Digital Auscultation Tool - Development of an Innovative Approach - Using Modern Technologies - to Improve the Diagnosis of Rare Lung Diseases - Expanded Data Collection Idiopathic Pulmonary Fibrosis
Phase: PHASE4
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

ABCD
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
TITLE PAGE
Study Protocol
Document Number:
c21962793-03
BI Study Number:
0352-2119
BI Investigational
Product(s):
Not applicable
Title:
Digital Auscultation Test -
Development of an Innovative Approach - using modern 
technologies - to improve the diagnosis of rare lung diseases –
expanded data collection Idiopathic Pulmonary Fibrosis 
Brief lay title
Not applicable
Protocol version 
identifier:
v3.0
Date of last version of
protocol:
03-Jul-2018
PASS:
No
EU PAS register number:
Study not registered
Active substance:
Not applicable
Medicinal product:
Not applicable
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Study Initiator:
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Straße 173
55216 Ingelheim am Rhein
Germany
Joint PASS:
No
Research question and 
objectives:
The aim of this study is the data collection for patients with 
Idiopathic Pulmonary Fibrosis (IPF) and symptom matched 
controls to create a database of lung auscultation sounds and 
basic patient characteristics.

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Country(-ies) of study:
Germany
Author:
Date:
17-Oct-2018
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Proprietary confidential information
© 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. 
All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used 
without prior written permission

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1.
TABLE OF CONTENTS
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 5
3.
RESPONSIBLE PARTIES.................................................................................... 6
4.
ABSTRACT........................................................................................................... 7
5.
AMENDMENTS AND UPDATES....................................................................... 9
6.
MILESTONES..................................................................................................... 10
7.
RATIONALE AND BACKGROUND................................................................ 11
7.1
MEDICAL BACKGROUND ......................................................................... 11
7.2
RATIONALE FOR PERFORMING THE STUDY ....................................... 12
7.3
BENEFIT - RISK ASSESSMENT ................................................................. 12
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 13
9.
RESEARCH METHODS .................................................................................... 14
9.1
STUDY DESIGN............................................................................................ 14
9.2
SETTING........................................................................................................ 14
9.2.1
Study sites ............................................................................................... 14
9.2.2
Study population ..................................................................................... 14
9.2.2.1
Inclusion criteria............................................................................... 15
9.2.2.2
Exclusion criteria ............................................................................. 15
9.2.3
Study visits .............................................................................................. 15
9.2.4
Study discontinuation.............................................................................. 16
9.2.4.1
Withdrawal of consent for study participation................................. 16
9.2.4.2
Discontinuation of the study by the sponsor.................................... 16
9.3
VARIABLES .................................................................................................. 17
9.3.1
Exposures ................................................................................................ 17
9.3.2
Outcomes................................................................................................. 17
9.4
DATA SOURCES........................................................................................... 17
9.5
STUDY SIZE.................................................................................................. 18
9.6
DATA MANAGEMENT................................................................................ 18
9.6.1
Data Entry ............................................................................................... 19
9.6.2
Source Documents................................................................................... 19
9.6.3
File Retention and Archiving.................................................................. 20
9.7
DATA ANALYSIS......................................................................................... 20
9.8
QUALITY CONTROL................................................................................... 20

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9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 21
9.10
OTHER ASPECTS ......................................................................................... 21
9.10.1
Data quality assurance............................................................................. 21
9.10.2
Study records........................................................................................... 21
9.10.2.1
Source documents ............................................................................ 22
9.10.2.2
Direct access to source data and documents .................................... 22
10.
PROTECTION OF HUMAN PATIENTS .......................................................... 23
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...................................................................................................... 23
10.2
STATEMENT OF CONFIDENTIALITY...................................................... 24
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 25
11.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 25
11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 26
11.3
REPORTING TO HEALTH AUTHORITIES................................................ 28
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 29
13.
REFERENCES .................................................................................................... 30
13.1
PUBLISHED REFERENCES......................................................................... 30
13.2
UNPUBLISHED REFERENCES................................................................... 30
14.
ANNEX................................................................................................................ 31
14.1
PATIENT AUSCULTATION INSTRUCTIONS .......................................... 31
14.2
Sub-study –stethoscope with similar characteristics....................................... 32
14.2.1
Rationale and Background ...................................................................... 32
14.2.2
Research Question and Objectives.......................................................... 32
14.2.3
Research Methods ................................................................................... 32
14.2.3.1
Sub-study design .............................................................................. 32
14.2.3.2
Selection of study population........................................................... 33
14.2.3.3
Variables .......................................................................................... 33
14.2.3.4
Data sources ..................................................................................... 33
14.2.3.5
Study size ......................................................................................... 33
14.2.3.6
Data analysis .................................................................................... 33

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2.
LIST OF ABBREVIATIONS
ACE
Angiotensin-Converting-Enzyme
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special interest
ATS
American Thoracic Society
BI
Boehringer Ingelheim
BMI
Body Mass Index
BP
Blood Pressure
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
DMP
Data Management Plan
DVP
Data Validation Plan
eCRF
Electronic Case Report Form
ERS
European Respiratory Society
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in first second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GEP
Good Epidemiological Practice
GPP
Good Pharmacoepidemiology Practice
HRCT
High Resolution Computer Tomography
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
MAH
Marketing Authorization Holder
mMRC
modified Medical Research Council 
PASS
Post-Authorization Safety Study
PR
Pulse rate
SAE
Serious Adverse Event
SDR
Source Data Review
SDV
Source Data Verification
SOP
Standard Operating Procedure
TCM
Trial Clinical Manager

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3.
RESPONSIBLE PARTIES
Function
Name / Location
Principal Investigator
Phone: 
Team Member Medical Affairs 
(TM MA)
Business Model & Health Care Innovation (BMHCI)
Co-Team Member Medical 
Affairs (Co-TM MA)
Business Model & Health Care Innovation (BMHCI)
GPV CT Coordinator
Boehringer Ingelheim Pharma GmbH & Co. KG
Pharmacovigilance
Trial Clinical Monitor
Statistical Analysis
Boehringer Ingelheim Pharma GmbH & Co. KG 
Biostatistics + Data Sciences
Data Management
Boehringer Ingelheim Pharma GmbH & Co. KG 
Biostatistics + Data Sciences
Programming
Boehringer Ingelheim Pharma GmbH & Co. KG 
Biostatistics + Data Sciences
Information Technology
Boehringer Ingelheim USA Corp.
IT R&D – Translational Medicine and Epidemiology

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
not applicable
Name of active ingredient:
not applicable
Protocol date:
Study
number:
Version/Revision:
Version/Revision 
date:
26-Jan-2018
0352-2119
v3.0
17-Oct-2018
Title of study:
Digital Auscultation Tool -
Development of an Innovative Approach - using modern technologies -
to improve the diagnosis of rare lung diseases – expanded data 
collection - Idiopathic Pulmonary Fibrosis.
Rationale and 
background:
Idiopathic Pulmonary Fibrosis (IPF) is a rare lung disease which is 
difficult to diagnose early. The assessment of “Velcro Crackles” by 
lung auscultation could be used as a screening tool. Crackles are not 
specific for IPF; however only in IPF can these be heard throughout 
the entire inspiration phase.
Research question 
and objectives:
The aim of this study is the data collection for patients with Idiopathic 
Pulmonary Fibrosis (IPF) and symptom matched controls to create a 
database of lung auscultation sounds and basic patient characteristics. 
Study design:
Single visit study without study medication
Targeting two groups of patients, the first group includes patients with 
a confirmed diagnosis of IPF and the other group includes patients 
with matched symptoms as control.
Population:
Patients with a confirmed diagnosis of IPF as well as symptom 
matched patients
Main inclusion criteria: Age ≥ 45 years; for patients with confirmed 
IPF diagnosis; a clinical diagnosis of IPF within the last 24 months, 
according to the ATS/ERS 2011 guideline; symptom matched patients 
– confirmed current condition of asthma, COPD, pneumonia, upper 
respiratory tract infection or acute bronchitis.
Main exclusion criteria: Body Mass Index >30,0 kg/m²
Variables:
Lung auscultation sounds, patient medical history and relevant patient 
demographic information

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Name of company:
Boehringer Ingelheim
Pharma GmbH & Co. KG
Name of finished medicinal 
product:
not applicable
Name of active ingredient:
not applicable
Protocol date:
Study 
number:
Version/Revision:
Version/Revision 
date:
26-Jan-2018
0352-2119
v3.0
17-Oct-2018
Data sources:
Lung auscultation recorded by electronic stethoscope; patient medical 
history and demographic data completed by the physician as well as 
symptom descriptions by the patient.
Study size:
!
100 patients with confirmed IPF diagnosis
!
100 patients with confirmed current condition of asthma, COPD, 
upper respiratory tract infection, acute bronchitis or pneumonia
Additional 70 patients (30 patients with confirmed IPF diagnosis and 
40 with confirmed current condition of asthma, COPD, upper 
respiratory tract infection, acute bronchitis or pneumonia) in the 
substudy.
Data analysis:
Descriptive statistics
Milestones:
Start of data collection
Q2 2018
End of data collection
Q1 2019
Final report of study results Q3 2019

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5.
AMENDMENTS AND UPDATES
Number
Date
Section 
of study 
protocol
Amendment or update
Reason
v2.0
03-Jul-
2018
4
Addition of sub-study, 
update of exclusion 
criterion on BMI, update 
of milestone timelines
Addition of sub-study, 
increase available patient 
population, adaptation to 
actual initiation date
v2.0
03-Jul-
2018
6
Milestones shifted by 1-
2 quarters.
Adaptation to actual start of 
data collection and addition 
of sub-study.
v2.0
03-Jul-
2018
9.2
Sample size increase 
from 200 to 250 patients 
Addition of sub-study
v2.0
03-Jul-
2018
9.2.2.2
Exclusion criterion 4: 
patients with a Body 
Mass Index (BMI) >30,0 
kg/m² (previously >28 
kg/m²)
Increase available of 
patient population, low 
impact on recording quality 
expected
v2.0
03-Jul-
2018
9.7
Addition of interim 
analysis
Addition of sub-study
v2.0
03-Jul-
2018
14.2
Addition of sub-study
Addition of sub-study
v.3.0
17-Oct-
2018
4, 
9, 
14.2.3.2
Increase sample size
Re-place patients who were 
auscultated with wrong 
version of the firmware of 
eKuore ONE device
v.3.0
17-Oct-
2018
4,
6
Milestones shifted by 
one quarter.
Prolongation of the sub-
study to complete 
additional recruitment

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6.
MILESTONES
Milestone
Planned Date
Start of data collection
Q2 2018
End of data collection
Q1 2019
Final report of study results
Q3 2019

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7.
RATIONALE AND BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening, interstitial lung disease 
of unknown aetiology. The median survival of patients with IPF is only 2 to 3 years [R11-
2587] after the diagnosis has been established/confirmed. Diagnosis of rare lung disease like
IPF still represents a significant challenge for patients and physicians.
Symptoms precede diagnosis by a median of 1 to 3 years with progression of asymptomatic 
to symptomatic IPF may occur over years to decades [R11-2587]. Reasons for diagnosis 
delay may include patient-dependent factors (e.g. reluctance to acknowledge symptoms that 
may herald health problems and a sedentary lifestyle masking dyspnoea at exercise), disease 
dependent factors (e.g. progressive onset and slow progression of IPF allows the disease to go 
undetected/un-diagnosed unless exacerbations occur), and physician-dependent factors (e.g. 
lack of awareness of rare diseases by general practitioners and even by lung specialists) [P12-
10276].
A swift and accurate diagnosis is imperative, especially as treatment initiation at a relatively 
early disease stage may have the greatest impact on reducing disease progression [R12-3657].
Careful lung auscultation combined with medical history and demographics support 
differential diagnosis in lung diseases.
7.1
MEDICAL BACKGROUND
Analysis done based on healthcare claims data of a large health plan in the United States 
yielded a prevalence estimate for IPF of between 14.0 and 42.7 per 100,000 persons [P11-
07084]. 
Early diagnosis of IPF is difficult due to several reasons [R17-2783]: Non-specificity of 
clinical symptoms at onset (non-productive cough, exertional dyspnoea), functional 
evaluations do not add to specificity of clinical suspicion, in addition, lung volume can 
remain unaltered if there is a concomitant emphysema, an association that can be justified by 
smoking exposure, which represents a common risk factor for both disorders.
It was proposed by several authors [P12-10276] that assessment of “Velcro Crackles” by lung 
auscultation could be an appropriate method for speedy, early diagnosis of IPF, potentially to 
be used as a screening tool.
During lung auscultation, a specific sound defined as Crackles, characterized by 
discontinuous, interrupted explosive sounds, loud, low in pitch are generally attributed to a 
rapid succession of explosive openings of small airways that closed prematurely during the 
previous expiration. Crackles have been subdivided according to their timing during 
inspiration (early or late) and by differences in their quality (“wet” or “dry”).
Crackles are not specific for IPF, and may occasionally be – also – heard in healthy 
individuals, over the anterior chest, because of closure of small airways in dependent areas of 
the lungs; however, these usually disappear after several deep breaths [P12-10276]. Follow-

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up of asymptomatic patients with Crackles can also reveal occurrence of congestive heart 
failure. Crackles may also be heard occasionally in patients with chronic obstructive 
pulmonary disease or bronchiectasis, probably due to greater traction forces being exerted on 
the small airways. However, Crackles in IPF are heard throughout the entire inspiration phase 
of the breathing cycle. Adventitious sounds associated with heart failure and pneumonia are 
higher in frequency and quite distinctly different from fine Crackles of IPF, and rales are 
present in only one in four patients with left heart congestion due to systolic heart failure.
7.2
RATIONALE FOR PERFORMING THE STUDY
The aim of this study is to generate and collect clinical data of lung auscultation sounds and 
patient characteristics for patients with Idiopathic Pulmonary Fibrosis (IPF) and symptom 
matched controls. The data will be included in a project database focusing on lung 
auscultation sounds combined with relevant demographic information and symptom
descriptions by the patients. In addition to data from the current study, the project database 
will also include data from healthy volunteers [c19451379] and additional fibrotic patients 
from a collaboration project [R17-4022].
Using this project database it is intended to develop, evaluate and validate a novel algorithm 
to classify IPF patients against non IPF patients. Such novel tool, once validated, will be able 
to aid physicians in IPF screening.
The need for the generation of additional new data emerges from the specificity of the lung 
auscultation protocol.
7.3
BENEFIT - RISK ASSESSMENT
There is no expected individual benefit for the study patients, as all patients are required to 
have a confirmed diagnosis of their disease.
Overall benefit is expected for future diagnosis and screening, supporting medical practice.
As the lung auscultations are going to be performed with a slightly longer duration than 
during a “routine examination”, in order to acquire high quality digital sound recordings, a 
small risk of transitory dizziness due to a hyperventilation should be considered as a potential 
adverse event during the recording procedure, requiring usual preparation for supporting the 
patient, if needed during the examination.

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8.
RESEARCH QUESTION AND OBJECTIVES
The aim of this study is the data collection for patients with IPF and symptom matched 
controls to create a database of lung auscultation sounds and basic patient characteristics.

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
Single visit for each study participant to record lung auscultation sounds and assess their vital 
signs, i.e. heart rate, blood pressure, etc. – see Section 9.2.3 for details.
This is a single visit, multi-centre study without any study medication or invasive procedure. 
The study is designed to collect recordings of lung auscultation sounds, as well as 
demographic and symptom information of two patient groups (IPF patients versus symptom 
matched controls).
Patients will be grouped based on their diagnosis at screening.
The end of the study is defined as when the last patient completes the visit.
Additionally a sub-study is planned to collect sound recordings using two different electronic 
stethoscopes sequentially from approximately 70 additional patients (see Section 14.2).
9.2
SETTING
9.2.1
Study sites
It is planned to collect sounds from approximately 200 patients from 10-12 specialized ILD 
centres, known to Boehringer Ingelheim from previous IPF studies. Due to the fact that IPF is 
a rare disease, the study focuses on specialized clinics with clinical study experience with 
Boehringer-Ingelheim as Sponsor in order to collect high quality data.
The additional sub-study is planned to collect sound recordings from approximately 70 
additional patients from 6 of the above mentioned study sites. 
9.2.2
Study population
The study population consists of patients with a confirmed diagnosis of IPF and patients with 
similar symptoms to have a symptom matched control group: 
!
patients with confirmed IPF diagnosis (N=100 in the main study and N=30 in the sub-
study)
!
patients with a confirmed current condition of asthma, COPD, upper respiratory tract 
infection, acute bronchitis or pneumonia as a symptom matched control group (N=100 in 
the main study and N=40 in the sub-study)
Enrolment will be competitive and the study will be closed when the planned number of 
patients has been reached. As no interactive response tool will be used in this study, each 
investigational site must notify the sponsor whenever a patient is enrolled. Therefore a 

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notification form will be provided by the sponsor. To maintain a balance between IPF and 
matched control patients, sites should not recruit more matched control patients than IPF 
patients in the timeframe of a month. Permission to recruit more than 40 patients in total 
(including sub-study) or to focus on one of the patient groups must be obtained from the 
TCM at Boehringer-Ingelheim. This will only be allowed after a careful review of the 
enrolment status and data quality.
9.2.2.1
Inclusion criteria
1. Male or female patients
2. Age ≥ 45 years at the day of the study visit
3. Diagnosis: 
a) For patients with confirmed IPF diagnosis - a clinical diagnosis of IPF within the last 
24 months from the day of the study visit, according to the ATS/ERS 2011 guideline 
[P11-07084]
or
b) For the symptom matched control – patients without a IPF diagnosis but with one of 
the confirmed current conditions as:
i.
asthma diagnosed according to GINA guidelines, 
ii.
COPD diagnosed according to GOLD guidelines, 
iii.
pneumonia,
iv.
upper respiratory tract infection, or
v.
acute bronchitis. 
4. Signed and dated written informed consent in accordance with GCP and local legislation 
prior to admission to the study
9.2.2.2
Exclusion criteria
1. Any other current respiratory condition other than the pulmonary disease which qualified 
the patient eligibility based on inclusion criterion 3
2. Any condition, according to investigator’s assessment, which will not allow the patient to 
comply with protocol assessments or need a legal representative
3. Patients with a history of lobectomy, pneumonectomy or lung transplant
4. Patients with a Body Mass Index (BMI) >30,0 kg/m²
5. Previous enrolment in this study
6. Women who are pregnant
A log, documenting all patients who have been invited for study participation, will be 
maintained in the study file, recording basic patient characteristics (e.g. gender, year of birth)
as well as information on informed consent (enrolment date) and eligibility (or reasons for 
non-eligibility). A record of all patients who have been invited for study participation at the 
study site should maintained, irrespective of whether the patient has been enrolled or whether 
auscultations have been recorded or not.
9.2.3
Study visits
Patients will be enrolled consecutively. The respective assessments and data to be collected 
are listed in Table 9.2.3: 1. All data will be collected during one visit, no follow-up visit is 
planned.

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Table 9.2.3:1 Visit flow chart and data collection parameters (for the visit flowchart for the 
substudy see Table 14.2.3.1:1)
Assessments
Visit 1
Informed consent1
X
Demographics
X
Medical history
X
Review of in-/exclusion criteria
X
Physical examination (including height and weight)
X
Vital signs including blood pressure
X
12-point lung auscultation
X
Symptom questionnaire
X
Adverse events recording
X
1 Prior to any study related procedure.
9.2.4
Study discontinuation
Patients may potentially be withdrawn from study procedures, but every effort should be 
made to keep the patients in the study.
Measures to control the withdrawal rate include careful patient selection and appropriate 
explanation of the study requirements and procedures.
The decision to withdraw from the study as well as the reason must be documented in the 
patient files and Case Report Forms (CRF).
9.2.4.1
Withdrawal of consent for study participation
Patients may withdraw their consent for study participation at any time without the need to 
justify the decision.
9.2.4.2
Discontinuation of the study by the sponsor
Boehringer Ingelheim reserves the right to discontinue the study overall or at a particular 
study site at any time for the following reasons:
1) Failure to meet expected enrolment goals overall or at a particular study site
2) Emergence of any safety information invalidating the earlier positive benefit-risk-
assessment that could significantly affect the continuation of the study
3) Violation the study protocol, or the contract impairing the appropriate conduct of the 
study
The investigator / the study site will be reimbursed for reasonable expenses incurred in case 
of study termination (except in case of the third reason).

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9.3
VARIABLES
The following parameters will be collected and assessed:
!
Patient demographics (age, gender, height, weight & body mass index)
!
Smoking status (current smokers, former smokers, and never smokers) and pack-years
!
IPF patients: Patient-reported date of first symptoms; date of IPF diagnosis was 
confirmed according to ATS/ERS 2011 guideline; method of confirmation (e.g. HRCT, 
biopsy); family history of IPF
!
Symptom matched control: confirmed diagnosis and date of diagnosis
!
Relevant current concomitant diseases/therapies potentially affecting auscultation, 
including specifically congestive heart failure and use of ACE inhibitors.
!
Past treatments/surgical interventions which potentially affect lung auscultation
!
Date and location of lung biopsy
!
Vital signs –blood pressure (systolic and diastolic) and pulse rate 
!
Spirometry data, if available from prior examination – FEV1, FVC
!
A one page abbreviated paper based questionnaire regarding symptoms experienced by 
the patient (dyspnea, sputum and cough)
!
Weight loss in past 4 weeks;
!
Occurrence of heartburn; clubbing of fingers
!
12-point auscultation – recording of sounds in 3M Littmann StethAssist software
!
Safety reporting – adverse events (see Section 11)
9.3.1
Exposures
No study medication is used in this study. 
There are no restrictions on the use of concomitant medication in this study.
9.3.2
Outcomes
There are no specific endpoints or outcomes on patient level. The aim of this study is the data 
collection only, the analysis (generation of the algorithm) will be completed on project level. 
9.4
DATA SOURCES
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and study records that include all observations and 
other data pertinent to the investigation on each study patient. 
Medical records collected through routine clinical care will be used to assess the 
inclusion/exclusion criteria of patients. Such medical records will be used for patient 
demographics, smoking history, diagnosis of IPF, asthma, COPD, upper respiratory tract 

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infection, acute bronchitis or pneumonia, relevant medical history (including surgeries and 
biopsy), as well as spirometry data. 
Systolic and diastolic blood pressure (BP) and pulse rate (PR) should be measured after the 
patient has rested for at least 5 minutes in a supine position. 
The investigator will use the modified Medical Research Council (mMRC) scale to assess the 
breathlessness state of the patient, as well as document the patient response to four questions 
related to the cough symptoms reported by the patients, as well as three questions related to 
sputum. Answers will be documented in the source transcribed by site staff into the eCRF.
Clubbing of fingers, heartburn, and weight loss will be assessed by yes/no questions, for 
weight loss, a percentage will be collected, if applicable.
For this study, a 12-point patient auscultation is required. In each defined region of the 
patient’s body, auscultation should be performed to maximize the sound quality according to 
the investigator’s experience as well as instructions in appendix 1. Site staff will receive 
hands-on training on the use of the stethoscope and the required software during site 
initiation. Manuals provided by the manufacturer will available in the site file. Auscultations 
will be recorded using a Littman Digital Stethoscope (Model 3200) and the 3M Littmann 
StethAssist software on a computer provided for the study.
All related AEs, serious and non-serious associated with the digital Auscultation as well as 
all related adverse events (ADRs) (serious and non-serious) and all AEs with fatal outcome
associated with BI products administered for indication IPF, COPD, asthma must be 
documented in the patient source documentation and reported to the sponsor, see Section 11
for details.
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.
All patients will be enrolled consecutively
9.5
STUDY SIZE
The sample size determination for this study is based on feasibility constraints that IPF is a 
rare disease and due to the explorative nature of the novel algorithm development which will 
be conducted at project level. 
9.6
DATA MANAGEMENT
A data management plan (DMP) will be created to describe all functions, processes, and 
specifications for data collection, cleaning and validation. The Case Report Forms (CRFs) 
will include programmable edits to obtain immediate feedback if data are missing (also 
negative answers, unknown), out of range, illogical or potentially erroneous. These rules may 
encompass simple checks such as range validation or presence/absence of data. Concurrent 

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manual data review may be performed based on parameters dictated by the DMP. A risk 
based source data review (SDR) and source data verification (SDV) process will be 
implemented, Details of the process will be specified in a separate monitoring manual.
The database will be housed in a physically and logically secure computer system. The 
system will meet the standards of the International Committee on Harmonization guideline 
E6R1 regarding electronic study data handling and the safety requirements of the FDA (US 
Food & Drug Administration) concerning systems for the data acquisition of clinical studies 
in accordance with “Title 21 Code of Federal Regulations (21 CFR Part 11): Electronic
Records; Electronic Signatures” Patient confidentiality will be strictly maintained.
9.6.1
Data Entry 
Data will be entered into an electronic CRF (eCRF) provided on a study laptop to the sites.
The final CRFs will be approved by the responsible principal investigator within the 
electronic data capture system.  
The data review and validation steps for the study are defined in the data validation plan 
(DVP).
The DVP includes all definitions of electronic checks and the defined manual checks, which 
will be performed directly in the eCRF or can be based on listings.
Electronic edit checks (eChecks) are performed automatically and directly when entering data 
into the CRF. Missing data entries or implausibilities are indicated to the user immediately.
Manual Checks are applied to verify the entered data validity and plausibility.
Queries can result from various sources:
!
Manual Checks by data management
!
Manual Checks by pharmacovigilance 
!
Source data review and verification during on-site monitoring 
9.6.2
Source Documents
The source documents are contained in the patient’s medical record. Data collected in the 
eCRFs must be traceable to these source documents in the patient’s medical records as far as 
this is routine documentation. All original source documentation is expected to be stored at 
the site for the longest possible time required by local applicable regulations. The site will be 
instructed to notify the Sponsor before any destruction of medical records of study 
participants.

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9.6.3
File Retention and Archiving
The study database and all study-specific documents will be archived by BI Pharma in 
accordance with BI SOPs.
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the 
investigator agrees to keep records, including the identity of participating patients, copies of 
all CRFs, SAE forms, source documents and adequate documentation of relevant 
correspondence (e.g. letters, meeting minutes, telephone calls reports). The records should be 
retained by the investigator according to local regulations, or as specified in the study 
contract, whichever is longer.
Each site will receive a study site file at study initiation which contains all documents 
necessary for the conduct of the study and is updated throughout the study. This file must be 
available for review in the event the site is selected for monitoring, audits, or inspections and 
must be safely archived for at least ten years after the completing participation in the study. 
In the event that archiving of the file is no longer possible at the site, the site will be 
instructed to notify the Sponsor.
9.7
DATA ANALYSIS
All variables mentioned in Section 9.3 will be presented descriptively.
Characteristics of the analytical methods for the analysis will be given in further detail in the 
study report or in a separate technical report.
An interim database lock will be conducted after the 200 patients of the initial main study 
have completed the study to provide early access for the explorative tests in the development 
of the classifying algorithm. 
A study report describing all data collected within this study will be produced after the last 
patient has completed the study.
Handling of missing data
Missing data will be described in the descriptive statistics without imputation.
9.8
QUALITY CONTROL
To improve and secure data quality of the collected auscultation sounds, sounds will be 
reviewed centrally to ensure high quality standards and to label defined features of the 
recordings for further analysis in the algorithm generation process based on a detailed 
guidance document. Central review and labelling will be started during the conduct phase of 
the study already to provide feedback to the sites where required.

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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 investigator. 
Source data review (SDR) and verification (SDV) is planned to be performed at all sites with 
enrolled patients. Informed consents and in/exclusion criteria will be checked for all patients. 
For the SDR/SDV of the remaining data an adaptive risk based approach will be 
implemented. 
9.9
LIMITATIONS OF THE RESEARCH METHODS
There is limited experience with the planned project level analysis using complex data 
including audio files, therefore the planned sample size is based on operational constraints 
rather than an elaborate calculation. But the explorative nature of the overall project will 
allow us to test several mathematical approaches to generate a robust algorithm. 
Due to operational constraints we are limited to a strictly defined symptom matched control 
group, which will not encompass the full range of lung sounds. Expanding the database in a 
second step to provide data for the further development and evaluation of the algorithm is 
being considered. 
9.10
OTHER ASPECTS
9.10.1
Data quality assurance
A quality assurance audit/inspection of this study may be conducted by the sponsor or 
sponsor’s designees or by Institutional Review Board (IRBs) / Independent Ethics Committee 
(IECs) or by regulatory authorities. The quality assurance auditor will have access to all 
medical records, the investigator’s study-related files and correspondence, and the informed 
consent documentation of this study.
Onsite monitoring including source data verification will be conducted at all sites enrolling 
patients. An additional check/ review of the quality assurance of this study can be performed.
9.10.2
Study records
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via remote 
data capture.

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9.10.2.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the CRFs 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.
All data need to be derived from source documents.
9.10.2.2
Direct access to source data and documents
The investigator / institution will permit study-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical study 
monitor, auditor and inspection by health authorities (e.g. US Food and Drug Administration
(FDA)). The Clinical Research Associate (CRA) / Clinical Monitor Local (CML) and auditor 
may review all eCRFs, and written informed consents. The accuracy of the data will be 
verified by reviewing the documents described in Section 9.10.2.1.

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10.
PROTECTION OF HUMAN PATIENTS
The study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) (to the extent applicable to the setting of this study and 
required by local regulations), Good Epidemiological Practice (GEP), Guidelines for Good 
Pharmacoepidemiology Practice (GPP), and relevant BI Standard Operating Procedures 
(SOPs). Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 
in the responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study patients against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File).
10.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments. In addition, every participating 
physician is to be advised by his/her ethics committee in accordance with the rules of 
professional conduct.
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.
The patient must be informed that his/her personal study-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Quality Medicine auditors appointed by Boehringer Ingelheim, by 
appropriate IRB / IEC members, and by inspectors from regulatory authorities.

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10.2
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Data generated as a result of the study need to be available for inspection on request by the 
participating physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory 
authorities, i.e. the competent authority.

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
11.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation patient 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.

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11.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION 
AND REPORTING
The investigator must collect and document in the eCRF from signing the informed consent 
onwards until the patient´s end of the study:
!
all related AEs, serious and non-serious associated with the digital Auscultation 
The investigator must report:
!
all related adverse events (ADRs) (serious and non-serious)
!
all AEs with fatal outcome
associated with BI products administered for indication IPF, COPD, asthma
All related AEs, 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 reported by a patient or observed 
otherwise constitutes an ADR using the information below. 
Causal relationship of adverse event
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest a reasonable causal relationship could be:
!
The event is consistent with the known pharmacology of the drug 
!
The event is known to be caused by or attributed to the drug class.
!
A plausible time to onset of the event relative to the time of drug exposure.
!
Evidence that the event is reproducible when the drug is re-introduced
!
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing 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).

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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 patient has been enrolled into the 
study, after having taken a BI product used for indication, investigator must report any drug 
exposure during pregnancy (DEDP) associated with BI products administered for 
indication IPF, COPD, asthma, which occurred in a female patient or in a partner to a male 
patient 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 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 by means of the Adverse Event Reporting 
form provided from signing the informed consent onwards until the end of the study via fax 
to BI Unique Entry point as specified in the Investigator Site File (ISF).
Type of Report
Timeline
All serious ADRs associated with BI products used for 
indication IPF, COPD, asthma
immediately within 24 hours
All AEs with fatal outcome in patients exposed to BI 
products used for indication IPF, COPD, asthma
immediately within 24 hours
All non-serious ADRs associated with BI products used 
for indication IPF, COPD, asthma
7 calendar days
All pregnancy monitoring forms (DEDP after intake of 
BI products used for indication  IPF, COPD, asthma)
7 calendar days

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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 AE reporting form.
Information required
For each reportable adverse event, the investigator should provide the information requested 
on the AE reporting 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 
BI marketed products in outlined indications under expedited reporting (not 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.
11.3
REPORTING TO HEALTH AUTHORITIES
Adverse event reporting to regulatory agencies will be done by the sponsor of the study
according to local and international regulatory requirements.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The rights of the investigator and of the sponsor with regard to publication of the results of 
this study are described in the investigator contract. As a general rule, no study results should 
be published prior to finalization of the Study Report.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P11-07084 
Raghu G, et al, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary 
Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary 
fibrosis: evidence-based guidelines for diagnosis and management. Am J 
Respir Crit Care Med 183 (6), 788 - 824 (2011)
P12-10276 
Cottin V, Cordier JF. Velcro crackles: the key for early diagnosis of 
idiopathic pulmonary fibrosis? Eur Respir J 40 (3), 519–521 (2012)
R11-2587 
Ley B, Collard HR, King TE. Clinical course and prediction of survival in 
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 183, 431 - 440 
(2011)
R12-3657
Bois RM du. An earlier and more confident diagnosis of idiopathic 
pulmonary fibrosis. Eur Respir Rev 21 (124), 141–146 (2012)
R17-4022 
Sgalla G, Walsh SLF, Sverzellati N, Fletcher S, Cerri S, Dimitrov B, et al. 
Correlation between lung sounds and HRCT signs of pulmonary fibrosis: a 
blinded prospective study. 27th Int Cong of the European Respiratory 
Society (ERS), Milan, 9 - 13 Sep 2017 (Poster)
R17-2783
Cicchitto G, Sanguinetti CM. Idiopathic pulmonary fibrosis: the need for 
early diagnosis. Multidiscip Respir Med 8, 53 (2013)
13.2
UNPUBLISHED REFERENCES
c19451379 
 – Non interventional study Development of an 
innovative approach - using modern technologies - to improve the diagnosis 
of rare lung diseases. 0352-2106

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14.
ANNEX 
14.1
PATIENT AUSCULTATION INSTRUCTIONS
For this study, a 12-point patient auscultation is required. In each defined region of the 
patient’s body, auscultation should be performed to maximize the sound quality according to 
the investigator’s experience.
Auscultations will be recorded using a Littman Digital Stethoscope (Model 3200) and the 3M 
Littmann StethAssist software on a computer provided for the study.
!
The auscultations should be performed while the patient is standing. If this is not 
possible due to the condition of the patient (patient not able to stand still for the 
duration of the auscultations), the auscultations can be performed while the patient is 
sitting. This should be documented accordingly in the CRF.
!
The auscultations should be performed in a quiet room with the least amount of 
background possible.
!
The stethoscope should not be moved during the recording of the auscultation. - if 
patient has a hairy chest, the investigator should consider wetting the skin of the 
patient in order to avoid the recording of non-respiratory sounds.
!
Patient should breathe with open mouth.
!
Patient should perform maximum exhalation, followed by maximuminspiration.
!
At each auscultation point breathing should be recorded for 15 seconds. 
!
The 12 auscultation points should be recorded as shown in Figure 14.1: 1 – the actual 
location can be recorded in software provided to record the sounds, any deviations 
should be recorded in the CRF.
!
If the patients experiences an intensive fit of coughing the recording of the 
auscultation point should be stopped and repeated.
!
All recordings for a patient should be recorded in one continuous session, on the same 
day. 
!
If auscultation results in any abnormal sound, the investigator should describe the 
location of the auscultation, patient positionand characteristics in the CRF.
Figure 14.1: 1
Auscultation Points used and Recording Sequence

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14.2
SUB-STUDY –STETHOSCOPE WITH SIMILAR CHARACTERISTICS
14.2.1
Rationale and Background
The main study is limiting the electronic stethoscope used to record the auscultation sounds 
to one device only, the Littmann 3200. Based on recent developments there are other devices 
available that have acoustic recording characteristics that are very similar to the Littmann 
3200. Therefore there is a need to evaluate whether the recording device used has an impact 
on the performance of classification algorithms developed based on recordings using the 
Littmann 3200.
14.2.2
Research Question and Objectives
The aim of this sub-study is the collection of auscultation recordings for patients with IPF 
and symptom matched controls using two different approved stethoscopes with similar 
characteristics (Littmann 3200 and Ekuore One) on the same patient to ensure the neutrality 
of the algorithm regarding the recording device. 
14.2.3
Research Methods
14.2.3.1
Sub-study design
After the completion of all assessments from the main study, and a 10 minute break, a second 
12-point auscultation using the Ekuore One attached to a Littman Cardiology stethoscope will 
be completed (see Table 14.2.3.1:1).
Table 14.2.3.1:1 Sub-study flow chart and data collection parameters
Assessments
Visit 1
Informed consent including consent to participate in sub-study1
X
Demographics
X
Medical history
X
Review of in-/exclusion criteria
X
Physical examination (including height and weight)
X
Vital signs including blood pressure
X
12-point lung auscultation using Littmann 3200
X
Symptom questionnaire
X
12-point lung auscultation using Ekuore One
X
Adverse events recording
X
1 Prior to any study related procedures.

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Study Protocol
BI Study Number 0352-2119
c21962793-03
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
14.2.3.2
Selection of study population
This sub-study will enrol patients from approximately 6 study sites participating in study 
0352-2119. Approximately 70patients who gave consent to both the main study and the sub-
study will be enrolled into the sub-study. The sub-study should include a sample of 
approximately 30 IPF patients and 40 symptom matched controls as defined in the main 
study. 
14.2.3.2.1 Inclusion criteria
1. Patients who have provided informed consent to participate in the main study 0352-
2119 as well as this sub-study prior to any study related procedures.
2. Patients who have been confirmed as meeting all in- and exclusion criteria (Section 
9.2.2.1 and Section 9.2.2.2).
The log of all patients participating in the study should include a clear indication whether the 
patient participated in the substudy or not.
14.2.3.3
Variables
In addition to the main-study the following parameters will be collected and assessed:
!
12-point auscultation – recording of sounds using the Ekuore One stethoscope
14.2.3.4
Data sources
For this sub-study the same assessments will be performed as in the main study (Section 9.4). 
Following the auscultation using the Littmann stethoscope, and a 10-minute break, another 12 
point auscultation using the Ekuore One will be performed following the same instructions 
(Section 14.1) but using different software for recording. Both recordings should be 
performed under the same conditions.
The Ekuore One device will be attached to a Littman Cardiology stethoscope. The 
auscultations will be recorded using an application on a mobile device provided for the study.
Site staff will receive hands-on training on the use of stethoscope and the required software. 
Documentation provided by the manufacturer will be available in the site file. 
14.2.3.5
Study size
The sample size determination for this study is based on feasibility constraints that IPF is a 
rare disease and the explorative nature of the project.
14.2.3.6
Data analysis
All variables mentioned in Section 9.3 and 14.2.3.3 will be presented descriptively. A 
comparison of Littmann 3200 and Ekuore One is outside of the scope of this study and the 
project. 

Boehringer Ingelheim
Page 34 of 34
Study Protocol
BI Study Number 0352-2119
c21962793-03
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-90-118_RD-01 (7.0) / Saved on: 09 Nov 2015
Characteristics of the analytical methods for the analysis will be given in further detail in the 
study report or in a separate technical report.

 
 
 
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