated as a result of the study need to be available for inspection on request by the 
participating physicians, the sponsor’s representatives, by the IRB/IEC and the regulatory 
authorities, i.e. the competent authority.
During the study, medical results and reports and personal information from the patients will 
be collected in patient files at the study sites. Those data important for the study will be 
collected pseudonymisedly via an electronic case report form and accumulated in a study
database. The pseudonymisation key is kept confidential by the investigator at the study site.
Before analysis, the data will be anonymized and the reports from this analysis will be 
provided to the sponsor of the study, Boehringer Ingelheim. After analysis and finalization of 
the study report, the anonymized data will be transferred to Boehringer Ingelheim.
The medical and personal patient data may be inspected by dedicated study site staff, by 
authorized dedicated monitors (CRAs) for quality checks and by health authority staff in case 
of an inspection. For those quality checks and authority inspection the patient releases the 
treating physician from the medical professional privilege.
Study data will be kept for 30 years and then be destroyed.
10.3
BENEFIT-RISK ASSESSMENT
The benefit to gain with this study will be reliable and evidence based information about a 
possible correlation of changes in patient reported outcomes (PRO) as cough and dyspnea to 
physical changes due to the course of the disease as shown in FVC. This might turn out to be 
a helpful early clinical sign of disease progression, easily to be noticed by the patient and to 
be reported – solicited or unsolicited – to the treating physician. Furthermore, this may help 
to further establish this PRO as a tool in clinical practice and improve monitoring of the 
patients.
Additionally, the medical community will get more and deeper knowledge of the severe lung 
disease PF-ILD and its treatment with nintedanib. Patients do not personally benefit from 
participating in this NIS while being treated, but they contribute to gaining better insight into 
the disease and thus to potential improvement of treatment options in the future.
The risks and strains for the patient caused by participating in this NIS are marginal. They 
will follow routine treatment and regular follow-up for their disease and the questionnaire is 
the only study-related task. There is no additional risk by study participation.

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BI Study Number 1199-0449                                                                         c34369089-02       
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10.4
INFLUENCE OF COVID- 19 PANDEMIC ON THE STUDY 
PARTICIPANTS
All patients to be included into this NIS suffer from a severe medical condition and are in 
need of treatment according to their treating physician’s assessment. The patients will be 
treated in usual care, all data documented during those visits, including the questionnaires, 
record examinations and information necessary during the course of the disease and 
nintedanib treatment. No additional visits or examinations are demanded or required other 
than in clinical routine. So there is no additional risk for the patients in the COVID-19 
pandemic caused by the study apart from their inherent risk as patients with a serious 
systemic disease affecting the lung.

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BI Study Number 1199-0449                                                                         c34369089-02       
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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavorable 
and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Adverse drug reaction
An adverse drug reaction (ADR) is defined as a response to a medicinal product which is 
noxious and unintended. Response in this context means that a causal relationship between a 
medicinal product and an adverse event is at least a reasonable possibility. Adverse reactions 
may arise from use of the product within or outside the terms of the marketing authorization 
or from occupational exposure. Conditions of use outside the marketing authorization include 
off-label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which
-
results in death, 
-
is life-threatening, 
-
requires in-patient hospitalization, or
-
prolongation of existing hospitalization, 
-
results in persistent or significant disability or incapacity, or 
-
is a congenital anomaly/birth defect 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe.
Medical and scientific 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.
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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BI Study Number 1199-0449                                                                         c34369089-02       
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Adverse events relating to gastrointestinal perforation and hepatic injury will be considered 
as AESIs.
Signs of hepatic injury are defined as:
•
ALT and/or AST ≥8 fold ULN
•
ALT and/or AST ≥3 fold ULN and total bilirubin ≥2 fold ULN in the same blood 
draw sample
These lab findings constitute a hepatic injury alert and any patient showing these lab 
abnormalities needs to be followed up according to the drug-induced liver injury (DILI) 
checklist. 
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed. Should the results meet the criteria of hepatic injury, the procedures described in 
the DILI checklist should be followed.

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BI Study Number 1199-0449                                                                         c34369089-02       
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11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files.
Collection of AEs
The 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.

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BI Study Number 1199-0449                                                                         c34369089-02       
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The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) criteria version 5.0 (2017) in the (e)CRF.
Pregnancy:
In rare cases, pregnancy might occur in a NIS. Once a patient has been enrolled in the study 
and has taken study medication, the investigator must report any drug exposure during 
pregnancy in a study participant within 7 days by means of Part A of the Pregnancy 
Monitoring Form to the sponsor’s unique entry point. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form (Part B). 
The ISF will contain the Pregnancy Monitoring Form (Part A and B). As pregnancy itself is 
not to be reported as an AE, in the absence of an accompanying serious ADR and/or AESI, 
only the Pregnancy Monitoring Form and not the NIS AE form is to be completed. If there is 
a serious ADR and/or AESI associated with the pregnancy a NIS AE form must be completed 
in addition. 
The following must be collected by the investigator in the (e)CRF from signing the informed 
consent onwards until the end of the study: 
all adverse drug reactions (ADRs) (serious and non-serious), 
all AEs with fatal outcome, 
all AESIs 
All ADRs and AESIs, 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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BI Study Number 1199-0449                                                                         c34369089-02       
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Expedited Reporting of AEs and Drug Exposure during Pregnancy to BI Pharmacovigilance
The following must be reported by the investigator on the NIS AE form and/or Pregnancy 
Monitoring Form from signing the informed consent onwards until the end of the study and 
provide o BI unique entry point: 
All serious ADRs associated with the studied 
medical product nintedanib
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to studied medical product 
nintedanib
immediately within 24 hours
All protocol specified AESIs 
Immediately within 24 hours
All non-serious ADRs associated with the 
studied medical product nintedanib
7 calendar days
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 and fax the NIS AE form.
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate (e)CRF page and the NIS AE form. 
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the Marketing Authorization 
Holder (MAH) according to local and international regulatory requirements. 

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BI Study Number 1199-0449                                                                         c34369089-02       
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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
Results of this non-interventional study will be disclosed on encepp.eu and clinicaltrials.gov
and a study specific publication plan will be developed to describe planned publications.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalization of the Study Report.
13.
REFERENCES
13.1
PUBLISHED REFERENCES
[1] Boehringer Ingelheim. Rosenstock B. CTP for Trial No. 1199.247; 
Document No. c03736471-02
[2] Cottin V et al. Eur Repir Rev 2018;27:180076
[3] Richeldi L et al. N. Engl. J. Med., 365 (2011), pp. 1079-1087
[4] Richeldi L et al. N. Engl. J. Med., 370 (2014), pp. 2071-2082
[5] Rivera-Ortega P et al. Ther Adv Respir Dis 2018;12:1753466618800618
[6] Crestani B et al. Lancet Respir Med. 2019;7(1):60-68.
[7] Flaherty KR et al. N Engl J Med 2019;381:1718-27
[8] Swigris JJ et al.; INBUILD Trial Investigators. ATS 2020, 116th Int Conf of the 
American Thoracic Society (ATS), Philadelphia, 15 - 20 May 2020. Am J Respir Crit 
Care Med 2020 ; 201; A2754
[9] Swigris JJ et al. Eur Respir Rev. 2018;27(150):180075
[10] BI Clinical Trial Report; BI trial number 1199.247
[11] Boehringer Ingelheim. Rosenstock B. CTP for Trial No. 1199.247; 
Document No. c03736471-02
[12] Salonen J et al. BMJ Open Respir Res. 2020.
[13] Kreuter M et al. Biomed Res Int. 2015;2015:123876.
[14] BI Clinical Trial Report; BI trial number 1199.247
13.2
UNPUBLISHED REFERENCES
Not applicable

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BI Study Number 1199-0449                                                                         c34369089-02       
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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None

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BI Study Number 1199-0449                                                                         c34369089-02       
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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
The study has already been accepted by ENCEPP.

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BI Study Number 1199-0449                                                                         c34369089-02       
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ANNEX 3. ADDITIONAL INFORMATION
Not applicable

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BI Study Number 1199-0449                                                                         c34369089-02       
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ANNEX 4. REVIEWERS AND APPROVAL SIGNATURES
Not applicable
Signatures will be provided electronically via approval workflow in the DMS for submission 
documents.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34369089
2.0
nis-protocol-1199-0449
Prospective observational investigation of possible correlations between change in
FVC and change in cough or dyspnea scores using the living with pulmonary fibrosis
questionnaire (L-PF) between baseline and after approximately 52 weeks of
nintedanib treatment in patients suffering from chronic fibrosing ILD with a
progressive phenotype
Approval-Clinical Trial Leader
08 Feb 2021 12:58 CET
Approval-Project Statistician
08 Feb 2021 13:05 CET
Approval-
 Safety Evaluation
Therapeutic Area
08 Feb 2021 14:10 CET
Approval-
 Medical Affairs
08 Feb 2021 14:58 CET
Approval-Team Member Medical
Affairs
08 Feb 2021 17:38 CET
Approval-Other
11 Feb 2021 01:58 CET

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Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34369089
2.0