Investigating Idiopathic Pulmonary Fibrosis in Greece
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
TITLE PAGE
Non-interventional Study Protocol
Document Number:
c11675456 - 02
BI Study Number:
1199.252
BI Investigational
Product(s):
Not Applicable
Title:
Investigating idiopathic pulmonary fibrosis in Greece 
(INDULGE IPF)
Brief lay title
INDULGE IPF
Protocol version 
identifier:
1.10
Date of last version of 
protocol:
22 February 2018
PASS:
No
EU PAS register 
number:
Not Applicable
Active substance:
Not Applicable
Medicinal product:
Not Applicable
Product reference:
Not Applicable
Procedure number:
Not Applicable
Marketing authorisation 
holder(s):
Not Applicable
Joint PASS:
No
Research question and 
objectives:
The main objective of the study is to gain detailed insights on the 
characteristics, management and outcomes of patients with IPF as 
treated under real-world, clinical practice conditions
The registry aims to provide information on disease characteristics 
(disease registry), treatment patterns, long-term effects of IPF  and 
economic aspects
Country(-ies) of study:
Greece
Author:

Boehringer Ingelheim
Page 2 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Marketing authorisation 
holder(s):
Not Applicable
In case of PASS, add:
MAH contact person:
Not Applicable
In case of PASS, add:
<EU-QPPV:>
Not Applicable
In case of PASS, add:
<Signature of EU-
QPPV:>
Not Applicable
Date:
22 February 2018
Page 1 of 70
Proprietary confidential information
© 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

Boehringer Ingelheim
Page 3 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
1.
TABLE OF CONTENTS
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 7
4.
ABSTRACT........................................................................................................... 8
5.
AMENDMENTS AND UPDATES..................................................................... 13
6.
MILESTONES..................................................................................................... 21
7.
RATIONALE AND BACKGROUND................................................................ 22
7.1
Definition ........................................................................................................ 22
7.2
Incidence and prevalence................................................................................ 22
7.3
Diagnosis......................................................................................................... 23
7.4
Natural course ................................................................................................. 24
7.5
Therapy ........................................................................................................... 24
7.6
Economic aspects............................................................................................ 25
7.7
Rationale for the present registry.................................................................... 25
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 26
9.
RESEARCH METHODS .................................................................................... 27
9.1
STUDY DESIGN............................................................................................ 27
9.2
SETTING........................................................................................................ 27
9.3
STUDY SITES................................................................................................ 27
9.3.1
Study Population ..................................................................................... 28
9.3.2
Withdrawal Criteria................................................................................. 28
9.3.3
Study Visits ............................................................................................. 29
9.3.4
Study Discontinuation............................................................................. 29
9.4
VARIABLES .................................................................................................. 30
9.4.1
Exposures ................................................................................................ 32
9.4.2
Outcomes................................................................................................. 32
9.4.3
Primary Outcomes................................................................................... 32
9.4.4
Secondary Outcomes............................................................................... 32
9.4.5
Covariates................................................................................................ 33
9.5
DATA SOURCES........................................................................................... 36
9.6
STUDY SIZE.................................................................................................. 36
9.7
DATA MANAGEMENT................................................................................ 37
9.8
DATA ANALYSIS......................................................................................... 38

Boehringer Ingelheim
Page 4 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.8.1
Main Analysis ......................................................................................... 38
9.9
QUALITY CONTROL................................................................................... 39
9.10
LIMITATIONS OF THE RESEARCH METHODS...................................... 39
9.11
OTHER ASPECTS ......................................................................................... 40
9.11.1
Data Quality Assurance........................................................................... 40
9.11.2
Study Records ......................................................................................... 40
9.11.2.1
Source Documents ........................................................................... 41
9.11.2.2
Direct Access to Source Data and Documents................................. 41
9.11.2.3
Storage of Records ........................................................................... 41
9.11.2.4
Completion of the Study .................................................................. 41
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 42
10.1
Study approval, patient information, and informed consent........................... 42
10.2
Statement of confidentiality............................................................................ 43
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 44
11.1
Definitions of adverse events.......................................................................... 44
11.2
Adverse event and serious adverse event collection and reporting................. 45
11.3
Reporting to health Authorities....................................................................... 47
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 48
13.
REFERENCES .................................................................................................... 49
13.1
PUBLISHED REFERENCES......................................................................... 49
13.2
UNPUBLISHED REFERENCES................................................................... 51
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 52
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 53
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 59
ANNEX 4 ASSESSMENTS OF VARIABLES ........................................................... 63
ANNEX 5. COMMORBIDITIES OF INTEREST (RECORDER WITH START, AND IF 
APPLICABLE STOP DATE) ............................................................................. 68
ANNEX 6. HIGH RESOLUTION COMPUTED TOMOGRAPHY CRITERIA FOR 
USUAL INTERSTITIAL PNEUMONIA PATERN (uip) [1]............................ 69
ANNEX 7. HISTOLOGICAL CRITERIA FOR UIP PATERN IN LUNG BIOPSY [1]70

Boehringer Ingelheim
Page 5 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
ALAT
Latin American Thoracic Association
AE
Adverse Event
AESI
Adverse Event of Special interest
ATS
American Thoracic Society
DLCO
Diffusion capacity for carbon monoxide
eCRF
Electronic Case Report Form
EMA
European Medicines Agency
ENCePP 
European Network of Centers for Pharmacoepidemiology and 
Pharmacovigilance 
ESC
European Society for Cardiology
ERS
European Respiratory Society
FDA
Food and Drug Administration
FVC
Forced vital capacity
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
GVP
Good Pharmacovigilance Practices
HRCT
High resolution chest computer tomography
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference of Harmonization 
IEC
Independent Ethics Committee
ICMJE
International Committee of Medical Journal Editors
IIP
Idiopathic Interstitial Pneumonia
ILD
Interstitial Lung Disease
IRB
Institutional Review Board
IPF
Idiopathic Pulmonary Fibrosis
JRS
Japanese Respiratory Society
LTx
Lung transplantation
LTOT
Long-term oxygen therapy
NAC
N-acetyl-cysteine
NIS
Non-Interventional Study
NHLBI
National Heart, Lung, and Blood Institute

Boehringer Ingelheim
Page 6 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
SAE
Serious Adverse Event
SEAP
Statistical Epidemiological Analysis Plan 
SmPC
Summary of Product Characteristics
SEAP
Statistical Epidemiological Analysis Plan 
TLC
Total lung capacity
UIP
Usual interstitial pneumonia
ΣΦΕΕ
Hellenic Association of Pharmaceutical Companies

Boehringer Ingelheim
Page 7 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
3.
RESPONSIBLE PARTIES
Trial Sponsor
Address:
Participating Investigators
A contact list of the participating investigators will be stored as a standalone (independent) document and 
will be available upon request.

Boehringer Ingelheim
Page 8 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Not applicable
Name of active ingredient:
Not applicable
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
29 August 2016
1199.252
1.10
22 February 2018
Title of study:
Investigating idiopathic pulmonary fibrosis in Greece (INDULGE IPF)
Rationale and 
background:
Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of
chronic, progressive fibrosing interstitial pneumonia of unknown 
cause, occurring primarily in older adults, limited to the lungs. IPF 
predominantly presents in older individuals (cases in persons aged less 
than 50 years are rare), with a preponderance in men and previous or 
current smokers. Patients present with unexplained chronic exertional 
dyspnea, and commonly with cough, bibasilar inspiratory crackles, and 
finger clubbing. IPF is associated with a poor prognosis. 
Overall, epidemiological data on the incidence and prevalence of IPF 
are limited, as stated in the consensus statement issued by 
ATS/ERS/JRS/ALAT. It is unknown if the incidence and prevalence of 
IPF are influenced by geographic, ethnic, cultural, or racial factors
While substantial efforts are being made to investigate the efficacy and 
safety of new drugs in controlled clinical trials, there is a lack of data 
on the condition and treatment of patients in clinical practice.
In Greece, Karakatsani et al conducted a multicenter research (survey) 
in 2009, using a one page questionnaire, in order to evaluate the 
incidence and prevalence of Interstitial Lung Diseases in Greece. 
Centers covering about 60% of the Greek population have been 
analyzed. A total of 967 cases of ILDs have been registered. The most 
frequent disease is sarcoidosis (34.1%), followed in decreasing order 
by idiopathic pulmonary fibrosis (19.5%). The annual incidence of IPF 
was estimated to be 0.93 cases per 100,000 whereas prevalence was 
estimated to be 3.38 cases per 100,000.
Since then, the diagnostic criteria, the international guidelines, the 
standard medical care and the composition of the population have 
changed. Moreover, a registry can document the introduction of new 
treatments and complement data that come from the randomized 
controlled trials.

Boehringer Ingelheim
Page 9 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Not applicable
Name of active ingredient:
Not applicable
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
29 August 2016
1199.252
1.10
22 February 2018
Research question 
and objectives:
The main objective of this IPF registry is to gain further knowledge on 
the characteristics, management, progression and outcomes of patients 
with IPF as treated under real-world, clinical practice conditions in 
Greece.
More specifically, this registry is going to:
•
Provide a comprehensive clinical picture for IPF
•
Track access to health care and cost of caring for IPF patients 
over time
•
Examine the implementation of treatment guidelines [2] used on 
patients diagnosed with IPF, according to the existing diagnosis 
guidelines [1]
Characterization of patients on different treatments
Study design:
National, multi-center, observational disease registry based on new 
data from a significant sample size of IPF patients in Greece.
Patients will be followed up for 2 years and information will be 
collected during this time period. This is a non-interventional study 
and primary data collected during study visits will be used.
Population:
About 300 patients are going to be included in the study in a consecutive 
manner, coming
from
seven
(7)
Centers
in
Greece
–
University
Pulmonology Clinics & Reference Centers of Public Hospital Setting – that
follow up around 70% - 80% of IPF patients within the Greek territory
from April 2017 to April 2019.
To be eligible for participation in the study patients must fulfill ALL 
the inclusion criteria and NONE of the exclusion criteria that are listed 
below:
Inclusion Criteria

Newly diagnosed (less than 6 months) or patients previously 
diagnosed with IPF (more than 6 months prior to baseline visit), 
based upon
the consensus statement jointly issued by 
ATS/ERS/JRS/ALAT in 2011 (see Annexes 6 and 7 on HRCT 
and histological criteria in Annex 6).
-
Exclusion of other known causes of ILD (e.g., domestic and 
occupational environmental exposures, connective tissue 
disease, and drug toxicity)
-
Evaluation of IPF with HRCT or combinations of HRCT and 
surgical lung biopsy, if available

Boehringer Ingelheim
Page 10 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Not applicable
Name of active ingredient:
Not applicable
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
29August 2016
1199.252
1.10
22 February 2018

Age ≥40 years old at the time of inclusion

Written informed consent for participation in the registry

Patients that can be further followed up by the investigator, 
during the scheduled study period
Exclusion Criteria

Expected lung transplantation within the following 6 months
Participation in clinical trials
Variables:
At baseline, a relevant patient history will be recorded including IPF-
related events up to 12 months prior to this visit. Further, the current 
status of IPF patients will be recorded regarding

Basic (Socio-)demographic data

Vital status

Physical and vital signs examination

Cardiopulmonary exercise testing (6-minute walk distance and 
CPET, if performed)

IPF risk factors

Co-morbidities

Risk of bleeding and thrombosis

Collection of pre-specified outcome data (only for newly 
diagnosed patients). Please, refer to Annex 3

Recording of therapeutic regimens. Assessment of the intensity 
of treatment, frequencies and resource utilization for pharmaco-
economic analyses. Methods and procedures used in the 
diagnosis of IPF and date of diagnosis (including HRCT and 
SLB)

IPF symptoms

Biomarker results of autoimmune disease

Assessment of function (lung function, cardiopulmonary exercise 
testing and/or exercise capacity if available)

IPF treatment modalities

Physician’s clinical rating of the probable course of IPF(please 
refer to Table 1

Clinical events and hospitalizations

Management of IPF and physician contacts

Boehringer Ingelheim
Page 11 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Not applicable
Name of active ingredient:
Not applicable
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
29 August 2016
1199.252
1.10
22 February 2018
The following will be documented at follow-up :

Clinical course of IPF

Vital status

Physical and vital signs examination

Pulmonary Function Tests (e.g. FVC, DLCO)

Cardiopulmonary exercise testing (6-minute walk distance and 
CPET, if performed)

Biomarker results of autoimmune disease

Risk of bleeding and thrombosis

Collection of pre-specified outcome data (only for newly 
diagnosed patients). Please, refer to Annex 3

Recording of therapeutic regimes. Assessment of the intensity of 
treatment, frequencies and resource utilization for pharmaco-
economic analyses

Clinical evaluation of the potential progression of IPF by the 
physician (please refer to paragraph 9.3 and Table 1)

Management of IPF and physician contacts
Data sources:
The study will mainly include the collection of new data recorded in a 
consecutive manner in an existing web based database (electronic case 
report form, e  CRF).Patients’ source data related to their medical 
history will be derived by the investigators from their medical records 
and will be documented in the relevant e - CRF section. Data will be 
collected by the study doctors as they occur according to standard 
clinical practice. No tests or laboratory procedures that diverge from 
standard clinical practice are requested.
Study size:
Approximately 300 patients are going to be included in the study from
the participating sites. The number of included patients as well as the 
duration of the study is not defined by a formal sample size and power 
calculation, but is mainly based on the availability of eligible IPF 
patients as well as the patient population in the selected sites. 
However, a precision table is provided.
Data analysis:
The objective of this registry is not to confirm or reject any predefined 
hypotheses. Therefore descriptive statistics will be used for the 
analysis following standard statistical and epidemiological methods.
Continuous variables will be listed as median with interquartile and 

Boehringer Ingelheim
Page 12 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
Not applicable
Name of active ingredient:
Not applicable
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
29 August 2016
1199.252
1.10
22 February 2018
other percentages, and as mean value with standard deviation (SD), 
along with minimum and maximum values. Categorical values will be 
listed as absolute and relative frequencies.
Stratified analyses will be performed among newly diagnosed patients 
as well as patients that were diagnosed in the past. For outcome 
analysis the newly diagnosed patients are the decisive one. Due to the 
limited number of patients and population heterogeneity, no causal 
relationship conclusion can be derived (no hypothesis testing).
Statistical analyses will be performed with IBM SPSS Statistics 
(Version 19.0).
Milestones:
Data collection start: April 2017
Data collection end:  June 2021
Final report of trial results: June 2022

Boehringer Ingelheim
Page 13 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
5.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study protocol
Amendment or update
Reason
1
07 Dec 2017
4.   ABSTRACT
Population: About 300 patients are going to be 
included in the study in a consecutive manner, 
coming
from
seven
(7)
Centers
in
Greece
–
University
Pulmonology
Clinics
& Reference
Centers of Public Hospital Setting – that follow up
around 70% - 80% of IPF patients within the 
Greek territory from April 2017 to April 2019.
Increase of the approximate 
number of patients to be included
in the study to 300, in order for 
the statistical power and validity 
of the study’s results to get 
strengthened. The increase of the 
sample size of the present registry
has been adopted due to the strong 
interest of the participating
investigators and due to the 
availability of eligible IPF
patients in the selected sites.
2
07 Dec 2017
4.   ABSTRACT
Study size: Approximately 300 patients are going 
to be included in the study from the participating 
sites. The number of included patients as well as the 
duration of the study is not defined by a formal 
sample size and power calculation, but is mainly 
based on the availability of eligible IPF patients as 
well as the patient population in the selected sites. 
However, a precision table is provided.
Increase 
of 
the 
approximate 
number of the expected to be 
included in the study patients to 
300, in order for the statistical 
power and validity of the study’s 
results to get strengthened. The 
increase of the sample size of the 
present registry has been adopted 
due to the strong interest of the 
participating
investigators 
and 
due to the availability of eligible
IPF patients in the selected sites.

Boehringer Ingelheim
Page 14 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Number
Date
Section of 
study protocol
Amendment or update
Reason
3
07 Dec 2017
4.   ABSTRACT
Milestones:
Data collection start: April 2017 
Data collection end: June 2021
Final report of trial results: June 2022
Update of the main milestones 
dates, so that the actual timelines 
and actual plan to be reflected 
accurately, based on the visit 
schedule of the protocol and 
taking into consideration that the 
first 
investigational 
site 
was 
activated on 04 April 2017 and 
the data collection initiated on 05 
Apr 2017.
4
07 Dec 2017
6. MILESTONES
Milestone
Planned Date
IRB/IEC approval
30 October 2016
Start of data collection
05 April 2017
End of data collection
05 June 2021
Final report of study 
results:
05 June 2022
Update of the main milestones 
dates, so that the actual timelines 
and actual plan to be reflected 
accurately, based on the visit 
schedule of the protocol and 
taking into consideration that the 
first 
investigational 
site 
was 
activated on 04 April 2017 and 
the data collection initiated on 05 
Apr 2017.

Boehringer Ingelheim
Page 15 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Number
Date
Section of 
study protocol
Amendment or update
Reason
5
29 Jan 2018
9.2 SETTING
Not applicable
Addition upon request from the 
reviewing group.
6
07 Dec 2017
9.3  STUDY SITES
Physicians managing IPF patients are eligible for
participation in the study considering their
qualifications, their past participation and
experience on similar clinical studies and their
capacity on recruiting and monitoring patients in
the study. In order to ensure adequate patient
numbers per center and high quality of data, expert
pulmonary centers will be involved. Seven Centers
- University Pulmonology Clinics / Reference
Centers of Public Hospital Setting have been
selected. Eligible patients will be included in a
consecutive manner at each site in order to avoid
selection bias. It is possible that the number of Sites
will increase in order to achieve representation of
the entire Greek territory. A minimum of 15 patients 
per year should be included per center, to ensure that 
centers have adequate patient numbers to get 
accustomed to the study procedures. The number of 
patients per center is defined in the contractual 
agreement of each Investigator but may be amended 
in consultation with the Sponsor, thus allowing the 
inclusion of more patients. Thus, the study will likely 
be representative for expert centers in Greece, 
representing the majority of expert centers in Greece.
Increase of participating centers 
up to seven (7) compared to the 
initially defined number of four 
(4) participating centers. The 
composition of the participating 
investigational sites has been 
modified, as follows: 
Five (5) University Pulmonology 
Clinics 
and two (2) Reference Centers 
from Public Hospitals

Boehringer Ingelheim
Page 16 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Number
Date
Section of 
study protocol
Amendment or update
Reason
7
07 Dec 2017
9.3.3 Study Visits
The registry is scheduled to run for 4 years in total (2 
years recruitment + 2 years follow up) (April 2017 to 
April 2021).
During the follow up period, data will be collected on 
standard clinical visits which usually are scheduled 
around: 3-months (+/- 1 month), 6-months (+/- 1 
month), 12-months (+/- 2 month), 18-months (+/- 2 
month) and 24 months (+/- 2 months), until the end 
of participation in the study. In case of events, 
unscheduled visits may be required.
The timeframe of the entire study 
duration has been updated so that 
to be in consistency with the 
actual timelines.
8
29 Jan 2018
9.4.2  Outcomes
See sections 9.4.3 & 9.4.4
Addition upon request from the 
reviewing group.
9
07 Dec 2017
9.4.5  Covariates
Table 
1. 
List 
of 
variables 
to 
be 
documented 
 
(if 
available) 
at 
scheduled visits
Table 1. List of variables to be documented (if 
available) at scheduled visits
Correction 
on 
the
tabulated
schedule
of
assessments, 
in 
Table 1 (List of variables to be 
documented 
(if 
available) 
at 
scheduled visits), where the mark 
X, which corresponds to the 
variable of (Possible)

Boehringer Ingelheim
Page 17 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Number
Date
Section of 
study protocol
Amendment or update
Reason
9
(continued)
07 Dec 2017
9.4.5  Covariates
Table 
1. 
List
of 
variables 
to 
be 
documented 
(if 
available) 
at 
scheduled visits
Variable (Please refer to Annex 4)
Assessment
Follow up**
(Possible) IPF risk factors
Cigarette smoking incl. pack years
(Categorized
as
never/past/current/unknown.
For
past/current, specify packs/year
and
for
past,
number
of
years
smoking one pack per day);
environmental
and
occupational
exposure; alcohol and substance
abuse; exposure to drugs associated
with IPF ; exposure to viral
infection
possibly
related
to
IPF;
gastro - oesophageal reflux;
genetic factors (family history); others
x
IPF risk factors, is deleted from 
the column of the Follow Up, since 
that type of data is collected in the 
context of baseline visit. 
The initially printed mark X at the 
follow up column is characterized 
as typo error, as it had been 
printed by mistake.

Boehringer Ingelheim
Page 18 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Number
Date
Section of 
study protocol
Amendment or update
Reason
10
07 Dec 2017
9.6 STUDY SIZE
This observational study will be analyzed using 
descriptive statistics following standard statistical 
and epidemiological methods. Approximately 300 
patients are expected to be included in the study in a 
consecutive manner between April 2017 and April 
2019 from the participating sites according to the 
feasibility procedure of the sites.
Increase 
of 
the 
approximate 
number of the expected to be 
included in the study patients to 
300, in order for the statistical 
power and validity of the study’s 
results to get strengthened. The 
increase of the sample size of the 
present registry has been adopted 
due to the strong interest of the 
participating
investigators 
and 
due to the availability of eligible
IPF patients in the selected sites.
In parallel, the timeframe of the 
enrolment 
period 
has 
been 
updated so that to be in line with 
the actual timelines.
11
16 Feb 2018
9.6 STUDY SIZE
Table 2 describes the expected precision for the 
description of a proportion, according to different 
sample sizes. Note that within Table 2 the first 
interval relates to an asymptotic 95% confidence 
interval and the second interval relates to an exact 
95% confidence interval (i.e. The Clopper-Pearson 
interval).
Due to the revision of Table 2 
which presents the confidence 
intervals,
based 
on 
the 
calculations from two different 
statistical methods. The revised 
Table 
2 
incorporates 
the 
respective calculations in relation 
to the new sample size of 300 
patients.

Boehringer Ingelheim
Page 19 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Number
Date
Section of 
study protocol
Amendment or update
Reason
12
16 Feb 2018
9.6 STUDY SIZE
Table 2. Precision of 
estimates for binary 
parameters
Table 2. Precision of estimates for binary parameters
(Sub) 
group 
size
Proporti
on
50%
40%
30%
20%
10%
50
(36.14%, 
63.86%)
(26.42%, 
53.58%)
(17.30%, 
42.70%)
(8.91%, 
31.09%)
(1.68%, 
18.32%)
(35.53%, 
64.47%)
(26.41%, 
54.82%)
(17.86%, 
44.61%)
(10.03%, 
33.72%)
(3.33%, 
21.81%)
100
(40.20%, 
59.80%)
(30.40%, 
49.60%)
(21.02%, 
38.98%)
(12.16%, 
27.84%)
(4.12%, 
15.88%)
(39.83%, 
60.17%)
(30.33%, 
50.28%)
(21.24%, 
39.98%)
(12.67%, 
29.18%)
(4.90%, 
17.62%)
200
(43.07%, 
56.93%)
(33.21%, 
46.79%)
(23.65%, 
36.35%)
(14.46%, 
25.54%)
(5.84%, 
14.16%)
(42.87%, 
57.13%)
(33.15%, 
47.15%)
(23.74%, 
36.86%)
(14.69%, 
26.22%)
(6.22%, 
15.02%)
300
(44.34%, 
55.66%)
(34.46%, 
45.54%)
(24.81%, 
35.19%)
(15.47%, 
24.53%)
(6.61%, 
13.39%)
(44.20%, 
55.80%)
(34.41%, 
45.79%)
(24.87%, 
35.53%)
(15.62%, 
24.98%)
(6.85%, 
13.97%)
Inclusion of the newly calculated 
confidence intervals, based on the 
new sample size (300 pts) into a 
revised Table 2. The revised 
Table 2 presents more accurately 
the 95% confidence intervals
based on the calculations from 
two different statistical methods, 
comparing to the original Table 2.

Boehringer Ingelheim
Page 20 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Number
Date
Section of 
study protocol
Amendment or update
Reason
13
07 Dec 2017
9.10 LIMITATIONS  
OF THE 
RESEARCH 
METHODS
The study is going to provide evidence regarding the 
situation in the IPF reference centers which are 
University Pulmonology Clinics and Pulmonology 
Clinics at Hospitals of Public Setting that follow up 
about 70%-80% of IPF patients in Greece.
Increase of participating centers 
up to seven (7) compared to the 
initially defined number of four 
(4) participating centers. The 
composition of the participating 
investigational sites has been 
modified, as follows: 
Five (5) University Pulmonology 
Clinics and two (2) Reference 
Centers from Public Hospitals

Boehringer Ingelheim
Page 21 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
6.
MILESTONES
Milestone
Planned Date
IRB/IEC approval
30 October 2016
Start of data collection
05 April 2017
End of data collection
05 June 2021
Final report of study results:
05 June 2022

Boehringer Ingelheim
Page 22 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
7.
RATIONALE AND BACKGROUND
7.1
DEFINITION
Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive 
fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, 
limited to the lungs[1]. It is characterized by progressive worsening of dyspnea and lung 
function and is associated with a poor prognosis. As stated in an international consensus 
statement jointly issued by ATS/ERS, JRS and ALAT, IPF is a distinct clinical entity 
associated with the histologic and/or radiologic appearance of usual interstitial pneumonia 
(UIP) [1]. The definition of IPF requires the exclusion of other forms of interstitial 
pneumonia including other idiopathic interstitial pneumonias (IIP) and interstitial lung 
disease (ILD) associated with environmental exposure, medication, or systemic disease [1].
IPF predominantly presents in older individuals (cases in persons aged less than 50 years are 
rare), with a preponderance in men and previous or current smokers. Patients present with 
unexplained chronic exertional dyspnea, and commonly with cough, bibasilar inspiratory 
crackles, and finger clubbing.
7.2
INCIDENCE AND PREVALENCE
Overall, epidemiological data on the incidence and prevalence of IPF are limited, as stated in 
the consensus statement issued by ATS/ERS/JRS/ALAT [1]. 
In a population-based study from New Mexico, the incidence of IPF was estimated at 10.7 
cases per 100,000 per year for men and 7.4 cases per 100,000 per year for women [1]. In the 
UK, an overall incidence rate of only 4.6 per 100,000 person-years was reported, however, 
with an estimated increase by 11% annually between 1991 and 2003 (not attributed to aging 
of the population or increased ascertainment of milder cases) [4]. In the USA, based on a 
large database of healthcare claims in a health plan, the incidence of IPF was estimated 
between 6.8 and 16.3 per 100,000 persons [5].
Prevalence estimates for IPF, as assessed in England, Japan, New Mexico, Norway, Italy and 
Greece , have varied widely from 1,82 to 35,51 cases per 100,000 in the general population
[2, 6-9, 26]. The wide range in these numbers is likely explained by the previous lack of 
uniform definition used in identifying cases of IPF, as well as by differences in study designs 
and populations [1]. In the USA, a recent analysis based on healthcare claims yielded a 
prevalence estimate between 4.0 - 42.7 per 100,000 persons depending on the case definition 
used [5]. Another study from the US, estimated a prevalence of 58.7 per 100,000 (95% CI 
56.3-61.2) for IPF, after correction of the estimate for its PPV after chart review [27]. It is 
unknown if the incidence and prevalence of IPF are influenced by geographic, ethnic, 
cultural, or racial factors [1]. In Italy, a relevant study from N. Agabiti,M. A. Porretta, L 
Bauleo, A. Coppola, et al, conducted at Lazio region, concluded that IPF incidence and 
prevalence in this large central-southern Italian region are strikingly similar to those derived 
from the hospital and general medicine databases of northern Europe and the United States. 
At the same time, this study stated that IPF incidence is more likely driven by 
industrialization, urbanization and western lifestyles than the ethnic variables characterizing 
different European regions[25]. In 2016, another study conducted in Lombardy, the most 
populous region of Italy, estimated the annual incidence and prevalence at 7.5 and 25.6 per 

Boehringer Ingelheim
Page 23 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
100,000 person-years, respectively. This same study indicated that prevalence of IPF 
increased across the years while incidence remained stable, concluding that survival with IPF 
has improved. However, Italian trends in incidence and prevalence of IPF are still unknown 
[26].
7.3
DIAGNOSIS 
According to the consensus statement jointly issued by ATS/ERS/JRS/ALAT in 2011, the 
diagnosis of IPF requires the following [1]:
•
Exclusion of other known causes of ILD (e.g., domestic and occupational 
environmental exposures, connective tissue disease, and drug toxicity).
•
The presence of a UIP pattern on HRCT in patients not subjected to surgical lung 
biopsy
•
Specific combinations of HRCT and surgical lung biopsy pattern in patients subjected 
to surgical lung biopsy
Figure 1. Diagnostic algorithm according to ATS/ESC/ERS/JRS/ALAT guidelines [1]
Suspected IPF
Identifiable causes for ILD?
HRCT
Surgical Lung 
Biopsy
MDD
IPF/Not IPF per Annex 6 & 7
Not IPF 
IPF 
Possible UIP*
Inconsistent w/ UIP*
Yes
No
Not UIP†
UIP†
Probable UIP†/Possible UIP†
Non classifiable fibrosis†
UIP*

Boehringer Ingelheim
Page 24 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
7.4
NATURAL COURSE
Data on the natural course of IPF are from retrospective and a few prospective studies, 
including the placebo arms of clinical trials (limited to short observation periods and by in-
/exclusion criteria). The previously reported median survival time of 2-3 years from the time 
of diagnosis could be an underestimate, at least when accounting for patients with preserved 
lung function. Notably, the natural course is unpredictable for a given patient at the time of 
diagnosis, while the majority of patients experience steady worsening (slow progression), 
other remain stable, or have rapid progression of disease [10-11]. 
Acute respiratory 
worsening either due to secondary complications (e.g. pneumonia, pulmonary embolism, 
pneumothorax or cardiac failure) or due to unknown reasons (in this case the term acute 
exacerbation is used) are suggested to occur in about 5-10% annually [1]. A recent 
retrospective review of 461 patients with IPF has found that the 1- and 3-year incidences of 
acute exacerbations were 14.2% and 20.7%, respectively [12].
7.5
THERAPY
The ATS/ESR/JRS/ALAT guideline finalized end of 2010 and issued in 2011 stated: “The 
committee did not find sufficient evidence to support the use of any specific pharmacologic 
therapy for patients with IPF.” [1]
A number of drugs are used for the treatment of IPF, including steroids, azathioprine and N-
acetylcysteine (and sometimes the latter three in combination). However, recently the NHLBI 
(part of the National Institutes of Health) has stopped the triple- drug therapy arm consisting
of prednisone, azathioprine, and N-acetylcysteine (NAC) of the US PANTHER trial due to 
safety concerns. [13]
The only drug that until recently had received regulatory approval for the treatment of mild or 
moderate IPF in Europe and Japan was pirfenidone, a pyridone compound with pleiotropic, 
anti-inflammatory, antifibrotic, and antioxidant properties, with antagonism of TGF-b1 
effects [14]. On October 2014, FDA approved simultaneously pirfenidone and nintedanib, a 
tyrosine kinase inhibitor that was researched and developed by Boehringer Ingelheim [15] for 
IPF treatment. Moreover, on January 15, 2015 EMA approved the use of nintedanib on all 
IPF stages. According to the updated Guidelines for IPF treatment, released on July of 2015, 
conditional recommendations have been made for treatment with novel agents such as 
pirfenidone and nintedanib, as well as antiacid treatment. The treatment of IPF patients 
should be individualized, according to the patient and the physician should calculate the 
benefit of using one intervention instead of another [2]. New drugs for IPF treatment will also 
be documented in this registry. 
As for supportive pharmacological and non-pharmacological therapy, the evidence is limited, 
too. This includes anticoagulants, long-term use of oxygen, mechanical ventilation and lung 
transplantation [1].

Boehringer Ingelheim
Page 25 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
7.6
ECONOMIC ASPECTS
IPF is of high interest for the health-care system as well as for payers when considering costs. 
However, data on economic issues are limited, while needed for assessing cost-effectiveness 
of interventions [16-17].
The current IPF Registry will be suitable for various cost analyses. All pharmaco- and health 
economic parameters will be derived from either one or both of the following ways and in 
most cases subsequently priced:
•
Assessment of the direct health resources use
•
Indirect health assessment with adjustment of recorded clinical outcomes.
7.7
RATIONALE FOR THE PRESENT REGISTRY
Long-term data on the natural course of IPF are missing. Further, there is lack of information 
on detailed patient characteristics. While in IPF substantial efforts are being made to 
investigate the efficacy and safety of new drugs in controlled clinical trials, there is a lack of 
data on the situation and treatment of patients in everyday clinical practice. In a call for 
action on an IPF registry by Wilson in 2008, it was noted that improved survival from this 
disease is dependent on better understanding of the epidemiology of the disease, its 
diagnostic spectrum and an analysis of outcomes from emerging therapies at a significant 
level. [17] In Greece, Karakatsani et al, conducted a multicenter research (survey) in 2009, 
using a one page questionnaire, in order to evaluate the incidence and prevalence of 
Interstitial Lung Diseases in Greece. The annual incidence of IPF was estimated to be 0.93 
cases per 100,000 whereas prevalence was estimated to be 3.38 cases per 100,000. Since 
then, the diagnostic criteria, the international guidelines [1] the standard medical care and the 
composition of the population have changed, whereas more studies have been conducted 
regarding the incidence and prevalence of IPF (please refer to Section 7.2). 
A registry can document the introduction of new treatments and complement data from the 
controlled randomized trials. The present clinical IPF registry will record standard 
epidemiological parameters by using a web-based electronic case report form. No additional 
biobank specimen will be collected (only already existing data will be used from 
examinations that have been performed according to the routine clinical practice of the 
physicians). IPF diagnosis will be based upon criteria, defined according to the consensus 
statement jointly issued by ATS/ERS/JRS/ALAT for the collection of standard practice data, 
and as it is also described in the inclusion criteria section. Moreover, in the present IPF 
registry, drug utilization and treatment patterns under clinical practice conditions will be 
documented in detail. Furthermore, health economic aspects will be investigated.

Boehringer Ingelheim
Page 26 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
8.
RESEARCH QUESTION AND OBJECTIVES
The overall objective of the present IPF Registry is to gain further insight on the 
characteristics, management, disease progression and the outcomes of patients with IPF, as 
diagnosed and treated under real-world, clinical practice conditions in Greece. 
More specifically, this registry will be used to:
•
Provide a comprehensive clinical picture of IPF
•
Track access to health care and cost of caring for IPF patients over time
•
Examine the implementation of treatment guidelines [2], used on patients diagnosed 
with IPF, according to the existing diagnosis guidelines [1]
•
Characterization of patients on different treatments
Furthermore, this project aims to provide information regarding survival and mortality 
causes, IPF exacerbations as well as IPF patient co-morbidities including myocardial 
infarction, CNS infarction, other arterial thromboembolic events, deep vein thrombosis, 
hemorrhage, gastrointestinal perforation and pulmonary hypertension (please refer to Annex 
3). In addition, data regarding IPF patient hospitalization will be collected and evaluated with 
regards to potential respiratory causes, and there will be documentation of treatment patterns 
and economic aspects. Patients will be followed up for 2 years and information regarding IPF 
treatment changes since the last visit will be collected.

Boehringer Ingelheim
Page 27 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.
RESEARCH METHODS
9.1
STUDY DESIGN
This IPF registry allows for structured, non-interventional collection of data. A similar 
protocol was prepared by the 
of the
 
(
). This Protocol is based on the main idea of the protocol 
created by the
 It is a national, multi-center, observational disease and 
outcomes registry based on new data from a significant sample size of Greek IPF patients. 
Participating physicians (experts in IPF) will not be subject to any instructions with regard to 
the diagnosis and therapy of their patients. All examinations performed depend on the 
discretion and clinical routine of the physician.
The Sponsor of the Study will be 
 and will own the data 
and have access to the data. Members of the National Scientific Committee (see title page) 
will oversee and give scientific advice for the study. 
An external Vendor (CRO) will provide the electronic database; the web based eCRF and 
will perform the statistical analyses and produce the relevant reports according to the 
Statistical Epidemiological Analysis Plan.
This IPF Registry is not a clinical trial (interventional study) according to the Ministerial 
Decision No 12/2003 of the Greek Legislation for Clinical Studies, but a non- interventional 
observation study.
9.2
SETTING
Not applicable
9.3
STUDY SITES
Physicians managing IPF patients are eligible for participation in the study considering their
qualifications, their past participation and experience on similar clinical studies and their
capacity on recruiting and monitoring patients in the study. In order to ensure adequate
patient numbers per center and high quality of data, expert pulmonary centers will be
involved. Seven Centers - University Pulmonology Clinics / Reference Centers of Public 
Hospital Setting have been selected. Eligible patients will be included in a consecutive
manner at each site in order to avoid selection bias. It is possible that the number of Sites
will increase in order to achieve representation of the entire Greek territory. A minimum of 
15 patients per year should be included per center, to ensure that centers have adequate patient 
numbers to get accustomed to the study procedures. The number of patients per center is 
defined in the contractual agreement of each Investigator but may be amended in consultation 
with the Sponsor, thus allowing the inclusion of more patients. Thus, the study will likely be 

Boehringer Ingelheim
Page 28 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
representative for expert centers in Greece, representing the majority of expert centers in 
Greece.
9.3.1
Study Population
Eligible for participation in the study patients must fulfill ALL the inclusion criteria and 
NONE of the exclusion criteria that are listed below and must be consecutively enrolled:

Newly diagnosed (less than 6 months) or patients previously diagnosed with IPF 
(more than 6 months from baseline visit), based upon the consensus statement 
jointly issued by ATS/ERS/JRS/ALAT in 2011 (see Annex 6 and Annex 7 for 
HRCT and histological criteria in Annex 6)
o
Exclusion of other known causes of ILD (e.g., domestic and occupational 
environmental exposures, connective tissue disease, and drug toxicity)
o
Assessment of IPF based on HRCT or combinations of HRCT and surgical 
lung biopsy, if available

Age ≥40 years old at the time of inclusion

Written informed consent for participation in the registry

Patients that can be followed up further, during the scheduled study period
None of the following Exclusion Criteria should be fulfilled:

Expected lung transplantation within the following 6 months

Participation in clinical trials
Patients will be included in a consecutive manner at each site in order to avoid selection bias.
It should be avoided to establish the registries at sites where already other registries are 
ongoing (if a patient participates in another registry/non - interventional study this needs to 
be documented and patients need to be analyzed separately).
A subject screening log should be kept at the site, 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 the information on the eligibility (or reasons for non-
eligibility) and date of signed informed consent. 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 study file at the study site.
9.3.2
Withdrawal Criteria
The patients reserve the right to withdraw consent at any time during the study, without the
need for justification and without any impact on their future treatment and care.
Withdrawal of consent means that the patient does not wish or cannot continue to participate 
in the study any more. 
The reasons for withdrawal may include the following:

Boehringer Ingelheim
Page 29 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015

Patient or legally accepted representative withdraws informed consent for 
participation in the study.

Inclusion or possible participation in any clinical trial, any time within the follow up 
period of the study, in which the patient has been exposed or is going to be exposed to 
an investigational product (pharmaceutical product or medical device) or intervention.

The patient was erroneously included in the registry

Decision of the investigator/physician

Important deviation/divergence from the protocol.
The Clinical Monitor at BI or BI’s designees must be immediately notified if a patient is 
discontinued prematurely for any of the instances reasons cited above.
Patients that withdraw from the study should be asked about the reason(s) for withdrawal and 
the occurrence of adverse events, and should be examined and evaluated by the investigator 
according to the procedures that are defined in the Final Visit (unless reason for 
discontinuation is erroneous enrolment of the patient into the study at baseline and unless 
patient has actively withdrawn consent for any kind of future contacts). 
If the patient specifically withdraws consent for future contact about the collection of further 
information, there will be no such contact whatsoever. However, it is possible to collect 
information regarding their survival status, if they are publicly available.
The investigators also reserve the right to remove a patient from the study, if according to 
their clinical judgment this is the necessary for the patient’s welfare.
If a patient is removed or withdrawn from the study for any reason, the date, vital status and 
reason must be documented in the relevant section of the electronic Case Report Form 
(eCRF).
9.3.3
Study Visits
The registry is scheduled to run for 4 years in total (2 years recruitment + 2 years follow up) 
(April 2017 to April 2021).
During the follow up period, data will be collected on standard clinical visits which usually 
are scheduled around: 3-months (+/- 1 month), 6-months (+/- 1 month), 12-months (+/- 2 
month), 18-months (+/- 2 month) and 24 months (+/- 2 months), until the end of participation 
in the study. In case of events, unscheduled visits may be required.
9.3.4
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. Violation of Good Clinical Practice (GCP) (as applicable), the study protocol, or the 
contract by a study site or investigator, disturbing the appropriate conduct of the study

Boehringer Ingelheim
Page 30 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason).
9.4
VARIABLES
At baseline, a relevant patient history will be recorded including IPF-related events up to 12 
months prior to this visit. The variables to be recorded are listed below as well as in Annex 4:

Basic (socio-)demographic data including age, gender and race 

Vital Status

Physical and vital signs examination

Cardiopulmonary exercise testing (6-minute walk distance and CPET, if 
performed)

IPF risk factors (e.g cigarette smoking including pack years, alcohol and 
substance abuse, environmental and occupational exposure, exposure to drugs 
associated with IPF , exposure to viral infection possibly related to IPF, gastro-
esophageal reflux, genetic factors - family history) 

Co-morbidities.

Risk of bleeding and thrombosis

Collection of pre-specified outcome data, only for newly diagnosed patients 
(such as acute respiratory worsening, exacerbations, hospitalization due to any 
cause and due to IPF). Please, refer to Annex 3

Recording of therapeutic regimens. Assessment of the intensity of treatment, 
frequencies and resource utilization for pharmaco-economic analyses. 

Methods and procedures used in the diagnosis of IPF and date of diagnosis 
(HRCT: UIP pattern, possible, inconsistent UIP pattern and not available and 
SLB: UIP pattern, probable, possible or inconsistent UIP pattern)

IPF symptoms: Dyspnea, cough, weight loss, fatigue, dizziness, chest pain, 
anxiety, clubbing, bibasilar crackles

Autoimmune Biomarker results (No additional specimen will be collected. Only 
already existing data will be used from exams that have been performed 
according to the routine clinical practice of the physicians),

Assessment of function (including lung function, cardiopulmonary exercise
testing and/or exercise capacity if available, laboratory values)

IPF treatment modalities (detailed information on prescribed drugs and dose; 
previous treatment; start and end dates of previous treatments; non-
pharmacological treatment; listing and score for lung transplantation). For the 
treatments that detailed information will be requested, please refer to Annex 4

Boehringer Ingelheim
Page 31 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015

Physician’s clinical rating of the probable course of IPF (stable, slow or rapid 
progression)

Clinical events and hospitalizations especially due to: (acute) respiratory 
worsening, including pneumonia, exacerbations of IPF, occurrence of pulmonary 
or cardiovascular complications, pulmonary rehabilitation, pulmonary embolism, 
pneumothorax, or cardiac failure 

Management of IPF and physician contacts
During follow up visits (prospectively until up to 2 years at least from the inclusion) 3-
months (+/- 1 month), 6-months (+/- 1 month), 12-months (+/- 2 month), 18-months (+/- 2 
month) and 24 months (+/- 2 months), documentation of events (or last follow up visit) will 
be carried out. The collection of data will be performed during standard clinical practice 
visits (i.e. visits should not be performed via telephone contact). In a special event where the 
physical presence of the patient is not possible, e.g. in case of temporary inability of the 
patient to visit the expert center, this visit could be performed through telephone contact and 
this should be recorded in patient’s history. Every effort should be made, however, to ensure 
that the next visit will be performed as planned by the patient in person. If this is not possible 
the patient will be censored for the rest of the study. Patient will be followed up until death, 
lung transplantation, consent withdrawal or end of study, whichever comes first and will be 
censored if one of the events occurs. The following data will be documented:

Clinical course of IPF (e.g. regarding symptoms, lung functionality, exercise 
ability, if available)

Vital status

Physical and vital signs examination

Cardiopulmonary exercise testing (6-minute walk distance and CPET, if 
performed)

Autoimmune Biomarker results (No additional specimen will be collected. Only 
already existing data will be used from exams that have been performed 
according to the routine clinical practice of the physicians)

Risk of bleeding and thrombosis

Outcomes of interest (such as acute respiratory worsening, exacerbations, 
hospitalization due to any cause and due to IPF). Please, refer to Annex 3

Recording of therapeutic algorithms (change/complement/interrupt treatment) 
and non-pharmacological treatment (e.g. start of LTOT, new listing for lung 
transplantation)

Physician’s clinical rating of the probable course of IPF (stable, slow or rapid 

Boehringer Ingelheim
Page 32 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
progression)

Assessment
of
treatment
intensity,
frequencies
and
resource
use
for 
pharmacoeconomic analyses for the treatments described under 11.3

Management of IPF and physician contacts
9.4.1
Exposures
Not Applicable
9.4.2
Outcomes
See sections 9.4.3 & 9.4.4 
9.4.3
Primary Outcomes
The main objective of this IPF registry is to gain further knowledge on the characteristics, 
management, progression and outcomes of patients with IPF as treated under real-world, 
clinical practice conditions in Greece.
More specifically, this registry is going to:
•
Provide a comprehensive clinical picture for IPF
•
Track access to health care and cost of caring for IPF patients over time
•
Examine the implementation of treatment guidelines [2], used on patients diagnosed 
with IPF, according to the existing diagnosis guidelines [1]
•
Characterization of patients on different treatments
For more detailed information, please refer to Annex 3.
9.4.4
Secondary Outcomes
This registry documents management and treatment of IPF-patients in real-world clinical
practice. One objective of this registry is to document drugs used for IPF.
The following drugs will be documented in detail in terms of drug name, dosage, start and 
stop dates, including combinations of the mentioned drugs:

Steroids

Immunomodulators
(azathioprine, cyclophosphamide,
cyclosporine 
A, 
mycophenolate mofetil etc)

N-Acetylcysteine

Pirfenidone

Nintedanib

Anticoagulants

Boehringer Ingelheim
Page 33 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015

Vit-K antagonist

Heparin

Antiplatlet therapy (if yes it will be specified if high dose antiplatlet therapy)

Aspirin (if yes it will be specified if used as antiplatelet)

GERD medication

PDE-5 inhibitor (sildenafil, tadalafil)

Endothelin receptor antagonist (bosentan, ambrisentan, macitentan)

Long term oxygen therapy

Listed for lung transplantation

NSAIDs, other than aspirin

Hormone replacement therapy

Hormonal contraceptives

Anti-VEGF drugs

NOAC

Other (specify)
9.4.5
Covariates
Due to the non - interventional nature and design of the observational study, this registry does 
not require diagnostic/therapeutic procedures or strict timeline visit schedule. Patients will 
receive treatment according to standard clinical practice with regards to visit frequencies, 
type of performed assessments and according to local prescription requirements.
Following identification of a potential patient, the investigator will follow the below listed 
procedures:
1.
Review of individual patient’s medical history, to confirm that the inclusion/exclusion 
criteria are met.
2.
Explanation of the study objectives to the patient and receipt of signed and dated 
informed consent, after providing the patient with sufficient time to read carefully and 
understand the information sheet.
3.
Data collection from the medical records of eligible for enrollment patients, as required 
by eCRF, and eCRF completion.
Please refer to Section 11.2 for details regarding Adverse Event and Serious Adverse Event 
Collection and Reporting.
A tabulated schedule of assessments that provide information regarding the recommended 
timeline of data collection and represents the standard clinical care of IPF treated patients is 
listed below in Table 1. The exact definitions of the variables can be found in Appendixes 2-
5.

Boehringer Ingelheim
Page 34 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Table 1. List of variables to be documented (if available) at scheduled visits
Variable (Please refer to Annex 4)
Assessment
Follow up**
Eligibility criteria
x
Baseline information (assessment)
(Socio-)demographic variables: age, gender, race, 
height,
index 
employment status, insurance status
x
Weight, blood pressure, heart rate
x
x
(Possible) IPF risk factors
Cigarette smoking incl. pack years
(Categorized as 
never/past/current/unknown. 
For 
past/current, 
specify 
packs/year and for past, number of years smoking one pack 
per day); environmental and occupational exposure; alcohol 
and substance abuse; exposure to drugs associated with IPF ;
exposure to viral infection possibly related to IPF; gastro-
oesophageal reflux; genetic factors (family history); others
x
Co-morbidities (Please refer to Annex 5)
x
x
IPF
Baseline information (assessment) on IPF
First symptoms; date of first diagnosis, dates and results of 
HRCT, surgical lung biopsy, bronchoalveolar lavage.
x
Symptoms
9.4.5.1
Dyspnea, cough fatigue, dizziness, chest pain, 
anxiety [20]
x
x
Functional assessment
Lung function test (VCin, FVC, FEV1, TLC; DLCO; pO2, 
pCO2) [21]
6-minute walk distance 
Cardiopulmonary exercise testing (CPET;)
x
x
Serologic evaluation– Autoimmune Biomarkers (laboratory values)
Rheumatoid factor, anti-cyclic citrullinated peptide, and anti-
nuclear antibody titer and pattern*
Others e.g. SCL-70, SS-A, SS-B
x
x

Boehringer Ingelheim
Page 35 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
BNP/NT-pro BNP
Hb, AST, ALT, total bilirubin
Pharmacological treatment( start date, stop date and daily dose)
Past/discontinued: drugs (e.g. steroids yes/no/unknown). 
Detailed list of drugs in Annex 4
x
x
Current: drugs by class and/or name 
x
x
Participation in IPF trial
x
x
Non-pharmacological treatment
x
x
Long-Term-Oxygen-Therapy (liquid and/or concentrate)
x
x
Lung transplantation score and assessment if the patient is currently 
listed for participation in lung transplantation
x
x
Physician assessment
Physician’s clinical rating of the probable course of IPF 
(stable, slow or rapid progression), based on available FVC 
results, 
DLCO 
results, 
physical 
examination, 
hospitalizations/events between the visits
x***
x
Management of IPF and physician contacts
Number of physician visits (own office, other physicians)
x***
x
Number and type of IPF related procedures
x***
x
Outcomes of Interest (please refer to Annex 3)
x***
(except 
for
mortality,
hospitalization, please see 
below) 
x
Clinical events and hospitalizations
specifically due to: (acute) worsening of respiratory function 
including pneumonia; IPF-exacerbations; manifest pulmonary 
or cardiovascular complications; pulmonary rehabilitation; 
pulmonary embolism; pneumothorax; cardiac failure (please 
refer to Annex 3 for detailed description of the outcomes of 
interest).
x***
x
Number of days in hospital or in rehabilitation; work days 
lost due to IPF
x***
x
Physical examination and vital signs 
x
x
Risk of bleeding and thrombosis
x
x

Boehringer Ingelheim
Page 36 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Survival status (vital status)(please refer to Annex 3)
x
For abbreviations, please refer to glossary.
* As recommended in the ATS/ERS guidelines for distinguishing connective tissue disease 
from IPF
**3-months (+/- 1 month), 6-months (+/- 1 month), 12-months (+/- 2 month), 18-months (+/-
2 month) and 24 months (+/- 2 months)
*** the past 12 months
9.5
DATA SOURCES
The study will mainly include the recording of new data through a web based system for data 
collection. Data will be collected by the study doctors as they occur according to standard 
clinical practice in the approximate visiting schedule indicated above. 
Source (primary) patient data related to their medical and IPF history will be collected by the 
investigators from the patient’s medical files/records and will be documented in the relevant 
eCRF section. 
Data regarding treatment modifications, concomitant treatments, study related routine clinical 
assessments, adverse events (ADRs) and survival status will also be collected. If a patient 
withdraws early from the study, they will be contacted via telephone at the end of the Study 
in order to evaluate their survival status. Another follow-up assessment should be performed 
if possible (unless reason for discontinuation is erroneous enrolment of the patient into the 
study at baseline), and data should be entered on the eCRF of the next planned visit unless the 
patient has actively withdrawn consent for any kind of future contacts.
9.6
STUDY SIZE
This observational study will be analyzed using descriptive statistics following standard 
statistical and epidemiological methods. Approximately 300 patients are expected to be 
included in the study in a consecutive manner between April 2017 and April 2019 from the 
participating sites according to the feasibility procedure of the sites.
The number of included patients as well as the duration of the study is not defined by a 
formal sample size and power calculation, but is based mainly on the availability of eligible 
IPF patients as well as patient population in the selected sites.
Table 2 describes the expected precision for the description of a proportion, according to 
different sample sizes. Note that within Table 2 the first interval relates to an asymptotic 95% 
confidence interval and the second interval relates to an exact 95% confidence interval (i.e. 
The Clopper-Pearson interval).

Boehringer Ingelheim
Page 37 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Table 2. Precision of estimates for binary parameters
(Sub) 
group size
Proportion
50%
40%
30%
20%
10%
50
(36.14%, 
63.86%)
(26.42%, 
53.58%)
(17.30%, 
42.70%)
(8.91%, 
31.09%)
(1.68%, 
18.32%)
(35.53%,
64.47%)
(26.41%,
54.82%)
(17.86%,
44.61%)
(10.03%,
33.72%)
(3.33%,
21.81%)
100
(40.20%, 
59.80%)
(30.40%, 
49.60%)
(21.02%, 
38.98%)
(12.16%, 
27.84%)
(4.12%, 
15.88%)
(39.83%,
60.17%)
(30.33%,
50.28%)
(21.24%,
39.98%)
(12.67%,
29.18%)
(4.90%,
17.62%)
200
(43.07%, 
56.93%)
(33.21%, 
46.79%)
(23.65%, 
36.35%)
(14.46%, 
25.54%)
(5.84%, 
14.16%)
(42.87%,
57.13%)
(33.15%,
47.15%)
(23.74%,
36.86%)
(14.69%,
26.22%)
(6.22%,
15.02%)
300
(44.34%, 
55.66%)
(34.46%, 
45.54%)
(24.81%, 
35.19%)
(15.47%, 
24.53%)
(6.61%, 
13.39%)
(44.20%, 
55.80%)
(34.41%, 
45.79%)
(24.87%, 
35.53%)
(15.62%, 
24.98%)
(6.85%, 
13.97%)
For continuous endpoints, precision of estimates will depend on parameter specific 
assumptions on mean and standard deviation. A generic display as given for binary endpoints 
is therefore less appropriate.
9.7
DATA MANAGEMENT
The registry will include the collection of new data that will be recorded in an existing web
based database in a consecutive manner (electronic case report form, eCRF) as well as 
transferring already existing data to the system from medical charts. The patients will be 
identified by subject identification number, site number, and study identification number.
Investigators will enter the data of their patients directly into an internet-based electronic case 
record form. At data entry, plausibility checks (e.g., range checks, conditional checks, etc.) 
will be performed. Data will be entered in the eCRF system by the study personnel at the 
Investigator’s site, according to the Investigator Instructions Manual. Data entered in the 
eCRF system will be automatically saved to a central database and changes tracked to 
provide an audit trail. When data have been entered, reviewed and edited, the Investigator 
shall sign the e-CRF electronically as per the agreed project process and data will be locked 
to prevent further editing.

Boehringer Ingelheim
Page 38 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Query management will be performed through built-in query management functionality
that will be incorporated into the eCRF.
Prior to the onset of data management activities, a detailed data management plan (DMP)
will be issued describing the procedure to be followed for processing all collected study
data in order to ensure they are valid, complete and accurate for statistical analysis. In
addition, aiming at ensuring the expected quality of data, a thorough data cleaning session 
will be applied. When all data have been properly validated and the quality control procedure 
has been completed, a declaration of database lock will take place so that it can be confirmed 
that all important actions have been properly performed. In addition, prior to database lock, 
and prior to the initiation of any statistical analysis activities a comprehensive statistical 
analysis plan (SAP) will be drafted. The SAP will also include information regarding the 
statistical software(s) to be used for the analysis of the study data and any data imputation 
methods that may be applied. 
9.8
DATA ANALYSIS
9.8.1
Main Analysis
The objective of this registry is neither to confirm nor to reject any predefined hypothesis; 
therefore the nature of the statistical analyses will be exploratory and descriptive.
Continuous variables will be listed as median with interquartile and other percentages, and as 
mean value with standard deviation (SD), along with minimum and maximum values
(depending on the underlying distribution). Categorical values will be listed as absolute and 
relative frequencies. All events during follow up will be described as incidence rates with 
95% confidence interval (CI). 
Stratified analyses will be performed among newly diagnosed patients (< 6 months) as well 
as patients that were diagnosed in the past (>= 6 months). In case of conflicting results those 
of the newly diagnosed will be the decisive. Due to limited number of patients and population
heterogeneity, no comparison between treatments can be done and no causal relationship 
conclusion can be derived (no hypothesis testing). Statistical analyses will be performed with 
IBM SPSS Statistics (Version 19.0).
If it was not avoidable to select patients from sites with other ongoing registries, patients 
enrolled in other registries in parallel need to be analyzed separately. In case of difference the 
results for the BI registry patients are decisive. 

Boehringer Ingelheim
Page 39 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.9
QUALITY CONTROL
In order to ensure the quality and integrity of data throughout the course of the study, proper 
quality control mechanisms and methods will be applied.
eCRF files from each participating site will be stored in CD-ROMs after completion of the 
study and will be distributed to the participating sites.
The investigators will be provided with a folder/file by the authorized representative of the 
study, in which they will be required to keep and store all study related documents. All study 
documents will be stored in this file by the Investigator. The contents of this file/folder may 
be subjected to audit/inspection by an authorized auditor, regulatory authorities or 
Institutional Review Boards (IRBs)
may conduct quality control visits 
of the study protocol and all related 
regulatory and BI procedures.
The Sponsor or designee (contracted CRO) will assure database quality by reviewing the data 
entered into the CRFs by investigational staff for completeness and accuracy, and in 
accordance with the data validation plan. 
9.10
LIMITATIONS OF THE RESEARCH METHODS
The basic limitations of the study relate to the general limitations that concern non -
interventional studies. Since this study is a non - interventional study, it could be possible 
that different parameters which were not assessed and thus remain unknown, might lead to 
overestimating/underestimating/non-detection 
of 
differences 
of 
specific 
patients’ 
characteristics. Selection bias on the patient level will be minimized by consecutive 
enrollment. Survival in IPF cohort studies is affected by the clinical characteristics and the 
related baseline patient conditions, as well as by the time interval between the diagnosis and 
the inclusion of the patient in the protocol. Patients that have been long diagnosed (at least 
more than 6 months before entering the study) with IPF and are included in the registry may 
be more likely to have a relatively more stable disease and/or better response in IPF 
management compared to the newly diagnosed patients; however, given the disease 
progression they will be in different disease stages. In this registry it will be possible to 
differentiate based on disease duration. 
In case patient is lost to follow up, every effort will be made to contact the patient, keep 
him/her involved and if possible inquire about the reason of loss to follow-up. In order to 
assess the effect of loss to follow-up, percentages of dropouts will be summarized and 
patients will be characterized and compared to the remaining patients.

Boehringer Ingelheim
Page 40 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
No re-evaluation of patients in this study is initially foreseen, something, that can lead to the 
conclusion that patients with overlapping diagnoses (like fibrosing interstitial pneumonia of 
unknown cause) have been included in the study, thus depicting the difficulties in differential 
diagnosis in clinical practice. However, given the fact that the participating sites are 
reference centers for IPF, and considering the eligibility criteria that apply for this study, the 
expected bias might be low. 
The study is going to provide evidence regarding the situation in the IPF reference centers 
which are University Pulmonology Clinics and Pulmonology Clinics at Hospitals of Public 
Setting that follow up about 70%-80% of IPF patients in Greece.
Given the small numbers and the heterogeneous population no comparisons and causal 
associations can be assessed.
9.11
OTHER ASPECTS
Any other aspect of the research method not covered by the previous sections.
9.11.1
Data Quality Assurance
Monitoring visits will be performed to all participating sites, especially the ones that follow 
up large number of patients. During follow up visits the Study monitor will verify the 
documentation of the informed consent and will perform source data verification with the 
patient’s medical records.
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Board (IRBs) / Independent Ethics Committee 
(IECs) or by regulatory authorities. The quality assurance auditor will have access to all 
medical records, the investigator’s study-related files and correspondence, and the informed 
consent documentation of this study.
9.11.2
Study Records
The individual patient’s Case Report Forms (CRFs) will be provided by the sponsor via an 
electronic data collection system (EDC).
Every doctor will have a study folder containing:
•
The registry contract between the physician and 
.
•
The protocol
•
The patient identification list (not allowed to be used off site)
•
An approval letter by the Scientific Committee/Ethics Committee for the 
specific site
•
Informed consent forms
•
eCRF Sample printouts

Boehringer Ingelheim
Page 41 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
9.11.2.1
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. 
9.11.2.2
Direct Access to Source Data and Documents 
The investigator / institution will permit study-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/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)). The Clinical Research Associate (CRA) / Clinical Monitor Local (CML) 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 9.11.2.
9.11.2.3
Storage of Records
Patient’s files and other source documents must be kept for the maximum time period 
permitted by the hospital/institution or as defined below. The investigator must consult with 
the sponsor in case they wish to transfer the files to a third party, move them to a different 
location or if they are not capable of maintaining them for the defined period. 
The investigator should keep the study files (e.g. source documents like medical files, 
contracts, electronic files and signed informed consent forms) for as long as it is defined by 
the applicable laws and regulations. The sponsor is responsible for maintaining the 
documents for at least 15 years. The archived data can be kept in electronic form so long as 
there are available backup copies in printed form, if it is required.
The participating sites are responsible for the archiving of the necessary documents/evidence 
for 15 years at least or for as long as it is required by the local legislation. Completion of 
study
9.11.2.4
Completion of the Study
The Institutional Review Board (Scientific/Administrative Board) in each participating 
hospital center needs to be notified about the end of the study (last patient out) or early 
termination of the study, unless it is differently required by the national regulations that 
govern the conduct of such studies in case these regulations have been amended until the 
completion of the study.

Boehringer Ingelheim
Page 42 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
10.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for 
Good Clinical Practice (GCP) (to the extent applicable to the NIS setting and required by 
local regulations), Good Epidemiological Practice (GEP), Guidelines for Good 
Pharmacoepidemiology Practice (GPP), and relevant BI Standard Operating Procedures 
(SOPs). Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 
in the responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious bre aches 
of the protocol/ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalization of the Study Report, either interim or final.
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and Competent Authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
More specifically, according to national regulatory requirements, both the protocol and the 
informed consent form (ICF) must be submitted to the Institutional Review Board
(Scientific/Administrative Board) of the participating hospitals in order to be granted 
approval. The Scientific/Administrative Board of the participating hospitals must approve 
any amendment to the protocol or the ICF before the implementation of the amendment or 
the use of ICF, according to local regulations. The present non – interventional study will be 
conducted according to the applicable national regulatory requirements that govern the 
conduct of such clinical trials.
The informed consent form (ICF) will be provided to the study centers in the Greek language. 
It is the responsibility of the treating physician in the study center to r eceive the voluntary 
informed consent form from the patient (or their authorized representative) according to the 
national ICH/GCP guidelines and the regulatory and legal requirements for participation in 
the registry before entering any patient data in the eCRF.
Prior to patient participation in the study, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient -
information form retained by the investigator as part of the study records. A signed copy of 

Boehringer Ingelheim
Page 43 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
the informed consent and any additional patient information must be given to each patient or 
the patient’s legally accepted representative.
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorized 
monitors (CML/CRA) or Quality Medicine auditors appointed by Boehringer Ingelheim, by 
appropriate IRB / IEC members, and by inspectors from regulatory authorities.
10.2
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the 
study need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
Patient’s private data are going to be used by Boehringer Ingelheim and will be kept 
according to the requirements of the EU Data Protection Directive (95/46/EC) [22]guidelines 
and the national legislation regarding protection of private data. Data will be collected with 
the use of key codes. The identification codes will be used instead of patient names in order 
to protect patient identities when referring to registry data. The level of disclosure should also 
be explained to the patient.
Only authorized staff (hospital staff, sponsor representatives including monitors, authority 
representatives) will have access to patient’s private data e.g. original source documents 
(medical records). The patient will agree to this specifically by providing informed consent 
and the appropriate statement will be included in the Informed Consent Form (ICF).
The physician must comply with the confidentiality policy as it is defined within the Registry 
Contractual Agreement. The physician will comply with the Protocol that has been approved 
by the Scientific Board/Ethics Committee. The physician is responsible for the conduct of all 
registry aspects in the study site and validates the integrity of all forwarded to the sponsor 
data with their signature.

Boehringer Ingelheim
Page 44 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavorable 
and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. 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 authorisation 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 hospitalisation, 
-
results in persistent or significant disability or incapacity, or 
-
is a congenital anomaly/birth defect 
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.

Boehringer Ingelheim
Page 45 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Adverse Event of Special Interest (AESI)
No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorisation. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of 
Nintedanib. For this reason the following AE collection and reporting requirements have 
been defined.
The following must be collected by the investigator in the (e)CRF from signing the informed 
consent onwards until the end of the study: 
-
all ADRs related to Nintedanib, taken for idiopathic pulmonary fibrosis (serious and non-
serious), 
-
all AEs with fatal outcome in patients exposed to Nintedanib, taken for idiopathic 
pulmonary fibrosis
All ADRs , including those persisting after study completion must be followed up until they 
are resolved, have been sufficiently characterized, or no further information can be obtained.
The investigator 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

Boehringer Ingelheim
Page 46 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal
relationship could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g.
situations where other drugs or underlying diseases appear to provide a more likely
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
study, after having taken Nintedanib for idiopathic pulmonary fibrosis , the investigator must 
report any drug exposure during pregnancy, which occurred in a female subject or in a 
partner to a male subject to the Sponsor by means of Part A of the Pregnancy Monitoring 
Form. The outcome of the pregnancy associated with the drug exposure during pregnancy 
must be followed up and reported by means of Part B of the Pregnancy Monitoring Form. 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 
Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS AE form from signing the 
informed consent onwards until the end of the study to the 
at 
 

Boehringer Ingelheim
Page 47 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Type of Report
Timeline
All 
serious 
ADRs
associated 
with 
Nintedanib, taken for idiopathic pulmonary 
fibrosis
immediately within 24 hours
All AEs with fatal outcome in patients 
exposed to Nintedanib, taken for idiopathic 
pulmonary fibrosis
immediately within 24 hours
All non-serious ADRs
associated with 
Nintedanib, taken for idiopathic pulmonary 
fibrosis
7 calendar days
All pregnancy monitoring forms
7 calendar days
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor upfront via telephone. 
This does not replace the requirement to complete and fax the NIS AE form.
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate (e)CRF pages and the NIS AE form. The NIS AE form and Pregnancy 
Monitoring Forms should be submitted to the
at 
  For details regarding Pregnancy Monitoring Forms, please refer to
Section 11.2,  paragraphs entitled, “Pregnancy” and “Expedited Reporting of AEs and Drug 
Exposure During Pregnancy.”
Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other than 
Nintedanib taken for IPF, according to the local regulatory requirements for spontaneous AE 
reporting at the investigator’s discretion by using the locally established routes and AE report 
forms. The term AE includes drug exposure during pregnancy, and, regardless of whether an 
AE occurred or not, any abuse, off-label use, misuse, medication error, occupational 
exposure, lack of effect, and unexpected benefit.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local 
and international regulatory requirements.

Boehringer Ingelheim
Page 48 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
Participating physicians and Boehringer Ingelheim will be informed on the progress and 
status of the IPF registry on a regular basis. An Annual Report will be issued that contains a 
section on project management (recruitment status, information on technical and 
administrative issues) and tabular listings of data. Further, meetings of the National Scientific 
Committee as well as investigator meetings are planned (preferably in the context of major 
Pulmonology Meetings).
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.
Following database lock, a final report that summarizes the tables of the analysis and 
explanatory text will be written by the Data Management. Data management according to our 
contractual agreement will prepare a final Study Report which will be used as a basis for the 
final Report that will be written internally. After approval from the members of the National 
Scientific Committee and the sponsor, a final version will be generated that may be u sed for 
regulatory purposes, but also as basis for the publications of the registry. Further, the results 
from the interim analyses will be available for abstracting/publishing in local or international 
conferences or scientific meetings.
Every effort will be made, given the collected data, in order to produce scientific publications 
that will in turn contribute to better care for IPF patients and justify the scientific effort. The 
publication strategy and the authors’ list will be agreed between the 
 of 
 and the participating investigators.
 
will be the official owner of all collected date and results. Every study publication should be 
consistent with BI’s publication policy and guided by the Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals
of the 
International Committee of Medical Journals (ICMJE) [24].
This study together with the results will be posted to the internet platform Clinicaltrials.gov 
(CT.gov), in the
EU electronic register of post-authorization studies
-ENCEPP 
(www.encepp.eu/encepp_studies/indexRegister.shtml)
and in the platform of Non -  
Interventional Study Registries [Dilon (www.dilon.sfee.gr)] according to local requirements. 
This webpage is for the electronic registry and is part of the Hellenic Association of 
Pharmaceutical Companies (SFEE) website.

Boehringer Ingelheim
Page 49 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
13.
REFERENCES
13.1
PUBLISHED REFERENCES
[1] Raghu G, et al, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis
An officialATS/ERS/JRS/ALATstatement: idiopathic pulmonary fibrosis: evidence-based 
guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011; 183 (6): 788 
- 824 (P11-07084)
[2] Raghu G, et al., An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: 
Treatment of Idiopathic Pulmonary Fibrosis: Executive Summary - An Update of the 
2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 2015(P15-07539)
[3] Coultas DB, Zumwalt RE, Black WC, Sobonya RE The epidemiology of interstitial 
lung diseases. Am J Respir Crit Care Med. 1994; 150, 967 - 972 (R03-2075)
[4] Gribbin J, Hubbard RB, Jeune I le, Smith CJP, West J, Tata LJ.
Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. 
Thorax 2006; 61 (11), 980 - 985 (R10-2818)
[5] Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence 
of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006; 174 (7), 810 - 816 
(R10-2858)
[6] Scott J, Johnston I, Britton J. What causes cryptogenic fibrosing alveolitis? A case-
control study of environmental exposure to dust. Br Med J. 1990; 301, 1015 - 1017 (R03-
2089)
[7] Iwai K, Mori T, Yamada N, Yamaguchi M, Hosoda Y. Idiopathic pulmonary fibrosis: 
epidemiologic approaches to occupational exposure. Am J Respir Crit Care Med. 1994; 
150, 670 - 675 (R11-0522)
[8] Plessen C von, Grinde O, Gulsvik A. Incidence and prevalence of cryptogenic 
fibrosing alveolitis in a Norwegian community. Respir Med. 2003; 97 (4), 428 - 435 
(R11-5070) 
[9] Karakatsani A, Papakosta D, Rapti A, Antoniou KM, Dimadi M, Markopoulou A, 
Latsi P, Polychronopoulos V, Birba G, Labrakis C, Bouros D. Epidemiology of interstitial 
lung disease in Greece. Respir Med. 2009; 103 (8), 1122 - 1129 (R11-5060)
[10] Raghu G. Idiopathic pulmonary fibrosis. A rational clinical approach. Chest 
1987:92:148- 54 (R16-3078)
[11] Selman M, Carrillo G, Estrada A, Mejia M, Becerril C, Cisneros J, Gaxiola M, 
Perez-Padilla R, Navarro C, Richards T, Dauber J, King TE, Pardo A, Kaminski N
Accelerated variant of idiopahic pulmonary fibrosis: clinical behavior and gene 
expression pattern. Plos One. 2007; 2 (5), e482 (R12-5556)

Boehringer Ingelheim
Page 50 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
[12] Song JW, Hong SB, Lim CM, Koh Y, Kim DS. Acute exacerbation of idiopathic 
pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J.2011; 37 (2), 356 -
363 (R11-4792)
[13] Clinical alert: commonly used three-drug regimen for idiopathic pulmonary fibrosis 
found harmful: NIH stops one treatment arm of trial; other two treatments to continue 
(last reviewed: 17 November 2011, last updated: 17 November 2011, first published: 21 
October 2011). Weblink: www.nlm.nih.gov/databases/alerts/2011_nhlbi_ifp.html (access 
date: 19 December 2011) ; Bethesda: U.S. National Library of Medicine (NLM), National 
Institutes of Health (2011) (P11-15103)
[14] European Medicines Agency (EMA). Esbriet. CHMP Public Assessment Report 
EMA/CHMP/115147/2011. 
London, 
16 
December 
2010. 
Weblink: 
www.ema.europa.eu/docs/en_GB/document_library/EPAR_Public_assessment_report/hu
man/002154/WC500103073.pdf. Accessed on 22 February 2012 (R16-3081)
[15] Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown 
KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, Juhel N, Klueglich M, Bois 
RM du. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.
N Engl J Med. 2011; 365 (12), 1079 - 1087 (P11-11216)
[16] Hagaman JT, Kinder BW, Eckman MH. Thiopurine S-methyltranferase testing in 
idiopathic pulmonary fibrosis: a pharmacogenetic cost-effectiveness analysis. Lung 2010; 
188, 125 - 132 (R13-2613)
[17] Fioret D, Mannino D, Roman J. In-hospital mortality, length of stay, and charges 
related to pulmonary fibrosis in the U.S. between 1993 and 2008, Pulmonary and Critical 
Care Medicine 2016; Vol 1(1): 15-22 (R16-3169)
[18] Wilson JW, du Bois RM, King TE, Jr. Challenges in pulmonary fibrosis: 8. The need 
for an international registry for idiopathic pulmonary fibrosis. Thorax 2008; 63:285-7
(R16-3079)
[19] Alpert JS. Are data from clinical registries of any value? Eur Heart J 2000:21:1399-
401 (R16-3077)
[20] Eakin EG, Resnikoff PM, Prewitt LM, Ries AL, Kaplan RM. Validation of a new 
dyspnea measure: the UCSD Shortness of Breath Questionnaire. Chest; 1998; 113 (3), 
619 - 624 (R04-1009)
[21] Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC
Lung volumes and forced ventilatory flows. Report Working Party Standardization of 
Lung Function Tests, European Community for Steel and Coal. Official Statement of the 
European Respiratory Society. Eur Respir J. 1993; 6 (Suppl 16), 5 - 40 (R94-1408)

Boehringer Ingelheim
Page 51 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
[22] European Union. Directive 95/46/EC of the European Parliament and of the council 
of 24 October 19995 on the protection of individuals with regard to the processing of 
personal data and on the free movement of such data. Off J Eur Commun (L281), 31 -
39(1995).   
Weblink:http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:31995L0046 (R16-
1679)
[23] IEA European Epidemiology Federation. Good Epidemiological Practice (GEP): 
IEA guidelines for proper conduct in epidemiologic research (November, 2007). 
Weblink: www.iea-europe.org/Documents.htm (R10-1564)
[24] Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly 
Work 
in 
Medical 
Journals
(ICMJE). 
Updated 
December 
2014. 
Weblink: 
http://www.icmje.org/icmje-recommendations.pdf. Accessed 29/10/2015 (R16-3080)
[25] Agabiti,M. A. Porretta, L Bauleo, A. Coppola, et al., Idiopathic Pulmonary Fibrosis 
(IPF) incidence and prevalence in Italy. Sarcoidosis Vasculitis and Diffuse Lung Diseases 
2014; 31; 191-197 (R16-1749)
[26] Harari et al., Epidemiology of Idiopathic Pulmonary Fibrosis in Northern Italy. PLoS 
ONE 11 (2): e0147072. doi:10.1371/journal.pone.0147072 (R16-1739)
[27] Esposito DB, Lanes S, Donneyong M, Holick CN, Lasky JA, Lederer D, Nathan SD, 
O'Quinn S, Parker J, Tran TN, Idiopathic pulmonary fibrosis in United States automated 
claims: incidence, prevalence, and algorithm validation. Am J Respir Crit Care Med 
192.2015; (10), 1200 - 1207 (R16-1737)
13.2
UNPUBLISHED REFERENCES
Not applicable

Boehringer Ingelheim
Page 52 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
Not Applicable

Boehringer Ingelheim
Page 53 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Note: Page number(s) refer to the first page number of the relevant Section. 
Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
1.1 Does the protocol specify timelines for 
1.1.1 Start of data collection
1.1.2 End of data collection
1.1.3 Study progress report(s) 
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register 
1.1.6 Final report of study results.
21
21
-
-
-
21
Comments:
1.1.3 Not required according to national requirements for non -interventional studies 
1.1.4 Not required as no interim analysis of data is scheduled
1.1.5 Not required as this study is not considered PASS
Section 2: Research question 
Yes
No
N/A
Page 
Number(s)

Boehringer Ingelheim
Page 54 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
2.1
Does the formulation of the research question and objectives 
clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address an important public 
health concern, a risk identified in the risk management plan, an emerging 
safety issue)
2.1.2 The objective(s) of the study?
22
& 
25
26
2.1.3 The target population? (i.e. population or subgroup to whom the 
study results are intended to be generalised)
2.1.4 Which formal hypothesis(-es) is (are) to be tested? 
2.1.5 If applicable, that there is no a priori hypothesis?
28
-
-
Comments:
2.1.4 & 2.1.5 This study is not intended for hypothesis testing and will mainly use descriptive statistical 
methods. Any performed analysis will be of investigational nature.
Section 3: Study design
Yes
No
N/A
Page 
Number(s)
3.1
Is the study design described? (e.g. cohort, case-control, randomised 
controlled trial, new or alternative design)
27
3.2
Does the protocol specify the primary and secondary (if 
applicable) endpoint(s) to be investigated?
3.3
Does the protocol describe the measure(s) of effect? (e.g. relative 
risk, odds ratio, deaths per 1000 person-years, absolute risk, excess risk, 
incidence rate ratio, hazard ratio, number needed to harm (NNH) per year)
Comments:
3.2 & 3.3 As explained in section 2 no hypothesis testing is going to be performed therefore no specific 
effects or endpoints are defined. 
Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1
Is the source population described?
28
4.2
Is the planned study population defined in terms of:
4.2.1 Study time period?
4.2.2 Age and sex?
4.2.3 Country of origin?
4.2.4 Disease/indication? 
4.2.5 Co-morbidity?
4.2.6 Seasonality?
28
28
28
28
-
4.3
Does the protocol define how the study population will be 
sampled from the source population? (e.g. event or inclusion/exclusion 
criteria)
28
Comments:
4.2.6 Seasonal fluctuation and form is not applicable in this study and does not apply to the population of the 
study and the disease under investigation. 
Section 5: Exposure definition and measurement
Yes
No
N/A
Page 
Number(s)

Boehringer Ingelheim
Page 55 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Section 5: Exposure definition and measurement
Yes
No
N/A
Page 
Number(s)
5.1
Does the protocol describe how exposure is defined and 
measured? (e.g. operational details for defining and categorising exposure)
5.2
Does 
the protocol 
discuss 
the 
validity 
of exposure 
measurement?
(e.g. precision, accuracy, prospective ascertainment, 
exposure information recorded before the outcome occurred, use of validation 
sub-study)
5.3
Is exposure classified according to time windows? (e.g. current 
user, former user, non-use)
5.4
Is exposure classified based on biological mechanism of action 
and 
taking 
into 
account 
the 
pharmacokinetics 
and 
pharmacodynamics of the drug?
5.5
Does the protocol specify whether a dose-dependent or 
duration-dependent response is measured?
Comments:
5.1, 5.2, 5.3, 5.4 & 5.5 This study is a descriptive epidemiological Study that does not investigate the effect 
of specific exposure in order to test a hypothesis.
Section 6: Endpoint definition and measurement
Yes
No
N/A
Page 
Number(s)
6.1
Does the protocol describe how the endpoints are defined and 
measured?
6.2
Does 
the 
protocol 
discuss 
the 
validity 
of 
endpoint 
measurement? (e.g. precision, accuracy, sensitivity, specificity, positive 
predictive value, prospective or retrospective ascertainment, use of validation 
sub-study)
Comments:
N/A
Section 7: Confounders and effect modifiers
Yes
No
N/A
Page 
Number(s)
7.1
Does the protocol address known confounders? (e.g. collection of 
data on known confounders, methods of controlling for known confounders)
7.2
Does the protocol address known effect modifiers? (e.g. collection 
of data on known effect modifiers, anticipated direction of effect)
Comments:
7.1 & 7.2 No confounders or effect modifiers are discussed since no hypothesis testing or assessment of 
effects is being performed.
Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.1
Does the protocol describe the data source(s) used in the study 
for the ascertainment of:
8.1.1 Exposure? (e.g. pharmacy dispensing, general practice prescribing, 
claims data, self-report, face-to-face interview, etc.)
8.1.2 Endpoints? (e.g. clinical records, laboratory markers or values, claims 
data, self-report, patient interview including scales and questionnaires, vital 
statistics, etc.)
8.1.3 Covariates?
32, 36
36
33

Boehringer Ingelheim
Page 56 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.2
Does the protocol describe the information available from the 
data source(s) on:
8.2.1 Exposure? (e.g. date of dispensing, drug quantity, dose, number of 
days of supply prescription, daily dosage, prescriber)
8.2.2 Endpoints? (e.g. date of occurrence, multiple event, severity measures 
related to event)
8.2.3 Covariates? (e.g. age, sex, clinical and drug use history, co-morbidity, 
co-medications, life style, etc.)
32,38
32-38
33
8.3
Is a coding system described for:
8.3.1 Diseases? (e.g. International Classification of Diseases (ICD)-10)
8.3.2 Endpoints? (e.g. Medical Dictionary for Regulatory Activities 
(MedDRA) for adverse events)
8.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical Therapeutic 
Chemical (ATC)Classification System)
8.4
Is the linkage method between data sources described? (e.g. based 
on a unique identifier or other)
37
Comments:
8.3 No codification system is applied.
Section 9: Study size and power
Yes
No
N/A
Page 
Number(s)
9.1 Is sample size and/or statistical power calculated?
36
Comments:
9.1The number of included patients as well as the duration of the Study is not defined by an official 
calculation of the sample size as the objective of the observational study is not to confirm or reject any 
predefined assumptions.
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1
Does the plan include measurement of excess risks?
10.2
Is the choice of statistical techniques described?
38
10.3
Are descriptive analyses included?
38
10.4
Are stratified analyses included?
38
10.5
Does the plan describe methods for adjusting for 
confounding?
10.6
Does 
the 
plan 
describe 
methods 
addressing 
effect 
modification?
Comments:
10.1 No excess risks are expected due to the design of the non - interventional observational study that aims 
in describing everyday clinical practice.
10.5, 10.6 No methods for adjusting for confounding or addressing effect modification are scheduled due t o 
the fact that no hypothesis testing or assessment of effects is being performed.
Section 11: Data management and quality control
Yes
No
N/A
Page 
Number(s)

Boehringer Ingelheim
Page 57 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Section 11: Data management and quality control
Yes
No
N/A
Page 
Number(s)
11.1
Is information provided on the management of missing data?
11.2
Does the protocol provide information on data storage? (e.g. 
software and IT environment, database maintenance and anti-fraud 
protection, archiving) 
37
11.3
Are methods of quality assurance described?
40
11.4 
Does the protocol describe possible quality issues related to 
the data source(s)?
40
11.5
Is there a system in place for independent review of study 
results?
-
Comments:
11.1 Since this is an observational study where the duration is not defined by an official calculation of the 
sample size, the objective is to collect data from IPF patients during their participation in the study.
11.5 The study design does not require an independent review of the results.
Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
12.1
Does the protocol discuss:
12.1.1 Selection biases?
12.1.2 Information biases?
(e.g. anticipated direction and magnitude of such biases, validation sub-study, 
use of validation and external data, analytical methods)
39
39
12.2
Does the protocol discuss study feasibility? (e.g. sample size, 
anticipated exposure, duration of follow-up in a cohort study, patient 
recruitment)
36
12.3 Does the protocol address other limitations?
39
Comments:
N/A
Section 13: Ethical issues 
Yes
No
N/A
Page 
Number(s)
13.1
Have requirements of Ethics Committee/Institutional Review 
Board approval been described?
42
13.2
Has any outcome of an ethical review procedure been 
addressed?
-
13.3
Have data protection requirements been described?
43
Comments:
N/A
Section 14: Amendments and deviations 
Yes
No
N/A
Page 
Number(s)
14.1
Does the protocol include a section to document future 
amendments and deviations?
13
Comments:
N/A

Boehringer Ingelheim
Page 58 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Section 15: Plans for communication of study results 
Yes
No
N/A
Page 
Number(s)
15.1
Are plans described for communicating study results (e.g. to 
regulatory authorities)?
48
15.2
Are plans described for disseminating study results externally, 
including publication?
48
Comments:
N/A

Boehringer Ingelheim
Page 59 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 3. ADDITIONAL INFORMATION
OUTCOME
DEFINITION
Mortality
a) Date of death
b)
Cause of death 
a.
Related to IPF
i.
Respiratory failure:
Is the consequence of lung failure leading to 
impaired gas exchange; that is, hypoxemia 
and/or hypercapnia
ii.
Acute exacerbation of IPF (see definition 
below)
iii.
Other related to IPF (please specify)
b.
Comorbid condition (please specify):
i.
Coronary heart disease 
ii.
Cerebrovascular disease 
iii.
Pneumonia/respiratory infection (see definition 
below)
iv.
Pulmonary embolism (see definition below)
v.
Pulmonary hypertension or Pulmonary arterial 
hypertension/right heart failure ( see definition 
below)
vi.
Lung cancer (see definition below)
c.
Other cause (please specify)
d.
Unknown
Acute exacerbation of IPF       
a)
Previous or concurrent diagnosis of idiopathic pulmonary 
fibrosis
b)
Unexplained worsening or development of dyspnea within 30 
days
c)
HRCT with new bilateral ground-glass abnormality and/or 
consolidation superimposed on a background reticular or 
honeycomb pattern consistent with usual interstitial pneumonia 
pattern
d)
No evidence of pulmonary infection by endotracheal aspirate or 
bronchoalveolar lavage
e)
Exclusion of alternative causes, including:
a.
Left heart failure
b.
Pulmonary embolism
c.
Identifiable cause of acute lung injury
Myocardial infarction              
a)
In patients not undergoing PCI or CABG: A patient has to fulfil 
either the criteria:
a.
Development of significant Q-waves in at least 2 
adjacent ECG leads.
Or at least 2 of the following three criteria:

Boehringer Ingelheim
Page 60 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
OUTCOME
DEFINITION
b.
Typical prolonged severe chest pain of at least 30 min
c.
ECG changes suggestive of myocardial infarction 
including ST-changes of T-wave inversion in the ECG).
d.
Elevation of troponin or CK-MB1 to more than upper 
level of normal (ULN) or, if CK-MB was elevated at 
baseline, re-elevation to more than 50% increase above 
the previous level.
b)
After PCI (within 24 h) Elevation of troponin or CK-MB1 to 
more than 3xULN or, if CK-MB is elevated at baseline, re-
elevation to more than 3xULN and a more than 50% increase 
above the previous level, and/or development of significant Q-
waves2 in at least two adjacent ECG leads.
c)
After coronary artery bypass grafting (within 72 h) Elevation of 
CK-MB1 to more than 5xULN or, if CK-MB was elevated at 
baseline, re-elevation to more than 5xULN and a more than 50% 
increase above the previous level, and/or development of 
significant Q-waves2 in at least two adjacent ECG leads.
1 Total CK if CK-MB was not available 2 A new Q-wave with a duration of at least 0.04 
seconds and a depth of more than a quarter of the
amplitude of the corresponding R-wave, in at least 2 adjacent leads
CNS Infarction                         
a)
Ischemic stroke
b)
Stroke caused by intracerebral hemorrhage
c)
Stroke caused by subarachnoid hemorrhage
d)
Stroke caused by cerebral venous thrombosis
e)
Stroke NOS
f)
Silent CNS infarction
g)
Silent cerebral hemorrhage
Other 
Arterial 
Thromboembolic 
events 
(excl. AMI, CNS Infarction, 
and Pulm embolism)
a)
Acute limb ischemia
b)
Acute mesenteric ischemia
c)
Renal infarction
d)
Other (free text)
Deep vein thrombosis
Confirmed by
-
Ultrasound  (dd-mm-yy)
-
Venography (dd-mm-yy)
and
Clinical 
presentation, 
i.e
symptomatic/asymptomatic 
(yes-no-
unknown)(such as leg pain, swelling, tenderness of the calf lower 
extremity) and arm discomfort
-
Edema, dilated venous collateral and discoloration (lower 
extremity)  
-
no clinical symptoms or signs

Boehringer Ingelheim
Page 61 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
OUTCOME
DEFINITION
Hemorrhage
a)
Location:
a.
Gastrointestinal hemorrhage
b.
Intracranial hemorrhage
c.
Rectal hemorrhage
d.
Epistaxis
e.
Hemorrhage NOS
b)
Severity: 
a.
Major bleeding, defined as meeting one or more of the 
following criteria):
i.
Overt bleeding associated with a reduction in 
hemoglobin of at least 20 grams per liter or 
leading to a transfusion of at least 2 units of 
blood or packed cells
ii.
Symptomatic bleeding in a critical area or 
organ: Intraocular, intracranial, intraspinal or 
intramuscular with compartment syndrome, 
retroperitoneal 
bleeding, 
intra-articular 
bleeding or pericardial bleeding
iii.
Life-threatening bleeding
iv.
Fatal bleeding
b.
Life-threatening bleeding, as defined as meeting one or 
more of the following criteria:
i.
Symptomatic intracranial bleed
ii.
Reduction in hemoglobin of at least 50 grams 
per liter
iii.
Transfusion of at least 4 units of blood or 
packed cells, associated with hypotension
requiring the use of intravenous inotropic 
agents
iv.
Necessitated surgical intervention
v.
Fatal bleeding
c)
Circumstances: 
c.
peri/postoperative
d.
accident/ injury
e.
other (please specify)
f.
unknown
Gastrointestinal perforation
a)
Perforation of gastric ulcer
b)
Perforation of duodenal ulcer
c)
Perforation of small-intestine diverticulum
d)
Perforation of colon diverticulum
e)
Peritonitis as a complication of appendicitis
f)
Perforation as procedural complication (endoscopy),

Boehringer Ingelheim
Page 62 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
OUTCOME
DEFINITION
g)
Others (please specify)
Pulmonary hypertension          
a)
Right-heart catheterization performed (mPAP>25 mmHg at rest)
b)
No RHC performed / Diagnosed by echocardiography or clinical 
diagnosis
Hospitalizations
a)
Date entry
b)
Date discharge 
c)
Hospitalization that requires mechanical ventilation (Yes/No)
d)
Hospitalization that includes ICU (Yes/No)
e)
Hospitalization due to respiratory cause (Yes/No)
If Yes:
a.
Due to Acute exacerbation
b.
Due 
to 
IPF 
worsening 
other 
than 
Acute 
Exacerbation
c.
Other respiratory causes, NOS (e.g. pneumonia, 
pneumothorax,…) – please specify

Boehringer Ingelheim
Page 63 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 4 ASSESSMENTS OF VARIABLES
Variable
Categories
Type of site
- Categorical:
General practice/primary care
Specialist office
Community hospital
University hospital
Out-patient health care centre
Anticoagulation clinics
Other (please specify)
Age [years]
Calculated as the difference between date of birth and date of 
informed consent, convert to years (divided by 365.25) and 
lower truncated to the integer. 
Continuous and categorized as: 
- 40-44
- 45-54
- 55-64
- 65-74
- ≥75
- Unknown
Additionally categorized as ≤65, >65
<Please specify the category of reference if comparisons are 
foreseen e.g.:

- ≤65 years vs.  >65 years old, 
Race
Categorized as: 
- American Indian or Alaska Native
- Asian
- Black or African American
- Native Hawaiian or other Pacific Islander
- White
- Other
Not reported
Gender
Categorized as:
Male
Female 
Smoking status
- Categorized as:
Never / Past / Current / Unknown
For the Past/Current, specify packs/year and for Past 
(number of years smoking one pack per day equivalent)
Drugs of abuse
- Categorized: 

Alcohol consumption:
Drinker/ex-drinker/non-drinker/unknown

Boehringer Ingelheim
Page 64 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Variable
Categories

Cocaine consumption:
Never / Past / Current / Unknown
Other,(please specify)
Family history of pulmonary fibrosis
- Categorized as: 
Yes/No/Unknown
Environmental 
and 
occupational 
exposures
- Any exposure ticked in this category (Yes/No/Unknown):

Metal dusts (brass, lead, and steel)

Wood dust (pine)

Farming

Raising birds

Hair dressing

Stone cutting/polishing

Asbestos

Solvents
Exposure to drugs associated with 
IPF
- Any exposure ticked in this category (Yes/No/Unknown):

Amiodarone

Bleomycine

Nitrofurantoine

Methotrexate
- Gold salts
Exposure to viral infection with 
potential association  with IPF
- Serum antibodies for (Positive/Negative/not available)

Ebstein-Barr Virus

Hepatitis C virus
Other positive (please specify)
Diagnostic procedures that were used 
during diagnostic workout             
- Date: DD-MMM-YYYY
- High-Resolution Computed Tomography [HRCT]
-
UIP pattern
-
Possible UIP pattern
-
Inconsistent UIP pattern
-
Not available 
- Histology (lung biopsy)
-
UIP pattern
-
Probable UIP pattern
-
Possible UIP pattern
-
Inconsistent with UIP or  
             non-classifiable
- Not available
Date when IPF was diagnosed
- Format: DD-MMM-YYYY
Lab values
At 
enrolment, 
to 
exclude 
connective 
tissue 
disease 
(positive/negative/not 
performed/unknown/performed 
but 
missing value) and value (units):

Boehringer Ingelheim
Page 65 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Variable
Categories

Rheumatoid factor 

Anti-cyclic citrulinated peptide (anti-CCP)

Anti-nuclear antibodies (ANAs)

Scl-70

SS-A

SS-B
Other biomarker of autoimmune disease (please specify)
Vital signs and physical examination
- Continuous and categorical, as appropriate.
- Categorized as Yes/No/Unknown and further categorized as 
(examples) :

Heart rate (BPM)

Blood pressure (mmHg)

Weight

Height

Date: DD-MMM-YYYY
Pulmonary function testing
- Continuous

FVC (mL, % pred)

VC (mL, % pred)

TLC (mL, % pred)

DLCO (mmol/min/kPa, % predicted Hb corrected)

FEV1 (mL, % pred)
- Further categorized as: Yes/No/Unknown
Date of pulmonary function testing: DD-MMM-YYYY
Biomarkers of autoimmune disease 
- Lab values of interest include (continuous):

Hb (g/dL), 

AST (µg/L)

ALT (µg/L)

Total bilirubin (mg/dL) 

BNP (ng/L)

NT pro-BNP (ng/L)
- Further categorized as: Yes/No/Unknown

Date: DD-MMM-YYYY
Bleeding risk 
- Genetic predisposition (please specify)
- Gastrointestinal ulcers
- Major injury or surgery 

Use of anticoagulants
Thrombotic risk 

Genetic predisposition (please specify)
Concomitant 
medications, 
please 
assess for each start/stop date and 
dose  
Any co-medication ticked in this category (Yes/No/Unknown)

Corticosteroids

NAC

Azathioprine

Cyclophosphamide

Boehringer Ingelheim
Page 66 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Variable
Categories

Cyclosporine A

Other immuno-suppressant (e.g. mycophenolate mofetil) 

Pirfenidone

Anticoagulant

Vit-K antagonist

Heparin

NOAC

Other

High-dose antiplatelet therapy

GERD medication

PDE-5 inhibitor

Endothelin receptor antagonist

Long-term Oxygen therapy

Listed for lung transplantation

NSAIDs

Hormonal contraceptives

Hormone replacement therapy

Anti-VEGF drugs
Current participation in pulmonary 
rehabilitation program 
- Categorized as: Yes/No/ Unknown
Listing for or participation in lung 
transplantation 
- Categorized as: Yes/No/Unknown
- Date since when: DD-MMM-YYYY
Vital status
Categorized as: Yes/No/Unknown

Pulmonary function testing
- Continuous

FVC (mL, % pred)

VC (mL, % pred)

TLC (mL, % pred)

DLCO (mmol/min/kPa, % predicted Hb corrected)

FEV1 (mL, % pred)
- Further categorized as: Yes/No/Unknown

Date of pulmonary function testing: DD-MMM-YYYY
Hospitalizations 
- Categorized as: Yes/No/Unknown If yes: further categorized 
as:

with/without ER use

with/without ICU use

with/without mechanical ventilation

with/without ambulance use
- Date of hospitalizations:

Known/Unknown

If known: DD-MMM-YYYY

Boehringer Ingelheim
Page 67 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Variable
Categories
- Discharge or death date:

Known/Unknown

If known: DD-MMM-YYYY

Boehringer Ingelheim
Page 68 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 5. COMMORBIDITIES OF INTEREST (RECORDER WITH 
START, AND IF APPLICABLE STOP DATE)

Previous Haemorrhages

Cardio and cerebrovascular comorbidities: Arterial hypertension, coronary artery disease (CAD), 
myocardial infarction (MI), congestive heart failure (CHF), CNS Infarction, transient ischaemic attack 
(TIA), peripheral artery disease, atrial fibrillation, deep venous thrombosis, pulmonary embolism, 
pulmonary  hypertension

Respiratory comorbidities: chronic obstructive pulmonary disease (COPD), emphysema (radiologic), 
asthma, pneumonia, obstructive sleep apnea

Renal comorbidities: chronic renal failure (see definition in Section14.2)

Hepatic comorbidities: chronic hepatic failure, cirrhosis

Gastrointestinal comorbidities: gastroesophageal reflux disease (GERD), gastric ulcer, appendicitis, 
abdominal surgery, inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis), GI cancer, 
diverticulitis, superior mesenteric artery syndrome

Metabolic comorbidities: T2/T1 diabetes mellitus, hyperlipidaemia, hypothyroidism

Neoplasms: lung, liver, stomach, colorectal, breast and oesophageal, prostate and cervix cancer
Depressive disorder, anxiety disorder.

Boehringer Ingelheim
Page 69 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 6. HIGH RESOLUTION COMPUTED TOMOGRAPHY 
CRITERIA FOR USUAL INTERSTITIAL PNEUMONIA 
PATERN (UIP) [1]
UIP Pattern (All Four Features)
Possible UIP Pattern (All Three 
Features)
Inconsistent with UIP Pattern 
(any of the Seven Features)
Subpleural, basal predominance
Reticular abnormality
Honeycombing with or without 
traction bronchiectasis
Absence of features listed as 
inconsistent with UP (see column 
‘Inconsistent with UIP Pattern’, 
on the right)
Subpleural, basal predominance
Reticular abnormality
Absence of features listed as 
inconsistent with UP (see column 
‘Inconsistent with UIP Pattern’, 
on the right)
Upper or mid-lung predominance
Peribronchovascular 
predominance
Extensive ground glass 
abnormality (extent>reticular 
abnormality)
Profuse micronodules (bilateral, 
predominantly upper lobes)
Discrete cysts (multiple, bilateral, 
away from areas of 
honeycombing)
Diffuse mosaic attenuation/air-
trapping (bilateral in three or more 
lobes)
Consolidation in 
bronchopulmonary 
segment(s)/lobe(s)

Boehringer Ingelheim
Page 70 of 70
Non-interventional Study Protocol
BI Study Number 1199.252
c11675456 - 02
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
ANNEX 7. HISTOLOGICAL CRITERIA FOR UIP PATERN IN LUNG 
BIOPSY [1]
UIP pattern (all 4 
criteria)
Probable UIP pattern
Possible UIP pattern 
(all 3 criteria)
Not UIP pattern (any 
of the 6 criteria)
Evidence of marked 
fibrosis/ architectural 
distortion,±honeycombing 
in a predominantly 
subpleural/paraseptal 
distribution 
Presence of patchy 
involvement of lung 
parenchyma by fibrosis
Presence of fibroblast foci
Absence of features 
against a diagnosis of UIP 
suggesting an alternate 
diagnosis (see fourth 
column ‘Not UIP 
pattern’)
Evidence of marked 
fibrosis/ architectural 
distortion,±honeycombing
Absence of either patchy 
involvement or 
fibroblastic foci, but not 
both
Absence of features 
against a diagnosis of UIP 
suggesting an alternate 
diagnosis (see fourth 
column ‘Not UIP 
pattern’) 
Or
Honeycomb changes 
only‡
Patchy or diffuse 
involvement of lung 
parenchyma by fibrosis, 
with or without 
interstitial inflammation
Absence of other 
criteria for UIP (see 
‘UIP Pattern column’)
Absence of features 
against a diagnosis of 
UIP suggesting an 
alternate diagnosis (see 
fourth column) ‘Not 
UIP pattern’)
Hyaline membranes*
Organizing 
pneumonia*†
Granulomas†
Marked interstitial 
inflammatory cell 
infiltrate away from 
honeycombing
Predominant airway 
centered changes
Other features 
suggestive of an 
alternate diagnosis
*Can be associated with acute exacerbation of idiopathic pulmonary fibrosis.
† An isolated or occasional granuloma and/or a mild component of organizing pneumonia pattern may rarely be 
coexisting in lung biopsies with an otherwise UIP pattern
.
‡This scenario usually represents end-stage fibrotic lung disease where honeycombed segments have been 
sampled but where a UIP pattern might be present in other areas. Such areas are usually represented by overt 
honeycombing on HRCT and can be avoided. By using HRCT the pre-operative targeting of biopsy sites is 
performed away from these areas.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11675456
2.0
clinical-trial-protocol-greece
Investigating idiopathic pulmonary fibrosis  in Greece (INDULGE IPF)
Approval-Team Member Medical
Affairs
22 Feb 2018 16:38 CET
Approval-
 Safety Evaluation
Therapeutic Area
22 Feb 2018 16:43 CET
Approval-Biostatistics
22 Feb 2018 16:45 CET
Approval-Medical 
23 Feb 2018 08:53 CET
Approval-On behalf of 
 or 
or 
28 Feb 2018 08:29 CET
Author-Other
28 Feb 2018 09:17 CET

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11675456
2.0