A Multicentre, Retrospective Chart Review Study to Describe the Clinical Profile of Idiopathic Pulmonary Fibrosis (IPF) Patients Treated With Nintedanib (OFEV®) in Real-world Practice in Spain.
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-124_RD-01 (4.0)
Protocol for non-interventional studies based on existing data
TITLE PAGE
Document Number:
c17367432-01
BI Study Number:
1199-0295
BI Investigational
Product(s):
Nintedanib (OFEV®)
Title:
A multicentre, retrospective chart review study to describe the 
clinical profile of idiopathic pulmonary fibrosis (IPF) patients 
treated with nintedanib (OFEV®) in real-world practice in Spain.
Protocol version 
identifier:
1.0
Date of last version of 
protocol:
11 May 2017
PASS:
No
EU PAS register 
number:
Not yet available
(study will be registered in EU PAS Register (ENCePP) and
clinicaltrials.gov)
Active substance:
Anatomical main group: L - Antineoplastic and 
immunomodulating agents
Therapeutic subgroup: L01 - Antineoplastic agents
Pharmacological subgroup: L01X - Other antineoplastic agents
Chemical subgroup: L01XE - Protein kinase inhibitors
Chemical substance: L01XE31 - Nintedanib
Medicinal product:
Nintedanib
Product reference:
EU/1/14/979
Procedure number:
EMEA/H/C/003821
Joint PASS:
No
Research question and 
objectives:
The present study has been designed to characterize IPF patients 
treated with nintedanib (OFEV®), at time of treatment initiation,
with respect to their clinical profile based on real-world data 
from January 2016 in Spanish Pulmonology Services. 
The primary objective of the study is to describe the distribution 
of patients across different lung function categories (%FVC and 
DLCO serving as surrogate markers for IPF severity) of IPF 
patients at the time of treatment initiation with nintedanib 
(OFEV®) in routine clinical practice.
The secondary objectives are:

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Protocol for non-interventional studies based on existing data
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001-MCS-90-124_RD-01 (4.0)
-
To 
describe 
demographic 
and 
clinical 
baseline 
characteristics of IPF patients at time of  treatment initiation 
with nintedanib (OFEV®)
-
To describe comorbidity prevalence at time of treatment 
initiation
-
To describe the distribution of patients across different lung 
function categories based on reimbursement threshold (FVC 
>80%, 50-80%, and <50%)
Country(-ies) of study:
Spain
Author:
(Trial Clinical Monitor)
Mobile:
Marketing authorisation 
holder(s):
MAH:
Boehringer Ingelheim International GmbH
Binger Straße 173
55216 Ingelheim am Rhein
This study is initiated, managed and sponsored by:
EU-QPPV:
Not applicable
Signature of EU-
QPPV:
Not applicable
Date:
11 May 2017
Page 2 of 41
Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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Protocol for non-interventional studies based on existing data
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001-MCS-90-124_RD-01 (4.0)
1.
TABLE OF CONTENTS
TITLE PAGE......................................................................................................... 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 6
4.
ABSTRACT........................................................................................................... 7
5.
AMENDMENTS AND UPDATES..................................................................... 11
6.
MILESTONES..................................................................................................... 12
7.
RATIONALE AND BACKGROUND................................................................ 13
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 15
9.
RESEARCH METHODS .................................................................................... 16
9.1
STUDY DESIGN............................................................................................ 16
9.2
SETTING........................................................................................................ 16
9.3
VARIABLES .................................................................................................. 16
9.3.1
Exposures ................................................................................................ 17
9.3.2
Outcomes................................................................................................. 17
9.3.2.1
Primary outcomes..................................................................................17
9.3.2.2
Secondary outcomes..............................................................................18
9.3.3
Covariates................................................................................................ 18
9.4
DATA SOURCES........................................................................................... 19
9.5
STUDY SIZE.................................................................................................. 19
9.6
DATA MANAGEMENT................................................................................ 20
9.7
DATA ANALYSIS......................................................................................... 20
9.7.1
Main analysis........................................................................................... 21
..................................................................................... 21
9.8
QUALITY CONTROL................................................................................... 21
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 22
9.10
OTHER ASPECTS ......................................................................................... 22
9.11
SUBJECTS...................................................................................................... 23
9.11.1
Withdrawal criteria.................................................................................. 23
9.12
BIAS................................................................................................................ 23
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 24

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11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 26
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 26
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 27
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 29
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY 
RESULTS............................................................................................................ 30
13.
REFERENCES .................................................................................................... 31
13.1
PUBLISHED REFERENCES......................................................................... 31
13.2
UNPUBLISHED REFERENCES................................................................... 32
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 33
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 34
ANNEX 3. ADDITIONAL INFORMATION.............................................................. 41

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001-MCS-90-124_RD-01 (4.0)
2.
LIST OF ABBREVIATIONS
6MWT
6 Minutes Walking Test
!"#$%
!&'()*+ ",-+./0+ 1' #'1*)+2'(3/, 
4 $5/16)3/, %+(*3+5*/,
78
7/'95*(&'5 8(&'09'*2
:!
:/2-'3'(3 !639/5*34
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
CRO
Contract Research Organization
eCRF
Electronic Case Report Form
DILD
Diffuse Interstitial Lung Disease
DLCO
Diffusing Capacity of the Lungs for Carbon Monoxide
DMP
Data Management Plan
EDC
Electronic Data Capture
"; <=$$>
"65/-'+( =6+0*?*'1 $'5,/( ?/5 $9+52+)/@*&*0+()'
FEV1
Forced Expiratory Volume in 1 second
FVC
Forced Vital Capacity
A$> :B:
A0/C+0 $9+52+)/@*&*0+()' :0*(*)+0 B5*+0 ://51*(+3/5
HRCT
High-resolution Chest Tomography
IEC
Independent Ethics Committee
IPF
Interstitial Pulmonary Fibrosis
D:E
:+5C/( #/(/F*1' 
B5+(,?'5 :/'??*)*'(3
G$>#
G/)+0 $9+52+)/@*&*0+()' #+(+&'5
#!H
#+5I'3*(& !639/5*J+3*/( H/01'5
2#K:
#/1*?*'1 #'1*)+0 K','+5)9 :/6()*0
L8%
L/( <8(3'5@'(3*/(+0 %3614
%!$
%3+3*,3*)+0 
!(+04,*, $0+(
%M
%3+(1+51 M'@*+3*/(
%2$:
%622+54 /? $5/16)3 :9+5+)3'5*,3*),
%E$
%3+(1+51 E-'5+3*(& $5/)'165'
%M
%3+(1+51 M'@*+3*/(
BD8 
B45/,*(' I*(+,' *(9*C*3/5
;8$
;,6+0 8(3'5,3*3*+0 $('62/(*+

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Protocol for non-interventional studies based on existing data
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001-MCS-90-124_RD-01 (4.0)
3.
RESPONSIBLE PARTIES
Team Member Medical Affairs
Medical Advisor
Medical 
Trial Clinical Monitor
Coordinator Investigator
Coordinator Investigator

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001-MCS-90-124_RD-01 (4.0)
4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
OFEV®
Name of active ingredient:
Nintedanib
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
11 May 2017
1199-0295
1.0
Not applicable
Title of study:
A multicentre, retrospective chart review study to describe the clinical
profile of idiopathic pulmonary fibrosis (IPF) patients treated with 
nintedanib (OFEV®) in real-world practice in Spain.
Rationale and 
background:
Nintedanib (OFEV®) is a small molecule tyrosine kinase inhibitor 
(TKI) that targets growth factor receptors, which have been shown to 
be involved in the mechanisms by which pulmonary fibrosis occurs.
Nintedanib (OFEV®) has been reimbursed for IPF in Spain on 
December 2015. There is no available data on its use in routine clinical 
practice after its marketing authorization.
Research question 
and objectives:
The present study has been designed to characterize IPF patients 
treated with nintedanib (OFEV®) with respect to their clinical profile 
based on real-world data from January 2016 in Spanish Pulmonology 
Services.
The primary objective of the study is to describe the distribution of 
patients across different lung function categories (%FVC and DLCO 
serving as surrogate markers for IPF severity) of IPF patients treated 
with nintedanib (OFEV®) in routine clinical practice, at the time of 
treatment initiation.
As no established severity grading exists, the stratification published 
by Nathan et al. [9] based on pulmonary function impairment and 
survival differences will be applied in the study.
Patients will be classified with regards to the FVC and DLCO serving 
as surrogates for severity:
FVC:
-
Mild IPF: FVC > 70% predicted 
-
Moderate IPF: FVC 50% to 70% predicted (*)
-
Severe IPF: FVC < 50% predicted 
(*) %FVC has been adapted from 55 to 50% to be aligned with 
nintedanib (OFEV®) clinical trials program. 
DLCO:
-
Mild IPF: DLCO >50% predicted
-
Moderate IPF: DLCO 35% to 50% predicted

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Protocol for non-interventional studies based on existing data
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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
OFEV®
Name of active ingredient:
Nintedanib
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
11 May 2017
1199-0295
1.0
Not applicable
-
Severe IPF: DLCO <35% predicted
The secondary objectives are:
o
To
describe 
demographic 
and 
clinical 
baseline 
characteristics of IPF patients at time of  treatment 
initiation with nintedanib (OFEV®)
o
To describe comorbidity prevalence at time of treatment 
initiation
o
To describe the distribution of patients across different 
lung function categories based on reimbursement threshold 
(FVC>80%, 50-80%, and <50%)
Study design:
Non-interventional study based on medical charts of multiple centers, 
of IPF patients treated with nintedanib (OFEV®). Patients will be 
characterized at time of treatment initiation (cross-sectional design). 
IPF patients with a confirmed diagnosis of IPF, who initiated treatment 
with nintedanib from 01 January 2016, will be selected. 
Population:
Approximately 35 Pulmonology Services of Hospitals in Spain will be 
the basis for the study. The sites will be distributed across whole Spain 
and will be selected according to previous experience in clinical trials, 
named-patient program and access to nintedanib (OFEV®).
The participating investigators will review all medical records of their 
IPF patient’s since 01 January 2016 and select all patients who initiated 
treatment with nintedanib (OFEV®) in the study period.
Variables:
All variables will be obtained from medical records:
- IPF diagnosis: method of diagnosis, date of diagnosis, , UIP pattern 
- At nintedanib (OFEV®) initiation:
- OFEV® treatment initiation date and dose 
- Patient demographics (age, sex, race)
- Physical examination (height, weight, BMI, 6 minutes walking 
test (6MWT))
- Smoking status
- Breathlessness grade 
- Pulmonary function: %FVC, %DLCO 
- Comorbidities
- Concomitant medication 
- Previous IPF treatment with pirfenidone, if any: initiation date, 

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Protocol for non-interventional studies based on existing data
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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
OFEV®
Name of active ingredient:
Nintedanib
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
11 May 2017
1199-0295
1.0
Not applicable
end date
- Number of exacerbations due to IPF in the previous year
Data sources:
Data will be collected by the Investigator from patient medical records 
and will be entered to an electronic case report form (eCRF) which 
will include all the study variables.
Study size:
For calculating the sample size, variables on the patient's lung function 
(FVC, DLCO) will be dichotomized.
The following table illustrates the precision of estimates of the 
prevalence of a specific lung function profile within the population of 
interest depending on the observed rate of affected patients and the 
sample size. The dropout rate is assumed to be 10% for all scenarios. 
Precision is estimated based on two-sided 95% confidence intervals.
Precision table:
150
135
50.4% (68 out 
of 135)
[41.9; 58.8]
±8.5
175
158
50.0% (79 out 
of 158)
[42.2;57.8]
±7.8
It can be seen that by raising the sample size from 100 to 150 patients, 
precision improves to less than ±5% for the small proportion of 8% 
and to less than 10% for the large sample of 50%. Precision can be 
N
N 
to 
be 
analyzed
% observed in 
subsample
95% CI
Precision 
100
90
7.8% (7 out of 
90)
[2.2; 13.3]
±5.6
150
135
8.1% (11 out 
of 135)
[3.5; 12.8]
±4.7
175
158
8.2% (13 out 
of 158)
[3.9;12.5]
±4.3
100
90
50.0% (45 out 
of 90)
[39.7; 60.3]
±11.3

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001-MCS-90-124_RD-01 (4.0)
Name of company:
Boehringer Ingelheim
Name of finished medicinal 
product:
OFEV®
Name of active ingredient:
Nintedanib
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
11 May 2017
1199-0295
1.0
Not applicable
further improved to less than ±4.5% for the small sample of 8% and to 
less than 8% for the large sample of 50% if 175 patients will be 
recruited.
Planning a recruitment of 175 patients allows for an acceptable 
precision of prevalence of a specific lung function profile estimates.
Data analysis:
Since the study is essentially descriptive the variables included in the 
study objectives will be analysed with measures of central tendency 
(mean and median), variability/dispersion (standard deviation and 
interquartile ranges), absolute and relative frequencies, and ranges. 
95% confidence intervals will be provided as appropriate.
Milestones:
Planned final protocol: May 2017
Planned start of data collection: September 2017
Planned end of data collection: December 2017
Planned final study report: March 2018

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5.
AMENDMENTS AND UPDATES
None.

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
01 September 2017
End of data collection
30 December 2017
Registration in the EU PAS 
register
May 2017
Final report of study results:
March 2018

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7.
RATIONALE AND BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is one of the most frequent forms of diffuse interstitial 
lung diseases (DILD). It is defined as a limited chronic fibrosing lung interstitial pneumonia 
of unknown cause associated with radiological or pathological pattern of usual interstitial 
pneumonia (UIP). Pathogenically, it is characterized by epithelial damage with fibroblast-
myofibroblast accumulation in the alveolar spaces; repeated injury of epithelial cells leads to 
an abnormal repair, an uncontrolled proliferation of fibroblasts, and differentiation thereof 
into myofibroblasts and excessive extracellular matrix deposition in the interstitial space [1]. 
Affected patients usually show common clinical features, such as dry cough and dyspnea; the 
disease usually appears as a restrictive ventilatory defect with decreased gas transfer capacity.
IPF usually affects people over 50 years of age. Various studies have been conducted to 
evaluate the incidence and prevalence of IPF. The most reliable data estimate that in 
European countries, IPF prevalence ranged from 1.25 per 100,000 population in Belgium to 
23.4 per 100,000 population in Norway. The annual IPF incidence ranged from 0.22 per 
100,000 population in Belgium to 7.94 per 100,000 population in the UK [2]. Based on this 
data, it is believed that, in Spain, IPF could be affecting around 7500 people[3]. Although the 
natural history of IPF is highly variable, the disease is associated with a poor prognosis, and 
the median survival is around three years [4].
The first international consensus on the diagnosis and treatment of IPF was published in 
2000. This consensus recognized that the histological pattern of UIP is the one that identifies 
IPF. Moreover, in this consensus it was included a group of functional criteria defining 
disease stabilization or progression, very useful when monitoring treatment response in every 
single patient. A new consensus in 2011 [5] (updated on treatment recommendations in 2015
[6]) has better established diagnostic criteria according to the findings on high-resolution 
chest tomography (HRCT) and lung biopsy and it has established new therapeutic 
recommendations[5]. The updated recommendations included a conditional recommendation 
for use of the new agents (pirfenidone and nintedanib), and also for the use of antiacids drugs. 
Nintedanib (OFEV®) is a small molecule tyrosine kinase inhibitor (TKI), targets growth 
factor receptors, which have been shown to be involved in the mechanisms by which 
pulmonary fibrosis occurs. Most importantly, nintedanib (OFEV®) inhibits platelet-derived 
growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth 
factor receptor [7].
The clinical efficacy of nintedanib (OFEV®) was studied in patients with IPF in two trials 
with identical design phase III, randomized, double-blind, placebo-controlled (INPULSIS-1 
[8] and INPULSIS-2[7]). Patients with baseline FVC predicted less than 50% or a factor of 
transfer of carbon monoxide (DLCO, corrected for haemoglobin) provided below 30% at 

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baseline were excluded from the trials. Patients were randomized in a ratio 3:2 to nintedanib 
(OFEV®) treatment with 150 mg or placebo treatment twice daily for 52 weeks. The primary 
endpoint was the annual loss of FVC. In the INPULSIS-1 trial significant differences were 
achieved in the primary endpoint, between the placebo group (204 patients) and the 
nintedanib (OFEV®) group (309 patients), the mean±SD loss of FVC observed was-
239.9±18.71 in placebo group and -114.7±15.3 in the nintedanib (OFEV®) group (p<0.0001). 
In the INPULSIS-2 trial significant differences were achieved in the primary endpoint, 
between the placebo group (219 patients) and the nintedanib (OFEV®) group (329 patients), 
the mean±SD loss of FVC observed was -207,3±19.31 in placebo group and -113.6±15.73 in 
the nintedanib group (p<0.0001). These results led to its approval on the 15th of January 2015
by the European Commission for the treatment of IPF in adults.
On June 2014 a named-patient use (NPU) program of nintedanib started in Spain offering the 
treatment to the same type of patients than in clinical trials (%FVC>50). Afterwards, on 
September 2014, pirfenidone was available on the market in Spain, for IPF patients with FVC 
between 50-80%. Therefore, nintedanib NPU program was limited to patients not responding 
to pirfenidone, or when pirfenidone was not reimbursed (FVC >80%), or with emphysema 
and/or not clear IUP pattern. On 15 January 2015, nintedanib (OFEV®) obtained the EU 
approval for all IPF patients and NPU program in Spain was also offered to all patients 
independent of their %FVC. On December 2015, OFEV® was finally available with 
reimbursement in Spain and nintedanib NPU program ended. Compared to pirfenidone, 
nintedanib reimbursement is not restricted based on FVC% predicted level. 
There is no available data on nintedanib use in routine clinical practice. For this reason, this 
retrospective chart review is proposed to characterize clinical profile of IPF patients treated 
with nintedanib (OFEV®) during routine clinical practice in Spain.

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001-MCS-90-124_RD-01 (4.0)
8.
RESEARCH QUESTION AND OBJECTIVES
The present study has been designed to characterize IPF patients treated with nintedanib 
(OFEV®) with respect to their clinical profile based on real-world data from Spanish 
Pulmonology Services. 
The primary objective of the study is to describe the distribution of patients across different 
lung function categories (%FVC and DLCO serving as surrogate markers for IPF severity) of 
IPF patients treated with nintedanib (OFEV®) in routine clinical practice, at the time of 
treatment initiation.
As no established severity grading exists, the stratification published by Nathan et al. [9]
based on pulmonary function impairment and survival differences will be appli
ed in the study: 
FVC:
-
Mild IPF: FVC > 70% predicted 
-
Moderate IPF: FVC 50% to 70% predicted (*)
-
Severe IPF: FVC < 50% predicted 
(*) %FVC has been adapted from 55 to 50% to be aligned with nintedanib (OFEV®) clinical trials program. 
DLCO:
-
Mild IPF: DLCO >50% predicted
-
Moderate IPF: DLCO 35% to 50% predicted
-
Severe IPF: DLCO <35% predicted
The secondary objectives are:
1.- To describe demographic and clinical baseline characteristics of IPF patients at time of 
treatment initiation with nintedanib (OFEV®)
2.- To describe comorbidity prevalence at time of treatment initiation
3.- To describe the distribution of patients across different lung function categories based on 
reimbursement threshold ( FVC >80%, 50-80%, and <50%)

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001-MCS-90-124_RD-01 (4.0)
9.
RESEARCH METHODS
9.1
STUDY DESIGN
This non-interventional study, based on medical charts, will be conducted in approximately 
35 Pulmonology Services of Hospitals in Spain. IPF patients will be characterized at time of 
nintedanib initiation (cross-sectional study design).
The participating investigators will review their IPF patient’s medical records since 01 
January 2016 up to the end of data collection date and identify all IPF patients who initiated 
nintedanib (OFEV®) during that time. To minimize selection bias, a simple randomization 
will be applied. The Investigator will share an anonymized list of all of 
 patients who meet 
selection criteria with the CRO. The list will include the minimum patient data to be 
identifiable by the investigator, for example, age, gender and treatment initiation date. Then,
CRO will generate a random sequence of the 5 patients to be included and will inform the 
Investigator.
As this is a non-interventional study, designed to reflect real-world clinical practice, the 
decision to start treatment with OFEV® is prior to and independent of the selection of the 
patient in the study and based on routine clinical practice and medical judgment criteria. In 
addition, no intervention, either diagnostic or therapeutic, will be applied to patients other 
than that used for routine clinical practice. 
9.2
SETTING
Approximately 35 Pulmonology Services of Hospitals in Spain will be the source of data 
collection. Sites will be selected according to previous experience in clinical trials, NPU 
program, and access to nintedanib (OFEV®).
9.3
VARIABLES
The following variables will be obtained from the patient medical records:
-
IPF diagnosis: method of diagnosis, date of diagnosis, , UIP pattern (according to 
international guideline, Raghu et al. 2011)
-
At nintedanib (OFEV®) initiation:

OFEV® treatment initiation date and dose 

Patient demographics (age, sex, race)

Physical examination (height, weight, BMI, 6 minutes walking test (6MWT))

Smoking status (current smokers, former smokers and never smokers)

Breathlessness grade mMRC [10]

Pulmonary function: %FVC, %DLCO

Concomitant medication (active substance, dose, initiation date, indication)

Previous IPF treatment with pirfenidone, if any: dose, initiation date, end date

Number of exacerbations due to IPF in the previous year

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
Comorbidities (Pulmonary infection, Emphysema (combined pulmonary fibrosis and 
emphysema), Pulmonary hypertension, Lung cancer, Gastroesophageal reflux, 
Cardiovascular diseases, Hypertension, Dyslipidemia, Diabetes mellitus, Obstructive 
sleep apnoea, Other)
9.3.1
Exposures
Patients in this study will have been prescribed nintedanib (OFEV®) treatment for their IPF
on or after 01 January 2016. Prescription of the treatment will have been done under the sole 
responsibility of the healthcare professional. The date of treatment initiation and the dose will 
be assessed. 
In Spain, nintedanib (OFEV®) is on the market since December 2015, however, in some 
regions of the country, nintedanib is only reimbursed in a limited type of IPF patients (for 
example, with a %FVC between 50% and 80% or just >50%), although the indication of local 
label include all type of IPF patients, independent of their pulmonary function.
9.3.2
Outcomes
9.3.2.1
Primary outcomes
The primary outcome of the study is the distribution of patients across different lung function 
categories (%FVC and DLCO serving as surrogate markers for IPF severity) of IPF patients 
at the time of treatment initiation with nintedanib (OFEV®) in routine clinical practice.
As no established severity grading exists, the stratification published by Nathan et al. [9]
based on pulmonary function impairment and survival differences will be applied. 
Patients will be classified with regards to the FVC and DLCO serving as surrogates for
severity:
FVC:
-
Mild IPF: FVC > 70% predicted
-
Moderate IPF: FVC 50% to 70% predicted (*)
-
Severe IPF: FVC < 50 % predicted
(*) %FVC has been adapted from 55 to 50% to be aligned with nintedanib (OFEV®) clinical 
trials program.
DLCO:
-
Mild IPF: DLCO >50% predicted
-
Moderate IPF: DLCO 35% to 50% predicted
-
Severe IPF: DLCO <35% predicted

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The study outcomes are defined as follows:
-
FVC is the total amount of air exhaled during the lung function test % predicted). 
-
DLCO is the extent to which oxygen passes from the air sacs of the lungs into the 
blood (% predicted).
9.3.2.2
Secondary outcomes
To describe demographic and clinical baseline characteristics of IPF patients at time of 
treatment initiation with nintedanib (OFEV®).
Descriptive statistics will be provided for the following variables:
-
IPF diagnosis: frequency of each method of diagnosis (SLB, HRCT), mean duration of 
the disease from diagnosis to treatment initiation, frequency of patients with associated 
emphysema, frequency of patients with UIP pattern (according to international guideline, 
Raghu et al. 2011)
-
At nintedanib (OFEV®) initiation:

OFEV® treatment initiation date and frequency of each dose 

Patient demographics (age, male and female, race)

Physical examination ( height, weight, BMI, mean distance of the 6 minutes walking 
test (6MWT))

smoking status (current smokers, former smokers and never smokers)

breathlessness grade mMRC [10]

concomitant medication (active substance, dose, initiation date, indication)

Mean Number and frequency of exacerbations due to IPF in the previous year
To describe comorbidity prevalence at time of treatment initiation: frequency of each 
comorbidity.
-
Comorbidities (Pulmonary infection, Emphysema (combined pulmonary fibrosis and 
emphysema), Pulmonary hypertension, Lung cancer, Gastroesophageal reflux, 
Cardiovascular diseases, Hypertension, Dyslipidemia, Diabetes mellitus, Obstructive 
sleep apnoea, Other)
To describe the distribution of patients across different lung function categories based on 
reimbursement threshold (FVC >80%, 50-80%, and <50%)
9.3.3
Covariates
Not applicable

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9.4
DATA SOURCES
Data collection will be limited to those available in the medical records of selected patients. 
All medical records of the 35 included centers will be screened for IPF patients and then 
patients who initiated treatment with nintedanib since 01 January 2016 up to the end of data 
collection date will be identified. 5 patients per site will be selected based on a simple 
randomization of all the patients from each physician.
Demographics and comorbidities will be obtained from the available information of patient’s 
medical records on the date of treatment initiation. 
Most of data will be available in the charts but as a routine clinical practice, some data could 
be missing. However, it will be recorded in the CRF if data for the respective variables was 
not available. Data will be included in an eCRF by investigators. 
9.5
STUDY SIZE
The following table illustrates the precision of estimates of the prevalence of a specific lung 
function profile within the population of interest depending on the observed rate of affected 
patients and the sample size. The dropout rate is assumed to be 10% for all scenarios. 
Precision is estimated based on two-sided 95% confidence intervals.
Table 1
Precision table
N
N to be 
analyzed
% observed 
in subsample
95% CI
Precision 
100
90
7.8% (7 out 
of 90)
[2.2; 13.3]
±5.6
150
135
8.1% (11 out 
of 135)
[3.5; 12.8]
±4.7
175
158
8.2% (13 out 
of 158)
[3.9;12.5]
±4.3
100
90
50.0% (45 
out of 90)
[39.7; 60.3]
±11.3
150
135
50.4% (68 
out of 135)
[41.9; 58.8]
±8.5
175
158
50.0% (79 
out of 158)
[42.2;57.8]
±7.8

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It can be seen that by raising the sample size from 100 to 150 patients, precision improves to 
less than ±5% for the small sample of 8% and to less than 10% for the large sample of 50%. 
Precision can be further improved to less than ±4.5% for the small proportion of 8% and to 
less than 8% for the large sample of 50% if 175 patients will be recruited.
Planning a recruitment of 175 patients allows for an acceptable precision of prevalence of a 
specific lung function profile (see section 9.3.2.1) estimates.
9.6
DATA MANAGEMENT
The data will be entered by the investigators themselves and/or authorized personnel directly 
in the electronic case report form (eCRF). A Data Management Plan (DMP) will be prepared 
to describe all functions, processes, and specifications for data collection, cleaning and 
validation.
Data Management will be performed by the CRO 
. This contract 
organization will be responsible for the development and implementation of the data 
management plan and preparation of the data handling report according to the sponsor´s 
standards.
The database will be housed in a physically and logically secure computer system maintained 
in accordance with a written security policy. The system will meet the standards of the 
International Committee on Harmonization guideline E6R1 regarding electronic study data 
handling. Patient confidentiality will be strictly maintained.
Once the study has been completed and all data from the last patient have been recorded, the 
database will be closed and statistical analysis will be performed.
9.7
DATA ANALYSIS
The proposed methods for statistical analysis presented below are a summary of the methods 
that will be applied in the study to analyse the data collected and to answer the study 
objectives. Missing data will not be imputed in the main analysis (but eventually in 
sensitivity analyses as deemed appropriate). When applicable, the presence of potential 
outliers will be indicated. Analysis will primarily be performed including these outliers.
However, excluding the respective patients in sensitivity analyses might be a reasonable 
approach to assess the impact of these outliers.
Analyses will be performed by the CRO 
. Since the study is essentially 
descriptive the variables included in the study objectives will be analysed with measures of 
central tendency (mean and median), variability/dispersion (standard deviation and 

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interquartile ranges), absolute and relative frequencies, and ranges. 95% confidence intervals 
will be provided as appropriate.
Missing values and data not available in the charts will be displayed in separate categories.
All the analyses will be performed using the Statistical Package for the Social Sciences 
(SPSS), version 22. 
9.7.1
Main analysis
For the primary objective absolute and relative frequencies of patients across different lung 
function categories will be calculated. 
For the secondary objectives:
To describe demographic and clinical baseline characteristics of IPF patients at time of 
treatment initiation with nintedanib (OFEV®) and prevalence of comorbidities, descriptive 
statistics and confidence interval at 95% will be calculated for the key variables defined. For 
the quantitative variables the number of evaluable patients and the measures of central 
tendency and dispersion (median, the standard deviation, the median, Q1 and Q3) will be 
obtained, and for the qualitative variables the absolute and relative frequencies relative to the 
total of patients and to the total of patients with data (total percentage and valid percentage, 
respectively) will be obtained.
For the secondary objective to describe the distribution of patients based on reimbursement 
threshold, 
absolute and relative frequencies of patients across different lung function 
categories will be calculated.
9.8
QUALITY CONTROL
To improve and secure data quality, automatic data checks upon data entry will be done 
within the eCRF. In the eCRF, plausible ranges of values for numeric data entries as well as 
logical data entries and listings will be provided for each entry field. Based on this, checks on 
completeness and plausibility will be performed upon data entry in the eCRF.
Validity of data entry thus is ensured by integrated validation checks performed by the 
system, indicating missing or implausible entries to the document list or investigator. All 
corrections will be visible from the system audit trail.

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No regular source data verification is planned in this study. However, in case of decreasing 
compliance (i.e. of missing data, data discrepancies, protocol violations, etc.) a for-cause 
audit or risk-based monitoring visit may be performed.
In addition, a quality assurance audit/inspection of 
 study may be conducted by the 
sponsor or sponsor’s designees or by Independent Ethics Committee (IECs) or by regulatory 
authorities. The quality assurance auditor will have access to all medical records, the 
investigator’s study-related files and correspondence, and the informed consent document (if 
applicable).
9.9
LIMITATIONS OF THE RESEARCH METHODS
A non-interventional study is the most suitable design to obtain information about the use of 
medicines in everyday therapeutic practice and thus for investigating questions regarding
routine clinical practice.
The selection criteria are less restrictive than the ones of a randomized clinical trial, which 
will permit the enrolment of a broader patient population. The choice of nintedanib (OFEV®) 
therapy will have been done before the study initiation at the discretion of the investigator. 
However, as the study is limited to the hospital setting, patients treated in other clinical 
settings may not be part of the sample. In addition only patients initiating nintedanib
(OFEV®) will be described and no information on IPF patients not initiating this treatment or 
on other treatments will be collected in this study. This has the limitation that it is not feasible 
to put the results into perspective to IPF patients initiating other kinds of treatments.
Another limitation is that data in medical records may have missing values and could reduce 
the validity of conclusions. However, the parameters collected in this study are those most 
frequently collected for IPF in real-world practice.
Precision of estimates could be improved with a higher sample size. However as it was stated 
in the sample size justification, provided an acceptable accuracy, and considering the scarce 
prevalence of the disease, it is a representative number of patients. 
Finally, due to the cross-sectional study design no conclusion on any causal association could 
be drawn.
9.10
OTHER ASPECTS
The study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IEC and competent authority (CA) according to national and 
international regulations. The IEC/CA will be notified about the end of the study (last patient 
included) or early termination of the study.

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9.11
SUBJECTS
Approximately 175 IPF patients from 35 Pulmonology Services in Spain are planned to be 
included in the study. 
To be eligible to participate in the study, patients must meet the following selection criteria.
Inclusion criteria: 
Patients could be included in the study if all of the following criteria are met:
1. The patient is at least 18 years old
2. The patient has IPF diagnosis according to most recent ATS/ERS/JRS/ALAT IPF 
guideline for diagnosis and management [5]
3. The patient newly initiated treatment with nintedanib (OFEV®) since 01 January 2016
up to end of data collection date, according to the approved local SmPC. 
Exclusion criteria:
Patients will be excluded if the following criterion is met:
1. Patients treated with nintedanib within a clinical trial or named-patient program or 
with any prior treatment of nintedanib.
9.11.1
Withdrawal criteria
Not applicable. Retrospective chart review, with no direct contact to patients. See section 10. 
9.12
BIAS
In order to ensure representativeness of patients among the whole country, each Investigator 
will include 5 patients. To minimize selection bias, a simple randomization will be applied. 
The Investigator will share an anonymized list of all of 
 patients who meet selection 
criteria with the CRO. The list will include the minimum patient data to be identifiable by the 
investigator, for example, age, gender and treatment initiation date. Then, CRO will generate 
a random sequence of the 5 patients to be included and will inform the Investigator. 

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10.
PROTECTION OF HUMAN SUBJECTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, current legislation in Spain concerning the conduct of observational
studies (Orden SAS/3470/2009), relevant BI Standard Operating Procedures (SOPs) and 
following Good Epidemiological Practice Guideline (GEP) and the guideline for good 
pharmacoepidemiological practice (GPP).
The study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IEC and CA according to national regulations. The same applies 
for the implementation of changes introduced by protocol amendments. 
Retrospective observational studies can be exempt from a written informed consent per local 
regulations and legal requirements, IRB / IEC often grants a waiver of consent for 
retrospective chart review studies. In order to avoid bias by exclusion of subjects that cannot 
be given informed consent for any reason like death, missing contact information etc., exempt 
from a written informed consent should be asked to Ethics Committees for such situations.
In case such a waiver is not given, prior to patient participation in the study, written informed 
consent must be obtained from each patient (or the patient’s legally accepted representative) 
according to ICH GCP and to the regulatory and legal requirements of the participating 
country. Each signature must be personally dated by each signatory and the informed consent 
and any additional patient-information form retained by the investigator as part of the study 
records. A signed copy of 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 BI in 
accordance with the local data protection law (Organic Law 15/1999 of 13 December on the 
Protection of Personal Data). The level of disclosure must also be explained to the patient.
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors appointed by BI, by appropriate IEC members, and by inspectors 
from regulatory authorities.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol.
eCRF will be provided by the CRO via remote data capture. All of the clinical data and 
site/investigator characteristics will be captured via a web-based Electronic Data Capture 
(EDC) system. The site staff will enter and edit the data via a secure network, with secure 
access features (username, password and secure identification – an electronic password 
system). A complete electronic audit trail will be maintained. 

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Individual patient medical information obtained as a result of this study is considered 
confidential. Patients must not be identified on the eCRF by name. Appropriately coded
identification (i.e. Patient numbers) must be used. Any supporting documentation must be 
redacted of any patient identifying information and the patient ID number must be clearly 
written on the documents.
The investigator / institution will permit study-related monitoring, audits, IEC review and 
regulatory inspection, providing direct access to all related source data / documents. 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 auditor and inspection by 
health authorities (e.g. AEMPS). 

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Even though this NIS is based on already existing (retrospective) data, AE management and 
AE reporting becomes relevant as data extraction from patient’s individual medical records 
will be performed (study data collection) and reviewed. AE management and reporting has to 
be implemented and followed as outlined in this section.
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An adverse event can therefore be any 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 judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.

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Adverse Event of Special Interest (AESI)
The term Adverse Event of Special Interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this study, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. 
The following are considered as AESIs:
No AESIs have been defined for this study.
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator shall maintain and keep detailed records of all AEs in their patient files. 
Collection of AEs
The study design is of non-interventional nature and the study is conducted within the 
conditions of the approved marketing authorization. Sufficient data from controlled 
interventional trials are available to support the evidence on the safety and efficacy of the 
studied BI drug. For this reason the following AE collection and reporting requirements have 
been defined.
The following must be collected by the investigator in the eCRF during the study data 
collection period:
-
all adverse drug reaction (ADRs) (serious and non-serious), 
-
all AEs with fatal outcome   
All ADRs , including those persisting after study completion must be followed up until they 
are resolved, have been sufficiently characterized, or no further information can be obtained.
The investigator carefully assesses whether an AE constitutes an ADR using the information 
below. 
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 

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Arguments that may suggest a reasonable causal relationship could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative etiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
•
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
study, after having taken Ofev®, the investigator must report any drug exposure during 
pregnancy, which occurred in a female subject or in a partner to a male subject to the Sponsor 
by means of Part A of the Pregnancy Monitoring Form. The outcome of the pregnancy 
associated with the drug exposure during pregnancy must be followed up and reported by 
means of Part B of the Pregnancy Monitoring Form. 
In the absence of a reportable AE, only the Pregnancy Monitoring Form must be completed, 
otherwise the NIS AE form is to be completed and forwarded as well within the respective 
timelines. 
Expedited Reporting of AEs and Drug Exposure During Pregnancy
The following must be reported by the investigator on the NIS AE form during the study data 
collection period. The starting point is the date of data extraction:
Type of Report
Timeline
All serious ADRs associated with Ofev®
immediately within 24 hours
All AEs with fatal outcome in patients 
immediately within 24 hours

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exposed to Ofev®
All non-serious ADRs associated with Ofev® 7 calendar days
All pregnancy monitoring forms
7 calendar days
The same timelines apply if follow-up information becomes available for the respective 
events. In specific occasions the Investigator could inform the Sponsor upfront via telephone. 
This does not replace the requirement to complete and fax the NIS AE form.
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the appropriate eCRF pages and the NIS AE form.
Reporting of related Adverse Events associated with any other BI drug
The investigator is encouraged to report all adverse events related to any BI drug other than 
the Ofev® administered for IPF according to the local regulatory requirements for 
spontaneous AE reporting at the investigator’s discretion by using the locally established 
routes and AE report forms. The term AE includes drug exposure during pregnancy, and, 
regardless of whether an AE occurred or not, any abuse, off-label use, misuse, medication 
error, occupational exposure, lack of effect, and unexpected benefit.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the MAH according to local 
and international regulatory requirements. 

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The results of this study will be published in a national journal and presented in both regional 
and national pneumology conferences. A publication plan will be prepared.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
1.
King TE, Jr., Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011; 
378(9807): 1949-61.
2.
Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of idiopathic 
pulmonary fibrosis: review of the literature. Eur Respir Rev. 2012 Dec 1;21(126):355-
61
3.
Xaubet A, Ancochea J, Bollo E, Fernandez-Fabrellas E, Franquet T, Molina-Molina 
M, Montero MA, Serrano-Mollar A. Guidelines for the diagnosis and treatment of 
idiopathic pulmonary fibrosis. Sociedad Espanola de Neumologia y Cirugia Toracica 
(SEPAR) Research Group on Diffuse Pulmonary Diseases. Arch Bronconeumol. 
2013; 49(8): 343-53.
4.
Kim HJ, Perlman D, Tomic R. Natural history of idiopathic pulmonary fibrosis. 
Respir Med. 2015; 109(6): 661-70.
5.
Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier 
JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, 
Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King 
TE, Jr., Kondoh Y, Myers J, Muller NL, Nicholson AG, Richeldi L, Selman M, 
Dudden 
RF, 
Griss 
BS, 
Protzko 
SL, 
Schunemann 
HJ. 
An 
official 
ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based 
guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011; 183(6): 
788-824.
6.
Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, Brozek JL, Collard 
HR, Cunningham W, Homma S, Johkoh T, Martinez FJ, Myers J, Protzko SL, 
Richeldi L, Rind D, Selman M, Theodore A, Wells AU, Hoogsteden H, Schunemann 
HJ. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of 
Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. 
Am J Respir Crit Care Med. 2015; 192(2): e3-19.
7.
Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, Kolb M. Mode 
of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. European 
Respiratory Journal. 2015; 45(5): 1434-45.
8.
Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, 
Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, 
Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-
Herceg R, Disse B, Collard HR. Efficacy and safety of nintedanib in idiopathic 
pulmonary fibrosis. N Engl J Med. 2014; 370(22): 2071-82.
9.
Nathan SD, Shlobin OA, Weir N, Ahmad S, Kaldjob JM, Battle E, Sheridan MJ, du 
Bois RM. Long-term course and prognosis of idiopathic pulmonary fibrosis in the 
new millennium. Chest. 2011; 140(1): 221-9.

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Protocol for non-interventional studies based on existing data
BI Study Number 1199-0295
c17367432-01
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001-MCS-90-124_RD-01 (4.0)
10.
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, 54 (1999), pp. 581-586
13.2
UNPUBLISHED REFERENCES
Not applicable

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BI Study Number 1199-0295
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001-MCS-90-124_RD-01 (4.0)
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
The stand-alone documents for this non-interventional study are:
-
Statistical Analysis Plan (SAP)
-
Data Management Plan (DMP)
-
Serious Adverse Event Report in Non-Interventional Studies (NIS (S)AE Form)
-
Pregnancy Monitoring Form
All of the above documents will be archived in the Trial Master File in its original master 
version.

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Protocol for non-interventional studies based on existing data
BI Study Number 1199-0295
c17367432-01
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001-MCS-90-124_RD-01 (4.0)
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS
ENCePP Checklist for Study Protocols (Revision 3)
Adopted by the ENCePP Steering Group on 01/07/2016
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)
welcomes innovative designs and new methods of research. This Checklist has been developed by 
ENCePP to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist is intended to 
promote the quality of such studies, not their uniformity. The user is also referred to the ENCePP 
Guide on Methodological Standards in Pharmacoepidemiology, which reviews and gives direct 
electronic access to guidance for research in pharmacoepidemiology and pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the section number of the protocol where 
this issue has been discussed should be specified. It is possible that some questions do not apply 
to a particular study (for example, in the case of an innovative study design). In this case, the 
answer ‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section 
should be used to explain why. The “Comments” field can also be used to elaborate on a “No” 
answer. 
This Checklist should be included as an Annex by marketing authorisation holders when submitting 
the protocol of a non-interventional post-authorisation safety study (PASS) to a regulatory 
authority (see the Guidance on the format and content of the protocol of non-interventional post-
authorisation safety studies). The Checklist is a supporting document and does not replace the 
format of the protocol for PASS as recommended in the Guidance and Module VIII of the Good 
pharmacovigilance practices (GVP).
Study title:
A multicenter, retrospective chart review study to describe the clinical profile of 
idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib (OFEV®) in real-
world practice in Spain
Study reference number:
1199-0295
Section 1: Milestones
Yes
No
N/A
Section
Number
1.1
Does the protocol specify timelines for 
1.1.1 Start of data collection1
6
1.1.2 End of data collection2
6
1.1.3 Study progress report(s)
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
6
                                                
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2 Date from which the analytical dataset is completely available.

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Section 1: Milestones
Yes
No
N/A
Section
Number
1.1.6 Final report of study results.
6
Comments:
The duration of the study is less than a year.
Section 2: Research question
Yes
No
N/
A
Section
Number
2.1
Does the formulation of the research question 
and objectives clearly explain: 
8
2.1.1 Why the study is conducted? (e.g. to address 
an important public health concern, a risk identified in 
the risk management plan, an emerging safety issue)
7
2.1.2 The objective(s) of the study?
8
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
7
2.1.4 Which hypothesis(-es) is (are) to be 
tested?
2.1.5 If applicable, that there is no a priori
hypothesis?
Comments:
Exploratory study
Section 3: Study design
Yes
No
N/
A
Section 
Number
3.1
Is the study design described? (e.g. cohort, case-
control, cross-sectional, new or alternative design) 
9.1
3.2
Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection?
9.4
3.3
Does the protocol specify measures of 
occurrence? (e.g. incidence rate, absolute risk)
9.7.1
3.4
Does the protocol specify measure(s) of 
association? (e.g. relative risk, odds ratio, excess risk, 
incidence rate ratio, hazard ratio, number needed to harm 
(NNH) per year)
3.5
Does the protocol describe the approach for the 
collection and reporting of adverse 
events/adverse reactions? (e.g. adverse events that 
will not be collected in case of primary data collection)
11
Comments:
Descriptive study. No measures of occurrence or association measures  are performed

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001-MCS-90-124_RD-01 (4.0)
Section 4: Source and study populations
Yes
No
N/A
Section 
Number
4.1
Is the source population described?
9.2 + 
9.3.1
4.2
Is the planned study population defined in terms 
of:
4.2.1 Study time period?
9.3.1
4.2.2 Age and sex?
9.11
4.2.3 Country of origin?
4.2.4 Disease/indication?
9.11
4.2.5 Duration of follow-up?
4.3
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria)
9.11
Comments:
Retrospective chart review study.
Section 5: Exposure definition and measurement
Yes
No
N/
A
Section
Number
5.1
Does the protocol describe how the study 
exposure is defined and measured?
(e.g. operational details for defining and categorising 
exposure, measurement of dose and duration of drug 
exposure)
9.3.1
5.2
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, use 
of validation sub-study)
5.3
Is exposure classified according to time 
windows? (e.g. current user, former user, non-use)
9.3.1
5.4
Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
Comments:
Observational study. Patients treated as per routine clinical practice.
Section 6: Outcome definition and measurement
Yes
No
N/
A
Section 
Number
6.1
Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated?
9.3
6.2
Does the protocol describe how the outcomes
are defined and measured? 
9.3

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001-MCS-90-124_RD-01 (4.0)
Section 6: Outcome definition and measurement
Yes
No
N/
A
Section 
Number
6.3
Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, prospective 
or retrospective ascertainment, use of validation sub-study)
6.4
Does the protocol describe specific endpoints 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services utilisation, 
burden of disease, disease management)
9.3
Comments:
Descriptive outcomes
Section 7: Bias
Yes
No
N/
A
Section
Number
7.1
Does the protocol describe how confounding will 
be addressed in the study?
7.1.1. Does the protocol address confounding by 
indication if applicable?
7.2
Does the protocol address:
7.2.1. Selection biases (e.g. healthy user bias)
9.12
7.2.2. Information biases (e.g. misclassification of 
exposure and endpoints, time-related bias)
9.9
7.3
Does the protocol address the validity of the 
study covariates?
Comments:
This study is only descriptive
Section 8: Effect modification
Yes
No
N/
A
Section
Number
8.1
Does the protocol address effect modifiers?
(e.g. collection of data on known effect modifiers, sub-group 
analyses, anticipated direction of effect) 
Comments:
This study is only descriptive
Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1
Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview)
9.3
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics)
9.3

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Section 9: Data sources
Yes
No
N/A
Section 
Number
9.1.3 Covariates?
9.2
Does the protocol describe the information 
available from the data source(s) on:
9.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose,  number of days of supply prescription, daily 
dosage,  prescriber)
9.3
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event)
9.3
9.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, lifestyle)
9.3
Is a coding system described for: 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System)
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD)-10, Medical Dictionary for Regulatory 
Activities (MedDRA))
9.3.3 Covariates?
9.4
Is a linkage method between data sources
described? (e.g. based on a unique identifier or other)
Comments:
General practice prescribing
Section 10: Analysis plan
Yes
No
N/
A
Section
Number
10.1 Is the choice of statistical techniques described? 
9.7
10.2 Are descriptive analyses included?
9.7
10.3 Are stratified analyses included?
9.3.2
10.4 Does the plan describe methods for adjusting for 
confounding?
10.5 Does the plan describe methods for handling 
missing data?
9.7
10.6 Is sample size and/or statistical power 
estimated?
9.5
Comments:
Section 11: Data management and quality 
control
Yes
No
N/
A
Section
Number
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
9.6
11.2 Are methods of quality assurance described?
9.8

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001-MCS-90-124_RD-01 (4.0)
Section 11: Data management and quality 
control
Yes
No
N/
A
Section
Number
11.3 Is there a system in place for independent 
review of study results? 
Comments:
Section 12: Limitations
Yes
No
N/
A
Section
Number
12.1 Does the protocol discuss the impact on the 
study results of:
12.1.1 Selection bias?
9.12
12.1.2 Information bias?
9.9
12.1.3 Residual/unmeasured confounding?
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods)
12.2 Does the protocol discuss study feasibility?
(e.g. study size, anticipated exposure, duration of follow-up 
in a cohort study, patient recruitment)
9.5
Comments:
This study is only descriptive
Section 13: Ethical issues
Yes
No
N/
A
Section
Number
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described?
10
13.2 Has any outcome of an ethical review procedure 
been addressed?
13.3 Have data protection requirements been 
described?
10
Comments:
Section 14: Amendments and deviations
Yes
No
N/
A
Section
Number
14.1 Does the protocol include a section to document 
amendments and deviations? 
5
Comments:

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Section 15: Plans for communication of study 
results
Yes
No
N/
A
Section
Number
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)?
12
15.2 Are plans described for disseminating study 
results externally, including publication?
12

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ANNEX 3. ADDITIONAL INFORMATION
Not applicable

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17367432
1.0
clinical-trial-protocol-version-01
A multicentre, retrospective chart review study to describe the clinical profile of
idiopathic pulmonary fibrosis (IPF) patients treated with nintedanib (OFEV) in
real-world practice in Spain.
Approval-Medical 
11 May 2017 15:18 CEST
Approval-Team Member Medical
Affairs
12 May 2017 14:34 CEST
Approval-
 Safety Evaluation
Therapeutic Area
15 May 2017 10:50 CEST
Approval-
 of Global
Epidemiology
19 May 2017 17:12 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17367432
1.0