A Multi-center, Longitudinal 12-week Pilot Study to Evaluate Cough Severity and Its Impact, Utilizing a Next Generation Cough Monitor, in Participants With Idiopathic Pulmonary Fibrosis (IPF) or Non IPF Pulmonary Fibrosis
Phase: NA
Conditions: Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

001-MCS-40-106_RD-03 (20.0) / Saved on: 20 Apr 2021
Protocol
 
Document Number:
c39406431-01
EudraCT No.
EU Study No.
N/A
BI Study No.
1490-0005
BI Investigational
Product(s)
Title
A multi-center, longitudinal 12-week pilot study to evaluate 
cough severity and its impact, utilizing a next generation cough 
monitor, in participants with idiopathic pulmonary fibrosis (IPF) 
or Non IPF Pulmonary Fibrosis
Lay Title
A study in people with pulmonary fibrosis to monitor cough with 
a wearable device
Clinical Phase
N/A
Clinical Trial Leader
On behalf of 
Phone 
/ Fax: 
Email:
Coordinating 
Investigator
Phone:
Email:
Current Version and 
Date
Version 1.0 / 16 Sep 2022  
Original Protocol 
Date
16 Sep 2022
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! 2022 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 SYNOPSIS
Company name
Boehringer Ingelheim 
Original Protocol date
16 Sep 2022
Revision date
N/A
BI study number
1490-0005
Title of study
A multi-center, longitudinal 12-week pilot study to evaluate cough 
severity and its impact, utilizing next generation cough monitoring, 
in participants with idiopathic pulmonary fibrosis (IPF) or Non IPF 
pulmonary fibrosis. 
Coordinating 
Investigator
Study site(s)
Multi-centre study in approximately 5-7 countries. 
Clinical phase
N/A
Study rationale
A further understanding of the similarities and differences in cough 
among persons with Non IPF forms of pulmonary fibrosis and IPF,
together with insight into the pattern and impact of cough in these 
patients is required. The current pilot aims to assess cough 
frequency, indirect measures of cough intensity and the association 
between objective cough measures and lung physiology and various 
patient-reported outcome measures in a patient cohort with Non IPF 
forms of pulmonary fibrosis and IPF. 
Study objective(s)
The primary objective of this study is to objectively quantify cough
frequency over 12 weeks in a cohort of subjects with IPF or Non IPF 
pulmonary fibrosis using a digitally enabled cough monitor. 
Additionally, we will assess the feasibility of hybrid study design, 
utilizing 
cough monitoring and remote video-assisted 
home spirometry. 
Study endpoints
Primary Endpoint: Cough count per hour (CC/hr) measured over a 
24-hour period at baseline visit, Week 4(V4), Week 8(V5), Week 12 
(V6).
Secondary Endpoints: 
∀
Change from baseline in CC/hr at Week 4, Week 8, Week 12
∀
FVC (mL) at baseline
∀
FVC (mL) at Week 12
∀
Change from baseline in FVC (mL) at Week 12
∀
Feasibility of remote cough data capture (defined as % of 
analysable data per 24-hour recording)
∀
Feasibility of hybrid study design (successful completion of all 
elements of remote visit)
Study design
Low intervention, 12-week pilot study, utilizing a digitally enabled 
cough monitor and hybrid study design, in subjects with IPF or Non 
IPF pulmonary fibrosis. 

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FLOW CHART
Study Periods
Screening*
Baseline*
Visit
Remote Study Visits
EoS Visit
Visit
1
2
3
4
5
6
7/EoS 
Days 
- 1 wk
1
3
28
56
82
84
Time window for visits
+ 2 days
± 5 days
± 5 days
- 2 days
± 5 days
Informed consent 
X
Review of in-/exclusion criteria
X
 
Demographics
X
Smoking Status/history  
X
Medical history (Comorbidities)
X
Pregnancy status (where available)
X
X
COVID-19 history (including vaccination status)
X
Non IPF Pulmonary Fibrosis (including ILD
diagnosis category) or IPF
X
Progressive Pulmonary Fibrosis Phenotype (Y/N)
X
Concomitant therapy (including prescription 
medications for Pulmonary Fibrosis)
X
X
X
X
Historical Pulmonary Function Tests (FVC & 
DLCO)2
X
Historical HRCT Pattern3 (UIP, Probable UIP, 
Indeterminate for UIP, Inconsistent w/UIP)
X
Physical examination
X
X
Vital signs4
X
X
SpO2
X
X
In-Office Spirometry5
X
X
Distribute & provide instruction on cough monitor
X
Distribute & provide instruction on home 
spirometer
X
Home Spirometry 
X7,9
X
X
X7,9
Reporting of AEs/SAEs10 & Unscheduled clinical 
visits
X
X
X
X
Videoconference remote visit
X
X
24-hour cough monitor 
 
recording11
X
X11
X11
X11
24-hour cough monitor data upload12
X
X
X
X
Remote Procedures Compliance Check 13
(Home spirometry, Videoconference remote visit 
(V4, V5),
& Cough recordings)
X
X
X
X
Return of cough monitor & home spirometer
X
Patient survey regarding use of cough monitor and 
home spirometer
X

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
PROTOCOL SYNOPSIS........................................................................................................2
FLOW CHART........................................................................................................................4
TABLE OF CONTENTS ........................................................................................................6
ABBREVIATIONS AND DEFINITIONS.............................................................................9
1.
INTRODUCTION...............................................................................................12
1.1
MEDICAL BACKGROUND.............................................................................12
1.2
DEVICE PROFILE ............................................................................................13
1.3
RATIONALE FOR PERFORMING THE STUDY ........................................14
1.4
BENEFIT - RISK ASSESSMENT.....................................................................14
1.4.1
Benefits.................................................................................................................14
1.4.2
Risks .....................................................................................................................15
1.4.3
Discussion.............................................................................................................15
2.
STUDY OBJECTIVES AND ENDPOINTS.....................................................16
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........16
2.1.1
Main objectives....................................................................................................16
2.1.2
Primary endpoint(s)............................................................................................16
2.1.3
Secondary endpoint(s) ........................................................................................16
3.
DESCRIPTION OF DESIGN AND STUDY POPULATION........................19
3.1
OVERALL STUDY DESIGN............................................................................19
3.2
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................19
3.3
SELECTION OF STUDY POPULATION.......................................................20
3.3.1
Main diagnosis for study entry ..........................................................................20
3.3.2
Inclusion criteria .................................................................................................20
3.3.3
Exclusion criteria ................................................................................................20
3.3.4
Discontinuation of patients from assessments..................................................21
3.3.4.1
Withdrawal of consent to participation.................................................................21
3.3.4.2
Discontinuation of the study by the contracting entity .........................................22
4.
TREATMENTS...................................................................................................23
4.1
INVESTIGATIONAL INTERVENTION........................................................23
4.1.1
Method of assigning patients to intervention group ........................................23
4.1.2
Storage conditions...............................................................................................23
4.1.3
Device accountability..........................................................................................23
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................24
4.2.1
Other treatments and emergency procedures..................................................24

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4.2.2
Restrictions ..........................................................................................................24
4.2.2.1
Restrictions regarding concomitant treatment ......................................................24
4.2.2.2
Restrictions on lifestyle.........................................................................................24
4.2.2.3
Contraception requirements..................................................................................24
4.3
DEVICE USE COMPLIANCE..........................................................................24
5.
ASSESSMENTS..................................................................................................25
5.1
ASSESSMENT OF EFFICACY........................................................................25
5.2
ASSESSMENT OF SAFETY.............................................................................28
5.2.1
Physical examination ..........................................................................................28
5.2.2
Vital signs.............................................................................................................29
5.2.3
Safety laboratory parameters ............................................................................29
5.2.4
Electrocardiogram ..............................................................................................29
5.2.5
Other safety parameters.....................................................................................29
5.2.6
Assessment of adverse events.............................................................................29
5.2.6.1
Definitions of AEs ................................................................................................29
5.2.6.2
Adverse event collection and reporting ................................................................30
5.5
OTHER ASSESSMENTS...................................................................................31
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................31
6.
INVESTIGATIONAL PLAN.............................................................................33
6.1
VISIT SCHEDULE.............................................................................................33
6.2
DETAILS OF STUDY PROCEDURES AT SELECTED VISITS ................36
6.2.1
Screening and run-in period(s)..........................................................................36
6.2.2
Intervention period .............................................................................................37
6.2.3
Study completion.................................................................................................37
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................38
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................38
7.2
PLANNED ANALYSES.....................................................................................38
7.2.1
General considerations .......................................................................................38
7.2.2
Handling of Intercurrent Events .......................................................................38
7.2.3
Primary objective analyses.................................................................................38
7.2.3.3
Supplementary Analyses.......................................................................................39
7.2.4
Secondary objective analyses.............................................................................40
7.2.6
Safety analyses.....................................................................................................41
7.2.8
Interim Analyses .................................................................................................42
7.3
HANDLING OF MISSING DATA ...................................................................42
7.4
RANDOMIZATION...........................................................................................42

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ABBREVIATIONS AND DEFINITIONS
(e)COA
(electronic) Clinical Outcome Assessment
ACE
Angiotensin-Converting Enzyme
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALAT
Asociación Latinoamericana de Tórax
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATS
American Thoracic Society
AUC
Area under the Curve
BI
Boehringer Ingelheim
C3M
Fragment of type III collagen released by matrix metalloproteinase
C6M
Fragment of type VIa1 collagen released by matrix metalloproteinase-2
CA
Competent Authority
CA-125 (19.9)
Cancer antigen-125 (19.9)
CBO
Clinical Biosample Operations
CCI
Commercially Confidential Information
CDP
Clinical development plan
CES
Cough Evaluable Set 
CI
Confidence Interval
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTCAE
Common Terminology Criteria for Adverse Events
CTgov
ClinicalTrials.gov
CTP
Clinical Trial Protocol
CTR
Clinical Study Report
DBL
Database Lock
DLCO
Diffusing Capacity of the Lungs for Carbon Monoxide
EC
Ethics Committee

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ECD
Early Clinical Development
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EoS
End of Study (corresponds with End of Trial)
ePRO
Electronic Patient Reported Outcome
ERS
European Respiratory Society
FAS
Full Analysis Set
FC
Flow Chart
FEV1
Forced expiratory volume in one second
FUP
Follow-up
FVC
Forced Vital Capacity 
GCP
Good Clinical Practice
GERD
Gastroesophageal Reflux Disease 
GPV
Global Pharmacovigilance
GRL
Global Regulatory Lead
HA
Health Authority
HRCT
High Resolution Computed Tomography
ICAM-1
Intracellular adhesion molecule 1
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
IPF
Idiopathic Pulmonary Fibrosis 
IRB
Institutional Review Board
ISF
Investigator Site File
JRS
Japanese Respiratory Society
 
 
LPLV
Last patient last visit
LRTI
Lower Respiratory Tract Infection
MMP-7
Matrix metalloproteinase 7
PF
Pulmonary Fibrosis
 

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PPF
Progressive Pulmonary Fibrosis 
 
PRO-C3
Fragment of N-terminal type III collagen
PRO-C6 
Fragment of C-terminal type VIa3 collagen
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Steering Committee 
 
SP-D
Surfactant protein-D
TA
Therapeutic Area
TAH
Therapeutic Area Head
TBA
Trial Bioanalyst
TBMA
Trial Biomarker Analyst
TMCP
Translational Medicine & Clinical Pharmacology
TMF
Trial Master File
UIP
Usual Interstitial Pneumonitis
URI
Upper Respiratory Tract Infection
 
VICM
Fragment of citrullinated vimentin released by MMP
WOCBP
Woman of childbearing potential

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1.4.2
Risks
The risks of utilizing a wearable cough monitor are minimal. Skin irritation caused by the 
adhesive used to apply the device to the chest wall is possible, though not anticipated, and if 
present would not be expected to be severe. Continuous audio recordings may raise concern 
for privacy breaches and/or inadvertent recording of conversations. The
 
biosensor data is fully encrypted on device and in transit to prevent unauthorized access to 
health information. 
 does not contain an open-air microphone and is not 
designed to acquire speech or other sounds from a patient's mouth. It is intended to acquire 
sounds of the lungs and airways including cough sounds, wheeze sounds and normal breath 
sounds. The file is reversed to avoid discernible speech (if incidentally acquired) being 
interpretable during a QA/QC session in addition to a speech filter being applied to the raw 
transmission data to remove speech signatures from review. Files are broken up into short 
<60 second segments to reduce the risk further of any post-processed file containing 
discernible speech over a long enough period of time to capture private conversations and 
information.
1.4.3
Discussion
In sum, patients have the opportunity in this pilot study to utilize new digital technology for 
self-monitoring and remote data upload from their homes. The study design also eases travel 
burden by including remote study visits. While both parameters may not have immediate 
benefit to the patient, they may have near term benefit for patients in upcoming trials of 
therapeutic interventions and have potential to advance the science supporting the use of 
wearable technology in routine clinical care. These potential benefits come with a small risk 
of skin irritation and the very unlikely prospect of data privacy breaches. In all, we believe 
the interventions in this study are non-invasive, nonintrusive, and likely to offer more benefit 
than risk to patients who choose to participate. 

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2.
STUDY OBJECTIVES AND ENDPOINTS
A further understanding of the similarities and differences in cough among persons with Non 
IPF forms of pulmonary fibrosis and IPF, together with insight into the pattern and impact of 
cough in these patients is required. The current pilot aims to assess cough frequency, indirect 
measures of cough intensity and the association between objective cough measures and lung 
physiology and various patient-reported outcome measures in a patient cohort with Non IPF 
forms of pulmonary fibrosis and IPF. We will perform these assessments with a digitally 
enabled cough monitor 
 and video assisted remote spirometry with the 
concurrent aim of assessing the feasibility of remote monitoring in persons with pulmonary 
fibrosis.
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary objective of this study is to objectively describe cough frequency, utilizing four 
24-hour cough recordings over 12 weeks in a cohort of subjects with Non IPF Pulmonary 
Fibrosis or IPF using the 
 cough monitor.
The secondary objectives for this study are: 
∀
Assess the relationship between objective cough frequency and FVC (mL)
∀
Assess feasibility of patient performed remote cough data upload
∀
Assess feasibility of hybrid study design (% successful completion of remote visits) 
2.1.2
Primary endpoint(s)
Primary Endpoints: Cough count per hour (CC/hr) measured over a 24-hour period at 
baseline visit, Week 4(V4), Week 8(V5), Week 12 (V6).
2.1.3
Secondary endpoint(s)
Secondary endpoints include: 
∀
Change from baseline in CC/hr at Week 4, Week 8, Week 12.
∀
FVC (mL) at baseline
∀
FVC (mL) at Week 12
∀
Change from baseline in FVC (mL) at Week 12
∀
Feasibility of remote cough data capture (defined as % of analysable data per 24-hour 
recording)
∀
Feasibility of hybrid study design (successful completion of all elements of remote visit)

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pilot study design will be pursued in which all subjects will utilize the 
 cough 
monitor to characterize their cough. 
3.3
SELECTION OF STUDY POPULATION
The study population will include subjects (aged 18 and above) with Non IPF Pulmonary 
Fibrosis (defined as > 10% fibrosis on high resolution Chest CT as per principal investigator 
assessment) or IPF who are residing in one of the target countries and follow the routine 
clinical practice of the participating sites. We will target enrolment of 25 subjects with Non 
IPF Pulmonary Fibrosis and 25 with IPF. 
Screening of patients for this study is competitive, i.e. screening for the study will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this study. Patients already in screening at this time will be allowed to continue to 
enrollment if eligible. 
A log of all patients enrolled into the study (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they chose to complete 
the study or not. 
3.3.1
Main diagnosis for study entry
The study population will include subjects (aged 18 and above) with Non IPF Pulmonary 
Fibrosis or IPF, who are residing in one of the target countries. The study population will be 
enriched (70% of study population) for persons with clinically significant cough at the 
Screening Visit, defined as having 
 
3.3.2
Inclusion criteria
Subjects fulfilling all the following inclusion criteria will be eligible for participation in the 
study: 
1. Provision of signed informed consent in writing prior to study data collection
2. Subject aged 18 years or over
3. Subject diagnosed with Non IPF Pulmonary Fibrosis (>10% fibrosis on HRCT by 
principal investigator assessment) or IPF as per ATS/ERS/JRS/ALAT Guidelines
[P22-03204] within the past 12 months
4. FVC > 40% predicted at baseline visit
5. Life expectancy > 6 months (per assessment of treating physician)
3.3.3
Exclusion criteria
Subjects fulfilling any of the following exclusion criteria will not be eligible for participation 
in the study: 
1. Current smokers
2. URI or LRTI (including COVID-19 infection) within 4 weeks of screening visit
3. Airflow obstruction (FEV1/FVC < 70%) at baseline or known history of significant 
spirometry response to bronchodilator
4. Cough due to etiology other than ILD (e.g., allergic rhinitis, GERD)

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5. Other respiratory disorders including, but not limited to, a current diagnosis of any 
obstructive disease including chronic obstructive pulmonary disease (COPD) and 
asthma, active tuberculosis, lung cancer in treatment or in medical history, sleep 
apnea, known alpha-1 antitrypsin deficiency, cor pulmonale, clinically significant 
pulmonary hypertension, clinically significant bronchiectasis, or other active 
pulmonary diseases.
6. Initiation or change in dose or type of anti-tussive medication, angiotensin-converting 
enzyme (ACE) inhibitors, opiates, and systemic or inhaled (excluding intranasal)
corticosteroids in the 4 weeks prior to study entry
7. Subject with ILD exacerbation as defined by investigators within 4 weeks prior to 
study entry
8. Subject participating in a clinical study of a systemic or inhaled drug at the time of 
enrollment 
9. Visual, cognitive, motor or health impairment that, as judged by the investigator, may 
cause concern regarding the subjects’ ability to complete study assessments 
10. Subject not being fluent and literate in one of the main languages of the country 
3.3.4
Discontinuation of patients from assessments
Patients may discontinue study participation or withdraw consent to study participation at any 
time (“withdrawal of consent”). If the patients agree, they should stay in the study. Even if 
continuing to wear the cough monitor is not possible, they should attend further study visits 
to collect important study data.
An individual patient will discontinue the study if: 
∀
The patient has repeatedly shown to be non-compliant with important study procedures 
and, in the opinion of both, the investigator and contracting entity representative, is not 
willing or able to adhere to the study requirements in the future.
∀
The patient can no longer perform the study procedures for medical reasons
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the study requirements and procedures prior to study enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue or withdraw consent to study participation and the reason must be 
documented in the patient files and CRF.
3.3.4.1
Withdrawal of consent to participation
Patients may withdraw their consent to participation at any time without the need to justify 
the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and the options for continued follow-up after discontinuation of remote 
monitoring and other study procedures.

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3.3.4.2
Discontinuation of the study by the contracting entity
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. New safety information invalidating the earlier positive benefit-risk-assessment, 
please see Section 1.4.
3. Deviations from GCP, the study protocol, or the contract impairing the appropriate 
conduct of the study.
Further assessment and follow up of patients affected will occur as described in Section 
3.3.4.1.
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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4.
TREATMENTS
4.1
INVESTIGATIONAL INTERVENTION
The 
cough monitor will be worn by all study participants over 4 24-hour 
recordings during the 12-week study period. No investigational medicinal product will be 
administered. Please see Section 1.2.  
4.1.1
Method of assigning patients to intervention group
All enrolled subjects will receive the intervention of utilizing a wearable cough monitoring 
device with an accompanying mobile application (App) for data. All enrolled subjects will 
also receive a home spirometry device and accompanying mobile application and study 
provisioned smart phone (for the study duration). 
4.1.2
Storage conditions
The 
 sensor and charger are provided to the patient with custom 
packaging.  This hardware can be stored and transported within standard environmental 
conditions (-25°C to 50°C, 15% to 93% RH ± 3%, 700hPa to 1,070hPa).  When not in use 
and between measurements the patient can store the wearable device on the charger.  The 
charger was designed to fit within a small footprint on a table or desktop.
4.1.3
Device accountability
The investigator or designee will receive the 
 system kit, as delivered by the 
contracting entity or delegate when the following requirements are fulfilled:
∀
Approval of the study protocol by the IRB / ethics committee and/or HA approval
∀
Availability of a signed and dated study protocol contract between the contracting entity
contracting entity or delegate and the investigational site,
∀
Approval / notification of the regulatory authority, e.g. competent authority,
∀
Availability of the curriculum vitae of the Principal Investigator,
∀
Availability of a signed and dated study protocol,
∀
Availability of the proof of a medical license for the Principal Investigator,
∀
Availability of FDA Form 1572 (if applicable).
Investigational devices are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused devices and/or devices upon study completion. 
The investigator or designee must maintain records of the product’s delivery to the study site, 
the inventory at the site, the use by each patient, and the return to the contracting entity of 
unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the study patients. The investigator or designee will 
maintain records that document adequately that the patients were provided the device(s) 
specified by the study protocol. At the time of return to the contracting entity the investigator

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or designee must verify that all unused supplies have been returned by the study protocol
patient and that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. 
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
As per the Exclusion criteria (3.3.3), persons who have had initiation of a change in dose of 
ACE-I therapy, inhaled steroid therapy (excluding intranasal), systemic corticosteroid, anti-
tussive therapy (including over the counter medications) or opiate therapy within 4 weeks of 
study entry are not eligible for inclusion. If a patient experiences a clinical deterioration
requiring initiation of or a change in dose of one of the aforementioned classes of medication
during the study period, the site principal investigator must notify the contracting entity
within 72 hours.
4.2.2.2
Restrictions on lifestyle
Patients can perform most forms of exercise, typical daily activities and shower while 
wearing the 
 device. Full submersion into water (e.g. swimming, hot tub use or 
baths) is not advised as it may lead to device malfunction and compromise any further data 
collection. 
4.2.2.3
Contraception requirements
No contraception requirements are necessitated by use of the 
 device. 
4.3
DEVICE USE COMPLIANCE
Compliance with cough recordings will be assessed based on patient adherence to cough 
monitoring (defined as % of time over the 24-hour recording period that the patient is 
wearing the cough monitor) and remote cough data capture (defined as % of analyzable data
per 24-hour recording).
Site staff will receive notification via email each time a patient completes a cough count 
recording with successful data upload. If the site does not receives this type of notification, 
the site should contact the patient to assess whether the patient requires assistance with any 
elements of the 24 hour cough recording and upload.  

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Spirometry will be conducted with the patient in a seated position. It is preferable that the 
same trained individual performs the PFTs for a given patient. The best of three efforts will 
be defined as the highest FVC obtained on any of three blows meeting the 2019 ATS/ERS 
criteria (with a maximum of eight attempts). Predicted normal values will be calculated 
according to GLI (Global Lung Initiative). Efforts should be made to schedule the spirometric 
measurements at approximately the same time of the day, at least within the same half-day 
(morning vs afternoon), with reference to baseline measurement (Visit 2). On days of study 
visits, patients should be encouraged to refrain from vigorous activity within 1 hour of 
pulmonary function testing. If treated with bronchodilators, washout should be advised before 
spirometry and documented in the source documents. If treated with bronchodilators, wash-
out of 24 hours for long acting and 8 hours for short acting bronchodilators should be 
observed before spirometry and documented in source. Spirometry results will be 
electronically transmitted. To ensure the quality of the spirometry measures, a manual 
overread will be performed by the spirometry vendor. Further instructions regarding FVC 
measurements will be provided in the ISF. 
Video supervised home spirometry measurements will be performed. Patients will receive 
instruction on the video supervised home spirometer use at the Baseline Visit (V2). The first 
“home spirometry” measure will be performed at home two days following the baseline study 
visit (with study coordinator instruction and video assisted supervision). Patients will also 
perform video supervised home spirometry measurements at remote Visits 4, 5, and 6. For 
the video-assisted home spirometry, patients will use a handheld spirometer 
 
together with a mobile phone with the installed 
App provided by site. These home 
spirometry measurements will not replace the onsite FVC measurement at Visit 2 and Visit 7
(Week 12).

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 Biosensor
As noted in Section 1.2, the 
 Biosensor will be used to capture 24-hour 
recordings of cough frequency data. Additionally, data acquired in this study using the 
 cough monitor might be analyzed further to e.g. build diagnostic, prognostic 
and predictive models and develop new algorithms for the analysis of cough data. This 
exploratory analysis might be performed in collaboration with an independent third party 
nominated by the contracting entity.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at Visit 2 and 7, as specified in the 
Flow Chart. It includes at a minimum general appearance, neck, lungs, cardiovascular 
system, abdomen, extremities, and skin. Measurement of height and body weight will be 
performed at Visit 2 and 7. The results must be included in the source documents. 

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5.2.2
Vital signs
Vital signs will be evaluated at Visit 2 and 7, as specified in the Flow Chart, prior to blood 
sampling. This includes systolic and diastolic blood pressure and pulse rate (electronically or 
by palpation count for 1 minute) in a seated position after 5 minutes of rest. The results must 
be included in the source documents. 
5.2.3
Safety laboratory parameters
Safety laboratory parameters will not be performed. 
5.2.4
Electrocardiogram
ECGs will not be routinely performed. 
5.2.5
Other safety parameters
Should the patient demonstrate a > 10% absolute or relative drop in forced vital capacity 
(FVC) during on-site or home spirometry, the site principal investigator will be notified and 
asked to assess whether any further evaluations are needed. 
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medical intervention and which does not necessarily have to have a 
causal relationship with this Intervention.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medical 
intervention, whether considered related or not.
The following should be recorded as an AE in the CRF (if applicable):
∀
AEs related to study procedures
∀
AEs or SAEs that fufill the following criteria: 
o
Events leading to lung transplantation
o
COVID-19 Infection 
o
Events leading to death  
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE), is defined as any AE, which fulfils at least one of the 
following criteria:
∀
results in death

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∀
is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe, 
∀
requires inpatient hospitalisation or prolongation of existing hospitalisation 
∀
results in persistent or significant disability or incapacity, 
∀
is a congenital anomaly / birth defect, 
∀
is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the patient and may require medial 
or surgical intervention to prevent one of the other outcomes listed in the above
definitions. 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 
hospitalisation or development of dependency or abuse. 
SAEs related to study procedures, or as defined in Section 5.2.6.1.1, should be recorded in 
the CRF.
No SAE reporting to drug safety will occur, hence no SAE reconciliation required.
5.2.6.1.3
AEs considered “Always Serious”
Not applicable
5.2.6.1.4
Adverse Events of Special Interest
Not applicable
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
∀
From signing the informed consent onwards until the individual patient’s end of study (= 
the End of Study (EoS) visit): all AEs (serious and non-serious) as defined in 
Section 5.2.6.1.1.
5.2.6.2.2
AE reporting to the contracting entity and timelines
Not applicable
5.2.6.2.3
Exemptions to SAE reporting
Not applicable 

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5.4
BIOBANKING
Not applicable
5.5
OTHER ASSESSMENTS
Resource use data will include unscheduled hospitalizations, healthcare provider visits, and 
emergency room use.
5.6
APPROPRIATENESS OF MEASUREMENTS
Cough count or frequency of cough is a standard and routine measure utilized in studies of 
anti-tussive therapy. In the current pilot, we will also measure, “cough intensity”, which is 
not routinely captured by current cough monitors. As such, it is not a measure that is 
routinely included in published literature to date. In the current study, we will assess cough

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intensity, measured as an analysis of a combination of the following parameters: cough 
duration (% of minute recordings taken up by cough), variability of  minute-to-minute 
cough%/minute, time interval of coughs (msec) on x axis, amplitude of cough on y-axis, 
AUC of cough per cough or cough spasm, and within cough power (measured by color -
clear, blue, yellow, red; worst color present and change in color over time).

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∀
Will be collected at the Screening/Baseline visit
6.2.2
Intervention period
Patients will receive the cough monitor and conduct cough recordings over a period of 12 
weeks from study entry until the End of Study visit. 
6.2.3
Study completion
Patients will complete study procedures at Visit 7/EOS and return the cough monitor, 
provisioned mobile phone and home spirometer at this visit. Completion of study procedures 
and return of the provisioned equipment at this visit will constitute study completion. 

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
This is an exploratory study with no treatment intervention aiming to assess the use of a new 
generation of cough monitoring device and describe cough frequency over 12 weeks. No 
confirmatory testing is performed and hence no null and alternative hypotheses are defined.  
A justification of the sample size is provided in Section 7.4.
7.2
PLANNED ANALYSES
7.2.1
General considerations
Cough count/hr will be log transformed for analysis.  Standard statistical parameters (number 
of non-missing values, mean, standard deviation (SD), median, quartiles, minimum and
maximum) or frequency tables will be calculated where appropriate. All individual data will 
be listed.
Patient analysis sets:
Entered Set (ES): those patients who were entered into the study.
Additional patient analysis sets may be defined in the SAP.
7.2.2
Handling of Intercurrent Events
This section is not applicable as there is no comparison of interventions.
7.2.3
Primary objective analyses
The cough count (CC) frequency, measured over 4 24-hour recordings in 12 weeks will be 
analysed as CC/hour and will be log-transformed for data summaries.  On each day for which 
cough monitoring is completed, the log-transformed cough count is calculated as:
Log-transformed cough count = log
Number of coughs
Length of recorded time (hours)
Cough count for each visit will be reported descriptively.  Summary statistics will be 
tabulated on original scale of CC/hr as well as the geometric mean and 95% confidence 
intervals after back-transforming the summarized log transformed data.  
 
  Summary measurements and individual values 
of CC/hr over time will also be presented graphically.
Additional details will be included in the SAP.

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The primary endpoints will be summarized in the same fashion as described above by each 
subgroup level.
7.2.3.3
Supplementary Analyses
Not applicable

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7.2.4
Secondary objective analyses
Secondary endpoints will be summarized descriptively by visit.  
Change from baseline in CC/hr at Week 4, Week 8, and Week 12 will be summarized in 
terms of absolute changes in CC/hr and in terms of geometric mean ratios.  Model based 
estimates for changes from baseline at Week 12, for example least squares means adjusted for 
baseline CC/hr or other covariates, may be calculated.
Standard descriptive statistical parameters will be tabulated for all other secondary endpoints.
To assess the relationship between objective cough frequency and FVC (mL), correlations
(spearman and Pearson) will be calculated between the following variables:
∀
Baseline CC/hr (log-transformed) and Baseline FVC (mL)
∀
Baseline CC/hr (log-transformed) and FVC (mL) at Week 12
∀
Baseline CC/hr (log-transformed) and change from baseline FVC (mL) at Week 12
∀
CC/hr at Week 12 (log-transformed) and FVC (mL) at Week 12
∀
Change in CC/hr at Week 12 (calculated from log-transformed values) and change
from baseline in FVC (mL) at Week 12
Graphical presentations of the secondary endpoints and correlations may also be produced.  
Further details will be included in the SAP.

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7.2.6
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced.
All enrolled patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Frequency and severity of adverse events related to the study procedure will be tabulated by 
system organ class and preferred term after coding according to the current version of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA) at database lock.

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7.2.8
Interim Analyses
Interim analyses will be performed as needed to inform subsequent studies. 
7.3
HANDLING OF MISSING DATA
Imputation of missing data will not be done.  Unless otherwise noted, analysis will be 
conducted using all patients with the endpoint available.
Missing or incomplete AE dates will be imputed according to BI standards.
7.4
RANDOMIZATION
but to gain experience using the 
 device in a real-world setting, therefore no 
randomization is needed for this single group study.
7.5
DETERMINATION OF SAMPLE SIZE
[P22-04417] was a phase 2a study which investigated the effect of inhaled RVT-1601 
(cromolyn sodium) on 24-hour average cough counts in patients with IPF.  97 patients were 
randomized to four arms (RVT-1601 10mg, 40mg, 80mg, or placebo for 12 weeks).  The 
baseline measurements of the mean 24-hour cough count were 38.0 ± 26.6 (RVT-1601 10mg; 
n=27); 36.8 ± 21.7 (RVT-1601 40mg arm; n=22); 35.7 ± 17.8 (RVT-1601 80mg arm; n=23); 
34.3 ± 19.6 (Placebo; n=25).
Assuming we observe similar standard deviations for cough count as the SCENIC trial, the 
table below reports the 95% confidence interval range we expect for the 24-hour cough count 
assuming a sample size of 50 patients that are normally distributed.  For example, when the 
sample size is 50, a two-sided 95% confidence interval for a mean will extend 7.484 from the 
observed mean, assuming that the standard deviation is known to be 27 and the confidence 
interval is based on the large sample z-statistic.
Table 7.5: 1 Confidence Interval ranges based on N=50 patients for different standard 
deviations
Standard Deviation
19
21
23
25
27
95% CI Range*
±5.266
±5.821
±6.375
±6.930
±7.484
*CI Range calculated using the NQuery 8, Version 8.2.7.0 program for “Confidence Interval for One Mean using 
Normal Distribution”

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8.
INFORMED CONSENT, STUDY RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The study will be carried out in accordance with the Medical Devices Directive (93/42/EEC) 
and the harmonised standards for Medical Devices (ISO 14155, current version).
The study will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014. Investigators and site staff must adhere to these 
principles. Deviation from the protocol, the principles of ICH GCP or applicable regulations 
as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the contracting entity or delegate immediately of any urgent 
safety measures taken to protect the study patients against any immediate hazard, as well as 
of any serious breaches of the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the 
contracting entity with regard to publication of the results of this study are described in the 
investigator contract. As a rule, no study results should be published prior to finalisation of 
the Study Report.
The certificate of insurance cover is made available to the investigator and the patients and is
stored in the ISF.
8.1
STUDY APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT
This study will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the study, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to 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 given sufficient time to consider participation in the study. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a study collaborator has given a supplementary explanation, the study collaborator also 

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signs (or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the contracting entity’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for study quality management. It is initiated by the assessment 
of critical data and processes for study subject protection and reliability of the results as well 
as identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced studys, documents the rationale and strategies for risk 
management during study conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in study conduct, study
design or monitoring approaches. 
A quality assurance audit / inspection of this study may be conducted by the contracting 
entity, contracting entity’s designees, or by IRB / IEC 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.
8.3
RECORDS
CRFs for individual patients will be provided by the contracting entity.
8.3.1
Source documents
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. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
study and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Before sending or uploading those copies, the investigator must ensure that all patient
identifiers (e.g. patient’s name, initials, address, phone number, social security number) have 
properly been removed or redacted from any copy of the patients’ source documents.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:
∀
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

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∀
Patient participation in the study (substance, study number, patient number, date patient
was informed)
∀
Dates of patient’s visits.
∀
Medical history (including study indication and concomitant diseases, if applicable)
∀
Medication history
∀
Adverse events and outcome events (onset date (mandatory), and end date (if available))
∀
Serious adverse events (onset date (mandatory), and end date (if available))
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)
∀
Completion of patient’s participation in the study (end date; in case of premature 
discontinuation document the reason for it).
∀
Prior to enrolment of a patient to this study, there must be documented evidence in the 
source data (e.g. medical records) that the study participant meets all inclusion criteria 
and does not meet any exclusion criteria. The absence of records (either medical records, 
verbal documented feedback of the patient or testing conducted specific for a protocol) to 
support inclusion / exclusion criteria does not make the patient eligible for the study.
8.3.2
Direct access to source data and documents
The investigator / institution will allow site study-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access must be provided to the CRF and all source 
documents / data, including progress notes, copies of laboratory and medical test results, 
which must always be available for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
contracting entity or delegate will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Study site(s):
The study site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the study (whatever is 
longer).
Contracting entity:
The contracting entity must retain the essential documents according to the contracting 
entity’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 

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8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook. 
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the contracting entity by using a patient identification number instead of the 
patient’s name. The code is only available at the site and must not be forwarded to the 
contracting entity. In case patient’s records will be forwarded e.g. for SAE processing or 
adjudication committees, personal data that can identify the patient will be redacted by the 
site prior to forwarding. Access to the patient files and clinical data is strictly limited: 
personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site 
as a result of the study need to be available for inspection on request by the participating 
physicians, the contracting entity’s representatives, by the IRB / IEC and the regulatory 
authorities.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs / IECs and patients will 
be informed as appropriate.
8.6
STUDY MILESTONES
The start of the study is defined as the date when the first patient in the whole study signs 
informed consent.
The end of the study is defined as the date of the last visit of the last patient in the whole 
study (“Last Patient Completed”). Early termination of the study is defined as the 
premature termination of the study due to any reason before the end of the study as specified 
in this protocol.
Temporary halt of the study is defined as any unplanned interruption of the study by the 
contracting entity with the intention to resume it.
Suspension of the study is defined as an interruption of the study based on a Health 
Authority request.

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8.7
ADMINISTRATIVE STRUCTURE OF THE STUDY
The study is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this study. Tasks and responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
BI has appointed a Clinical Trial Leader responsible for coordinating all required activities, in 
order to 
-
manage the study in accordance with applicable regulations and internal SOPs,
-
direct the study team in the preparation, conduct, and reporting of the study,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
In the participating countries the study will be performed by the respective local or regional 
BI-organisation (Operating Unit, OPU) in accordance with applicable regulations and BI
SOPs.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the study are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service will be used in this study. Details will be provided in the Central 
Laboratory Manual, available in the ISF.

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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P18-00823
Van Manen MJ, Birring SS, Vancheri C, Cottin V, Renzoni EA, Russell 
AM, Wijsenbeek MS. Cough in idiopathic pulmonary fibrosis. European 
Respiratory Review. 2016 Sep 1;25(141):278-86.
P22-03204
Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, 
Kreuter M, Lynch DA, Maher TM, Martinez FJ, Molina-Molina M. 
Idiopathic pulmonary fibrosis (an update) and progressive pulmonary 
fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice 
guideline. American Journal of Respiratory and Critical Care Medicine. 
2022 May 1;205(9):e18-47.
P22-04417
Martinez FJ, Wijsenbeek MS, Raghu G, Flaherty KR, Maher TM, Wuyts 
WA, Kreuter M, Kolb M, Chambers DC, Fogarty C, Mogulkoc N. Phase 
2B study of inhaled RVT-1601 for chronic cough in idiopathic pulmonary 
fibrosis: a multicenter, randomized, placebo-controlled study (SCENIC 
trial). American journal of respiratory and critical care medicine. 2022 May 
1;205(9):1084-92. 
P22-05773
Lee J, White E, Freiheit E, Scholand MB, Strek ME, Podolanczuk AJ, et al. 
Cough-specific quality of life predicts disease progression among patients 
with interstitial lung disease: Data from the pulmonary fibrosis foundation 
patient registry. Chest. 2022.
R12-1608
Ryerson C, Abbritti M, Ley B, Elicker B, Jones K, Collard H. Cough 
predicts prognosis in idiopathic pulmonary fibrosis. Respirology. 
2011;16(6):969-975.
R16-0722
Schwartz MI, King TE. Interstitial lung disease. 5th ed. People’s Medical 
Publishing House; 2011.
R20-2419
Graham BL, Steenbruggen I, Miller MR, et al., American Thoracic Society,
European Respiratory Society. Standardization of spirometry 2019 update:
an official American Thoracic Society and European Respiratory Society
technical statement. Am J Respir Crit Care Med 2019;200(8):e70-e88.
R20-3543
Olson A, Hartmann N, Schlenker-Herceg R, Wallace L. Prevalence of 
progressive fibrosing interstitial lung disease. In: Rare ILD/DPLD. 
European Respiratory Society; 2018.
R22-2496
Araos J, Alegria L, Garcia P, Cruces P, Soto D, Erranz B et al. Near-Apneic 
Ventilation Decreases Lung Injury and Fibroproliferation in an Acute 
Respiratory Distress Syndrome Model with Extracorporeal Membrane 
Oxygenation. American Journal of Respiratory and Critical Care Medicine. 
2019;199(5):603-612.
R22-2497
Froese AR, Shimbori C, Bellaye PS, Inman M, Obex S, Fatima S, Jenkins 
G, Gauldie J, Ask K, Kolb M. Stretch-induced activation of transforming 
growth factor-β1 in pulmonary fibrosis. American journal of respiratory and 
critical care medicine. 2016 Jul 1;194(1):84-96. 
R22-2498
Man W, Kyroussis D, Fleming T, Chetta A, Harraf F, Mustfa N et al. 
Cough Gastric Pressure and Maximum Expiratory Mouth Pressure in 
Humans. American Journal of Respiratory and Critical Care Medicine. 
2003;168(6):714-717.

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R22-2499
Sharpey-Schafer E. Effects of coughing on intra-thoracic pressure, arterial 
pressure and peripheral blood flow. The Journal of Physiology. 
1953;122(2):351-357.
R22-2500
Wakwaya Y, Ramdurai D, Swigris JJ. Managing cough in idiopathic 
pulmonary fibrosis. Chest. 2021;160(5):1774–82.
9.2
UNPUBLISHED REFERENCES
Not applicable

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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
Patient will be provided with User Manuals for the study devices

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.

 
 
 
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