IPF Italian Observational Study (FIBRONET)
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

Boehringer 
'-1lll1v Ingelheim 
Non-interventional Study Protocol 
Note: This template complies with the current European Medicines Agency requirements on 
format, layout and content of a PASS protocol. Please do not change the structure. 
Document Number: 
Not applicable 
BI Study Number: 
1199.262 
BI Investigational 
Not Applicable 
Product(s): 
Title: 
!PF Italian Observational Study (FJBRONET) 
Protocol version 
1.0 
identifier: 
Date of last version of 
26June 2015 
protocol: 
PASS: 
No 
EU PAS register 
Not Applicable 
number: 
Active substance: 
Not applicable 
Medicinal product: 
Not applicable 
Product reference: 
Not applicable 
Procedure number: 
<Procedure number> 
Marketing 
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authorization holder(s): 
Joint PASS: 
No 
Research question and 
long-tenn data on the natural course of IPF in Italy are scarce. Further, 
is limited information on IPF in tenns of patient characteristics and 
objectives: 
klisease management. The purpose of the present study is to evaluate the 
management and clinical course of patients with IPF as 
ltreated under real-world in Italian Pulmonary Centres, in terms o1 
lung function and exercise tolerance during 12 months of 
K>bservation. 

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BI Study Number 1199.262 
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Country(-ies) of study: 
particular, the study aims to provide information on disease 
k:haracteristics and treatment modalities (at enrolment) and on disease 
tprogression, HRQoL and health care sector-related costs according to the 
Italian National Health Service (INHS) point of view (during 12 months 
!Of observation). 
OBJECTIVES 
Primary objective 
I. 
In a sample of Italian IPF diagnosed patients, to describe the 
clinical course during 12 months of observation, in terms of: 
• 
symptoms 
• 
lung function (VC, FVC, FEVJ, TLC, DLCO, p02, 
pC02) 
• 
exercise tolerance (6-minute walk distance test). 
Seco11dary objectives 
I. 
Description of characteristics of IPF patients at enrollment in 
tenns of: 
o 
key (socio-) demographic data 
o 
IPF risk factors, comorbidities 
o 
IPF disease severity and manifestation (including lung 
function, cardiopulmonary exercise testing and/or exercise 
capacity if available, laboratory values) 
o 
Methods used for IPF diagnosis 
o 
IPF 
treatment 
modalities 
(detailed 
infonnation 
on 
prescribed drugs and dose; non-phannacological treatment; 
lung transplantation) 
2. 
To describe the frequency of exacerbations during 12 months of 
observation. 
3. 
To describe HRQoL variation, measured with SGRQ, EuroQol 
(EQ) 5-dimension 5-level (EQ-5D-5L) descriptive system and 
EQ VAS, during 12 months of observation. 
4. 
To describe health care sector-related costs from diagnosis up 
to the end of 12-months follow-up according to the Italian 
National Health Service (INHS) point of view. 
Author: 
 
Marketing authorisation 
Not Applicable 
holder(s): 
Jn case of PASS, add: 
Not Applicable 
MAH contact person: 
In case of PASS, add: 
<EU-QPPV:> 
Not Applicable 

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In case of PASS, add: 
Not Applicable 
<Signature of EU-
QPPV:> 
Date: 
26th June 2015 
Proprietary confidential information 
© 2015 Boehringer lngelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This docwnent may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission 

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Non-interventional Study Protocol 
BI Study Number 1199.262 
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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ....................................................................................... 4 
2. 
LIST OF ABBREVIATIONS ................................................................................ 6 
3. 
RESPONSIBLE PARTIES .................................................................................... 8 
4. 
AMENDMENTS AND UPDATES ..................................................................... 18 
5. 
MILESTONES ..................................................................................................... 19 
6. 
RA TIO NALE AND BACKGROUND ................................................................ 20 
7. 
RESEARCH QUESTION AND OBJECTIVES ................................................. 23 
7.1 
OBJECTIVES ................................................................................................. 23 
8. 
RESEARCH METHODS .................................................................................... 24 
8.1 
STUDY DESIGN ............................................................................................ 24 
8.2 
SETTING ........................................................................................................ 24 
8.3 
VARIABLES .................................................................................................. 25 
8.4 
DATA SOURCES ........................................................................................... 30 
8.5 
STUDY SIZE .................................................................................................. 30 
8.6 
DATA MANAGEMENT ................................................................................ 32 
8.7 
DATAANALYSIS ......................................................................................... 32 
8.8 
QUALITY CONTROL ................................................................................... 35 
8.8.1 
STUDY MONITORING ......................................................................... 35 
8.8.2 
GUIDELINES FOR EPIDEMIOLOGICAL STUDIES ......................... 36 
8.8.3 
CONFIDENTIALITY OF STUDY DOCUMENTS AND SUBJECT 
RECORDS .............................................................................................. 36 
8.8.4 
INVESTIGATOR'S FILES I RETENTION OF DOCUMENTS ........... 36 
8.8.5 
LIMITATIONS OF THE RESEARCH METHODS .............................. 37 
8.9 
OTHER ASPECTS ......................................................................................... 38 
8.9.1 
INFORMED CONSENT, DATA PROTECTION, STUDY RECORDS38 
8.9.2 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT .............................................................................................. 38 
8.9.3 
DATA QUALITY ASSURANCE .......................................................... 38 
8.9.4 
RECORDS .............................................................................................. 39 
8.9.5 
SOURCE DOCUMENTS ....................................................................... 39 
8.9.6 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............ 39 
8 .9. 7 
ST A TEMENT OF CONFIDENTIALITY .............................................. 39 
8.9.8 
COMPLETION OF STUDY ................................................................... 40 

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BI Study Number 1199.262 
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8.9.9 
PROTOCOL VIOLATIONS ................................................................... 40 
8.9.10 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY .................................................................. 40 
9. 
PROTECTION OF HUMAN SUBJECTS .......................................................... 41 
10. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ....................................................................................................... 42 
10.1 
DEFINITIONS OF ADVERSE EVENTS ...................................................... 42 
10.2 
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 43 
10.3 
REPORTING TO HEATH AUTHORITIES .................................................. 45 
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
............................................................................................................................. 46 
11.1 
OPERATIVE MANAGEMENT OF MEDICAL WRITING ASPECTS ....... 46 
11.2 
GHOSTWRITING AND GUEST/GHOST AUTHORSHIP .......................... 47 
11.3 
DETERMINING ORDER OF AUTHORSHIP .............................................. 47 
12. 
REFERENCES .................................................................................................... 48 
12.1 
PUBLISHED REFERENCES ......................................................................... 48 
12.2 
UNPUBLISHED REFERENCES ................................................................... 51 
ANNEX 1. LIST OF ST AND-ALONE DOCUMENTS .............................................. 52 
ANNEX 2. ENCEPP CHECK.LIST FOR STUDY PROTOCOLS .............................. 53 
ANNEX 3. ADDITIONAL INFORMATION .............................................................. 54 

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BI Study Number 1199.262 
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2. 
LIST OF ABBREVIATIONS 
AE 
ALAT 
ATS 
BAL 
BITSPA 
BMI 
CI 
CNS 
CRA 
CRF 
CTCAE 
CTMF 
DLCO 
eCRF 
ENCePP 
EQ-5D-5L 
ERS 
FVC 
FEVl 
GCP 
GERD 
GPP 
 
HRCT 
HRQoL 
IB 
IEC 
ILD 
INHS 
IPF 
IRB 
ISF 
JRS 
LCM 
LHA 
LTOT 
LTx 
MAH 
Adverse Event 
Latin American Thoracic Association 
American Thoracic Society 
BronchoAlveolar Lavage 
Boehringer Ingelheim Italy S.p.A. 
Body Mass Index 
Confidence Interval 
Central Nervous System 
Clinical Research Associate 
Case Report Form 
Common Terminology Criteria for Adverse Events 
Clinical Trial Master File 
Diffusion Lung Capacity for carbon monoxide 
Electronic Case Report Form 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance 
EuroQol 5-dimension 5-level 
European Respiratory Society 
Forced vital capacity 
Forced expiratory volume in the 1st second 
Good Clinical Practice 
Gastroesophageal Reflux Disease 
Good Pharmacoepidemiology Practice 
 
High Resolution chest Computer Tomography 
Health Related Quality of Life 
Investigator's Brochure 
Independent Ethics Committee 
Interstitial Lung Disease 
Italian National Health Service 
Idiopathic Pulmonary Fibrosis 
Institutional Review Board 
Investigator Site File 
Japanese Respiratory Society 
Local Clinical Monitor 
Local Health Authority 
Long-Term Oxygen Therapy 
Lung Transplantation 
Market Authorization Holder 

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Non-interventional Study Protocol 
BI Study Number 1199.262 
Vers. 1.0. 26th June 2015 
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MedDRA 
 
MMF 
 
MST 
NIS 
p.o. 
PCC 
PRO 
q.d. 
QoL 
SAE 
SAP 
s.c. 
SGRQ 
SPC 
SD 
t.i.d. 
vc 
TLC 
UIP 
Medical Dictionary for Drug Regulatory Activities 
 
Mycophenolate MoFetil 
 
Medical Subteam 
Non-interventional Study 
per os (oral) 
Protocol Challenge Committee 
Patient Related Outcomes 
quaque die (once a day) 
Quality of Life 
Serious Adverse Event 
Statistical Analysis Plan 
subcutaneous 
St. George's Hospital Respiratory Questionnaire 
Summary of Product Characteristics 
Standard Deviation 
ter in die (3 times a day) 
Vital Capacity 
Total Lung Capacity 
Usual Interstitial Pneumonia 

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BI Study Number 1199.262 
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3. 
RESPONSIBLE PARTIES 
List of all main responsible parties, including the principal investigators who signed this page, will be kept in a 
stand-alone document to be listed in Annex l and it will be available upon request. 
SIGNATURE PAGE 
This study protocol has been carefully reviewed and agreed upon by: 
Associate Medical Advisor 
Boehringer Ingelheim 
Milano 
For Contract Research Organization, 
Clinical Operation 
 
 
 
Statistician 
 
 
A 
Date, signature 
Date, signature 
 
Date, signature 

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Name of company: 
Boehringer lngelheim 
Name of finished medicinal product: 
Not applicable 
Name of active ingredient: 
Not applicable 
Protocol date: 
26th June 2015 
Title of study: 
Rationale and 
background: 
Study number: 
1199.262 
Version/Revision: 
1.0 
IPF Italian observational study 
Version/Revision date: 
26/06/2015 
Idiopathic Pulmonary Fibrosis (IPF) is a rare disease of unknown etiology that is 
characterized by progressive fibrosis of the interstitium of the lung, leading to 
decreasing lung volume and progressive pulmonary insufficiency [1](2], presenting 
more frequently in men than in women and is usually diagnosed in people over 50 
years of age, particularly those with a history of cigarette smoking [2]. 
Idiopathic Pulmonary Fibrosis is usually associated with a poor prognosis: the clinical 
course of IPF can be unpredictable [3][ 4]. IPF progression is associated with an 
estimated median survival time of 2 to 5 years following diagnosis [1][2]. The 5-year 
survival for IPF ranges between 20% and 40% [4]. 
Recognizing IPF in clinical practice can be challenging as symptoms often appear 
similar to those of more common diseases. This contributes to delay the diagnosis 
which is usually made 6 to 24 months after initial symptoms [7][8]. An earlier 
diagnosis of IPF is a prerequisite for earlier treatment and, potentially, improvement of 
the long-term clinical outcome [1]. A multidisciplinary approach involving a 
pulmonologist, radiologist and pathologist expert in interstitial lung disease has been 
shown to improve the accuracy of IPF diagnosis[2][5][6]. 
A Multidisciplinary Consensus Statement on the Idiopathic Interstitial Pneumonias 
published by the American Thoracic Society (ATS) and the European Respiratory 
Society (ERS) in 2000 proposed specific major and minor criteria for establishing the 
diagnosis of IPF [2]. However, in 201 1, new simplified and updated criteria for the 
diagnosis and management of IPF were published by the A TS, ERS, together with the 
Japanese Respiratory Society (IRS) and Latin American Thoracic Association (ALA T) 
[2]. Currently, a diagnosis of IPF requires: 
• 
Exclusion of other known causes of Interstitial Lung Disease (ILD) (e.g., 
domestic and occupational environmental exposures, connective tissue 
disease, and drug toxicity). 
• 
The presence of a Usual Interstitial Pneumonia (UIP) pattern on High 
Resolution chest Computed Tomography (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. 
It is possible to make the diagnosis of IPF by HRCT alone, obviating the need for 
surgical lung biopsy [1][2]. 
Except lung transplantation, that in a small portion of patients provides a chance of 
long-term survival, there is currently no therapy that reverses or cures the lung 
damage. Conventional IPF treatments such as corticosteroids, cyclophosphamide, 
cyclosporine and azathioprine are not approved treatments for IPF, and their efficacy 
is questionable. Other treatments with anti-fibrotic action are currently being 
investigated. Pirfenidone has been the first product to receive EU approval and 
recently approved in USA, as a treatment for mild to moderate IPF because in these 
cases it significantly reduces the decline of lung function. 

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Research 
question and 
objectives: 
Nintedanib, a tyrosine kinase inhibitor has been recently approved in EU and in USA 
for the treatment of patients with IPF. Nintedanib has shown to have a clinical benefit 
on slowing of deterioration in lung capacity with evidence of reduction of the rate of 
decline in lung function as indicated by absolute volume FVC. 
Finally oxygen therapy and non pharmacological treatment, such as pulmonary 
rehabilitation are usually recommended. 
Dyspnea and cough are hallmark symptoms of IPF, and both appear to have important 
effects not only on Health-Related Quality of Life (HRQoL) but also on survival [ 15). 
IPF patients have unpredictable acute exacerbations, which could occur even with mild 
physiological impairment. Moreover IPF patients experience depressive symptoms, 
which are correlated to HRQoL impairment and fatigue. HRQoL is further worsened 
as daily activities become limited and patients grow increasingly oxygen dependent, 
debilitated, and dependent on others [15). Not only prevalence ofIPF is higher in men 
and in the older age groups, but also burden and cost of disease varies accordingly 
[14). In fact, higher increase in hospital admissions was found in men and older age 
groups by Navaratnam and colleagues [14). They also estimated that the financial 
burden from IPF inpatient care alone in England is currently £ 16 million and will be 
almost £20 million by 2020. 
Long-term data on the natural course of IPF in Italy are scarce. Further, there is limited 
information on lPF in terms of patient characteristics and disease management. The 
purpose of the present study is to evaluate the characteristics, management and clinical 
course of patients with IPF as treated under real-world in Italian Pulmonary Centres, in 
terms of symptoms, lung function and exercise tolerance during 12 months of 
observation. 
In particular, the study aims to provide information on disease characteristics and 
treatment modalities (at enrollment) and on disease progression, HRQoL and health 
care sector-related costs according to the Italian National Health Service (INHS) point 
of view (during 12 months of observation). 
OBJECTIVES 
Primary objective 
l . In a sample of Italian IPF diagnosed patients to describe the clinical course 
during 12 months of observation, in terms of: 
• 
symptoms 
• 
lung function (VC, FVC, FEVl, TLC, DLCO, p02, pC02, Sa02, 
Pa02 and PaC02 at rest) 
• 
exercise tolerance (6-minute walk distance test). 
Seco11dary objectives 
l . Description of characteristics of IPF patients at enrollment in terms of: 
o 
key (socio-) demographic data 
o 
IPF risk factors, comorbidities 
o 
IPF disease severity and manifestation (including lung function, 
cardiopulmonary exercise testing and/or exercise capacity if available, 
laboratory values) 
o 
Methods used for IPF diagnosis 
o 
IPF treatment modalities (detailed information on prescribed drugs and 

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Study design: 
Population: 
dose; non-pharmacological treatment; lung transplantation) 
2. 
To describe the frequency of exacerbations during 12 months of observation. 
3. 
To describe HRQoL variation, measured with SGRQ, EuroQol (EQ) 5-
dimension 5-level (EQ-5D-5L) descriptive system and EQ VAS, during 12 
months of observation. 
4. 
To describe health care sector-related costs from diagnosis up to the end of 12-
month follow-up according to the Italian National Health Service (INHS) point 
of view. 
This is an observational, multicenter prospective cohort study based on newly 
collected data, involving 20 Italian Pulmonary Centers highly experienced in the 
disease management of IPF. 
The enrolment period will last 18 months. During this period, about 200 consecutive 
patients will be included in agreement with the inclusion/exclusion criteria. Patients 
will be followed up for I year, with 3 intermediate evaluations after 3 (+/-1), 6 (+/-1) 
and 9 (+/-!)months from baseline (such visits are referred as being the current clinical 
practice in Italy for IPF patients management). 
No treatment will be administered to the patients on the protocol basis, since this is an 
observational study and the assessment and treatment of the enrolled patients is based 
only on the investigators' clinical routine practice. 
Patients newly diagnosed with !PF less than 3 months before the patient's inclusion 
visit referring to pulmonary centers will be consecutively enrolled according to the 
following criteria: 
Inclusion Criteria 
1. 
Patients aged>=40 years 
2. 
Written informed consent to both participation in the study and privacy 
3. 
Physician diagnosed IPF during the last 3 months based upon recent 
ATS/ERS/JRS/ALAT guidelines 2011 (see Tables Al-A2 for HRCT and 
histology criteria): 
• 
Exclusion of other known causes of ILD (e.g. domestic and 
occupational environmental exposures, connective tissue disease and 
drug toxicity) 
• 
Assessment of IPF based on HRCT or HRCT and surgical lung biopsy 
(see Tables Al -A2 for details) if available. 
4. 
Patient with further follow-up possible with enrolling investigator during 
planned study period 
5. 
Patients capable of discernment and able to read or write in Italian language. 
if;xclusion Criteria 
6. 
Inclusion in clinical trials or other IPF/ILD registries 
7. 
Lung transplantation expected within the next 6 months 
8. 
Pregnancy or breast feeding 
Study-exit Criteria 
9. 
Inclusion in clinical trials 
10. Consent withdrawal (from patient or legally accepted representative) 
11. The patient was erroneously included in the study 
12. Pregnancy or breast feeding 
13. Any other reason as agreed to by the investigator and the BITSPA clinical 

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monitor 
Variables: 
Study Visits 
Visit I 
Vlsit2 
Visit 3 
Visit4 
Visit S 
Baseline 
Follow-up 
Follow-up 
Follow-ap 
Follo.,·-•p 
I 
2 
3 
4 
Mollllls 
0 
3 (+/-1) 
6 (+/.I) 
9 (+/. I) 
12 (+/.I) 
Eligibility criteria 
Inclusion and exclusion criteria, 
x 
Informed consent and privacy 
form 
Baseline information 
(Socio-)demographic variables: 
age, gender, race, body mass 
index, geographic location, 
x 
educational degree, marital 
status, housing situation and 
employment status 
Potential IPF risk factors 
Cigarette smoking (including 
pack/years), environmental 
x 
x 
x 
x 
x 
exposure, drug exposure, family 
history, other 
Comorbidities 
Atherothrombotic disease 
including coronary heart disease, 
previous myocardial infarction, 
cerebrovascular disease, 
x 
x 
x 
x 
x 
peripheral arterial disease, 
gastroesophageal reflux disease, 
pulmonary hypertension, 
emphysema, lung cancer, renal 
insufficiency 
Baseline information on IPF 
First symptoms; date of first 
diagnosis; if performed, dates 
x 
and results of H RCT, surgical 
lung biopsy, bronchoalveolar 
lavage 
IPF Symptoms 
Cough, Fatigue, Dizziness, Chest 
x 
x 
x 
x 
x 
pain, Clubbing, Bibasilar 
crackles 
Functional assessment 
Lung function test (VC, FVC, 
FVC % predicted, FEY I, TLC, 
DLCO, DLCO % predicted, 
x 
x 
x 
x 
x 
p02, pC02, Sa02, Pa02 and 
PaC02 at rest); 6-minute walk 
distance (if performed) 
Exacerbations 
Onset and end date 
x 
x 
x 
x 
x 
Descrintion ofmanaPement <if 

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available) 
Pharmacological treatments 
related to both IPF and 
adverse events (drug, dosage 
regimen, start I end date or 
ongoing): 
Steroids, anticoagulants, 
x 
x 
x 
x 
x 
immunomodulators 
(azathioprine, 
cyclophosphamide, MMF, etc), 
N-Acetylcysteine, Pirfenidone, 
Nintedanib 
Presence on listing for lung 
x 
x 
x 
x 
x 
transplantation (yes/no) 
Non Pharmacological 
treatment 
- Pulmonary rehabilitation; 
x 
x 
x 
x 
x 
- Long-Term Oxygen Therapy 
(liquid and/or concentrate). 
Health-care resource 
consumption related to both IPF 
and fPF-related adverse events: 
hospitalization (inward and day-
hospital), emergency room 
x 
x 
x 
x 
x 
access, specialist visits, General 
Practitioner visits, laboratory 
tests or examinations, imaging 
sessions, pharmacological and 
non-pharmacological treatments 
Patient Reported Outcomes 
Questionnaires/scales 
HRQoL 
EQ-5D-5L descriptive system 
and EQ VAS; Saint George 
x 
x 
x 
Respiratory Questionnaire 
(SGRQ) 
Adherence to therapy 
Morisky medication Adherence 
x 
x 
x 
Scale 4 items (MMAS-4) 
Anxiety a nd Depression 
Hospital Anxiety and Depression 
x 
x 
x 
Scale (HADS) 
Dyspnea 
Modified Medical Research 
x 
x 
x 
Council Dyspnea Scale 
Survival Status 
x 
x 
x 
x 
Adverse Events and Adverse 
Drug Reactions 
description, onset and resolution 
x 
x 
x 
x 
date, relation with drugs, 
severity, seriousness. 
Clinical events 
CNS infarction mvocardial 
x 
x 
x 
x 
x 

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Data sources: 
Study size: 
infarction, other arterial 
thromboembolic events, deep 
vein thrombosis, hemorrhage, 
gastrointestinal perforation, 
pulmonary hypertension) 
Visit 2 (3+/-1 month), Visit 3 (6+/-1 month) and Visit 4 (9+/-1 month) are referred as 
being the current clinical practice in Italy for /PF patients management. 
Diagnostic Tools/Patient Reported Outcomes Questionnaires 
• 
Modified Medical Research Council Dyspnea Scale (MMRC); 
• 
Morisky medication Adherence Scale 4 items (MMAS-4); 
• 
EuroQoL-SD SL; 
• 
Hospital Anxiety and Depression Scale (HADS); 
• 
Saint George Respiratory Questionnaire (SGRQ). 
The following procedures will be applied at each study visit according to routine 
clinical practice: 
• 
Lung function test (VC, FVC, FEVl, TLC; DLCO; p02, pC02; Sa02, Pa02 
and PaC02 at rest); 
• 
6-minute walked distance test. 
Data will be collected at baseline, 3, 6, 9 and 12-month follow up and the following 
questionnaire and scales will be administered to patients: Modified Medical Research 
Council Dyspnea Scale (MMRC); Morisky medication Adherence Scale 4 items 
(MMAS-4); EuroQoL-SD SL; Hospital Anxiety and Depression Scale (HADS); Saint 
George Respiratory Questionnaire (SGRQ). (see Variables section for details). 
The sample size was determined on the basis of feasibility criteria. In fact, according 
to the volume of patients managed by the centers involved in this study, inclusion of 
200 
subjects 
(I 0 
patients/center) 
with 
the 
characteristics 
defined 
at 
Inclusion/Exclusion criteria paragraphs is deemed reasonable for enrolment period (1 8 
months). 
An evaluation of the possible achievable precision of the estimates was performed 
considering the primary objective of the study and literature data, when available. 
The primary objective of the study is to describe the clinical course during 12 months 
of observation, in terms of symptoms, lung function and exercise tolerance. Assuming 
a drop-out rate ranging from of 20% to 40% , the total number of evaluable patients at 
12-month follow-up visit is expected to range between 120 and 160 subjects. Drop-out 
rate was hypothesized by considering mortality rate in IPF patients and natural drop-
out from studies. Literature data about the clinical course of outcomes of interest in 
IPF patients in a real-life context are scanty. Nishiyama et al. [3S] conducted a study 
on 93 IPF patients and assessed the pulmonary function. The mean (±SD) of FVC, 
FEVI , DLCO were 2.37 (±0.73) L, 1.93 (±O.S7) L and 
9. 19 (±3.92) mL*min-
1 *mmHg-1 respectively. According to the data of a recently completed trial on 
patients with IPF by Swigris et al [3 7], the mean (±SD) baseline 6-min walked 
distance was 372.9 (±82.63) meters. Regarding the most common IPF symptoms, 
clubbing, dyspnea (evaluated by means of a mMRC score 
crackles and cough 
frequencies are 43%, 44%, 67% and 73% respectively [34] [3S]. 
Table I shows the two-sided 95% confidence interval (Cl) for expected frequency of 
!PF symptoms for a sample size n=l 20 and 160, using the large sample normal 
approximation [36}. 

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Data analysis: 
Expected 
95%CI 
freguencl'. 
IPF symptoms 
n=120 
-
-
Clubbing 
43% 
34.1% 
51.9% 
Dyspnea (mMRC score 
44% 
35.1% 
52.9% 
Crackles 
67% 
58.6% 
75.4% 
Cough 
73% 
65.1% 
80.9% 
n=160 
-
Clubbing 
43% 
35.3% 
50.7% 
Dyspnea (mMRC score 
44% 
36.3% 
51.7% 
Crackles 
67% 
59.7% 
74.3% 
Cough 
73% 
66.1% 
79.9% 
Table 2 shows the two-sided 95% CI for expected mean ofFVC, FEVl, DLCO and 6-
min walked distance for sample sizes of n=l20 (drop out=40%) and n=l60 (drop 
out=20%), assuming the SD reported in the table and the confidence interval is based 
on the large sample z statistic [36]. IPF is a degenerative disease, therefore it is 
expected a worsening of symptoms, lung function and exercise tolerance. However, a 
conservative evaluation was performed by taking into account the two-sided 95% 
confidence interval. 
Table 2 two-sided 95% Cl of expected FVC, FEVJ, DLCO and 6-min walked distance 
mean with sample sizes n= 120 and 160. Cells are gray when the relative error -
calculated as the ratio between 95% CJ half-width and expected mean - is lower than 
30%. 
Expected 
SD 
95%CI 
mean 
n=120 (drop out=40%) 
FVC (L) 
2.37 
0.73 
2.24 
2.50 
FEVl (L) 
1.93 
0.57 
1.83 
2.03 
DLCO (mL *min- I *mmHg-1) 
9.19 
3.92 
8.49 
9.89 
6-min walked distance (m) 
372.9 
82.63 
358.12 
387.68 
n=160 (drop out=20%) 
FVC (L) 
2.37 
0.73 
2.26 
2.48 
FEVl (L) 
1.93 
0.57 
1.84 
2.02 
DLCO (mL*min-1 *mmHg-1) 
9.19 
3.92 
8.58 
9.80 
6-min walked distance (m) 
372.9 
82.63 
360. 1 
385.70 
The statistical analysis will be performed on all evaluable patients who enter the study 
and meet the inclusion criteria. Patients with missing values will not be excluded from 
the analysis, their data will not be replaced; frequency of missing data will be given for 
all analyzed variables. 
Descriptive analysis will be composed of means, medians, quantiles, proportions (with 
their respective 95% confidence intervals, CI) and contingency tables according to the 
nature of the variables. As a dispersion measurements, the standard deviation and the 
interquartile range will be calculated. All events during follow-up will be described as 
incidence rates with 95% CI. 
The study objectives will be evaluated as follows: 

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Primary objective 
To describe the clinical course off PF during 12 months of observation 
At each follow up visit the frequency of IPF symptoms (cough, fatigue, dizziness, 
chest pain, clubbing, bibasilar crackles) will be provided and the variation between 
visits will be described too mostly in terms of incident and worsening symptoms. 
Moreover, the score of the Modified Medical Research Council Dyspnea Scale for the 
evaluation of dyspnea at each follow up visit will be calculated together with the 
variation since baseline and between follow up visits. 
The following outcomes will be also considered during the 12-month observation: 
lung function parameters (like VC, FVC, FEY!, TLC, DLCO, p02, pC02; Sa02, 
Pa02 and PaC02 at rest) and patient's exercise capacity (evaluated by means of 6-
minute walked distance test, if available). The outcomes will be described at each 
follow up by means of descriptive statistics and the variation between visits will be 
provided too. 
Seco11dary objectives 
#I Description of /PF patie11ts at e11rollme11t (socio-demographic data, /PF risk 
factors, comorbidities, disease severity a11d ma11ifestatio11, methods (or diagnosis, 
treatment modalities) 
IPF patients enrolled at baseline will be described in terms of socio-demographic 
variables (e.g. age, gender, race, body mass index, educational degree, and 
employment status) and potential IPF risk factors (such as smoking habits, 
environmental exposure, drug exposure, other factors). 
The absolute and relative frequency (N, %) distributions of patients according to 
ongoing comorbidities (such as gastroesophageal reflux disease, pulmonary 
hypertension, emphysema, lung cancer, coronary heart disease, depression) will be 
also provided at baseline. 
Treatment modalities will be described 
at each visit by means of frequency 
distribution of patients according to ongoing therapies for IPF; pharmacological (such 
as steroids, anticoagulants, immunomodulators, N-acetylcysteine, pirfenidone, etc .. ) 
and non-pharmacological (such as long term oxygen and pulmonary rehabilitation) 
therapies will be considered and described in terms of drug, dosage regimen and 
duration/number of sessions (including start and stop dates). The frequency of patients 
on listing for lung transplantation at baseline will be also provided. 
The adherence to anti-IPF medications will be assessed too by means of the Morisky 
medication Adherence Scale 4 items (MMAS-4) scale considering evaluable patients 
with ongoing anti-IPF medications who have at least 3 out of 4 items of the scale 
filled-in [25,26,27]. The distribution of patients according to the four items of the scale 
will be also provided. 
Finally, descriptive statistics of the Hospital Anxiety and Depression Scale (HADS) 
scores will be provided to describe patients' levels of anxiety and depression. 
#2 To describe the freque11cv ofexacerbatio11s duri11g 12 mo11ths ofobservatio11 
The proportion of patients with at least one exacerbation after 12 months of 
observation will be computed as the ratio between the number of patients with one or 
more episodes of exacerbation occurred during 12 months of follow up over the total 
number of evaluable patients. Patients who drop-out without having exacerbations 
before the end of the study, will be considered in the denominator of the proportion of 
interest. The median number of episodes of exacerbation per patient will also be 
provided. Finally time to first exacerbation will be analyzed by Kaplan-Meier curves. 

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Milestones: 
#3 To describe the HRQOL variation during 12 months ofobservatio11 
The descriptive statistics will be produced for EQ-5D-5L descriptive system index and 
VAS. Moreover, the difference of scores between baseline and available follow up 
visits will be calculated too. Similarly, the descriptive statistics of St. Georges 
Respiratory Questionnaire scores (symptoms, activity and impacts and total score) will 
be calculated. Graphs of mean HRQoL scores according to visits will also be provided 
to show the trend of variation, if any. 
#4 To describe health care sector-related costs during 12 months of observation 
In order to describe health care sector-related costs at diagnosis and from diagnosis up 
to the end of 12-month follow-up according to the INHS point of view, a two steps 
approach will be followed: (i) first of all the resource consumption since diagnosis will 
be collected or estimated and then (ii) a monetary value will be assigned to the 
collected or estimated resource consumption. 
(i) Health care resource consumption exclusively related to both IPF and !PF-related 
adverse events will be computed during observational period in terms of 
pharmacological and non-pharmacological treatments, number of (inward and day-
hospital) hospitalizations, number of emergency room visits, number of General 
Practitioner visits, laboratory tests or examinations (spirometry, BAL, saturation), 
number of imaging sessions. Health care resources consumed during a three-month 
span of time between date of diagnosis and inclusion in the study will be 
retrospectively collected via an ad hoc section of the case report form (CRF) and/or 
estimated.(ii) In order to estimate the economic impact on health care sector-related 
costs of the above mentioned health services (hospital admissions, visits, treatments, 
examinations) consumption, a monetary value to each event recorded will be assigned, 
as defined by the Italian Ministry of Health through the tariff in force for outpatient 
setting (28]. The cost of hospitalization will be valued according to the most recent 
available diagnosis-related group (DRG) tariffs; finally pharmacological treatments 
will be costed at consumer price. 
All costs will be expressed in €. A monthly (or yearly) cost will be provided by taking 
into account patients according to duration of observation and parametrizing each 
patient to the I-year observation period. 
Cost of Illness (COI) will be analyzed via descriptive statistics (mean; standard 
deviation; median; minimum and maximum). 
Non-parametric bootstrap method will be applied to COI data for calculating 95% 
confidence intervals. 
• 
First patient in: December 2015 
• 
Last patient in: May 2017 
• 
Last patient out: May 2018 
• 
Final study report: October 2018 

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4. 
AMENDMENTS AND UPDATES 
Any change or addition to the protocol requires a written protocol amendment that must be 
approved by BITSP A and all main responsible parties, the principal investigator and the 
relevant EC before implementation. Amendments only affecting administrative aspects of the 
study do not require formal protocol amendments or EC approval but the ECs have to be 
informed of such administrative changes. 

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5. 
MILESTONES 
The first patient enrolled in the study is expected in December 2015. The end of the data 
collection (including the follow-up period) is expected within May 2018, depending on the 
effective enrolment period necessary to collect data from two hundred patients. 
Milestone 
Planned Date 
Start of data collection 
31 December 2015 
End of data collection 
31May2018 
Final report of study results: 
31 October 2018 

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6. 
RATIONALE AND BACKGROUND 
Idiopathic pulmonary fibrosis (IPF) is a rare disease of unknown etiology that is 
characterized by progressive fibrosis of the interstitium of the lung, leading to decreasing 
lung volume and progressive pulmonary insufficiency [I ][2], presenting more frequently in 
men than in women and is usually diagnosed in people over 50 years of age, particularly 
those with a history of cigarette smoking [2]. 
Several potential risk factors for the development of IPF have been identified. These include 
environmental and occupational exposures, tobacco smoking, comorbidities (in particular 
gastroesophageal reflux disease [GERD]), and genetic polymorphisms. The identification of 
risk factors for IPF is critically important as it may inform prevention strategies, early 
diagnosis, and novel therapies [ 16]. 
There is a strong association (prevalence of approximately 90%) between gastroesophageal 
reflux and IPF [17-20]. Moreover, although a causal relationship is unclear, it has been 
hypothesized that gastroesophageal reflux may be a risk factor for microaspiration, and this 
may be important in the pathogenesis and natural history ofIPF [21]. 
IPF also appears to be more common in men compared to women, however, some postulate 
this may be due to sex differences in historical smoking patterns rather than an inherent sex-
related risk for IPF [ 16]. 

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Idiopathic Pulmonary Fibrosis is usually associated with a poor prognosis: the clinical course 
of IPF can be unpredictable [3 ][ 4]. IPF progression is associated with an estimated median 
survival time of 2 to 5 years following diagnosis [ 1 ][2]. The 5-year survival for IPF ranges 
between 20% and 40% [ 4]. 
Recognizing IPF in clinical practice can be challenging as symptoms often appear similar to 
those of more common diseases. This contributes to delay the diagnosis which is usually 
made 6 to 24 months after initial symptoms [7,8]. An earlier diagnosis of IPF is a prerequisite 
for earlier treatment and, potentially, improvement of the long-term clinical outcome[!]. A 
multidisciplinary approach involving a pulmonologist, radiologist and pathologist expert in 
interstitial lung disease has been shown to improve the accuracy ofIPF diagnosis[2][5][6]. 
A Multidisciplinary Consensus Statement on the Idiopathic Interstitial Pneumonias published 
by the American Thoracic Society (A TS) and the European Respiratory Society (ERS) in 
2000 proposed specific major and minor criteria for establishing the diagnosis of IPF[2]. 
However, in 2011, new simplified and updated criteria for the diagnosis and management of 
IPF were published by the ATS, ERS, together with the Japanese Respiratory Society (JRS) 
and Latin American Thoracic Association (ALAT)[2]. Currently, a diagnosis ofIPF requires: 
• 
Exclusion of other known causes of Interstitial Lung Disease (ILD) (e.g., domestic 
and occupational environmental exposures, connective tissue disease, and drug 
toxicity). 
• 
The presence of a Usual Interstitial Pneumonia (UIP) pattern on High Resolution 
chest Computed Tomography (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. 
It is possible to make the diagnosis of IPF by HRCT alone, obviating the need for surgical 
lung biopsy [ l ][2]. 
Except lung transplantation, that in a small portion of patients provides a chance of long-
term survival, there is currently no therapy that reverses or cures the lung damage. 
Conventional IPF treatments such as corticosteroids, cyclophosphamide, cyclosporine and 
azathioprine are not approved treatments for IPF, and their efficacy is questionable and may 
increase mortality and exacerbation rates. Other treatments with anti-fibrotic action are 
currently being investigated. Pirfenidone has been the first product to receive EU and US 
approval as a treatment for mild to moderate IPF, because in these cases it significantly 
reduces the decline of lung function. Pirfenidone has antifibrotic and anti-inflammatory 
activity with a modest treatment effect. 
Nintedanib, a tyrosine kinase inhibitor has been recently approved in EU and in USA for the 
treatment of patients with IPF. Nintedanib has shown to have a clinical benefit on slowing of 
deterioration in lung capacity with evidence of reduction of the rate of decline in lung 
function as indicated by absolute volume FVC. 

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Finally oxygen therapy and non pharmacological treatment, such as pulmonary rehabilitation 
are usually recommended. 
Dyspnea and cough are hallmark symptoms of IPF, and both appear to have important effects 
not only on quality of life (QoL) but also on survival [ 15]. IPF patients have unpredictable 
acute exacerbations, which could occur even with mild physiological impairment. At least 
half of hospitalizations are thought to be due to acute exacerbations of IPF [ 16]. Acute 
exacerbations of IPF are defined as an unexplained worsening or development of dyspnea. 
Their yearly incidence is between 10 and 15% of all patients. The prognosis of exacerbations 
is poor, with mortality ranging from 78% to 96% [22]. Other causes of exacerbations such as 
pulmonary embolism, congestive heart failure, pneumothorax, or infection need to be 
excluded. 
Moreover, IPF patients experience depressive symptoms, which are correlated to QoL 
impairment and fatigue. QoL is further worsened as daily activities become restricted and 
patients grow increasingly oxygen dependent, debilitated, and dependent on others [ 15]. Not 
only prevalence of IPF is higher in men and in the older age groups, but also burden of 
disease [ 14]. In fact, higher increase in hospital admissions was found in men and older age 
groups by Navaratnam and colleagues [14]. They also estimated that the financial burden 
from IPF inpatient care alone in England is currently £ 16 million and will be almost £20 
million by 2020. 

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7. 
RESEARCH QUESTION AND OBJECTIVES 
Long-term data on the natural course of IPF in Italy are scarce. Further, there is limited 
information on IPF in te1ms of patient characteristics and disease management. The purpose 
of the present study is to evaluate the characteristics, management and clinical course of 
patients with IPF as treated under real-world in Italian Pulmonary Centres, in terms of 
symptoms, lung function and exercise tolerance during 12 months of observation. 
In particular, the study aims to provide information on disease characteristics and treatment 
modalities (at enrollment) and on disease progression, HRQoL and health care sector-related 
costs according to the Italian National Health Service (INHS) point of view (during 12 
months of observation). 
7.1 
OBJECTIVES 
Primary objective 
l . In a sample of IPF diagnosed patients to describe the clinical course during 12 months 
of observation, in tenns of: 
• 
symptoms 
• 
lung function (VC, FVC, FEVl , TLC, DLCO, p02, pC02; Sa02, Pa02 and 
PaC02 at rest) 
• 
exercise tolerance (6-minute walk distance test) 
Secondary objective 
1. Description of characteristics of IPF patients at enrollment in terms of: 
• 
key (socio-) demographic data 
• 
IPF risk factors, comorbidities 
• 
IPF disease severity and manifestation (including lung function, cardiopulmonary 
exercise testing and/or exercise capacity if available, laboratory values) 
• 
Methods used for IPF diagnosis 
• 
IPF treatment modalities (detailed information on prescribed drugs and dose; non-
pharmacological treatment; lung transplantation) 
2. To describe the frequency of exacerbations during 12 months of observation. 
3. To describe HRQoL variation, measured with SGRQ, EuroQol (EQ) 5-dimension 5-
level (EQ-5D-5L) descriptive system and EQ VAS, during 12 months of observation. 
4. To describe health care sector-related costs from diagnosis up to the end of 12-month 
follow-up according to the Italian National Health Service (INHS) point of view. 

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8. 
RESEARCH METHODS 
8.1 
STUDY DESIGN 
This is an observational, multicenter prospective cohort study based on newly collected data, 
involving 20 Italian Pulmonary Centers highly experienced in the disease management of 
IPF. 
The enrolment period will last 18 months. During this period, about 200 consecutive patients 
will be included in agreement with the inclusion/exclusion criteria. Patients will be followed 
up for 1 year, with 3 intermediate evaluations after 3 (+/-1), 6 (+/-1) and 9 (+/-1) months 
from baseline (such visits are referred as being the current clinical practice in Italy for IPF 
patients management). 
No treatment will be administered to the patients on the protocol basis, since this is an 
observational study and the assessment and treatment of the enrolled patients is based only on 
the investigators' clinical routine practice. 
8.2 
SETTING 
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
or not. 
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. Any administrative reasons that could significantly affect continuation of the study 
according to signed site contract 
3. Violation of GCP, the study protocol, or the contract by a study site or investigator, 
disturbing the appropriate conduction of the study 
The investigator I the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason). 
All patients referring to pulmonary centers will be consecutively enrolled according to the 
following criteria: 
Inclusion Criteria 
l . Patients aged>=40 years 
2. Written informed consent to both participation in the study and privacy 

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3. Physician diagnosed IPF during the last 3 months based upon recent 
ATS/ERS/JRS/ALAT guidelines 2011 (see Tables Al-A2 for HRCT and histology 
criteria): 
• 
Exclusion of other known causes of ILD (e.g. domestic and occupational 
environmental exposures, connective tissue disease and drug toxicity) 
• 
Assessment of IPF based on HRCT or HRCT and surgical lung biopsy (see 
Tables Al-A2 for details) if available. 
4. Patient with further follow-up possible with enrolling investigator during planned 
study period 
5. Patients capable of discernment and able to read or write in Italian language. 
Exclusion Criteria 
1. Inclusion in clinical trials or other IPF/ILD registries 
2. Lung transplantation expected within the next 6 months. 
3. Pregnancy or breast feeding 
Study-exit Criteria 
1. Inclusion in clinical trials 
2. Consent withdrawal (from patient or legally accepted representative) 
3. The patient was erroneously included in the study 
4. Pregnancy or breast feeding 
5. Any other reason as agreed to by the investigator and the BITSPA clinical monitor 
8.3 
VARIABLES 
This is 
a non-interventional study and does not impose a therapy protocol, 
diagnostic/therapeutic procedure, or a visit schedule. Patients will be treated according to the 
local prescribing information and routine medical practice in terms of visit frequency and 
types of assessments performed and only these data will be collected as part of the study. The 
treating physician is asked to complete if possible at every patient visit the appropriate CRF. 
Primary endpoints will be: symptoms, lung function (VC, FVC, FEVI, TLC, DLCO, p02, 
pC02; Sa02, Pa02 and PaC02 at rest), exercise tolerance (6-minute walked distance test) 
both at baseline and at follow-up visits. 
Secondary endpoints will be: (socio-) demographic data, IPF risk factors, comorbidities, IPF 
disease severity and manifestation (including lung function, cardiopulmonary exercise testing 
and/or exercise capacity if available, laboratory values), methods used for IPF diagnosis, IPF 
treatment modalities (prescribed drugs and dose; non-pharmacological treatment; lung 
transplantation); exacerbations SGRQ and EuroQol (EQ) 5-dimension 5-level (EQ-5D-5L). 
Finally health care resources will be collected 

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Below is the recommended assessment schedule that most likely mirrors the patterns of 
routine clinical care of most patients. 
Study Visits 
Visit 1 
Vlslt2 
Vlslt3 
Vlslt4 
Baseline 
Follow-up 1 
Follow-up 2 
Follow-up 3 
Months 
0 
3 (+/-1) 
6 (+/-I) 
9 (+/- 1) 
Eligibility criteria 
Inclusion and exclusion criteria, 
x 
Informed consent and privacy form 
Baseline information 
(Socio-)demographic variables: age, 
gender, race, body mass index, 
geographic location, educational 
x 
degree, marital status, housing situation 
and employment status 
Potential IPF risk factors 
Cigarette smoking (including 
x 
x 
x 
x 
pack/years), environmental exposure, 
drug exposure, family history, other 
Comorbidities 
Atherothrombotic disease including 
coronary heart disease, previous 
myocardial infarction, cerebrovascular 
disease, peripheral arterial disease, 
x 
x 
x 
x 
gastroesophageal reflux disease, 
pulmonary hypertension, emphysema, 
lung cancer, renal insufficiency 
Baseline information on IPF 
First symptoms; date of first diagnosis; 
if performed, dates and results of 
x 
HRCT, surgical lung biopsy, 
bronchoalveolar lavage. 
IPF Symptoms 
Cough, Fatigue, Dizziness, Chest pain, 
x 
x 
x 
x 
Clubbing, Bibasilar crackles. 
Functional assessment 
Lung function test (VC, FVC, FVC % 
predicted, FEV I, TLC, DLCO, DLCO 
% predicted, p0 2, pC02; Sa02, Pa0 2 
x 
x 
x 
x 
and PaC02 at rest); 6-minute walk 
distance (if performed) 
Exacerbations 
Onset and end date 
x 
x 
x 
x 
Description of management (if 
available) 
Pharmacological treatments related 
to both IPF and adverse events (drug, 
dosage regimen, start I end date or 
ongoing): 
x 
x 
x 
x 
Steroids, anticoagulants, 
immunomodulators (azathioprine, 
cvclophosphamide, MM F, etc), N-
Vlslt5 
Follow-up 4 
12 (+/-1) 
x 
x 
x 
x 
x 
x 

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Study Visits 
Visit 1 
Visit2 
Visit 3 
Visit4 
Baseline 
Follow-up 1 
Follow-up 2 
Follow-up 3 
Months 
0 
3 (+/-1) 
6 (+/- 1) 
9 (+/- 1) 
Acetylcysteine, Pirfenidone, 
Nintedanib 
Presence on listing for lung 
x 
x 
x 
x 
transplantation (yes/no) 
Non Pharmacological treatment 
- Pulmonary rehabilitation; 
x 
x 
x 
x 
- Long-Term Oxygen Therapy (liquid 
and/or concentrate). 
Health-care resource consumption 
related to both !PF and lPF-related 
adverse events: hospitalization (inward 
and day-hospital), emergency room 
access, specialist visits, General 
x 
x 
x 
x 
Practitioner visits, laboratory tests or 
examinations, imaging sessions, 
pharmacological and non-
pharmacological treatments 
Patient Reported Outcomes 
Questionnaires/scales 
HRQoL 
EQ-5D-5L descriptive system and EQ 
x 
x 
VAS; Saint George Respiratory 
Questionnaire (SGRQ) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival Status 
x 
x 
x 
Adverse Events and Adverse Drug 
Reactions 
description, onset and resolution date, 
x 
x 
x 
relation with drugs, severity, 
seriousness. 
Clinical events 
CNS infarction; myocardial infarction; 
other arterial thromboembo!ic events; 
x 
deep vein thrombosis; hemorrhage; 
x 
x 
gastrointestinal perforation; pulmonary 
hypertension) 
Visit 2 (3+/-1 month), Visit 3 (6+/-1 month) and Visit 4 (9+/-1 month) are referred as being 
the current clinical practice in Italy for IPF patients management. 
Visits 
Follow-up 4 
12 (+/- 1) 
x 
x 
x 
x 
 
 
 
x 
x 
x 

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Data will be collected at baseline, 3, 6, 9 and 12-month follow up visits for routine clinical 
practice and the following questionnaire and scales will be administered to patients: Modified 
Medical Research Council Dyspnea Scale (MMRC); Morisky medication Adherence Scale 4 
items (MMAS-4); EuroQoL-5D 5L; Hospital Anxiety and Depression Scale (HADS); Saint 
George Respiratory Questionnaire (SGRQ) (see Variables section for details). 
The following procedures will be applied at each study visit according to routine clinical 
practice: 
Lung function test (VC, FVC, FEVI, TLC; DLCO; p02, pC02; Sa02, Pa02 and 
PaC02 at rest); 
6-rninute walked distance test. 
Acute exacerbation ofIPF (AE-IPF) will be defined as a sudden acceleration of the disease or 
an idiopathic acute injury superimposed on diseased lung that leads to a significant decline in 
lung function. It will be evaluated according to clinical judgement. 
EuroQoL-SD 
The quality of life will be evaluated by the EQ-5D-5L a standardize measure of health status 
developed EuroQol Group to provide a simple generic measure of health status for clinical 
and economic evaluation [38, 48]. EQ-5D-5L is filled in by patients, it's easy from a 
cognitive point of view, since it takes only few mi nuts for filling. 
EQ-5D-5L consists of 2 sections: "EQ-5D descriptive system" and EQ visual analogue scale 
(EQ VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. 
The EQ VAS indicate the health status self-assessed by the patient on a visual analogue scale 
from 0 to 100, where 100 is the "best imaginable health state" and 0 the "worst imaginable 
health state". It can be used as a quantitative measure of health as judged by respondents. 
The questionnaire will be completed by patients at enrolment, 6-, and 12-month follow up 
visits. 
St. George's Respiratory Questionnaire (SGRO) 
Health Related Quality of Life will be assessed by the St. George's Respiratory 
Questionnaire, developed to measure health in chronic airflow limitation. It is a disease-
specific instrument designed to measure health impairment in terms of impact on overall 
health, daily life, and perceived well-being in patients with obstructive airways disease [39] . 
It consists of 2 parts and 3 different components as follows: 
Part 1 (Symptoms component): addresses the frequency of respiratory symptoms and its 
purpose is to assess the patient's perception of his/her recent respiratory problems. 
Part 2: addresses the patient's current state. 
-
Activities component measures disturbances to daily physical activity; 

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-
Impact component covers a range of disturbances of psycho-social function. 
Three component scores are calculated: symptoms, activity and impacts on daily life. 
Moreover a total score will be calculated, with lower scores corresponding to better health 
(40, 41). 
It has good discriminative and evaluative properties; it was developed and validated in both 
asthma and COPD, although it has also been validated for use in bronchiectasis and has been 
applied to patients with sarcoidosis. It takes 8-15 minutes to complete and it can be easily 
self-administered to patients. The Italian version of this questionnaire is available. 
The questionnaire will be completed by patients at enrolment, 6- and 12-month follow up 
visits. 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8.4 
 
 
 
 
 
 
DATA SOURCES 
Source data will be medical records usually collected during routine clinical practice other 
than study-specific questionnaires. 
Collected variables are defined based on study objectives and according to the observational 
nature of the study. They consist in data routinely collected in clinical practice, so they are 
expected to be available in medical charts. 
The study data will be collected by means of remote data capture using an electronic case 
report form (eCRF). Investigators will be provided a user-friendly paper form which is 
intended as a supportive tool for data collection and will be filled in according to each site 
specific need (it will not be considered as a source data). 
Patient-reported outcomes, i.e. scales and questionnaires, will be collected on paper and they 
will constitute source data. 
8.5 
STUDY SIZE 
The sample size was determined on the basis of feasibility criteria. In fact, according to the 
volume of patients managed by the centers involved in this study, inclusion of 200 subjects 
(10 patients/center) with the characteristics defined at Inclusion/Exclusion criteria paragraphs 
is deemed reasonable for enrolment period (l 8 months). 
An evaluation of the possible achievable precision of the estimates was performed 
considering the primary objective of the study and literature data, when available. 
The primary objective of the study is to describe the clinical course during 12 months of 
observation, in terms of symptoms, lung function and exercise tolerance. Assuming a drop-
out rate ranging from of 20% to 40%, the total number of evaluable patients at 12-month 
follow-up visit is expected to range between 120 and 160 subjects. Drop-out rate was 
hypothesized by considering mortality rate in IPF patients and natural drop-out from studies. 
Literature data about the clinical course of outcomes of interest in IPF patients in a real-life 
context are scanty. Nishiyama et al. [35] conducted a study on 93 IPF patients and assessed 
the pulmonary function. The mean (±SD) of FVC, FEY I, DLCO were 2.37 (±0.73) L, 1.93 
(±0.57) Land 9.19 (±3.92) mL*min-l*mmHg-1 respectively. According to the data ofa 
recently completed trial on patients with IPF by Swigris et al [37], the mean (±SD) baseline 

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6-min walked distance was 
372.9 (±82.63) meters. Regarding the most common !PF 
symptoms, clubbing, dyspnea (evaluated by means of a mMRC score 2:2), crackles and cough 
frequencies are 43%, 44%, 67% and 73% respectively [34, 35). 
Table 1 shows the two-sided 95% confidence interval (CD for expected frequency of IPF 
symptoms for a sample size n= 120 and 160, using the large sample normal approximation 
[36). 
IPF symptoms 
n=l20 
Expected 
frequency 
Clubbing 
43% 
Dyspnea (mMRC score 2:2) 
44% 
Crackles 
67% 
Cough 
73% 
n=l60 
Clubbing 
43% 
Dyspnea (mMRC score 2:2) 
44% 
Crackles 
67% 
Cough 
73% 
95%CI 
34.1% 
51.9% 
35.1% 
52.9% 
58.6% 
75.4% 
65.1% 
80.9% 
35.3% 
50.7% 
36.3% 
51.7% 
59.7% 
74.3% 
66.1% 
79.9% 
Table 1 two-sided 95% CI of expected frequency for !PF symptoms with sample sizes n=120 and 160. Cells are 
gray when the relative error - calculated as the ratio between 95% CJ half-width and expectedji-eq11ency - is 
lower than 30%. 
Table 2 shows the two-sided 95% CI for expected mean of FVC, FEVl , DLCO and 6-min 
walked distance for sample sizes of n=l20 (drop out=40%) and n=l60 (drop out=20%), 
assuming the SD reported in the table and the confidence interval is based on the large 
sample z statistic [36]. IPF is a degenerative disease, therefore it is expected a worsening of 
symptoms, lung function and exercise tolerance. However, a conservative evaluation was 
performed by taking into account the two-sided 95% confidence interval. 
Expected 
mean 
n=120 (drop out=40%) 
FVC {L) 
2.37 
FEVl (L) 
1.93 
DLCO (mL *min-I *mmHg-1) 
9.19 
6-min walked distance (m) 
372.9 
n=160 (drop out=20%) 
FVC (L) 
2.37 
FEVI (L) 
1.93 
SD 
0.73 
0.57 
3.92 
82.63 
0.73 
0.57 
95%CI 
2.24 
1.83 
8.49 
358.12 
2.26 
2.50 
2.03 
9.89 
387.68 
2.48 
1.84 
2.02 
DLCO (mL*min-1 *mmHg-1) 
9.19 
3.92 
8.58 
9.80 
6-min walked distance (m) 
372.9 
82.63 
360. I 
385.70 
Table 2 two-sided 95% CI of expected FVC, FEVl, DLCO and 6-min walked distance mean with sample sizes 
n= 120 and 160. Cells are gray when the relative error - calculated as the ratio between 95% CJ half-width and 
expected mean - is lower than 30%. 

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8.6 
DAT A MANAGEMENT 
The CROs in charge of the study is 
 
The data entered into the eCRFs by investigational staff will be reviewed for completeness 
and accuracy and the site personnel will be instructed to data entry data into the eCRFs and to 
make any required corrections or additions during the phone training. The eCRF will be 
provided by online edit checks. The Data Manager will perform the cleaning session by 
running post-entry checks by means of validation programs and data listings specific for the 
study. During this process, if clarifications are needed, the Data Manager will raise queries by 
means of data query forms through the application. Designated investigator site staff is 
required to respond to the query and make the correction to the database. 
Patients violating inclusion or exclusion criteria will not be considered for analyses. A 
description of reasons of violation will be provided anyway. After these actions have been 
completed and the database has been declared to be completed and accurate, it will be locked 
and made available for data analysis. Any changes to the database after that time can only be 
made by joint written agreement between the Medical Adviser, the Study Statistician and the 
Data Manager. Only authorized and well-documented updates to the study data will be 
possible after database lock. 
Each participating site will maintain appropriate medical and research records for this study, 
in compliance with GPP and regulatory and institutional requirements for the protection of 
confidentiality of subjects. 
Patient initials or names will not be recorded in the database: patients will be associated to a 
unique identifier, assigned as a progressive number within each site. Due to the observational 
nature of the study no independent review of the data will be performed. 
Data access rules, as well as data transfer to Sponsor, will be detailed in the Data 
Management Plan. 
8.7 
DATA ANALYSIS 
The statistical analysis will be performed on all evaluable patients who enter the study and 
meet the inclusion criteria. Patients with missing values will not be excluded from the 
analysis, their data will not be replaced; frequency of missing data will be given for all 
analyzed variables. 
Descriptive analysis will be composed of means, medians, quantiles, proportions (with their 
respective 95% confidence intervals, CI) and contingency tables according to the nature of 
the variables. As a dispersion measurement the standard deviation and the interquartile range 
will be calculated. All events during follow-up will be described as incidence rates with 95% 
CI. 
Statistical analysis will be performed using the SAS software. 
The study objectives will be evaluated as follows: 
Primary objective 

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To describe the clinical course of/PF during 12 months of observation 
At each follow up visit the frequency of IPF symptoms (cough, fatigue, dizziness, chest pain, 
clubbing, bibasilar crackles) will be provided and the variation between visits will be 
described too mostly in terms of incident and worsening symptoms. Moreover, the score of 
the Modified Medical Research Council Dyspnea Scale for the evaluation of dyspnea at each 
follow up visit will be calculated together with the variation since baseline and between 
follow up visits. 
The following outcomes will be also considered during the 12-month observation: lung 
function parameters (like VC, FVC, FEVl , TLC, DLCO, p02, pC02; Sa02, Pa02 and 
PaC02 at rest) and patient's exercise capacity (evaluated by means of 6-minute walked 
distance test, if available). The outcomes will be described at each follow up by means of 
descriptive statistics and the variation between visits will be provided too. 
Secondary objectives 
#1 Description of /PF patients at enrollment (socio-demographic data, /PF risk factors, 
comorbidities, disease severitv a11d manifestatio11, methods (or diagnosis, treatment 
modalities) 
IPF patients enrolled at baseline will be described in te1ms of socio-demographic variables 
(e.g. age, gender, race, body mass index, educational degree, and employment status) and 
potential IPF risk factors (such as smoking habits, environmental exposure, drug exposure, 
other factors). 
The absolute and relative frequency distributions of patients (N, %) according to ongoing 
comorbidities (such as 
gastroesophageal reflux disease, pulmonary hypertension, 
emphysema, lung cancer, coronary heart disease, depression) will be also provided at 
baseline. 
Treatment modalities will be described at each visit by means of frequency distribution of 
patients according to ongoing therapies for IPF; pharmacological (such as steroids, 
anticoagulants, 
irnmunomodulators, 
N-acetylcysteine, 
pirfenidone, 
etc .. ) 
and 
non-
pharmacological (such as long term oxygen and pulmonary rehabilitation) therapies will be 
considered and described in terms of drug, dosage regimen and duration/number of sessions 
(including start and stop dates). The frequency of patients on listing for lung transplantation 
at baseline will be also provided. 
 
 
 
 
 
 
 
#2 To describe the frequency of exacerbations during 12 months of observation 
The proportion of patients with at least one exacerbation after 12 months of observation will 
be computed as the ratio between the number of patients with one or more episodes of 

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exacerbation occurred during 12 months of follow up over the total number of evaluable 
patients. Patients who drop-out without having exacerbations before the end of the study, will 
be considered in the denominator of the proportion of interest. The median number of 
episodes of exacerbation per patient will be provided. Finally time to first exacerbation will 
be analyzed by Kaplan-Meier curves. 
#3 To describe the HRQoL variation during 12 months of observation 
The digits for EQ-SD-SL 5 dimensions can be combined in a 5-digit number describing the 
respondent's health state. An appropriate algorithm will be used to summarize data in an 
overall score ranging from -1 (worse-than-death health status) to 1 (best health status) [38, 
48]. 
The descriptive statistics will be produced for EQ-SD-SL descriptive system index and VAS 
. Moreover, the difference of scores between baseline and available follow up visits will be 
calculated too. 
Similarly, the descriptive statistics of St. Georges Respiratory Questionnaire scores 
(symptoms, activity and impacts and total score) will be calculated. The St. Georges 
Respiratory Questionnaire is a self-completed questionnaire for measuring impaired health in 
patients with chronic lung disease. The descriptive statistics of weighted single scores 
(symptoms, activity and impacts and total score) will be calculated. Graphs of mean HRQoL 
scores according to visits will also be provided to show the trend of variation, if any. 
#4 To describe health care sector-related costs during 12 months of observation 
In order to describe health care sector-related costs at diagnosis and from diagnosis up to the 
end of 12-month follow-up according to the INHS point of view, a two steps approach will be 
followed: (i) first of all the resource consumption since diagnosis will be collected or 
estimated and then (ii) a monetary value will be assigned to the collected or estimated 
resource consumption. 
(i) Health care resource consumption exclusively related to both IPF and !PF-related adverse 
events will be computed during observational period in terms of pharmacological and non-
pharmacological treatments, number of (inward and day-hospital) hospitalizations, number of 
emergency room visits, number of General Practitioner visits, laboratory tests or 
examinations (spirometry, BAL, saturation), number of imaging sessions. Health care 
resources consumed during a three-month span of time between date of diagnosis and 
inclusion in the study will be retrospectively collected via an ad hoc section of the case report 
form (CRF) and/or estimated. 
(ii) In order to estimate the economic impact on health care sector-related costs of the above 
mentioned 
health services (hospital 
admissions, 
v1s1ts, treatments, 
examinations) 
consumption, a monetary value to each event recorded will be assigned, as defined by the 
Italian Ministry of Health through the tariff in force for outpatient setting [28]. The cost of 
hospitalization will be valued according to the most recent available diagnosis-related group 
(DRG) tariffs; finally pharmacological treatments will be costed at consumer price. 

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All costs will be expressed in €. A monthly (or yearly) cost will be provided by taking into 
account patients according to duration of observation and parametrizing each patient to the I -
year observation period. 
Cost of Illness (COi) will be analyzed via descriptive statistics (mean; standard deviation; 
median; minimum and maximum). 
Non-parametric bootstrap method will be applied to COi data for calculating 95% confidence 
intervals. 
8.8 
QUALITY CONTROL 
The Quality control will be managed in accordance with 
 procedures as 
agreed with BITSP A. 
8.8.1 
STUDY MONITORING 
On site and remote monitoring will be performed by 
 who has been 
designated by BITSP A. 
It is understood that the monitor(s) will contact and/or visit the Investigator/centre before the 
study start up, regularly throughout the study and after the study data collection will have 
been completed, and that they will be permitted to inspect the various study records: eCRFs, 
filled questionnaire, Investigator study file and source data (source data is any data that is 
recorded elsewhere to the eCRFs), provided that subject confidentiality is respected. 
The purposes of these visits/phone contacts are: 
• 
to assess the progress of the study; 
to review compliance with the study protocol; 
to discuss any emerging issue; 
• 
to check the eCRFs for accuracy and completeness; 
to validate the contents of the eCRFs against the source documents (only by on side 
visits). 
Prior to each on site monitoring visit, the Investigator or staff will record all data generated 
since the last visit on the eCRFs. The Investigator and/or study staff will be expected to be 
available for at least a portion of the monitoring visit to answer questions and to provide any 
missing information. 
During each remote monitoring contact, the Investigator or staff will will be expected to be 
available for the phone call to answer questions and to provide any missing information. 

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8.8.2 
GUIDELINES FOR EPIDEMIOLOGICAL STUDIES 
The guidelines for Good Pharmacoepidemiology Practices (GPP) in non-interventional 
studies as well as recommendations for non-interventional study and principles of 
epidemiology studies will be respected [ 4 7]. This study is not in the scope of Good Clinical 
Practice (GCP) studies, but for several applicable aspects it will be managed according to it. 
8.8.3 
CONFIDENTIALITY OF STUDY DOCUMENTS AND SUBJECT 
RECORDS 
All study documents are provided by the Sponsor to the Investigator and his/her appointed 
staff in confidence. None of this material may be disclosed to any party not directly 
involved in the study without written permission from BITSP A. 
The Investigator must assure that the subject's anonymity will be maintained. The 
Investigator will keep a separate list with at least the initials, the subject's study numbers, 
names and telephone numbers. The Investigator will maintain this for the longest period of 
time allowed by his/her own institution and, in any case, until further communication from 
BITSPA. 
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available. Only the subject 
number will be recorded in the case report form. Study findings stored on a computer will be 
stored in accordance with local data protection laws. 
The investigators will maintain a list to enable subjects' records to be identified. However, if 
the results of the study are published, the subject's identity will remain confidential. 
Personal data - including sensitive data - collected during the execution of the activities will 
be processed in accordance with the local laws on data protection. 
8.8.4 
INVESTIGATOR'S FILES I RETENTION OF DOCUMENTS 
The Investigator must maintain adequate and accurate records to enable the conduct of this 
cohort study and the study data to be subsequently verified. These documents should be 
classified into two different separate categories ( 1) Investigator's Study File, and (2) subject 
clinical source documents. 
The Investigator's Study File will contain the observational protocol study/amendments, 
EC/IRB approval with correspondence, sample informed consent, staff curriculum vitae and 
authorization forms and other appropriate documents/correspondence etc. 
Subject clinical source documents would include subject hospital/clinic records, physician's 
and nurse's notes, appointment book, original laboratory reports, pathology and special 
assessment reports, signed informed consent and privacy forms, consultant letters and 
subject screening and enrollment logs. The Investigator must keep these two categories of 
documents on file according to local regulations after completion or discontinuation of the 

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study. After that period of time the documents may be destroyed, subject to local 
regulations. 
Should the Investigator wish to assign the study records to another party or move them to 
another location, BITSP A must be notified in advance. 
8.8.5 
LIMITATIONS OF THE RESEARCH METHODS 
This is a descriptive epidemiological study which puts patients under observation for one 
year prospectively. However information, selection and/or recall bias have to be taken into 
account, as in all epidemiological studies. 
Investigators could select patients in order to enroll those ones who most probably will be 
followed up (selection bias). In order to limit this bias, monitoring visits could be randomly 
performed in sites to verify whether enrolment was performed consecutively. 
Recall bias could mostly affect healthcare resources consumption: this is the reason why it 
will be evaluated during prospective phase on a regular basis. The information are usually 
recorded in medical charts or there are questionnaires filled in during visit: this also should 
limit bias of information. 
As regards confounding, the aim of the study is descriptive, i.e. no causality nor associations 
to treatments will be evaluated. It has to be kept in mind that the study regards a relatively 
rare, fast progressing disease, rare outcomes and a very heterogeneous patient population. 
As far as generalizability of results, the study aims to provide information on IPF patients 
enrolled in the study; it does not mean to be generalized to all Italian IPF patients because 
sites are selected. In order to avoid patient selection during recruitment, sampling is based on 
consecutive enrolment. 
In order to validate the CRF content a qualitative pre-test will be performed, by simulating 
data capture during study conduction. 
As far as recognizing IPF in clinical practice can be challenging as symptoms often appear 
similar to those of more common diseases, such asthma, chronic obstructive pulmonary 
disease (COPD) and congestive heart failure. If IPF is suspected, diagnosis can be 
challenging but a multidisciplinary approach involving a pulmonologist, radiologist and 
pathologist expert in interstitial lung disease has been shown to improve the accuracy of IPF 
diagnosis. Therefore in order to maximize exposure measurement validity, all patients with 
diagnosis of IPF in the last 3 months will be enrolled. Diagnosis will be evaluated by clinical 
judgement. 
Finally, target sample size is considered to be achievable during the enrolment period on the 
basis of preliminary feasibility considerations. Anyway, due to study design and inclusion 

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criteria the number of enrolled patients is expected to be consistent with the total number of 
treated patients. 
8.9 
OTHER ASPECTS 
8.9.1 
INFORMED CONSENT, DATA PROTECTION, STUDY RECORDS 
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) and relevant BITSPA Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient. 
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. 
8.9.2 
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)/lndependent 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 according to ICH GCP and to the regulatory and legal requirements of Italy. 
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. 
The patient must be informed that his/her personal study-related data will be used by 
Boehringer lngelheim 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 I her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
lngelheim, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
8.9.3 
DATA QUALITY ASSURANCE 
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor's designees or by IRBs/IECs or by regulatory authorities. The quality assurance 

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auditor will have access to all medical records, the investigator's study-related files and 
correspondence, and the informed consent documentation of this study at any time according 
to the Sponsor's Standard Operating Procedures, in order to verify whether the study is being 
conducted in agreement with GPP. 
The Investigators and Institution must permit study-related monitoring, audits, IRBs/IECs 
review or regulatory inspection, providing direct access to source data/documents. 
8.9.4 
RECORDS 
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on 
paper or via remote data capture. 
8.9.5 
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 
8.9.6 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
The investigator I institution will permit study-related monitoring, audits, IRB /!EC review 
and regulatory inspection, providing direct access to all related source data I 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. FDA). The Clinical Research 
Associate (CRA) I on site monitor 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 
8.9.7 
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. 

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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 I IEC and the regulatory authorities. 
8.9.8 
COMPLETION OF STUDY 
The IRB/IEC/competent authority in Italy will be notified about the end of the study (date of 
termination of observational study, last patient patient out date, number of patients observed) 
or early termination of the observation. 
8.9.9 
PROTOCOL VIOLATIONS 
Not applicable 
8.9.10 
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY 
Not applicable 

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9. 
PROTECTION OF HUMAN SUBJECTS 
This study was designed and shall be implemented and reported in accordance with the Guide 
on Methodological Standards in Pharmacoepidemiology (Revision 3, July 2014) of the 
European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), 
the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) 
guidelines, with the ethical principles laid down in the Declaration of Helsinki and with the 
laws and regulations of Italy in which the research is carried out, whichever affords the 
greater protection of the individual. 
The study will be notified to the Health Authority according to the legal requirements in Italy 
as unique participating country. 
Subjects selection will not start before the approval of the EC/IRB and notification of the 
study to the Health Authority. This study does not include treatments or diagnostic 
examinations other than those prescribed in the ordinary clinical practice, therefore no 
insurance agreements are applicable. 

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10. 
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS 
10.1 
DEFINITIONS OF ADVERSE EVENTS 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any unfavourable 
and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Adverse reaction 
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. 
Adverse Event of Special Interest (AESI) 

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Proprietary confidential infonnation 0 2015 Boehringer Jngelheim International GmbH or one or more of its affiliated companies 
The term AES! 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. 
10.2 
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 authorization. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BITSPA 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 for the BITSP A product administered for the 
disease in scope of the study: 
all ADRs (serious and non-serious), 
all AEs with fatal outcome , 
all pregnancies 
All AD Rs, 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 

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• 
• 
• 
• 
• 
• 
The event is known to be caused by or attributed to the drug class . 
A plausible time to onset of the event relative to the time of drug exposure . 
Evidence that the event is reproducible when the drug is re-introduced 
No medically sound alternative etiologies that could explain the event (e.g . 
preexisting or concomitant diseases, or co-medications). 
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome). 
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished). 
Arguments that may suggest that there is no reasonable possibility of a causal 
relationship could be: 
• 
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned) 
• 
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). 
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger. 
• 
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned). 
• 
Disappearance of the event even though the study drug treatment continues or remains 
unchanged. 
Intensity of adverse event 
The intensity of the AE should be judged based on the following: 
Mild: 
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe: 
Incapacitating or causing inability to work or to perform usual activities 
Pregnancy: 
In rare cases, pregnancy might occur in a study. Once a subject, has been enrolled into the 
study after having taken the BITSPA drug taken for the disease in scope of 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 
Expedited Reporting of AEs and Drug Exposure During Pregnancy 

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The following must be reported by the investigator on the NIS AE form (or pregnancy 
monitoring form if applicable) from signing the informed consent onwards until the end of 
the study for the BITSPA product administered for the disease in scope of the study: 
Type of Report 
Timeline 
All SADRs 
immediately within 24 hours 
All AEs with fatal outcome 
immediately within 24 hours 
All non-serious ADRs 
7 calendar days 
All pregnancies 
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 BITSP A drug 
The investigator is encouraged to report all adverse events related to any BITSPA drug other 
than the BITSP A drug taken for the disease in scope of the study 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. 
10.3 
REPORTING TO HEATH AUTHORITIES 
Adverse event reporting to regulatory agencies will be done by the MAH according to local 
and international regulatory requirements. Also the investigator is encouraged to report all 
adverse event related to any drug to LHA according to local regulatory requirements. 

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11. 
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS 
The end of the data collection (including the follow-up period) for this observational study is 
expected within 2018, depending on the enrolment period necessary to collect data from at 
least two hundred patients. 
The final study report should be submitted as soon as possible within 12 months of the end of 
data collection. 
The final study report, including the statistical and clinical evaluations, shall be prepared and 
sent to the Advisory Board, for agreement and signature. 
At the end of the study a summary of the final study report will be provided to all ECs/IRBs, 
to the Italian Competent Authority, only if requested, and to Investigators. 
BITS PA is entitled to publish and/or present any results of this study at scientific meetings; 
BITSPA furthermore reserves the right to use such data for industrial purposes. 
Investigators will inform the Advisory Board and BITSPA before using the results of the 
study for publication or presentation, and agree to provide the Sponsor with a copy of the 
proposed presentation. Data from individual study sites shall not be published separately 
before main study paper based on global data collected will be published. 
11.1 
OPERATIVE MANAGEMENT OF MEDICAL WRITING ASPECTS 
The results of this study will be published or presented at scientific meetings. Participant 
Investigator agrees to submit all manuscripts or abstracts to BITSPA prior to submission. 
This allows the sponsor to protect proprietary information and to provide comments based on 
information from other studies that may not yet be available to the Investigator. 
In accordance with standard editorial and ethical practice, BITSPA will generally support 
publication of multicenter studies only in their entirety and not as individual center data. In 
this case, the Study Advisory Board will be designated. 
The investigator has to provide the sponsor all data derived by the investigator from the 
study. During the study, only the sponsor may make study information available to other 
study investigators or to regulatory agencies, except as required by law or regulation. Except 
as otherwise allowable in the clinical study site agreement, any public disclosure (including 
publicly accessible websites) related to the protocol or study results, other than study 
recruitment materials, is the sole responsibility of the sponsor. 
Manuscript authorship for any peer-reviewed publication will appropriately reflect 
contributions to the production and review of the document. All publications and 
presentations must be prepared in accordance with this section and the Study Site Agreement, 
which has to be written consequently. 

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Proprietary confidential information 0 2015 Boehringer lngelheim International GmbH or one or more of its affiliated companies 
BITSP A also adheres to any additional standards concerning authorship required by a 
specific journal or congress to which the publication is submitted. The responsible 
individuals at BISPA apply, at a minimum, the following criteria to determine who is named 
as an author on a publication: 
• 
Substantial contributions to the concept and design, acquisition of data, or analysis 
and interpretation of data 
• 
Drafting of the publication or revising it critically for important intellectual content 
• 
Final approval of the version to be published 
• 
Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
Authorship criteria and obligations apply equally to BITSPA employees and non-employees. 
Each listed author must have participated in the work enough to take public responsibility for 
appropriate portions of the content. 
Individuals contributing to the publication but not meeting authorship criteria may be 
appropriately acknowledged in the publication. 
11.2 
GHOSTWRITING AND GUEST/GHOST AUTHORSHIP 
Ghostwriting, guest authorship, and ghost authorship are strictly prohibited. The contribution 
of a writer, which, when performed under the direction of the author(s), is considered a form 
of specialized, technical assistance, is acknowledged in the earliest draft in which the writer is 
involved. 
11.3 
DETERMINING ORDER OF AUTHORSHIP 
Author order is determined by mutual agreement at the earliest possible time, with due 
consideration to overall contributions to the study, to the publication, or to scientific 
knowledge of the subject matter. 

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12. 
REFERENCES 
12.1 
PUBLISHED REFERENCES 
I. Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic 
Pulmonary Fibrosis. An official A TS/ERS/JRS/ ALA T statement: idiopathic pulmonary 
fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit 
Care Med. 2011; 183(6): 788-824. 
2. 
American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. 
International consensus statement. American Thoracic Society (A TS), and the European 
Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664. 
3. 
Bjoraker JA, Ryu JH, Edwin MK, Myers JL, Tazelaar HD, Schroeder DR, Offord KP 
( 1998). Prognostic significance of histopathologic subsets in idiopathic pulmonary 
fibrosis. Am J Respir Crit Care Med. 157 (1): 199- 203. 
4. 
King, TE Jr., Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole 1, Glassberg MK, 
Gorina E, Hopkins PM, for the ASCEND Study Group. 2006. Classification and natural 
history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc. 3 (4): 285-292. 
5. Flaherty KR, King TE, Raghu G, Lynch JP, Colby TV, Travis WD, Gross BH, 
Kazerooni EA, et al. 2004. Idiopathic interstitial pneumonia: what is the effect of a 
multidisciplinary approach to diagnosis?. Am J Respir Crit Care Med. 170 (8): 904-910. 
6. 
Flaherty KR, Andrei AC, King TE Jr, Raghu G, Colby TV, Wells A, Bassily N, Brown 
K, et al. 2007. Idiopathic interstitial pneumonia: do community and academic physicians 
agree on diagnosis?. Am J Respir Crit Care Med. 175 (I 0): 1054-1060 
7. 
Meltzer EB, Noble PW. Idiopathic pulmonary fibrosis. Orphanet J Rare Dis 2008; 3: 8. 
8. Lamas DJ, Kawut SM, Bagiella E, et al. Delayed access and survival in idiopathic 
pulmonary fibrosis: a cohort study. Am J Respir Crit Care Med 2011; 184: 842-84 7. 
9. 
Nalysnyk L, Cid-Ruzafa J, Rotella P and EsserD. Incidence and prevalence of idiopathic 
pulmonary fibrosis: review of the literature. Eur Respir Rev 2012; 21: 126, 355- 361 
10. Ley B, Elicker BM, Hartman TE, Ryerson CJ, Vittinghoff E, Ryu JH, Lee JS, Jones KD, 
Richeldi L, King TE Jr, Collard HR. Idiopathic Pulmonary Fibrosis: CT and Risk of 
Death. Radiology. 2014 Nov;273(2):570-9. 
11. Behr J: The diagnosis and treatment of idiopathic pulmonary fibrosis. Dtsch Arztebl Int 
2013; 110(51-52): 875-81. 
12. Agabiti Nl , Porretta MA, Bauleo L, Coppola A, Sergiacomi G, Fusco A, Cavalli F, 
Zappa MC, Vignarola R, Carlone S, Facchini G, Mariotta S, Palange P, Valente S, 
Pasciuto G, Pezzuto G, Orlandi A, Fusco D, Davoli M, Saltini C, Puxeddu E. Idiopathic 
Pulmonary Fibrosis (IPF) incidence and prevalence in Italy. Sarcoidosis Vase Diffuse 
Lung Dis. 2014 Oct 20;31(3): 191-7. 
13. Kim DS, Collard HR, King TE Jr. Classification and natural history of the idiopathic 
interstitial pneumonias. Proc Am Thorac Soc 2006; 3: 285-292. 

Boehringer Ingelheim 
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14. Navaratnam V, Fogarty AW, Glendening R, McKeever T, Hubbard RB. The increasing 
secondary care burden of idiopathic pulmonary fibrosis: hospital admission trends in 
England from 1998 to 2010. Chest. 2013 Apr;143(4):1078-84. 
15. Ryerson CJ, Berkeley J, Carrieri-Kohlman VL, Pantilat SZ, Landefeld CS, Collard HR. 
Depression and functional status are strongly associated with dyspnea in interstitial lung 
disease. Chest 2011;139:609e16. 
16. Ley B, Collard HR.Epidemiology of idiopathic pulmonary fibrosis. Clin Epidemiol. 2013 
Nov 25;5:483-92. 
17. Tobin RW, Pope CE II, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased 
prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am 
JRespirCritCareMed 1998;158: 1804-1808. 
18. Patti MG, Tedesco P, Golden J, Hays S, Hoopes C, Meneghetti A, Damani T, Way LW. 
Idiopathic pulmonary fibrosis: How often is it really idiopathic? J Gastrointest Surg 
2005;9:1053-1056; discussion 
19. Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, Sillery JK, Pope CE 
II, Pellegrini CA. High prevalence of abnormal acid gastro-oesophageal reflux in 
idiopathic pulmonary fibrosis. Eur Respir J 2006;27: 
142. 
20. Sweet MP, Patti MG, Leard LE, Golden JA, Hays SR, Hoopes C, Theodore PR. 
Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung 
transplantation. J Thorac Cardiovasc Surg 2007; 133: 1078-1084. 
21. Lee JS, Collard HR, Raghu G, Sweet MP, Hays SR, Campos GM, Golden JA, King TE 
Jr. Does chronic microaspiration cause idiopathic pulmonary fibrosis? Am J Med 
20IO;123 :304-311. 
22. Agarwal R, Jindal SK (2008). "Acute exacerbation of idiopathic pulmonary fibrosis: a 
systematic review". Eur J Intern Med. 19 (4): 227-235 
23. Brazier et al "Testing the validity of the Euroqol and comparing it with the SF-36 Health 
Survey questionnaire", Qua! Life Res 1993; 2:169-180. 
24. Dolan P. Modeling valuations for EuroQol health states. Medical Care. 1997; 35:1095-
1108 
25. Morisky DE, Green LW, Levine OM. Concurrent and predictive validity of a self-
reported measure of medication adherence. Med Care. 1986 Jan;24(1):67-74. 
26. Morisky DE, DiMatteo MR. Improving the measurement of self-reported medication 
nonadherence: Final response. J Clin Epidemio 2011; 64:258-263. 
27. Morisky DE, Malotte CK, Choi P, et al. A Patient Education Program to Improve 
Adherence Rate with Antituberculosis Drug Regimens. Health Education Quarterly 
1990; 17:253-268. 
28. Ministero della sanita, "Nomenclatore tariffario delle prestazioni ambulatoriali" 
DM22.07.96; G.U. n° 216 del 14.09.1993 
29. Augustine S. Lee a, Isabella Mira-Avendano a, Jay H. Ryu b, Craig E. Daniels The 
burden of idiopathic pulmonary fibrosis: An unmet public health need. Respir Med. 2014 
Jul; 108(7):955-67. 

Boehringer lngelheim 
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Proprietary confidential information © 2015 Boehringer lngelheim International GmbH or one or more of its affiliated companies 
30. Nagai A, Chiyotani L. Lung cancer in patients with idiopathic pulmonary fibrosis. 
Tohoku J Exp Med. 1992Jul;167(3):231-7. 
31. Ryerson CJ, Hartman T, Elicker BM, et al. Clinical features and outcomes in combined 
pulmonary fibrosis and emphysema in idiopathic pulmonary fibrosis. Chest. 2013 
Jul; 144( 1 ):234-40. 
32. Shorr AF, Wainright JL, Cors CS, Lettieri CJ, Nathan SD. Pulmonary hypertension in 
patients with pulmonary fibrosis awaiting lung transplant. Eur Respir J. 2007 
Oct;30( 4):715-21. 
33. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of 
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006 Oct 1; 174(7):810-6. 
34. Cottin V, Nunes H, Brillet PY, et al. Groupe d' Etude et de Recherche sur les Maladies 
Orphelines Pulmonaires (GERM OP). Combined pulmonary fibrosis and emphysema: a 
distinct underrecognised entity. Eur Respir J. 2005 Oct;26(4):586-93. 
35. Nishiyama 0, Taniguchi H, Kondoh Y, et al. A simple assessment of dyspnoea as a 
prognostic 
indicator in 
idiopathic pulmonary fibrosis. 
Eur Respir J. 
2010 
Nov;36(5): 1067-72. 
36. Dixon, W.J., Massey, F.J. Introduction to Statistical Analysis. 4th Edition McGraw-Hill 
(1983) pp. 80-85 
37. Jeffrey J Swigris, Frederick S Wamboldt, Juergen Behr, Roland M du Bois, Talmadge E 
King, Ganesh Raghu, Kevin K Brown The 6 minute walk in idiopathic pulmonary 
fibrosis: 
longitudinal 
changes 
and 
minimum 
important 
difference 
Thorax 
2010;65: l 73el 77. doi: 1O.ll36/thx.2009.113498 
38. EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of 
life. Health Policy. 1990Dec;16(3): 199-208. 
39. Jones PW. St. George's Respiratory Questionnaire: MCID. Copd. 2005;2: 75-9 I Jones P, 
Lareau S, Mahler DA. Measuring the effects of COPD on the patient. Respir Med. 
2005;99 Suppl B:Sl 1-8 
40. Jones PW, Quirk FH, Baveystock CM. The St George's Respiratory Questionnaire 
Respir Med 1991 ;85(Suppl B):25-3 l . 
41. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure for 
chronic airflow limitation - the St George's Respiratory Questionnaire. Am Rev Respir 
Dis 1992;145:1321-7. 
42. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr 
Scand 1983;67:361-70. 
43. Herrmann C. International experiences with the Hospital Anxiety and Depression 
Scale-a review of validation data and clinical results. J Psychosom Res 1997;42: 17-41. 
44. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the 
Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients 
with chronic obstructive pulmonary disease. Thorax l 999;54:581-6. 
45. Bourbeau J, Ford G, Zackon H, Pinsky N, Lee J, Ruberto G. Impact on patients' health 
status following early identification of a COPD exacerbation. Eur Respir J 2007;30:907-
13. 

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46. de Torres JP, Pinto-Plata V, Ingenito E, Bagley P, Gray A, Berger R, Celli B. Power of 
outcome measurements to detect clinically significant changes in pulmonary 
rehabilitation of patients with COPD. Chest 2002;12l:1092-8. 
47. Epstein M. International Society of Pharmacoepiderniology. Guidelines for good 
pharmacoepiderniology 
practices 
(GPP). 
Pharmacoepiderniol 
Drug 
Saf 2005 
Aug; 14(8):589-95. 
48. Scalone L., Cortesi P.A., Ciampichini R., Belisari A., D' Angiolella L.S., Cesana G., 
Mantovani L.G. Italian Population-Based Values of EQ-5D Health States VALUE IN 
HEALTH 16 (2013) 814-822 
12.2 
UNPUBLISHED REFERENCES 
Not applicable. 

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
Number 
Document 
Date 
Title 
Reference Number 
1 
1 
26th June, 2015 
List of BITSPA 
allocated Team 
2 
2 
26th June, 2015 
List of all main 
Principal 
Investigators 
participant to the 
study 
3 
3 
26th June, 2015 
List of Advisory 
Board members 
4 
4 
26th June, 2015 
List of
 
allocated Team 
5 
5 
26th June, 2015 
Assessment of IPF 
with HRCT or/and 
surgical lung 
biopsy 
6 
6 
26th June, 2015 
Approval/signature 
page 

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS 
A copy of the ENCePP Checklist for Study protocols (version 2) available at website: 
encepp.eu/standards_and_guidanceslindex.html completed and signed by the main authors of 
the study protocol should be included in Annex 2. 
The checklist will facilitate the review of the protocol and evaluation of whether investigators 
have considered important methodological aspects. 
In question 9.5 of the Checklist, Revision 1: 
"Study start" means "Start of data collection " 
"Study progress" means "Progress report(s)" 
"Study completion " means "End of data collection" 
"Reporting" means "Final report of the study results" 

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ANNEX 3. ADDITIONAL INFORMATION 
None.