Observational Analysis on the Socio-economic Impact of IPF in Spain
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Non-interventional Study Protocol
TITLE PAGE
Document Number:
c17915891-01
BI Study Number:
1199-0296
BI Investigational
Product(s):
Not applicable.
Title:
Observational Analysis on the Socio-economic Impact of IPF in Spain.
Brief lay title
OASIS-IPF study
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
15 Jun 2017
PASS:
No
EU 
PAS 
register 
number:
Not yet available
(study will be registered in EU PAS Register (ENCePP) and
clinicaltrials.gov)
Active substance:
Not applicable. 
Medicinal product:
Not applicable. 
Product reference:
Not applicable.
Procedure number:
Not applicable.
Marketing authorisation 
holder(s):
MAH: 
Boehringer Ingelheim International GmbH 
Binger Straße173 
55216 Ingelheim am Rhein 
This study is initiated, managed and sponsored by: 
Boehringer Ingelheim España, S.A 
C/ Prat de la Riba, 50 
08174 Sant Cugat del Vallés (Barcelona)
Joint PASS:
No

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Research question and 
objectives:
Primary Objective:
-
To compare the economic impact of Idiopathic Pulmonary Fibrosis
(IPF) according to FVC % predicted level (FVC<50%, FVC 50-
80%, FVC>80%), in adult patients through estimation of annual 
direct and indirect costs associated with the disease at one year.
Secondary Objectives:
-
To estimate the QoL of the patients with IPF according to FVC % 
predicted level, through SGRQ and EQ-5D-5L questionnaires and 
the Barthel index.
-
To explore the determinants of costs and QoL in patients with IPF 
according to FVC % predicted level
-
To characterize acute IPF exacerbations over one year (frequency 
and cost) according to FVC % predicted level.
-
To estimate the impact of FVC deterioration, in cost and QoL of the 
patient.
-
To explore the impact of the disease on the patient’s caregiver 
through Zarit Burden Interview questionnaire at 6 and 12 month.
Country of study:
Spain
Author:
Mobile:
  
Marketing authorisation 
holder(s):
Boehringer Ingelheim International GmbH 
Binger Str. 173 
D-55216 Ingelheim am Rhein 
Germany
MAH contact person:
Not applicable.
EU-QPPV:
Not applicable.
Signature of EU-
QPPV:
Not applicable.
Date:
15 Jun 2017
Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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1.
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
1.
TABLE OF CONTENTS.....................................................................................................3
2.
LIST OF ABBREVIATIONS..............................................................................................5
3.
RESPONSIBLE PARTIES..................................................................................................6
4.
ABSTRACT.........................................................................................................................7
5.
AMENDMENTS AND UPDATES...................................................................................14
6.
MILESTONES...................................................................................................................15
7.
RATIONALE AND BACKGROUND..............................................................................16
8.
RESEARCH QUESTION AND OBJECTIVES ...............................................................17
9.
RESEARCH METHODS ..................................................................................................18
9.1
STUDY DESIGN......................................................................................................18
9.2
SETTING..................................................................................................................18
9.2.1
Study sites.....................................................................................................18
9.2.2
Study population...........................................................................................19
9.2.3
Study visits ...................................................................................................19
9.2.4
Study discontinuation ...................................................................................21
9.3
VARIABLES ............................................................................................................22
9.3.1
Exposures .....................................................................................................22
9.3.2
Outcomes......................................................................................................22
9.3.2.1 Primary outcomes...........................................................................22
9.3.2.2 Secondary outcomes.......................................................................22
9.3.3
Covariates.....................................................................................................24
9.4
DATA SOURCES.....................................................................................................24
9.5
STUDY SIZE............................................................................................................25
9.6
DATA MANAGEMENT..........................................................................................25
9.7
DATA ANALYSIS...................................................................................................26
9.7.1
Main analysis................................................................................................26
9.8
QUALITY CONTROL.............................................................................................29
9.9
LIMITATIONS OF THE RESEARCH METHODS................................................29
9.10 OTHER ASPECTS ...................................................................................................30
9.10.1 Data quality assurance..................................................................................30

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9.10.2 Study records................................................................................................30
9.10.2.1 Source documents...........................................................................30
9.10.2.2 Direct access to source data and documents ..................................31
9.10.3 Completion of study .....................................................................................31
10. PROTECTION OF HUMAN SUBJECTS ........................................................................32
10.1 Study approval, patient information, and informed consent.....................................32
10.2 Statement of confidentiality......................................................................................33
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS.....................................................................................................................34
11.1 Definitions of adverse events....................................................................................34
11.2 Adverse event and serious adverse event collection and reporting...........................35
11.3 Reporting to health Authorities.................................................................................37
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .......38
13. REFERENCES ..................................................................................................................39
13.1 PUBLISHED REFERENCES...................................................................................39
13.2 UNPUBLISHED REFERENCES.............................................................................40
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS..........................................................41
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS ..........................................42
ANNEX 3. ADDITIONAL INFORMATION..........................................................................43

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2.
LIST OF ABBREVIATIONS
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
BI
Boehringer Ingelheim
BMI
Body Mass Index
CA
Competent Authority
CCDS
Company Core Data Sheet
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
DLCO
Diffusing capacity of the lung for carbon monoxide
eCRF
Electronic Case Report Form
EQ-5D-5L
EuroQoL five dimensions questionnaire 5L
ENCePP 
European 
Network 
of 
Centres 
for 
Pharmacoepidemiology 
and 
Pharmacovigilance 
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
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
MAH
Marketing Authorisation Holder
Activities
NIS
Non-Interventional Study
PASS
Post-Authorization Safety Study
QoL
Quality of Life
SAE
Serious Adverse Event
SGRQ
St. George’s Respiratory Questionnaire
UIP
usual interstitial pneumonia
6MWD
6 Minutes Walk Distance test

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3.
RESPONSIBLE PARTIES
Team Member Medical Affairs (TMMA)
Trial Statistician
Market Access TA Respiratory
Market Access-HEOR Spain
Coordinating Investigators (CI) in Spain 
 (Granada)
 (Barcelona)
 (Lugo)
 (Madrid)

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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:
15 Jun 2017
1199-0296
1.0
Not applicable
Title of study:
Observational Analysis on the Socio-economic Impact of Idiopathic Pulmonary 
Fibrosis (IPF) in Spain.
Rationale and 
background:
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, and associated with the histopathologic and/or radiologic pattern of usual 
interstitial pneumonia (UIP) (1).
On the other hand, there is no evidence on the costs of patients with IPF in Spain 
based on actual clinical practice. The only study carried out in Spain is based on 
Delphi panels and concluded that the management of patients with IPF in Spain, 
especially patients with rapid disease progression, has a high economic impact on 
the NHS (2). Nevertheless the study did not provide any information on the 
burden of disease by level of severity or from the societal perspective. 
The cost associated with acute exacerbations represents nearly half of the total 
cost of managing patients with IPF (2). Therefore, considering that low forced 
vital capacity (FVC) has proven the most consistent risk factor for acute 
exacerbation of IPF (3) is expected that patients with low FVC (FVC < 50%) 
have higher cost.  
The overall burden associated with IPF patients in Spain remains unknown. It is 
of great interest to develop studies analyzing the Cost-of-illness to define the 
magnitude of the disease in monetary terms and thereby to prove what the real 
impact of the disease is on the Spanish society (4). On the other hand, the social 
impact of IPF is also unknown, so studies that analyze the social perspective1, in 
addition to the economic perspective, are necessary.
The management of IPF in Spain is complex (see the image below – IPF patient 
pathway in Spain). Patients are diagnosed in a hospital and then may initiate
treatment (antifibrotic or not). If patients receive an antifibrotic drug, they have to 
collect this in the hospital pharmacy. The follow-up visits are in the hospital 
                                                
1 The perspective of society is the broadest of all perspectives because it is the only one that considers the 
benefit to society as a whole. Theoretically, all direct and indirect costs are included in an economic evaluation 
performed from a societal perspective. Costs from this perspective include patient morbidity and mortality and 
the overall costs of giving and receiving medical care. An evaluation from this perspective also would include 
all the important consequences an individual could experience. In countries with nationalized medicine, society 
is the predominant perspective. (Waning, B., Montagne, M., & McCloskey, W. W. (2001). 
Pharmacoepidemiology: Principles and practice. New York: McGraw-Hill.)

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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:
15 Jun 2017
1199-0296
1.0
Not applicable
(pulmonologist). Patients also go to the primary care physician regularly.
The present study aims at estimating the economic and -social impact of 
Idiopathic Pulmonary Fibrosis (IPF) in Spain.

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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:
15 Jun 2017
1199-0296
1.0
Not applicable
Research 
question and 
objectives:
Primary Objective:
-
To compare the economic impact of Idiopathic Pulmonary Fibrosis (IPF) 
according to FVC % predicted level (FVC<50%, FVC 50-80%, FVC>80%), 
in adult patients through estimation of annual direct and indirect costs 
associated with the disease at in one year.
Secondary Objectives:
-
To estimate the QoL of the patients with IPF according to FVC % predicted 
level, through SGRQ and EQ-5D-5L questionnaires and the Barthel Index at 
baseline.
-
To explore the determinants of costs and QoL in patients with IPF according 
to FVC % predicted level.
-
To characterize acute IPF exacerbations along one year (frequency and cost) 
according to FVC % predicted level at baseline.
-
To describe the variation of costs and QoL with IPF progression (according 
to the FVC deterioration).
-
To explore the impact of disease on the patient’s caregiver through Zarit 
Burden Interview questionnaire at 6 and 12 month.
Study design:
Non-interventional multicenter study based on newly collected data of Idiopathic 
Pulmonary Fibrosis patients followed-up for one year in secondary care settings 
(Pulmonology Services). IPF patients will be enrolled in a consecutive manner 
over a period of 6 month.
Population:
Inclusion criteria:
-
Female and male patients ≥ 40 years of age.
-
Patients diagnosed with Idiopathic Pulmonary Fibrosis (IPF) according to 
last ATS/ERS/JRS/ALAT IPF guideline for diagnosis and management 
consensus (1).
-
Written informed consent prior to participation.
Exclusion criteria:
-
Inability for the patient to understand or complete the written Informed
Consent or patient questionnaires or to understand Spanish.
-
Current participation in any clinical trial.
-
Patients for whom further follow-up is not possible at the enrolling site.
Variables:
-
Sociodemographic variables: age, gender, employment, net incomes.
-
Anthropometric variables: weight, height and BMI.
-
Characteristics of IPF: date of IPF diagnosis, FVC (ml), FVC % predicted, 
FVC rate reduction during one year, DLCO, the Barthel index, 6MWD and 

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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:
15 Jun 2017
1199-0296
1.0
Not applicable
concomitant diseases related to IPF.
-
Smoking status.
-
Work with animals (now or in the past)
-
IPF related resource use: primary and secondary care visits, outpatient visits, 
emergency visits (primary care and hospital), hospitalizations, ICU with and 
without intubation, outpatient tests and other examinations, use of transport, 
use of formal and informal caregiver,
pharmacological and non-
pharmacological treatments related to IPF, orthopedic material, formal social 
services, economic aid and structural adaptations. This data will be collected 
from the patient’s medical records and by the patient through an interview 
during the visits and an individual patient’s diary.
-
Days off work due to IPF
-
Sociodemographic variables for the caregiver (if applicable): age, gender, 
employment, and relationship with the patient.
-
IPF related days off work from patient’s caregiver (if applicable)
-
QoL of the patients (SGRQ and EQ-5D-5L questionnaires)
-
QoL of the patients’ caregiver (Zarit Burden Interview questionnaire)
-
Acute IPF exacerbations (An acute, clinically significant respiratory 
deterioration characterized by evidence of new widespread alveolar 
abnormality)2 (5).
Data sources:
This non-interventional study will be based on both newly collected data and 
existing information. Data on patient QoL, caregiver burden, anthropometric 
variables, acute IPF exacerbations, use of resources, characteristics of IPF, will be 
collected from routine clinical care using medical records and patient’s diary.
Such medical records will also be used for sociodemographic and anthropometric 
variables, characteristics of IPF, smoking status, IPF related resource use and IPF 
days off work.
Three visits per patient will be performed as per clinical practice (the closest visit 
to 6 months or 12 months after baseline). 
To be completed by the physician (newly data and existing information): 
-
Patient demographics and medical data
To be completed by the patient along the study (newly data):  
-
Patient diary
                                                
2 Actue IPF exacerbation: An acute, clinically significant respiratory deterioration characterized by evidence of 
new widespread alveolar abnormality

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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:
15 Jun 2017
1199-0296
1.0
Not applicable
To be completed by the patient at inclusion visit , 6 month and 12 month (newly 
data): SGRQ and EQ-5D-5L
To be completed by the caregiver at inclusion visit, 6 month and 12 month:
-
Zarit Burden Interview
The direct costs over the 12 month follow-up period will be quantified by 
multiplying the recorded natural units of use of resources by the unit costs 
obtained by consulting Spanish databases or similar studies. The opportunity cost 
method will be used to calculate informal care costs. The indirect costs will be 
estimated by applying salary costs based on the latest data published by the 
Spanish Instituto Nacional de Estadística (INE) (6) from the salary structure 
survey, adjusted to age
Study size:
In view of the lack of Spanish studies that analyze the economic impact of 
Idiopathic Pulmonary Fibrosis (IPF) according to deterioration in the predicted 
forced vital capacity (FVC), and as this is a non-interventional study based on 
newly collected data, it was decided to observe all the patients with IPF that meet 
the inclusion/exclusion criteria during the inclusion period. Based on the 
investigation into the viability of recruitment, we expect to include 200 patients 
approximately. 
The primary objective of the study, if the sample size allow, is to compare the 
economic impact according to FVC levels at one year. This would mean opting 
for a balanced sample size for the three comparison groups. However, knowing 
the approximate patient prevalence according to predicted FVC (5-11% predicted 
FVC <50%, 51-73% predicted FVC 50-80%, and 22-38% predicted FVC >80%) 
(7) sponsor’s internal data and the expert panel group (investigator  coordinators) 
data) we expect to find:

10-22 patients with predicted FVC <50%.

102-143 patients with predicted FVC 50-80%.

43-76 patients with predicted FVC >80%.
Depending on the final distribution obtained in terms of number of patients for 
each comparison group and given the exploratory nature of this study, it is 
expected that comparisons between some groups will have a descriptive 
approach, although the expected comparison analyses will be carried out as stated 
in this protocol. Although the expected number of patients with predicted FVC 
<50% is small, it should at least provide first insights into the costs within this 
patient subgroup.
In view of the lack of previous data on the cost of the disease according to the 
study’s primary endpoint in Spain, this will be the first Spanish cost comparison 
study according to predicted FVC.

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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:
15 Jun 2017
1199-0296
1.0
Not applicable
Data analysis:
-
A descriptive analysis of all variables collected will be performed.
-
For each patient, the annual direct costs (primary and secondary care visits, 
outpatient 
visits, 
emergency 
visits 
-primary 
care 
and 
hospital-, 
hospitalizations, ICU with and without intubation, outpatient tests and other 
examinations, pharmacological and non-pharmacological treatments, use of 
transport, formal caregiver, orthopedic material, formal social services, 
economic aid and structural adaptations), and indirect costs (days off work 
and informal caregiver) will be quantified. Direct costs will be quantified by 
multiplying the natural units of use registered for each resource by the unit 
costs consulted in Spanish databases (Oblikue eSalud database3) or similar 
studies (similar literature published). Indirect costs will be estimated by 
applying the wage costs from the latest data published by the National 
Statistics Institute survey of the salary structure.
-
Mean, standard deviation, % confidence interval of the mean, median and 
interquartile range will be calculated for the scores obtained with the SGRQ 
questionnaire collected and absolute and relative frequencies will be 
calculated for the scores obtained with the EQ-5D-5L questionnaire 
collected.
-
If sample size allows for it, bivariate and multivariate analysis will be 
performed in order to explore the variables impacting costs and QoL for each 
study subpopulation (FVC<50%, FVC 50-80%, FVC>80%). Taking into 
account that the final number of patients expected for the FVC <50% stratum 
could be small and the limitations that a multivariate analysis might have, an 
exploratory bivariate analysis could be performed for this group with relevant 
variables. The bivariate analysis will include all the sociodemographic and 
clinical variables collected. Parametric (t-test, ANOVA) and non-parametric 
(Mann-Whitney, Kruskal-Wallis) exploratory statistical tests will be 
performed.
-
Descriptive analyses will be carried out of the total number of acute  IPF-
related exacerbations as well as the use of resources and costs associated with 
the events according to the predicted FVC at the time of inclusion (FVC 
<50%, FVC 50-80%, FVC >80%).
-
Descriptive analyses will be carried out of direct and indirect costs and 
patient quality of life according to the change in FVC over one year (<10%, 
from -5% to -10%, and >-5%).
                                                
3 The eSalud platform is the access portal to the Spanish healthcare costs database set up by Oblikue Consulting.
Source: Spanish Health Costs Database: eSalud [Internet]. Barcelona: Oblikue Consulting, S.L. 2007 [date of 
access]. Available from: http://www.oblikue.com/bddcostes/

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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:
15 Jun 2017
1199-0296
1.0
Not applicable
Milestones:
Planned start of data collection: October-2017 
Planned end of data collection: May-2019
Planned final study report: September-2019

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5.
AMENDMENTS AND UPDATES
None

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6.
MILESTONES
Milestone
Planned Date
IEC approval
July 2017
Start of data collection
October 2017
End of data collection
May 2019
Final report of study results
September 2019

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7.
RATIONALE AND BACKGROUND
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, and associated with 
the histopathologic and/or radiologic pattern of UIP (1). FVC is a reliable, valid, and 
responsive measure of disease status in patients with Idiopathic Pulmonary Fibrosis (8).
There are no large-scale studies of the incidence or prevalence of IPF on which to base 
formal estimates. Prevalence estimates for IPF have varied from 2 to 29 cases per 100,000 in 
the general population (9, 10, 11, 12, 13). 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). It is estimated that IPF affects about 7,500 
people in Spain (14), however prevalence and incidence for IPF in Spain has not been studied 
and is uncertain.
On the other hand there is no evidence on the cost of patients with IPF in Spain based on 
actual clinical practice. The only study carried out in Spain is based on Delphi panels and
concluded that the management of patients with IPF in Spain, especially patients with rapid 
disease progression, has a high economic impact on the NHS. In that study the parameter that 
varied the annual cost per patient the most was the resource use associated with acute 
exacerbations (2). Nevertheless the study did not provide any information on the burden of 
disease by level of severity or from the societal perspective, nor took into account 
pharmacological costs as pirfenidone had not been reimbursed and was only available 
through compassionate use when the analysis was performed.
The cost associated with acute exacerbations represents nearly half of the total cost of 
managing patients with IPF (2). Therefore, considering that low forced vital capacity (FVC) 
has proven the most consistent risk factor for acute exacerbation of IPF (3) is expected that 
patients with low FVC (FVC < 50%) have higher cost. Furthermore, the recent introduction 
of new antifibrotic agents (nintedanib, pirfenidone) changed the therapeutic strategy, so did 
the total cost of the disease. 
The overall burden associated with IPF patients in Spain remains unknown. It is of great 
interest to develop studies analyzing the Cost-of-illness to define the magnitude of the disease 
in monetary terms and thereby to prove what the real impact of the disease is on the Spanish 
society (4). On the other hand, the social impact4 (15) of IPF is also unknown, so studies that 
analyze the social perspective in addition to the economic one, are necessary.
The present study arises with the objective of estimating the economic and social impact of 
Idiopathic Pulmonary Fibrosis (IPF) in Spain.
                                                
4 The perspective of society is the broadest of all perspectives because it is the only one that considers the 
benefit to society as a whole. Theoretically, all direct and indirect costs are included in an economic evaluation 
performed from a societal perspective. Costs from this perspective include patient morbidity and mortality and 
the overall costs of giving and receiving medical care. An evaluation from this perspective also would include 
all the important consequences an individual could experience. In countries with nationalized medicine, society 
is the predominant perspective.

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8.
RESEARCH QUESTION AND OBJECTIVES
This non-interventional study based on newly collected data will address the following 
questions.
Primary Objective:
-
To compare the economic impact of Idiopathic Pulmonary Fibrosis (IPF) according to 
FVC % predicted level (FVC<50%, FVC 50-80%, FVC>80%), in adult patients through 
estimation of annual direct costs (primary and secondary care visits, outpatient visits, 
emergency visits -primary care and hospital-, hospitalizations,…), and indirect costs 
(days off work and informal caregiver) associated with the disease during one year
Secondary Objectives:
-
To estimate the QoL of the patients with IPF according to FVC % predicted level, 
through SGRQ and EQ-5D-5L questionnaires and the Barthel Index at baseline.
-
To explore the determinants of costs and QoL in patients with IPF according to FVC % 
predicted level.
-
To characterize acute IPF exacerbations along one year (frequency and cost) according 
to FVC % predicted level at baseline.
-
To describe the variation of costs and QoL with IPF progression (according to the FVC 
deterioration).
-
To explore the impact of disease on the patient’s caregiver through Zarit Burden 
Interview questionnaire at 6 and 12 month.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
Descriptive prospective non-interventional multicenter study based on newly collected data
of Idiopathic Pulmonary Fibrosis patients followed-up for one year in secondary care settings 
(Pulmonology Services).
Idiopathic Pulmonary Fibrosis patients who attend to a routine follow-up visit and fulfil
inclusion/exclusion criteria will consecutively enrolled by the investigator of each center. 
Once patients give their informed consent, the investigator will collect in the Case Report 
Form (CRF) specifically designed for the study, the corresponding sociodemographic, 
clinical data and healthcare and non-healthcare resource use registered in the medical records 
and provided by the patients. Also, patients will be invited to complete the study 
questionnaires in the inclusion visit (T0), approximately at their six month visit (T6) and 
twelve month visit (T12). Patients will also have a patient diary where collect data (see 
section 9.4) between follow-up visits along 12 month.
Three visits per patient will be performed as per clinical practice (the closest visit to 6 months 
or 12 months after baseline). The inclusion period of the study will be from Oct 2017 to April 
2018 and the follow-up will be 12 months for each patient and until April 2018 for the last 
patient.
9.2
SETTING
9.2.1
Study sites
It is planned that data of approximately 200 patients from approximately 25 sites (secondary 
care sites – Pulmonology services where IPF is diagnosed and managed) in Spain will be 
collected. All Idiopathic Pulmonary Fibrosis patients who are diagnosed with IPF and attend 
to a routine visit during the inclusion period and fulfill inclusion/exclusion criteria and 
provide informed consent to participate will be included in the study. 
Since the primary objective of the study is to compare the annual total cost per patient in 
Spain, it is necessary to ensure that study population is representative of the entire national 
territory. Therefore, patients will be consecutively recruited from centers in different 
geographical areas according to the distribution of the overall population in this area. Site 
selection will be performed in order to secure representativeness of the IPF population. It has 
been settled that each investigator has to include approximately 8 patients.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the Investigator Site File (ISF).   

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9.2.2
Study population
Patients can be included if all of the following criteria are met:
Inclusion criteria:
1. Female and male patients ≥ 40 years of age.
2. Patients diagnosed with Idiopathic Pulmonary Fibrosis (IPF) according to last 
ATS/ERS/JRS/ALAT IPF guideline for diagnosis and management consensus (1)
3. Written informed consent prior to participation.
Exclusion Criteria:
1. Inability for the patient to understand or complete the written Inform Consent or 
patients questionnaires or to understand Spanish.
2. Current participation in any clinical trial.
3. Patients for whom further follow-up is not possible at the enrolling site.
9.2.3
Study visits
The visit flow chart list all data collected and indicates with an “x”, the visit when they are 
collected. All data collected must be supported in the patient’s source documentation.
Visit flow chart and data collection parameters:
T0
Baseline 
Visit
T6
6 month visit 
(+/- 2 month)
T12
12 month visit 
(+/- 1 month)
Patient Informed Consent
x
Patient’s informal caregiver Informed Consent (if 
applicable)
x
x
x
Inclusion / Exclusion Criteria
x
Date of Birth (Age)
x
Gender
x
Employment status (employment and net incomes)
x
x
x
Anthropometric variables (weight, height and BMI)
x
x
x
Date of IPF diagnosis
x
FVC (ml, %)
x
x
x
FVC % predicted 1
x
x
x
FVC rate change by year
x
x
DLCO (mmol/min/kPa)
x
x
x
DLCO % predicted
x
x
x
The Barthel index
x
x
x

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T0
Baseline 
Visit
T6
6 month visit 
(+/- 2 month)
T12
12 month visit 
(+/- 1 month)
6MWD
x
x
Smoking status2
x
x
x
Environmental and occupational exposures3
x
Drugs of abuse4
x
Exposure to drugs associated with pulmonary 
fibrosis5
x
Exposure to viral infection with potential 
association  with IPF6
x
Concomitant diseases related to IPF (lung 
transplantation included
x
x
x
pharmacological and non-pharmacological 
treatments related to IPF
x
x
x
Patient diary review
x
x
x
IPF related resource use: primary and secondary 
care visits, outpatient visits, emergency visits 
(primary care and hospital), hospitalizations, ICU 
with and without intubation, outpatient tests and 
other examinations, use of transport, use of formal 
and informal caregiver, 
x
x
IPF related resource use: orthopedic material, 
formal social services, economic aid and structural 
adaptations.
x
Days off work due to IPF
x
x
Sociodemographic variables for the caregiver (if 
applicable): age, gender, employment and 
relationship with the patient.
x
Work productivity from informal patient’s 
caregiver (if applicable)
x
x
QoL of the patients (SGRQ and EQ-5D-5L 
questionnaires)
x
x
x
QoL of the informal patient’s caregiver (Zarit 
Burden Interview). If applicable.
x
x
x
Acute IPF exacerbations7
x
x
x
Safety: Adverse Drug Reactions (serious and non-
serious), fatal AE, pregnancy
x
x
x
1 Patient group (FVC<50%, FVC 50-80%, FVC>80%) will be automatically calculated within the eCRF based 
on available patient data (16):
Men: FVC % predicted (%)= 100 FVC/(0,0678 T – 0,0147 E – 6.0548)
Women: FVC % predicted (%)= 100 FVC /(0,0454 T – 0,0211 E – 2.8253)
(FVC is FVC in liters, T is height in cm and E is age in years)

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2 Ex-smoker: subject who has not smoked for a period ≥ 6 months since the current date.
To measure the amount a person has smoked over a long period of time we use pack-year. It is calculated by 
multiplying the number of packs of cigarettes smoked per day by the number of years the person has smoked. 
For example, 1 pack year is equal to smoking 1 pack per day for 1 year, or 2 packs per day for half a year, 
and so on:
Number of pack-years = (packs smoked per day) × (years as a smoker) or
Number of pack-years = (number of cigarettes smoked per day/20) × number of years smoked.
3 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
4 Categorized: Alcohol consumption: Drinker/ex-drinker/non-drinker/unknown. Cocaine consumption: Never / 
Past / Current / Unknown. Other
5 Any exposure ticked in this category (Yes/No/Unknown): Amiodarone, Bleomycine, Nitrofurantoine, 
Methotrexate. Gold salts
6 Serum antibodies for (Positive/Negative/not available): Ebstein-Barr Virus, Hepatitis C virus - Other positive
7 Actue IPF exacerbation: An acute, clinically significant respiratory deterioration characterized by evidence of 
new widespread alveolar abnormality
Study visits have been schedule according to routine care in clinical practices. 
9.2.4
Study discontinuation
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular study site.
2. Administrative reasons i.e. lack of recruitment.
3. Violation of the protocol, the contract, or applicable laws and regulations for non-
interventional studies (including Good Epidemiological Practices (GEP), Good Clinical 
Practice (GCP)), which could disturb the appropriate conduct of the NIS.
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason).
A patient can be withdrawn from the study for the following reasons:
-
A patient or legally accepted representative withdraws consent
-
The patient was erroneously included in the registry
-
Any other reason as agreed to by the Investigator and the BI Clinical Monitor
The Clinical Monitor at BI or BI’s designees must be immediately notified if a patient is 
discontinued prematurely for any of the reasons cited above.
The Investigator should indicate the date, and reason/s for discontinuation and data should be 
entered on the Electronic Case Report Form (eCRF) of the next planned visit.

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9.3
VARIABLES
9.3.1
Exposures
Not applicable as this is a non-drug related study.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
Main sociodemographic and clinical variables will be collected in order to describe 
population included in the study.
In order to compare the economic impact of Idiopathic Pulmonary Fibrosis (IPF) according to 
FVC % predicted level (FVC<50%, FVC 50-80%, FVC>80%) in adult patients through 
estimation of annual direct5 and indirect costs6 associated with the disease, the following 
outcomes will be collected in the eCRF:
-
IPF related resource use along 12 months (visit T6 and/or visit T12): primary and 
secondary care visits (T6, T12), outpatient visits (T6, T12), emergency visits (primary 
care and hospital) (T6, T12), hospitalizations (T6, T12), ICU with and without 
intubation (T6, T12), outpatient tests and other examinations (T6, T12), use of transport
(T6, T12), use of formal and informal caregiver (T6, T12), pharmacological and non-
pharmacological treatments (except treatments administered in hospitalization) (T6, 
T12), orthopedic material (T12), formal social services (T12), economic aid and 
structural adaptations (T12). 
-
IPF related days off work along 12 months (visit T6 and visit T12)
9.3.2.2
Secondary outcomes
In order to estimate the QoL of patients with IPF according to predicted FVC% through the 
SGRQ and EQ-5D-5L questionnaires and the Barthel index.
-
Health-related quality of life (QoL) will be investigated with the St George’s 
Respiratory Questionnaire (SGRQ) and the EQ-5D-5L questionnaire. Quality of life will 
be assessed at visits T0, T6 and T12.
(See section 9.7.1)
In order to explore the determinants of costs and QoL in patients with IPF according to FVC 
% predicted level, the following variables will be collected in the CRF at visit T0 and T12:
-
Sociodemographic variables: age, gender, employment, net incomes (T0).
-
Anthropometric variables: weight, height and BMI (T0).
-
Characteristics of IPF: date of IPF diagnosis (T0), FVC (ml) (T0, T6, T12), FVC % 
predicted (T0, T6 and T12), FVC rate change by year (T0 and T12), DLCO (T0, T6 and 
T12), the Barthel Index (T0, T6 and T12), 6MWD (T0 and T12), concomitant diseases 
                                                
5 Direct costs: cost incurred for medical products and services used for the prevention, detection, and treatment 
of a disease.
6 Indirect costs: costs incurred from missing work which is loss of productivity

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related to IPF (T0, T6 and T12), pharmacological and non-pharmacological treatments 
related to IPF (T0, T6 and T12).
-
Smoking status (T0, T6 and T12).
-
Work with animals (now or in the past) (T0)
-
Use of formal and/or informal caregiver (T0, T6 and T12).
The number of exacerbation7 (5) events observed during the study period will also be 
explored for the cost and QoL determinants. 
In order to characterize acute IPF exacerbations (5) during one year according to FVC % 
predicted level at one year, the following variables will be collected in the eCRF along the 
study (12 months). 
-
Acute exacerbation related resource use: primary and secondary care visits, outpatient 
visits, emergency visits (primary care and hospital), hospitalizations, ICU with and 
without intubation, outpatient tests and other examinations, use of transport, use of 
formal and informal caregiver, pharmacological and non-pharmacological treatments
(except treatments administered in hospitalization) , orthopedic material, formal social 
services, economic aid and structural adaptations.
-
Acute exacerbation related days off work 
-
The direct costs will be quantified by multiplying the recorded natural units of use of 
resources by the unit costs.
In order to estimate the direct and indirect costs according to FVC deterioration the following 
variables will be collected in the eCRF along the study (T0, T6 and T12). 
-
FVC % predicted along the study (T0, T6 and T12)
Men: FVC % predicted (%)= 100 FVC/(0,0678 T – 0,0147 E – 6.0548)   
Women: FVC % predicted (%)= 100 FVC /(0,0454 T – 0,0211 E – 2.8253)  
(FVC is FVC in liters, T is height in cm and E is age in years).
-
The calculated variable will be stratified into the following subgroups: ≤-10%, from -
10% to -5%, and >-5% (9).
-
IPF related resource use (visit T6 and/or visit T12): primary and secondary care visits, 
outpatient visits, emergency visits (primary care and hospital), hospitalizations, ICU 
with and without intubation, outpatient tests and other examinations, use of transport, 
use of formal and informal caregiver, pharmacological and non-pharmacological 
treatments, orthopedic material, formal social services, economic aid and structural 
adaptations.
-
IPF related days off work 
In order to explore the impact of the disease on the patient’s caregiver, the Zarit Burden 
Interview will be performed at visits T0, T6 and T12.
                                                
7 Actue IPF exacerbation: An acute, clinically significant respiratory deterioration characterized by evidence of 
new widespread alveolar abnormality

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9.3.3
Covariates
See Section 9.2.3
9.4
DATA SOURCES
This non-interventional study will be based on newly collected data. However, medical 
records collected through routine clinical care will be used to assess the inclusion/exclusion 
criteria of patients. 
Such medical records will also be used for sociodemographic and anthropometric variables, 
characteristics of IPF, smoking status, IPF related resource use and IPF days off work.
Barthel Index will be used to score the ability of a patient to care for himself.  It consists of 
10 items, the values assigned to each item are based on time and amount of actual physical 
assistance required if a patient is unable to perform the activity. The final scores range from 0 
and 100. Patient scoring 100 is continent, feeds himself, dresses himself, gets up out of bed 
and chairs, bathes himself, walks at least a block, and can ascend and descend stairs.
Spanish validated version will be used.
Patients will be asked to complete a patient diary along the study, to record IPF related 
resource used and days off work to avoid memory omissions. Investigator will reconcile data 
from patient diary and medical records and check incongruences with the patients during the 
visits. Reconciled data will be entered in the eCRF.
Patients will be also asked to complete at visit T0, T6 and T12 the SGRQ and EQ-5D-5L 
questionnaires.
The St. George’s Respiratory Questionnaire (SGRQ) is a 50-item questionnaire developed to 
quantify the impact of the disease on the health and QoL perceived by patients with 
respiratory diseases. It consists of 50 items divided into 3 scales: symptoms (frequency and 
severity of respiratory symptoms), activity (activity limitations due to dyspnoea) and impact 
(psychological and social functioning disorders caused by the disease). The final scores range 
from 0 (fewest limitations) to 100 (most limitations). Spanish validated version will be used.
The EQ-5D-5L consists of a questionnaire and a visual analogue scale (EQ-VAS). The EQ-
VAS is a self-rated health status using a VAS. The EQ-VAS records the subject’s perceptions 
of their own current overall health. The self-assessment questionnaire is self-reported 
description of the subject’s current health in 5 dimensions i.e., mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression. The subject is asked to grade their own 
current level of function in each dimension into one of five degrees of disability (no 
problems, slight problems, moderate problems, severe problems, and extreme problems). 
This decision results in a 1-digit number expressing the level selected for that dimension. The 
digits for 5 dimensions can be combined in a 5-digit number describing the respondent’s 
health state. Spanish validated version will be used.
Caregivers who have signed the specific written informed consent form will be asked to 
complete the Zarit Burden Interview. It is a self-report measure. The revised version contains 

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22 items. Each item on the interview is a statement which the caregiver is asked to endorse 
using a 5-point scale. Response options, in the Spanish version, range from 0 (Never) to 4 
(Nearly Always). The final scores range from 0 and 88: Little or no burden (≤ 421), mild to 
moderate burden (22-40), moderate to severe burden (41-60) and severe burden (≥ 61).
9.5
STUDY SIZE
In view of the lack of Spanish studies that analyse the economic impact of Idiopathic 
Pulmonary Fibrosis (IPF) according to deterioration in the predicted forced vital capacity 
(FVC), and as this is a prospective observational study, it was decided to observe all the 
patients with IPF that meet the inclusion/exclusion criteria during the inclusion period. Based 
on the investigation into the viability of recruitment, we expect to include approximately 200 
patients. 
The primary objective of the study is to compare the economic impact according to FVC 
levels.  This would mean opting for a balanced sample size for the three comparison groups. 
However, knowing the approximate patient prevalence according to predicted FVC (5-11% 
predicted FVC <50%, 51-73% predicted FVC 50-80%, and 22-38% predicted FVC >80%)
(8), and the sponsor’s internal data, we have estimated to find:

10-22 patients with predicted FVC <50%.

102-143 patients with predicted FVC 50-80%.

43-76 patients with predicted FVC >80%.
Depending on the final distribution obtained in terms of number of patients for each 
comparison group and given the exploratory nature of this study, it is expected that 
comparisons between some groups will have a descriptive approach, although the expected 
comparison analyses will be carried out as stated in this protocol (explorative statistical 
model if sample size allows). Although the expected number of patients with predicted FVC 
<50% is small, it should at least provide first insights into the costs within this patient 
subgroup.
In view of the lack of previous data on the cost of the disease according to the study’s 
primary endpoint in Spain, this will be the first Spanish cost comparison study according to 
predicted FVC.
9.6
DATA MANAGEMENT
A data management plan (DMP) will be created to describe all functions, processes, and 
specifications for data collection, cleaning and validation. The electronic Case Report Forms 
(eCRFs) will include programmable edits to obtain immediate feedback if data are missing 
(also negative answers, unknown), out of range, illogical or potentially erroneous. These rules 
may encompass simple checks such as range validation or presence/absence of data. 
Concurrent manual data review may be performed based on parameters dictated by the DMP. 
Ad hoc queries to the sites may be generated and followed up for resolution. A source data 
quality audit may be initiated to ensure that the data in the database is accurate. 
The database will be housed in a physically and logically secure computer system maintained 
in accordance with a written security policy. The system will meet the standards of the 

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International Committee on Harmonization guideline E6R1 regarding electronic study data 
handling. Patient confidentiality will be strictly maintained.
9.7
DATA ANALYSIS
A statistical analysis plan will be drawn up specifying all the analyses to be performed. 
However, a summary of the anticipated statistical analysis is provided below.
A descriptive analysis will be performed of all the variables recorded for the study 
population. For the continuous variables, we will calculate the mean, the standard deviation, 
the 95% confidence interval (CI) of the mean, the median, max. and min. and the interquartile 
range (IQR). Categorical variables will be presented as absolute and relative frequencies 
(percentages) and 95% CIs.
For all exploratory statistical tests, a significance level alpha of 0.05 will be assumed. The 
data analysis will be performed by using the SAS statistical package, version 9.4 or later.
Missing values will not be imputed in the main analysis. However, if considering only 
observed values for an analysis is felt to bias the results. post-hoc sensitivity analyses 
including imputation techniques might be applied.
For each questionnaire, its indications will be followed (for example, calculating the score 
considering the number of available items or missing all data).
9.7.1
Main analysis
a)
To compare the economic impact of Idiopathic Pulmonary Fibrosis (IPF) according to 
predicted FVC% (FVC<50%, FVC 50-80%, FVC>80%), in adult patients through the 
estimation of annual direct and indirect costs associated with the disease.
Annual direct IPF-related costs (primary and secondary care visits, outpatient visits, 
emergency visits -primary care and hospital-, hospitalisations, ICU with and without 
intubation, outpatient tests and other examinations, pharmacological and non-
pharmacological treatments, orthopedic material, use of transport, formal caregiver, 
formal social services, economic aid and structural adaptations) and indirect costs (days 
off work and informal caregiver) will be quantified for each patient over the follow-up 
period of 12 month.
The direct costs over the 12 month follow-up period will be quantified by multiplying the 
recorded natural units of use of resources by the unit costs obtained by consulting 
Spanish databases or similar studies. The opportunity cost method will be used to 
calculate informal care costs. The indirect costs will be estimated by applying salary 
costs based on the latest data published by the Spanish Instituto Nacional de Estadística 
(INE) (6) from the salary structure survey, adjusted to age. 
In order to obtain the most recent unit costs, they will be consulted at the time of the 
analysis. All costs will be expressed in euros for the year 2018, updating as necessary the 
costs from previous periods according to the cumulative consumer price index (CPI) 
since the publication of the cost up to December 31, 2017.

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For the primary objective of the study, the characteristics of the subpopulations defined 
by the categorisation of the deterioration in predicted FVC (FVC <50%, FVC 50-80%, 
FVC >80%) at the time of inclusion (T=0) will be described. The Chi-square test will be 
used for the comparisons of the qualitative (categorical) variables. For the comparisons 
of the quantitative (continuous) variables, analysis of variance (ANOVA) or Kruskal-
Wallis tests will be performed. Results of all statistical tests must be interpreted purely 
exploratorily.
9.7.2
Further analysis
The following analyses will be performed according to secondary objectives.
a)
To estimate the QoL of patients with IPF according to predicted FVC% through the 
SGRQ and EQ-5D-5L questionnaires and the Barthel index.
For the SGRQ, the mean, the SD, the 95% CI of the mean, the median, max and min and 
the IQR will be calculated from the scores obtained on the three scales (symptoms, 
activity, impact) and from the total score in each subpopulation (FVC <50%, FVC 50-
80%, FVC >80%).
For the EQ-5D-5L questionnaire, as the data are not continuous but ordinal, the 
information will be presented in terms of absolute and relative frequencies for each 
subpopulation (FVC <50%, FVC 50-80%, FVC >80%) by levels in each dimension. The 
EQ-5D-3L comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some 
problems, extreme problems
A missing response in either of the questionnaires will exclude the patient from the 
specific analyses.
b)
To explore the determinants of costs and QoL in patients with IPF according to predicted 
FVC%
If sample size allows, bivariate exploratory methods e.g. analysis of variance (ANOVA), 
Kruskal-Wallis test will also be applied to explore predictors of costs and quality of life 
for each study subpopulation (FVC <50%, FVC 50-80%, FVC >80%) such as 
sociodemographic and clinical variables collected. 
Taking into account that the expected final number of patients of the FVC <50% stratum 
could be small, with less of 20 patients, and the limitations that a multivariate analysis 
might have, an exploratory bivariate analysis could be performed with those variables 
considered as relevant.
Some variables may be categorised to provide practical information in the clinical 
setting. 
If sample size allows, multivariate exploratory analyses (e.g. generalized linear models)
will be applied which include costs and quality of life as dependent variables, and the 
explanatory variables will be discussed based on previous bivariate analyses and clinical 

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relevance. Sample size and constraints imposed by the analysis models may prevent to 
include all variables of interest in this setting.
c)
To characterize acute IPF exacerbations (frequency and cost) according to FVC% 
predicted level
The total number of acute IPF-related exacerbations as well as the use of resources and 
costs associated with the events during one year according to the predicted FVC at the 
time of inclusion (FVC <50%, FVC 50-80%, FVC >80%) will be described. 
For the quantitative (continuous) variables, we will calculate the mean, the SD, the 95% 
CI of the mean, the median and the IQR. Qualitative (categorical) variables will be 
presented as absolute and relative frequencies (percentages). 
d)
To describe the cost and QoL variation associated with the lung capacity deterioration 
(change among the FVC % predicted level along 12 month)
Descriptive analyses will be carried out of direct and indirect costs and patient quality of 
life according to the change in FVC (<-10%, from -10% to -5%, and >-5%) between T0 
and T12.
For the quantitative (continuous) variables, we will calculate the mean, the 95% CI, the 
median and the IQR. Qualitative (categorical) variables will be presented as absolute and 
relative frequencies (percentages).
When sample size is minimum, subgroup analyses will be explored for the following 
subgroup variables (or others, if deemed appropriate, defined in the SEAP):
-
% FVC predicted in T0 (FVC >80%, FVC 50-80% and FVC <80%)
-
antifibrotic treatment vs non antifibrotic treatment
-
one acute IPF exacerbation vs. more than one acute IPF exacerbation during study 
period.
e)
To assess the QoL of the caregiver through the Zarit Burden Interview questionnaire.
Caregiver quality of life will be explored using the Zarit questionnaire. Caregiver quality 
of life will be assessed at visits T0, T6 and T12. 
We will report the responses to the 22 items that make up the instrument, as well as the 
total score for the questionnaire. The distribution of caregiver burden will be described 
according to the following categories (17): 
little or no burden

Zarit score ≤21
Mild to moderate burden

Zarit score >21 and ≤40
Moderate to severe burden

Zarit score >40 and ≤60
Severe burden

Zarit score ≥61

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9.8
QUALITY CONTROL
To improve and secure data quality, automatic data checks upon data entry will be done 
within the eCRF. In the eCRF, plausible ranges of values for numeric data entries as well as 
logical data entries and listings will be provided for each entry field. Based on this, checks on 
completeness and plausibility will be performed upon data entry in the eCRF. 
Validity of data entry thus is ensured by integrated validation checks performed by the 
system, indicating missing or implausible entries to the document list or investigator. All 
corrections will be visible from the systems audit trail. 
No regular source data verification is planned in this study. However, in case of decreasing 
compliance (i.e. of missing data, data discrepancies, protocol violations, etc.) a for-cause 
audit or risk-based monitoring visit will be performed.
Telephone Monitoring is planned in this study. A Monitoring Plan will be created to describe 
the telephone monitoring procedures.  
9.9
LIMITATIONS OF THE RESEARCH METHODS
The intention of this NIS is to collect data about direct and indirect costs related to IPF in a 
real world setting. A NIS is the most suitable instrument for obtaining information about the 
use of resources everyday clinical practice and thus for investigating prospectively questions 
in everyday clinical practice. 
Consecutive enrolment will be employed to minimize selection bias. The entry criteria are 
non-restrictive which will permit the enrolment of a broad patient population. Selection bias 
may also occur due to loss to follow-up.
There are several different types of bias that could influence the data collection and analysis, 
such as selection, information, and channelling bias. Selection bias could occur at the site 
level and the patient level. To minimize the site level selection bias, the goal is to have 
participating sites that have access to patients from all the stratums (FVC<50%, FVC 50-
80%, FVC>80%). To minimize selection bias at the patient level, consecutive enrolment is 
performed. Information bias will be minimized by the use of standard eCRF, questionnaire 
and physicians’ training on the study protocol. 
An additional limitation is related with the setting selected of the study, that could lead to a 
under estimation of the healthcare resources consumed as Primary Care resource use or 
resource related with visits to another hospital or specialist will not be collected.
Comorbidities that could impact resource utilization may not be fully captured, and may vary 
by subgroup
Other limitation is related to the sample size in some subgroups, this factor may limit some 
testing. And also, even though include 25 Spanish hospitals, study sites may not be fully 
representative of the Spanish IPF population. 

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9.10
OTHER ASPECTS
9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Board (IRBs) / Independent Ethics Committee 
(IECs) or by regulatory authorities. The quality assurance auditor will have access to all 
medical records, the investigator’s study-related files and correspondence, and the informed 
consent documentation of this study.
9.10.2
Study records
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via remote 
data capture. Data will be captured via a web-based Electronic Data Capturing system. The 
site staff will enter and edit the data via a secure network, with secure access features 
(username, password and secure identification – an electronic password system).  A complete 
electronic audit trail will be maintained. Patients must not be identified on the eCRF by 
name. Appropriately coded identification (i.e. Patient numbers) must be used.  All 
patient/caregiver questionnaires will be paper-based and will be left at the site upon 
completion by the patient.
9.10.2.1
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.
The following source documents are expected in this study:
To be completed by the physician: 
-
Patient demographics and medical data
To be completed by the patient along the study:  
-
Patient diary
To be completed by the patient at visit T0, T6 and T12:
-
SGRQ
-
EQ-5D-5L
To be completed by the caregiver at visit T0, T6 and T12:
-
Zarit Burden Interview

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9.10.2.2
Direct access to source data and documents
The investigator / institution will permit study-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/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 9.10.2.1.
9.10.3
Completion of study
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the study (last patient / patient out, unless specified differently in Section 9.2) or 
early termination of the study. 

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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 Harmonised 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 the patient´s physician
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol / ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalization of the Study Report.
Insurance Cover: as non-interventional study and according the local regulations the 
insurance policy is not applicable.
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and Competent Authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the study, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to GEP and GPPand
to the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the study records. A signed copy of 
the informed consent and any additional patient information must be given to each patient or 
the patient’s legally accepted representative.
Prior to patient’s caregiver participation in the study, written informed consent must be 
obtained from them according to GEP and GPPand 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 information form retained by the investigator as part 
of the study records. A signed copy of the informed consent and any additional patient 
information must be given to each patient or the patient’s legally accepted representative.
The patient and patient’s caregiver (if applicable) 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.

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The patient and patient’s caregiver (if applicable) must be informed that his / her medical 
records may be examined by authorised 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.
Data generated as a result of the study need to be available for inspection on request by the 
participating physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory 
authorities, i.e. the competent authority (CA).

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11.
MANAGEMENT 
AND 
REPORTING 
OF 
ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavorable
and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorization or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event is defined as any AE which
•
results in death, 
•
is life-threatening, 
•
requires in-patient hospitalization, or
•
prolongation of existing hospitalization, 
•
results in persistent or significant disability or incapacity, or 
•
is a congenital anomaly/birth defect.
Life-threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.

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Adverse Event of Special Interest (AESI)
The term Adverse Event of Special Interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this study, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. 
No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional and non-drug related nature. Sufficient data from 
controlled interventional trials are available to support the evidence on the safety and efficacy 
of the studied BI drug. For this reason the following AE collection and reporting 
requirements have been defined.
The following must be collected by the investigator in the (e)CRF from signing the informed 
consent onwards until the end of the study: 
•
all adverse drug reaction (ADRs) (serious and non-serious), 
•
all AEs with fatal outcome  
All ADRs, including those persisting after study completion must be followed up until they 
are resolved, have been sufficiently characterized, or no further information can be obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below. 
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug.
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced.
•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).

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•
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
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) criteria in the (e)CRF.
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
study, the investigator must report any drug exposure during pregnancy, which occurred in a 
female subject or in a partner to a male subject to the Sponsor by means of Part A of the 
Pregnancy Monitoring Form. The outcome of the pregnancy associated with the drug 
exposure during pregnancy must be followed up and reported by means of Part B of the 
Pregnancy Monitoring Form. 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 

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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: 
Type of Report
Timeline
All serious ADRs associated with a BI drug taken 
for the disease in scope of the study
immediately within 24 hours
All AEs with fatal outcome in patients exposed 
to a BI drug taken for the disease in scope of the 
study
immediately within 24 hours
All non-serious ADRs associated with a BI drug
taken for the disease in scope of the study
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.
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 taken for 
the disease in scope of the study other than the 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.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
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.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
1.
Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official 
ATS/ERS/JRS/ALAT statement: Idiopathic Pulmonary Fibrosis: evidence-based 
guidelines for diagnosis and management. Am J Respir Crit Care Med. 
2011;183(6):788–824.
2.
Morell et al. Treatment patterns, resource use and costs of Idiopathic Pulmonary Fibrosis 
in Spain – results of a Delphi Panel. BMC Pulmonary Medicine (2016) 16:7. DOI 
10.1186/s12890-016-0168-6.
3.
Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King TE Jr, Lasky JA, 
Loyd JE, Noth I, Olman MA, et al.; Idiopathic Pulmonary Fibrosis Clinical Research 
Network Investigators. Acute exacerbations of idiopathic pulmonary fibrosis. Am J 
Respir Crit Care Med 2007;176:636–643.
4.
Rice D. Cost of illness studies: what is good about them? Inj Prev. 2000 September; 6(3): 
177–179.
5.
Collard HR, Ryerson CJ, Corte TJ,et al. Acute Exacerbation of Idiopathic Pulmonary 
Fibrosis. An International Working Group Report. Am J Respir Crit Care Med. 2016 
Aug 1;194(3):265-75.
7.
du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, Lancaster 
L, Noble PW, Raghu G, Sahn SA, Szwarcberg J, Thomeer M, Valeyre D, King TE Jr. 
Ascertainment of individual risk of mortality for patients with Idiopathic Pulmonary 
Fibrosis. Am J Respir Crit Care Med. 2011 Aug 15;184(4):459-66.
8.
du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, King TE Jr, 
Lancaster L, Noble PW, Sahn SA, Thomeer M, Valeyre D, Wells AU. Forced vital 
capacity in patients with Idiopathic Pulmonary Fibrosis: test properties and minimal 
clinically important difference. Am J Respir Crit Care Med. 2011 Dec 15;184(12):1382-
9.
9.
Scott J, Johnston I, Britton J. What causes cryptogenic fibrosing alveolitis? A case-
control study of environmental exposure to dust. BMJ 1990;301:1015–1017.
10. 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.
11. Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of interstitial lung 
diseases. Am J Respir Crit Care Med 1994;150:967–972.
12. von Plessen C, Grinde O, Gulsvik A. Incidence and prevalence of cryptogenic fibrosing 
alveolitis in a Norwegian community. Respir Med 2003;97:428–435.
13. Karakatsani A, Papakosta D, Rapti A, Antoniou KM, Dimadi M, Markopoulou A, Latsi
P, Polychronopoulos V, Birba G, Ch L, et al.; Hellenic Interstitial Lung Diseases Group. 
Epidemiology of interstitial lung diseases in Greece. Respir Med 2009;103:1122–1129.
14. Antoni Xaubet, Julio Ancochea, Elena Bollo, Estrella Fernández-Fabrellas, Tomás Franquet, Maria 
Molina-Molina, Maria Angeles Montero, Anna Serrano-Mollar, Guidelines for the Diagnosis and 
Treatment of Idiopathic Pulmonary Fibrosis. Archivos de Bronconeumología (English Edition), Volumen 
49, Issue 8, August 2013, Pages 343-353.
15. Waning, B., Montagne, M., & McCloskey, W. W. (2001). Pharmacoepidemiology: 
Principles and practice. New York: McGraw-Hill

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16. Castellsaguer J, Burgos F, Roca J, Sunyer J. Prediction equations for forced spirometry 
from European origin population. Respir Med. 1998;92:401–7.
17. Hérbert, R., Bravo, G., & Préville, M. (2000). Reliability, validity, and reference values 
of the Zarit Burden Interview for assessing informal caregivers of community-dwelling 
older persons with dementia. Canadian Journal on Aging, 19, 494-507.
13.2
UNPUBLISHED REFERENCES
6.
Instituto Nacional de Estadística (2015) Encuesta anual de estructura salarial. 
http://www.ine.es

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
The stand-alone documents for this non-interventional study are: 
-
Patient Informed Consent Form 
-
Patient’s Caregiver Informed Consent Form
-
Statistical Analysis Plan (SAP)
-
Data Management Plan (DMP) 
-
Monitoring Plan (MP)
-
Serious Adverse Event Report in Non-Interventional Studies (NIS (S)AE Form) 
-
Pregnancy Monitoring Form 
-
Publication Plan 
All of the above documents will be archived in the Trial Master File in its original master 
version.

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
Not applicable.

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ANNEX 3. ADDITIONAL INFORMATION
1. Patient diary
2. SGRQ questionnaire
3. EQ-5D-5L questionnaire
4. Zarit Burden Interview questionnaire
5. Barthel questionnaire

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17915891
1.0
clinical-trial-protocol-version-01
Observational Analysis on the Socio-economic Impact of IPF in Spain
Approval-Medical 
16 Jun 2017 14:43 CEST
Approval-Biostatistics
19 Jun 2017 14:37 CEST
Approval-Therapeutic Area 
23 Jun 2017 13:42 CEST
Approval-
 Safety Evaluation
Therapeutic Area
23 Jun 2017 14:33 CEST
Approval-Team Member Medical
Affairs
03 Jul 2017 17:12 CEST

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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17915891
1.0