An International Study to Characterize the Disease Behaviour of Idiopathic Pulmonary Fibrosis and Interstitial Lung Disease During the Peri-Diagnostic Period
Phase: NA
Conditions: Idiopathic Pulmonary Fibrosis, Interstitial Lung Disease
Sponsor: Hoffmann-La Roche

 
 
Official Title: 
 
AN INTERNATIONAL STUDY TO CHARACTERISE THE DISEASE 
BEHAVIOUR OF IDIOPATHIC PULMONARY FIBROSIS AND 
INTERSTITIAL LUNG DISEASE DURING THE PERI-DIAGNOSTIC 
PERIOD 
NCT Number: NCT03261037 
Document Date: Protocol Version 1: 26-April-2017 
 
 

 
FINAL PROTOCOL APPROVAL 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, Switzerland. 
However, it may be implemented in individual countries by Roche’s local affiliates, including 
Genentech, Inc. in the United States. The information contained in this document, especially any 
unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an Investigator, potential Investigator, or consultant, for review 
by you, your staff, and an applicable Ethics Committee or Institutional Review Board. It is 
understood that this information will not be disclosed to others without written authorization from 
Roche except to the extent necessary to obtain informed consent from persons to whom the drug 
may be administered. 
 
F. Hoffmann-La Roche Ltd 
Protocol MA39297, Version 1, 26 April 2017 
 
PROTOCOL 
TITLE: 
AN INTERNATIONAL STUDY TO CHARACTERIZE THE 
DISEASE BEHAVIOUR OF IDIOPATHIC PULMONARY 
FIBROSIS AND INTERSTITIAL LUNG DISEASE 
DURING THE PERI-DIAGNOSTIC PERIOD 
PROTOCOL NUMBER: 
MA39297 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2016-005114-22 
IND NUMBER: 
N/A 
TEST PRODUCT: 
N/A 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
See electronic date stamp below 
 
 
 
 
26-Apr-2017 11:30:59
Title
Approver's Name
Company Signatory (Clinical)
Date and Time (UTC)

 
F. Hoffmann-La Roche Ltd 
Protocol MA39297, Version 1, 26 April 2017 
2 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .................................................................... 6 
PROTOCOL SYNOPSIS ...................................................................................... 7 
1 
BACKGROUND .......................................................................................... 18 
1.1 
Background on Idiopathic Pulmonary Fibrosis and 
Interstitial Lung Disease (IPF/ILD) ......................................... 18 
1.2 
Background on Test Product ................................................. 20 
1.3 
Study Rationale ..................................................................... 20 
2 
OBJECTIVES AND ENDPOINTS ............................................................... 22 
3 
STUDY DESIGN ......................................................................................... 24 
3.1 
Description of the Study......................................................... 24 
3.2 
End of Study and Length of Study ......................................... 29 
3.3 
Rationale for Study Design and Patient Population ............... 29 
3.3.1 
Rationale for Disease Response–based Endpoints ............... 30 
4 
MATERIALS AND METHODS .................................................................... 31 
4.1 
Patients .................................................................................. 31 
4.1.1 
Inclusion Criteria .................................................................... 31 
4.1.2 
Exclusion Criteria ................................................................... 31 
4.2 
Method of Treatment Assignment and Blinding ..................... 32 
4.3 
Study Treatment .................................................................... 32 
4.4 
Concomitant Therapy ............................................................ 32 
4.4.1 
Permitted Therapy ................................................................. 32 
4.5 
Study Assessments ............................................................... 32 
4.5.1 
Informed Consent Forms and Enrolment Log ........................ 32 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................. 32 
4.5.3 
Physical Examinations (including vital signs) ......................... 33 
4.5.4 
Disease-relevant Assessments ............................................. 33 
4.5.5 
Home-based Assessments .................................................... 34 

 
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Protocol MA39297, Version 1, 26 April 2017 
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4.5.5.1 
Daily Spirometry .................................................................... 34 
4.5.5.2 
Daily Physical Functional Capacity Assessments .................. 34 
4.5.6 
Laboratory and Other Biological Samples ............................. 34 
4.5.7 
Optional Biomarker Samples ................................................. 34 
4.5.8 
Patient-Reported Outcomes (PRO) ....................................... 36 
4.6 
Patient, Study, and Site Discontinuation ................................ 37 
4.6.1 
Patient Discontinuation from Study ........................................ 37 
4.6.2 
Study Discontinuation ............................................................ 37 
4.6.3 
Site Discontinuation ............................................................... 38 
5 
ASSESSMENT OF SAFETY ....................................................................... 38 
5.1 
Safety Plan ............................................................................ 38 
6 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 38 
6.1 
Determination of Sample Size ............................................... 38 
6.2 
Summaries of Conduct of Study ............................................ 39 
6.3 
Summaries of Demographic and Baseline 
Characteristics ....................................................................... 40 
6.4 
Primary and Secondary Analyses .......................................... 40 
6.4.1 
Primary Endpoint ................................................................... 40 
6.4.2 
Secondary Endpoints ............................................................ 40 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 41 
6.5 
Biomarker Analyses ............................................................... 42 
6.6 
Interim Analyses .................................................................... 42 
7 
DATA COLLECTION AND MANAGEMENT ............................................... 42 
7.1 
Data Quality Assurance ......................................................... 42 
7.2 
Electronic Case Report Forms ............................................... 43 
7.3 
Patient-Reported Outcome Data ........................................... 43 
7.4 
Source Data Documentation .................................................. 43 
7.5 
Use of Computerized Systems .............................................. 44 
7.6 
Retention of Records ............................................................. 44 
8 
ETHICAL CONSIDERATIONS .................................................................... 45 

 
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Protocol MA39297, Version 1, 26 April 2017 
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8.1 
Compliance with Laws and Regulations ................................ 45 
8.2 
Informed Consent .................................................................. 45 
8.3 
Institutional Review Board or Ethics Committee .................... 46 
8.4 
Confidentiality ........................................................................ 46 
9 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 47 
9.1 
Study Documentation ............................................................ 47 
9.2 
Protocol Deviations ................................................................ 47 
9.3 
Site Inspections ..................................................................... 47 
9.4 
Administrative Structure......................................................... 47 
9.5 
Publication of Data and Protection of Trade Secrets ............. 48 
9.6 
Protocol Amendments ........................................................... 48 
10 REFERENCES ........................................................................................... 49 
 
 
 
 

 
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Protocol MA39297, Version 1, 26 April 2017 
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LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 22 
Table 2 
Sample Size Scenarios ............................................................... 39 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 25 
Figure 2 
Collaboration Platform................................................................. 28 
Figure 3 
Study Digital Ecosystem ............................................................. 29 
Figure 4 
Daily FVC Measurements over Time .......................................... 56 
 
LIST OF APPENDICES 
Appendix 1  
Schedule of Activities .................................................................. 54 
Appendix 2  
Hand-Held Spirometry: Example of Disease Behavior in an 
Individual Patient ......................................................................... 56 
 

 
F. Hoffmann-La Roche Ltd 
Protocol MA39297, Version 1, 26 April 2017 
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PROTOCOL ACCEPTANCE FORM 
TITLE: 
AN INTERNATIONAL STUDY TO CHARACTERIZE THE 
DISEASE BEHAVIOUR OF IDIOPATHIC PULMONARY 
FIBROSIS AND INTERSTITIAL LUNG DISEASE DURING 
THE PERI-DIAGNOSTIC PERIOD 
PROTOCOL NUMBER: 
MA39297 
VERSION NUMBER: 
1 
EUDRACT NUMBER: 
2016-005114-22 
IND NUMBER: 
N/A 
TEST PRODUCT: 
N/A 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files. Please return a copy of 
the signed form {as instructed by XX [e.g., your local study monitor, the CRO]} [or] 
{to the contact provided below}. 
{Name}  
{Address} 
 
 
 
 

 
F.  H off m a n n -L a R o c h e Lt d  
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7  
 
P R O T O C O L S Y N O P SI S  
TI T L E:  
A N I N T E R N A TI O N A L S T U D Y T O C H A R A C T E RI Z E  
T H E DI S E A S E B E H A VI O U R O F I DI O P A T HI C P U L M O N A R Y 
FI B R O SI S  A N D I N T E R S TI TI A L L U N G DI S E A S E  
D U RI N G T H E P E RI -DI A G N O S TI C P E RI O D  
P R O T O C O L 
N U M B E R:  
M A 3 9 2 9 7  
V E R SI O N N U M B E R:  
1 
E U D R A C T  N U M B E R:  
2 0 1 6 -0 0 5 1 1 4 -2 2  
I N D N U M B E R: 
N/ A  
T E S T P R O D U C T:  
N/ A  
P H A S E:  
N/ A  
I N DI C A TI O N: 
I DI O P A T HI C P U L M O N A R Y FI B R O SI S / I N T E R S TI TI A L L U N G 
DI S E A S E  
S P O N S O R:  
F. H off m a n n -L a R o c h e Lt d  
 
O bj e cti v e s a n d E n d p oi nt s  
T h er e i s li mit e d d at a a v ail a bl e o n t h e e arl y c o ur s e of I P F a n d I L D. Oft e n cli ni ci a n s 
r e q uir e d et ail e d i nf or m ati o n o n di s e a s e b e h a vi or i n or d er t o e st a bli s h a w or ki n g 
di a g n o si s a n d t o d e ci d e o n f urt h er p ati e nt m a n a g e m e nt . Thi s st u d y will c h ar a ct eri z e 
t h e di s e a s e b e h a vi or of I P F a n d I L D i n t h e p eri-di a g n o sti c p eri o d. T hi s o bj e cti v e will b e 
a c hi e v e d b y  u si n g a m ulti di m e n si o n al a p pr o a c h a s s e s si n g c h a n g e s i n p ul m o n ar y 
f u n cti o n, m e a s ur e d b y d ail y h a n d h el d s pir o m etr y, a s s e s si n g p h y si c al f u n cti o n al 
c a p a cit y, m e a s ur e d b y a c c el er o m etr y, a n d ot h er a s p e ct s of di s e a s e b e h a vi or 
( s y m pt o m s a n d q u alit y of lif e), b y u si n g v ari o u s P R O m e a s ur e s.  
F or t hi s st u d y, t h e p eri -di a g n o sti c p eri o d c o v er s :  
•  
t h e pr e-di a g n o sti c p eri o d (fr o m i n cl u si o n  i nt o t h e st u d y t o di a g n o si s; f or a 
m a xi m u m of 1 2 m o nt h s).  
•  
t h e p o st-di a g n o sti c p eri o d (fr o m t h e di a g n o si s t o t h e st art of dr u g tr e at m e nt wit hi n 
6 m o nt h s or a m a xi m u m of 6 m o nt h s aft er di a g n o si s if n o tr e at m e nt i s st art e d).  
S p e cifi c o bj e cti v e s a n d c orr e s p o n di n g e n d p oi nt s f or t h e st u d y  ar e o utli n e d  b el o w 
(T a bl e 1).  

 
F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol  M A 3 9 2 9 7, V er si o n 1, 2 6 A pril 2 0 1 7  
1 0  
di s c u s si o n a m o n g I L D e x p ert s i s k n o w n t o i n cr e a s e t h e a c c ur a c y of t h e di a g n o si s of 
I P F/I L D. 
All p ati e nt s will b e m a n a g e d at t h e di s cr eti o n of t h e I n v e sti g at or t a ki n g i nt o a c c o u nt 
l o c al cli ni c al pr a cti c e g ui d eli n e s a n d st a n d ar d s of c ar e a s w ell a s a v ail a bl e cli ni c al 
e vi d e n c e f or p ati e nt s wit h s u s p e ct e d I P F/I L D or di a g n o s e d wit h I P F/I L D.  
T h e st u d y s c h e m a i s s h o w n i n Fi g ur e 1.  
Fi g ur e  1 
St u d y S c h e m a  
 
I L D =i nt er stiti al l u n g di s e a s e; I P F =i di o p at hi c p ul m o n ar y fi br o si s 
Fr o m i n cl u si o n i nt o t h e st u d y, p ati e nt s will b e f oll o w e d f or a m a xi m u m of 1 2 m o nt h s i n 
t h e pr e-di a g n o si s a s s e s s m e nt p eri o d. F oll o wi n g t h or o u g h a s s e s s m e nt s a n d di a g n o s e s, 
t hr e e gr o u p s of p ati e nt s will b e i d e ntifi e d: 
•  
P ati e nt s di a g n o s e d wit h I P F.  
•  
P ati e nt s di a g n o s e d wit h a n I L D ot h er t h a n I P F.  
•  
P ati e nt s di a g n o s e d wit h a c o n diti o n t h at i s n ot a n I L D.  
 
F or i n di vi d u al p ati e nt s, t h e e n d of t h e st u d y will b e a s f oll o w s:  
•  
S h o ul d n o di a g n o si s b e m a d e 1 2 m o nt h s aft er i n cl u si o n i nt o t h e st u d y, t h e p ati e nt 
will l e a v e t h e st u d y.  
•  
P ati e nt s di a g n o s e d wit h a n o n -I L D c o n diti o n will l e a v e t h e st u d y o n t h e d at e of 
di a g n o si s.  

 
F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol  M A 3 9 2 9 7, V er si o n 1, 2 6 A pril 2 0 1 7  
1 1  
•  
P ati e nt s di a g n o s e d wit h I P F or n o n -I P F I L D will r e m ai n a n d b e f oll o w e d i n t h e 
st u d y u p t o t h e st art of dr u g tr e at m e nt ( wit hi n si x m o nt h s) or a m a xi m u m of s i x 
m o nt h s if n o dr u g tr e at m e nt i s pr e s cri b e d.  
“ St art of dr u g tr e at m e nt”  i s d efi n e d a s t h e d at e w h e n  tr e at m e nt c o m m e n c e s . T hi s 
i n cl u d e s t h e e v e nt of a p ati e nt r e c ei vi n g I P F or I L D dr u g tr e at m ent fr o m a p h y si ci a n 
ot h er t h a n t h e i n v e sti g at or.  
A c c or di n gl y , t h e t ot al l e n gt h of t h e st u d y i s v ari a bl e f or e a c h p ati e nt, wit h a m a xi m u m of 
1 8 m o nt h s.  
Sit e vi sit s will b e c o n d u ct e d at a mi ni m u m at b a s eli n e, di a g n o si s, a n d e n d -of -st u d y f or 
e a c h i n di vi d u al p ati e nt. D uri n g e a c h st u d y p eri o d ( pr e - a n d p o st -di a g n o sti c p eri o d), 
e v er y p ati e nt s h o ul d h a v e at l e a st o n e sit e vi sit, s c h e d ul e d at t h e di s cr eti o n of t h e 
I n v e sti g at or. D uri n g t h e s e vi sit s, a n y r el e v a nt i nf or m ati o n s u c h a s tr e at m e nt s gi v e n a n d 
r e s ult s fr o m H R C T s, r a di o gr a p h s, D LC O , l u n g bi o p si e s et c. will b e c oll e ct e d, a s 
a v ail a bl e.  
T h e 6 M W T a n d F V C m e a s ur e m e nt s will b e a s s e s s e d o n -sit e a s p er t h e S c h e d ul e of 
A cti viti e s ( A p p e n di x 1).  
T h e st u d y  will b e c o n d u ct e d u n d er t h e l e a d er s hi p of a St e eri n g C o m mitt e e.  
I n t h e a b s e n c e of t h e u s e of a n y t h er a p e uti c a g e nt, a n I n d e p e n d e nt R e vi e w C o m mitt e e 
I R C/I R F or a D at a S af et y M o nit ori n g B o ar d ( D S M B)/ D at a M o nit ori n g C o m mitt e e ( D M C) 
will n ot b e n e e d e d i n t hi s st u d y.  
P ati e nt st u d y -s p e cifi c a s s e s s m e nt s / st u d y kit  
U p o n st u d y e nr oll m e nt, e a c h p ati e nt will r e c ei v e a st u d y kit wit h a u ni q u e i d e ntifi er 
c o nt ai ni n g t h e f oll o wi n g:  
•  
H a n d -h el d s pir o m et er ( D e vi c e t o m e a s ur e d ail y F V C at h o m e).  
•  
A c c el er o m et er ( D e vi c e t o c o nti n u o u sl y m e a s ur e d ail y a cti viti e s , s u c h a s st e p s p er 
d a y, p h y si c al a cti vit y l e v el).  
•  
A t a bl et c o m p ut er f or t h e vi s u ali z ati o n of t h e s pir o m etr y a n d a c c el er o m etr y d at a 
a n d c o n d uit f or d at a tr a n s mi s si o n t o t h e c oll a b or ati o n pl atf or m; t h e t a bl et will b e 
pr e -c o nfi g ur e d t o o nl y all o w u s e f or t h e p ur p o s e of t h e st u d y.  
•  
A u s er m a n u al f or t h e a b o v e m e nti o n e d d e vi c e s.  
I n a d diti o n P R O m e a s ur e s will b e a s s e s s e d. P ati e nt s will c o m pl et e s p e cifi c 
q u e sti o n n air e s (t h e Ki n g’ s Bri ef I nt er stiti al L u n g Di s e a s e [ K -BI L D], m o difi e d M e di c al 
R e s e ar c h C o u n cil [ m M R C], E ur o Q o L Fi v e -Di m e n si o n 5- l e v el v er si o n [ E Q-5 D -5 L], a n d 
F ati g u e A s s e s s m e nt S c al e [ F A S] q u e sti o n n air e s), a n d vi s u al a n al o g u e s c al e s ( V A S) 
f or co u g h , ur g e t o c o u g h, a n d f ati g u e at i n cl u si o n i n t h e st u d y a n d aft er w ar d s j u st pri or 
or d uri n g  vi sit s , u p o n r e q u e st fr o m t h e I n v e sti g at or. 
I n v e sti g at or s a n d c oll a b or ati o n pl atf or m / di git al e c o -s y st e m   
I n v e sti g at or s will b e l o c at e d at t erti ar y r ef err al c e nt er s (IP F /IL D  c e nt er s) a s w ell a s 
s m all er c o m m u nit y sit e s.  

 
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Protocol MA39297, Version 1, 26 April 2017 
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The study will provide a digital collaboration platform (Figure 2) allowing investigators 
from community centers to interact with experts from tertiary centers (pulmonologists, 
radiologists, pathologists etc.), thus creating a “virtual” MDT. The investigators from 
community center will be able to upload any results of diagnosis-relevant assessments 
such as radiographs, HRCT images. This virtual MDT will then be able to discuss each 
patient’s case. This platform is for the exclusive use of the investigators; the study 
sponsor will not have access to it. 
The use of the platform as a means of collaboration is not mandatory for participating 
sites. However, investigators will access the data from daily spirometry and 
accelerometry of their patients on the platform. Patient data will only be accessible by 
the treating physician (investigator) who can then decide to share them with the virtual 
MDT. These patient data will also be transferred in an anonymized way to the study 
database on a daily basis. 
 
Figure 2 
Collaboration Platform 
 
ILD=interstitial lung disease; IPF=idiopathic pulmonary fibrosis; MDT=multi-disciplinary team 
 

 
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Protocol MA39297, Version 1, 26 April 2017 
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Figure 3 shows the overall study digital ecosystem. 
Figure 3 
Study Digital Ecosystem  
 
Number of Patients 
Approximately 180 patients will be enrolled at about 50 study centers in seven 
countries (Canada, Russia and Europe).  
It is assumed that approximately 40% of the patients will be diagnosed with IPF and 
the remaining 60% of patients will either be diagnosed with a non-IPF ILD 
(approximately 50%) or with a disease other than ILD or no diagnosis (approximately 
10%, i.e. approx. 18 patients). Thus, approximately 72 patients with IPF and 90 
patients with non-IPF ILD are anticipated to have data available for the evaluation of 
the primary and secondary objectives of the study.  
Patients leaving the study prematurely will not be replaced. 
At least one tertiary center will be included in every participating country. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Signed Informed Consent Form 
2. Able to comply with the study protocol, in the investigator’s judgment – for 
example, the ability to use the provided spirometer and tablet and the ability to 
fill in the required patient reported outcomes questionnaires 

 
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Protocol MA39297, Version 1, 26 April 2017 
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3. Age ≥50 years 
4. Suspicion of IPF/ILD: Radiological evidence of IPF/ILD in symptomatic patients 
(unexplained dyspnea on exertion and/or cough) 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Participation in any investigational study within 28 days prior to inclusion 
2. History of clinically significant cardiac disease that could explain the patient’s 
symptomatology in the opinion of the investigator 
3. Known history of any connective tissue disease, including, but not limited to, 
rheumatoid arthritis, scleroderma, systemic lupus erythematosus, or mixed 
connective tissue disease. 
End of Study 
The end of the clinical study is defined as the date at which the last data point which is 
required for the statistical analysis is received. 
Length of Study 
The first patient is expected to enroll in Q3 of 2017, and enrollment is anticipated to 
continue for approximately 12 months. The last patient will complete the clinical study 
in early 2020 at the latest. For each patient, the total length of the study is variable (up 
to 18 months) and depends on local clinical practice. 
Investigational Medicinal Products 
There is no investigational drug involved in the study. 
Statistical Methods 
Primary Analysis 
The main purpose of this study is hypothesis generation regarding the impact on 
pulmonary function in terms of the change in FVC, as measured by daily handheld 
spirometry, in patients suspected to suffer from IPF. 
The primary endpoint of the study is the time-adjusted semi-annual FVC decline (in mL) 
in patients with IPF during the peri-diagnostic period. 
For the cohort under observation (i.e. patients diagnosed with IFP), the estimated time-
adjusted FVC decline (mL) will be presented descriptively, along with the 
corresponding two-sided 95% confidence interval. 
The statistical analysis of the primary endpoint will be performed by calculating the 
mean FVC decline in the corresponding study cohort (i.e., patients diagnosed with IPF). 
The mean FVC declines will be calculated using the estimated FVC decline for each 
individual patient. The individual FVC decline will be estimated by applying a linear 
regression model to all data points collected during the study period.  
The mean FVC decline (mL) will also be provided for pre-specified time periods at 3, 6 
or 12 months, together with corresponding 95% confidence intervals. 

 
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Protocol MA39297, Version 1, 26 April 2017 
16 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
6MWT 
6-minute walk test 
ALAT 
Latin American Thoracic Association 
ATS 
American Thoracic Society 
BAL 
bronchoalveolar lavage 
BMI 
body mass index 
 
 
CI 
confidence interval 
CRO 
contract research organization 
DLCO 
carbon monoxide diffusing capacity 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EQ-5D-5L 
EuroQoL Five-Dimension questionnaire (5-level 
version) 
ERS 
European Respiratory Society 
EU 
European Union 
FAS 
Fatigue Assessment Scale 
FVC 
forced vital capacity 
HRCT 
high-resolution computed tomography 
ICH 
International Council for Harmonisation 
ILD 
Interstitial lung disease 
IMP 
investigational medicinal product 
IND 
investigational New Drug (application) 
IPF 
idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
JRS 
Japanese Respiratory Society 
K-BILD 
King’s Brief Interstitial Lung Disease questionnaire 
LPLV 
last patient, last visit 

 
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Protocol MA39297, Version 1, 26 April 2017 
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MDT 
multi-disciplinary team 
mMRC 
modified Medical Research Council questionnaire 
 
 
NGS 
next-generation sequencing 
PRO 
patient-reported outcome 
UIP 
usual interstitial pneumonia 
VAS 
visual analogue scale 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
 
 
 

 
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Protocol MA39297, Version 1, 26 April 2017 
18 
1 
BACKGROUND 
1.1 Background on Idiopathic Pulmonary Fibrosis and Interstitial Lung 
Disease (IPF/ILD) 
IPF is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia 
of unknown cause, occurring primarily in older adults, limited to the lungs, and 
associated with the radiologic and/or histopathologic pattern of usual interstitial 
pneumonia (UIP). The definition of IPF requires the exclusion of other forms of interstitial 
pneumonia including other idiopathic interstitial pneumonias and interstitial lung disease 
(ILD) associated with environmental exposure, medication, or systemic disease 
(American Thoracic Society and European Respiratory Society 2002).  
The classification of interstitial lung diseases (ILDs) requires multidisciplinary expertise 
with input from various clinical experts, including pulmonologists, thoracic radiologists, 
and lung pathologists (Ryerson and Collard 2013). 
Idiopathic pulmonary fibrosis is a rare disease; recent age- and gender-adjusted 
prevalence estimates range from 27.9 to 63.0 per 100,000 in the United States (US) by 
narrow and broad criteria for IPF definition, respectively. The prevalence ranged from 
1.25 to 23.4 cases per 100,000 population in European Union (EU) (Fernández Pérez et 
al. 2010; Nalysnyk et al. 2012; Raghu et al. 2006). The observed variability in IPF 
prevalence may be explained by the differences in diagnostic criteria used, case 
definition, study population and study design. IPF is most prevalent in middle-aged and 
elderly patients, and most studies have found a higher frequency in men than in women 
(Nalysnyk et al. 2012). 
Symptoms of IPF have usually been present for at least 6 months before the diagnosis is 
made. The initial clinical presentation is typically that of slowly progressive dyspnea and 
nonproductive cough. Digital clubbing occurs in up to 50% of patients. Lung auscultation 
reveals fine end inspiratory crackles, initially at the base of the lung and ultimately 
diffusely (Raghu et al. 2011). In advanced disease, features of right heart failure develop. 
Pulmonary function tests demonstrate a restrictive pattern, with a decrease in carbon 
monoxide diffusing capacity (DLCO), and oxygen desaturation on exertion. Chest 
radiographs show diffuse interstitial opacities with volume loss, and high-resolution 
computed tomography (HRCT) scans show a characteristic pattern of peripheral 
(subpleural), bibasilar, reticulonodular abnormalities associated with architectural 
distortion, honeycomb changes, and traction bronchiectasis (Raghu et al. 2011). 
IPF is believed to result from a series of microinjuries to the alveolar epithelium, 
triggering release of profibrotic mediators. The characteristic pathologic finding on biopsy 
of lung tissue is a pattern of UIP with subepithelial fibroblastic foci throughout the lung. 

 
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Inflammation, although it may initially be present, is not typically a prominent 
histopathologic finding. Rather, an unremitting fibrotic response relocates from the 
alveolar space to the interstitium, with fibroblast and myofibroblast proliferation, 
organization into fibroblastic foci, and excessive collagen deposition and accumulation 
(American Thoracic Society and European Respiratory Society 2002; du Bois 2010). 
Although the majority of patients have a history of cigarette smoking, the etiology of IPF 
remains unknown. 
The diagnosis of IPF carries a bleak prognosis, with progressive disability due to 
respiratory insufficiency (Hallstrand et al. 2005). Data from the placebo arm of several 
controlled clinical trials suggest that the rate of decline in forced vital capacity (FVC) in 
patients with IPF is approximately 150 to 200 mL/yr in patients with IPF(Demedts et al. 
2005; Ley et al. 2011; Raghu et al. 2004,  2008). Estimated survival, in the absence of 
treatment, is between three to five years after diagnosis (American Thoracic Society and 
European Respiratory Society 2002; Bjoraker et al. 1998; Douglas et al. 2000; Gribbin et 
al. 2006; Hyldgaard et al. 2014; Kim et al. 2006; Mapel et al. 1998; Olson et al. 2007).  
A diminished quality of life in patients with IPF is well established, with impaired energy 
level and decreased level of independence in concert with respiratory symptoms 
(Swigris et al. 2005).  
To date, two anti-fibrotic drugs have been approved for use in IPF: pirfenidone and 
nintedanib; both therapies have shown to significantly slow the progression of lung 
function decline in IPF (Raghu et al. 2015), although the disease remains incurable.  
In terms of current clinical practice, there is limited data available on the early course of 
disease in symptomatic patients with suspicion of IPF/ILD. Thus, the peri-diagnosis 
period (see definition section 2) including the pre- and post-diagnosis periods is critical 
to the assessment of disease behavior, the timely accurate diagnosis and the decision to 
treat. The study will not focus on asymptomatic stages of disease when discovery would 
rely on imaging techniques for lung cancer screening purposes or incidental finding.  
This study will characterize the disease behavior of IPF and ILD patient in the peri-
diagnostic period, having as aim to increase the knowledge of the progressive nature of 
IPF/ILD already at early phases of assessment.  
This objective will be achieved using a multidimensional approach assessing changes in 
pulmonary function, measured by daily handheld spirometry as well as assessing 
physical functional capacity. 

 
F.  H off m a n n -L a R o c h e Lt d  
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2 0  
1. 2  B a c k gr o u n d o n T e st Pr o d u ct  
T h er e i s n o i n v e sti g ati o n al  dr u g i n v ol v e d i n t h e st u d y a s p ati e nt s will st o p t h e st u d y 
b ef or e r e c ei vi n g dr u g tr e at m e nt f or I P F/I L D.  
1. 3  St u d y R ati o n al e  
T h e pr o p o s e d st u d y will e nr oll s y m pt o m ati c p ati e nt s wit h s u s pi ci o n of I P F/I L D. I n t er m s 
of c urr e nt cli ni c al pr a cti c e, t h er e i s li mit e d  d at a a v ail a bl e o n t h e e arl y c o ur s e of di s e a s e 
a n d oft e n cli ni ci a n s r e q uir e d et ail e d i nf or m ati o n o n di s e a s e b e h a vi or i n or d er t o e st a bli s h 
a w or ki n g di a g n o si s a n d t o d e ci d e o n f urt h er p ati e nt m a n a g e m e nt.  
I n a n er a of eff e cti v e a nti-fi br oti c t h er a p y, e arl y d et e cti o n of di s e a s e pr o gr e s si o n s h o ul d 
pr o vi d e t h e o p p ort u nit y t o t ail or t h er a p y t o a n i n di vi d u al’ s di s e a s e ( R u s s ell et al. 2 0 1 6) . 
T h er ef or e, a st u d y t o c h ar a ct eri z e t h e di s e a s e b e h a vi or of I P F/I L D p ati e nt s d uri n g t h e 
p eri -di a g n o sti c p eri o d w o ul d pr o vi d e d at a o n t h e e arl y c o ur s e of di s e a s e. B y f oll o wi n g 
p ati e nt s’ l u n g f u n cti o n b ef or e a n d aft er di a g n o si s u si n g h o m e s pir o m etr y , l e v el s of 
p h y si c al a cti vit y , a s w ell a s s elf -a s s e s s m e nt d at a fr o m t h e p ati e nt ( p ati e nt r e p ort e d 
o ut c o m e s; P R O), t h e st u d y w o ul d pr o vi d e p ot e nti all y m or e r a pi d i nf or m ati o n o n di s e a s e 
b e h a vi or a n d e v e nt u all y pr o gr e s si o n c o m p ar e d t o u s u al cli ni c m e a s ur e m e nt s t h at o c c ur 
o nl y e v er y 3 -6 m o nt h s.  
T h e m ai n g o al s of t hi s st u d y ar e t o a s s e s s:  
•  
t h e di s e a s e b e h a vi or i n e arl y I P F/I L D p ati e nt s d uri n g t h e p eri-di a g n o sti c p eri o d  
•  
t h e f e a si bilit y of h a n d h el d s pir o m etr y i n a m ulti-c e nt er st u d y a n d it s p ot e nti al u s e i n 
d ail y cli ni c al pr a cti c e  
S e v er al s m all, g e n er all y si n gl e c e nt er cli ni c al tri al s h a v e a s s e s s e d t h e utilit y of h a n d h el d 
s pir o m etr y a n d p h y si c al f u n cti o n al c a p a cit y e v al u ati o n s i n p ati e nt s wit h I P F. I n di vi d u al s 
wit h a di a g n o si s of I P F w er e  r e cr uit e d a s a s u b gr o u p of t h e Pr o s p e cti v e O b s er v ati o n of 
Fi br o si s i n t h e L u n g Cli ni c al E n d p oi nt s ( P R O FI L E) st u d y ( J e n ki n s et al. 2 0 1 5) . On e of 
t h e o bj e cti v e s of t h e st u d y w a s t o d et er mi n e t h e f e a si bilit y a n d r eli a bilit y of m e a s uri n g 
d ail y F V C i n i n di vi d u al s wit h I P F ( S e e A p p e n di x 2 – E x a m pl e  of Di s e a s e B e h a vi or i n a n 
I n di vi d u al P ati e nt u si n g h o m e s pir o m etr y) ( R u s s ell et al. 2 0 1 6). D ail y m e a s ur e m e nt s 
w er e r e c or d e d b y 5 0  p ati e nt s wit h I P F u si n g h a n d h el d s pir o m et er s ( C ar e F u si o n, U nit e d 
Ki n g d o m) f or a m e di a n p eri o d of 2 7 9 d a y s. A n e x c ell e nt c orr el ati o n w a s o b s er v e d 
b et w e e n h a n d h el d s pir o m etr y a n d h o s pit al -o bt ai n e d r e a di n g s. M or e o v er, t h e r at e of 
d e cli n e i n F V C f oll o wi n g t h e u s e of h a n d h el d s pir o m et er s w a s hi g hl y pr e di cti v e of 
o ut c o m e a n d s u b s e q u e nt m ort alit y w h e n m e a s ur e d at 3, 6, a n d 1 2  m o nt h s. T h e 
c o n cl u si o n of t h e st u d y w a s t h at d ail y h o m e s pir o m etr y m e a s ur e m e nt s i n p ati e nt s wit h 
I P F ar e cli ni c all y hi g hl y i nf or m ati v e a n d, f or t h e m aj orit y of p ati e nt s, q uit e f e a si bl e t o 

 
F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol  M A 3 9 2 9 7, V er si o n 1, 2 6 A pril 2 0 1 7  
2 1  
p erf or m. H o w e v er,  t h e s e o b s er v ati o n s m erit t o b e r e p e at e d a cr o s s m ulti pl e c e nt er s a n d 
c o u ntri e s t o e n s ur e g e n er ali z a bilit y.  
Wit hi n r e s pir at or y m e di ci n e, h o m e di s e a s e m o nit ori n g i n t h e f or m of p e a k fl o w 
m e a s ur e m e nt i s alr e a d y a f e at ur e of a st h m a s elf -m a n a g e m e nt a n d i n l u n g tr a n s pl a nt-
r e ci pi e nt s. P ot e nti al cli ni c al a d v a nt a g e s of r o uti n e h o m e m o nit ori n g i n I P F i n cl u d e e arl y 
d et e cti o n of r a pi dl y d e cli ni n g F V C a n d m o nit ori n g of r e s p o n s e t o t h er a pi e s. H o m e 
m o nit ori n g c o ul d b e u s e d t o d eli v er p er s o n ali z e d p ati e nt c ar e e n a bli n g e ar l y 
i d e ntifi c ati o n a n d tr e at m e nt of I P F r el at e d c o m pli c ati o n s ( R u s s ell et al. 2 0 1 6). 
T hi s st u d y will f oll o w p ati e nt s wit h s u s p e ct e d I P F/I L D al s o wit h r e s p e ct t o t h eir l e v el of 
p h y si c al a cti vit y.  
A G er m a n st u d y i n v e sti g at e d t h e l e v el s of p h y si c al a cti vit y i n p ati e nt s wit h I P F a n d t h e 
p ot e nti al a s s o ci ati o n s b et w e e n p h y si c al a cti vit y a n d l u n g f u n cti o n, e x er ci s e c a p a cit y, 
s y m pt o m s, a n d q u alit y -of -lif e ( B a h m er et al. 2 0 1 6). F ort y -ei g ht p ati e nt s wit h I P F w er e 
i n cl u d e d a n d p h y si c al a cti vit y ( st e p s p er d a y, p h y si c al a cti vit y l e v el, a n d mi n ut e s of 
m o d er at e a cti vit y) w a s m e a s ur e d b y a c c el er o m etr y ( S e n s e W e ar br a c el et) f or 1  w e e k. 
T h e st u d y s h o w e d t h at f ati g u e a n d e x er ci s e c a p a cit y w er e str o n g a n d i n d e p e n d e nt 
pr e di ct or s of p h y si c al a cti vit y i n p ati e nt s wit h I P F. H o w e v er, t hi s st u d y w a s s h ort a n d di d 
n ot f o c u s o n p ul m o n ar y f u n cti o n a s s e s s m e nt s.  
A s s e s s m e nt s t h at a n al y z e t h e c o ur s e of I P F ( di s e a s e b e h a vi or) ar e li k el y t o b e c o m e a n 
i m p ort a nt a s p e ct of d e ci si o n m a ki n g i n a n u p c o mi n g c o n s e n s u s p a p er fr o m t h e 
E ur o p e a n R e s pir at or y S o ci et y ( E R S). St u d y M A 3 9 2 9 7 will c o ntri b ut e t o t h e i m pr o v e m e nt 
i n t h e r a pi d a s s e s s m e nt of di s e a s e b e h a vi or.  
T hi s st u d y will i n v e sti g at e c o ur s e of t h e di s e a s e i n p ati e nt s wit h s u s p e ct e d I P F/I L D. B y 
r e c ei vi n g d at a fr o m d ail y h o m e s pir o m etr y m e a s ur e m e nt s, tr e ati n g p h y si ci a n s m a y h a v e 
a n i m pr o v e d c h a n c e of d et e cti n g a n e arl y d e cli n e i n l u n g f u n cti o n w hi c h m a y gi v e 
s u p p orti v e i nf or m ati o n i n di a g n o sti c dil e m m a’ s or g ui d e tr e at m e nt d e ci si o n s.  
T hi s st u d y al s o i nt e n d s t o f o st er b ett er c oll a b or ati o n s b et w e e n I P F t erti ar y r ef err al 
c e nt er s (I P F/I L D c e nt er s) a n d c o m m u nit y c e nt er p ul m o n ol o gi st s b y cr e ati n g a f u n cti o n al 
“ virt u al” m ulti -di s ci pli n ar y t e a m ( M D T) w hi c h c a n w or k t o g eth er f or t h e b e n efit of t hi s 
p ati e nt p o p ul ati o n.  
I n s u m m ar y, t h e k e y b e n efit s of t h e st u d y will i n cl u d e: 
•  
P r o vi di n g d at a o n t h e e arl y c o ur s e of di s e a s e a s oft e n cli ni ci a n s r e q uir e f urt h er 
i nf or m ati o n o n di s e a s e b e h a vi or i n or d er t o e st a bli s h a w or ki n g di a g n osi s a n d t o 
d e ci d e o n f urt h er p ati e nt m a n a g e m e nt.  

 
F. Hoffmann-La Roche Ltd 
Protocol MA39297, Version 1, 26 April 2017 
24 
treatment in patients with IPF  
● Evaluation of the collaboration 
platform 
● Evaluation of the usefulness, practicality, and 
scalability of the collaboration platform (“virtual 
MDT”) in normal clinical practice by means of a 
survey among investigators at the end of the 
study 
● Evaluation of the digital solution 
set up for the patients 
● Evaluation of the usefulness and practicality of 
the digital solution provided to the patients by 
means of a patient questionnaire (daily 
spirometry, accelerometry) 
6MWT=6-minute walk test; FVC=forced vital capacity; ILD=interstitial lung disease;  
IPF=idiopathic pulmonary fibrosis; MDT= multi-disciplinary team; PRO=patient-reported outcome 
a) Defined by Collard and colleagues (Collard et al. 2016) 
 
3 
STUDY DESIGN 
3.1 Description of the Study 
This is an international clinical study, without investigational medicinal product, that will 
enroll patients with a suspected diagnosis of IPF/ILD. The principal aim of the study is to 
characterize the disease behavior of IPF and ILD in the peri-diagnostic period, primarily 
based on changes in pulmonary function (according to changes in FVC measured by 
daily handheld spirometry performed at home and by site spirometry) and changes in 
physical functional capacity (measured by daily accelerometry performed at home and 6-
minute walk tests [6MWT] measured on site).  
A patient will be eligible for inclusion if the Investigator has a suspicion that the patient 
may have IPF/ILD based on symptoms and radiological evidence. Investigators will 
discuss the benefits and risks of the study with the patient. The patient will subsequently 
be invited to participate in the study and to provide informed consent.  
The study conduct will be facilitated by a digital ecosystem consisting of the devices 
used for the home-based assessments and the digital collaboration platform used to 
enable a “virtual” MDT. Patients with suspected IPF/ILD should be carefully evaluated 
for identifiable causes of ILD. A multidisciplinary discussion among ILD experts is known 
to increase the accuracy of the diagnosis of IPF/ILD. 
All patients will be managed at the discretion of the Investigator taking into account local 
clinical practice guidelines and standards of care as well as available clinical evidence 
for patients with suspected IPF/ILD or diagnosed with IPF/ILD.  
The study schema is shown in Figure 1. 

 
F.  H off m a n n -L a R o c h e Lt d  
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Fi g ur e 1  
St u d y S c h e m a  
 
I L D =i nt er stiti al l u n g di s e a s e; I P F =i di o p at hi c p ul m o n ar y fi br o si s 
Fr o m i n cl u si o n i nt o t h e st u d y, p ati e nt s will b e f oll o w e d f or a m a xi m u m of 1 2 m o nt h s i n 
t h e pr e-di a g n o si s a s s e s s m e nt p eri o d.  
F oll o wi n g t h or o u g h a s s e s s m e nt s a n d di a g n o s e s, t hr e e gr o u p s of p ati e nt s will b e 
i d e ntifi e d: 
•  
P ati e nt s di a g n o s e d wit h I P F.  
•  
P ati e nt s di a g n o s e d wit h a n I L D ot h er t h a n I P F.  
•  
P ati e nt s di a g n o s e d wit h a c o n diti o n t h at i s n ot a n I L D.  
P ati e nt m a n a g e m e nt will b e i n a c c or d a n c e wit h l o c al cli ni c al pr a cti c e a n d c urr e ntl y 
a v ail a bl e g ui d eli n e s.  
F or i n di vi d u al p ati e nt s, t h e e n d of t h e st u d y will b e a s f oll o w s:  
•  
S h o ul d n o di a g n o si s b e m a d e 1 2 m o nt h s aft er i n cl u si o n i nt o t h e st u d y, t h e p ati e nt 
will l e a v e t h e st u d y.  
•  
P ati e nt s di a g n o s e d wit h a n o n -I L D c o n diti o n will l e a v e t h e st u d y o n t h e d at e of 
di a g n o si s.  

 
F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol  M A 3 9 2 9 7, V er si o n 1, 2 6 A pril 2 0 1 7  
2 6  
•  
P ati e nt s di a g n o s e d wit h I P F or n o n -I P F I L D will r e m ai n a n d b e f oll o w e d i n t h e 
st u d y u p t o t h e st art of dr u g tr e at m e nt ( wit hi n si x m o nt h s) or a m a xi m u m of s i x 
m o nt h s if n o dr u g tr e at m e nt i s pr e s cri b e d.  
“ St art of dr u g tr e at m e nt” i s d efi n e d a s t h e d at e t h e tr e at m e nt c o m m e n c e s. T hi s i n cl u d e s 
t h e e v e nt of a p ati e nt r e c ei vi n g I P F or I L D dr u g tr e at m e nt fr o m a p h y si ci a n ot h er t h a n t h e 
i n v e sti g at or. T h e p ati e nt will b e i n str u ct e d t o r e p ort s u c h a tr e at m e nt i m m e di at el y t o t h e 
i n v e sti g at or. 
A c c or di n gl y t h e t ot al l e n gt h of  t h e st u d y i s v ari a bl e f or e a c h p ati e nt, wit h a m a xi m u m of 
1 8 m o nt h s.  
Sit e vi sit s will b e c o n d u ct e d at a mi ni m u m at b a s eli n e, di a g n o si s, a n d e n d -of -st u d y f or 
e a c h i n di vi d u al p ati e nt. D uri n g e a c h st u d y p eri o d ( pr e - a n d p o st -di a g n o sti c p eri o d), 
e v er y p ati e nt s h o ul d h a v e at l e a st o n e sit e vi sit, s c h e d ul e d at t h e di s cr eti o n of t h e 
I n v e sti g at or. D uri n g t h e s e vi sit s, a n y r el e v a nt i nf or m ati o n s u c h a s tr e at m e nt s gi v e n a n d 
r e s ult s fr o m H R C T s, r a di o gr a p h s, D LC O , l u n g bi o p si e s et c. will b e c oll e ct e d, a s a v ail a bl e.  
T h e 6 M W T a n d F V C m e a s ur e m e nt s will b e a s s e s s e d o n -sit e a s p er t h e S c h e d ul e of 
A cti viti e s ( A p p e n di x 1).  
T h e st u d y will b e c o n d u ct e d u n d er t h e l e a d er s hi p of a St e eri n g C o m mitt e e ( s e e 9. 4 ).  
I n t h e a b s e n c e of t h e u s e of a n y t h er a p e uti c a g e nt, a n I n d e p e n d e nt R e vi e w C o m mitt e e 
(I R C/I R F) or a D at a S af et y M o nit ori n g B o ar d ( D S M B)/ D at a M o nit ori n g C o m mitt e e ( D M C) 
will n ot b e n e e d e d i n t hi s st u d y.  
P ati e nt st u d y -s p e cifi c a s s e s s m e nt s  / st u d y kit  
U p o n st u d y e nr oll m e nt, e a c h p ati e nt will r e c ei v e a st u d y kit wit h a u ni q u e i d e ntifi er 
c o nt ai ni n g t h e f oll o wi n g:  
•  
H a n d -h el d s pir o m et er  
o  D e vi c e t o m e a s ur e d ail y F V C at h o m e.  
•  
A c c el er o m et er  
o  D e vi c e t o c o nti n u o u sl y m e a s ur e d ail y a cti viti e s s u c h a s st e p s p er d a y, 
p h y si c al a cti vit y l e v el.  
•  
A t a bl et c o m p ut er f or t h e vi s u ali z ati o n of t h e s pir o m etr y a n d a c c el er o m etr y d at a 
a n d c o n d uit f or d at a tr a n s mi s si o n t o t h e c oll a b or ati o n pl atf or m; t h e t a bl et will b e 
pr e -c o nfi g ur e d t o o nl y all o w u s e f or t h e p ur p o s e of t h e st u d y.  

 
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2 7  
•  
A u s er m a n u al f or t h e a b o v e m e nti o n e d d e vi c e s.  
At t h e e nr oll m e nt vi sit, p ati e nt s will r e c ei v e tr ai ni n g o n t h e pr o p er u s e of t h e d e vi c e s fr o m 
t h e st u d y kit a n d t h e h o m e b a s e d a s s e s s m e nt s a n d will b e pr o vi d e d wit h a st e p-b y -st e p 
m a n u al h el pi n g t h e m c o m pl et e t h e s pir o m etr y a s s e s s m e nt s s u c c e s sf ull y. Vi s u ali zi n g 
t h eir d at a o n t h eir t a bl et s i s t h o u g ht t o all o w t h e m t o e v al u at e t h eir c o n diti o n a n d al s o t o 
i m pr o v e p ati e nt a d h er e n c e t o t h e st u d y.  
I n a d diti o n P R O m e a s ur e s will b e a s s e s s e d. P ati e nt s will c o m pl et e s p e cifi c 
q u e sti o n n air e s (t h e Ki n g’ s Bri ef I nt er stiti al L u n g Di s e a s e [ K -BI L D], m o difi e d M e di c al 
R e s e ar c h C o u n cil [ m M R C], E ur o Q o L Fi v e -Di m e n si o n 5- l e v el v er si o n [ E Q-5 D -5 L], a n d 
F ati g u e A s s e s s m e nt S c al e [ F A S] q u e sti o n n air e s), a n d vi s u al a n al o g u e s c al e s ( V A S) f or 
c o u g h , ur g e t o c o u g h, a n d f ati g u e at t h e i n cl u si o n i n t h e st u d y a n d aft er w ar d s j u st pri or 
or at a s c h e d ul e d sit e vi sit, u p o n r e q u e st fr o m t h e I n v e sti g at or.  
I n v e sti g at or s a n d c oll a b or ati o n pl atf or m / di git al e c o -s y st e m  
I n v e sti g at or s will be l o c at e d at t erti ar y r ef err al c e nt er s (I P F/I L D c e nt er s) a s w ell a s 
s m all er c o m m u nit y c e nt er s.  
T h e st u d y will pr o vi d e a di git al c oll a b or ati o n pl atf or m all o wi n g i n v e sti g at or s fr o m 
c o m m u nit y c e nt er s t o i nt er a ct wit h e x p ert s fr o m t erti ar y c e nt er s ( p ul m o n ol o gi st s, 
r a di ol o gi st s, p at h ol o gi st s et c.), t h u s cr e ati n g a “ virt u al” M D T. T h e i n v e sti g at or s fr o m 
c o m m u nit y c e nt er s will b e a bl e t o u pl o a d a n y r e s ult s of di a g n o si s -r el e v a nt a s s e s s m e nt s 
s u c h a s r a di o gr a p h s, H R C T i m a g e s. T hi s virt u al M D T will t h e n b e a bl e t o di s c u s s e a c h 
p ati e nt’ s c a s e. T hi s pl atf or m i s f or t h e e x cl u si v e u s e of t h e i n v e sti g at or s; t h e st u d y 
s p o n s or will n ot h a v e a c c e s s t o it.  
T h e u s e of t h e pl atf or m a s a m e a n s of c oll a b or ati o n  i s n ot m a n d at or y f or p arti ci p ati n g 
sit e s. H o w e v er, i n v e sti g at ors will a c c e s s t h e d at a fr o m d ail y s pir o m etr y a n d 
a c c el er o m etr y of t h eir p ati e nt s o n t h e pl atf or m . P ati e nt d at a will o nl y b e a c c e s si bl e b y 
t h e tr e ati n g p h y si ci a n (i n v e sti g at or) w h o c a n t h e n d e ci d e t o s h ar e t h e m wit h t h e virt u al 
M D T .  
H o m e s pir o m etr y a n d a c c el er o m etr y d at a will al s o b e tr a n sf err e d fr o m t h e p ati e nt t a bl et 
t o t h e st u d y d at a b a s e i n a n a n o n y mi z e d f or m at, o n a d ail y b a si s. 
I n v e sti g at or tr ai ni n g will i n cl u d e tr ai ni n g o n t h e u s e of t h e c oll a b or ati o n pl atf or m. 
T h e c oll a b or ati o n pl atf or m (“ virt u al” M D T) t h at will b e u s e d i n t hi s st u d y i s o utli n e d i n 
Fi g ur e 2.  

 
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Figure 2 
Collaboration Platform 
 
ILD=interstitial lung disease; IPF=idiopathic pulmonary fibrosis; MDT=multi-disciplinary team 
Figure 3 shows the overall study digital ecosystem. 

 
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Figure 3 
Study Digital Ecosystem 
 
 
The ‘Study Portal for Investigators’ is a repository for study documents, including the 
protocol, any manuals and study updates/newsletters. It will also provide the links to the 
collaboration platform and the eCRF. 
3.2 End of Study and Length of Study 
The end of the clinical study is defined as the date at which the last data point which is 
required for the statistical analysis is received. 
The first patient is expected to enroll in Q3 of 2017, and enrollment is anticipated to 
continue for approximately 12 months. The last patient will complete the clinical study in 
early 2020 at the latest. For each patient, the total length of the study is variable and 
depends on local clinical practice. 
3.3 RATIONALE FOR STUDY DESIGN AND PATIENT POPULATION 
This study will enroll patients with suspected IPF/ILD. In terms of current clinical practice, 
there is limited data available on the early course of disease and often clinicians require 
detailed information on disease behavior in order to establish a working diagnosis and to 
decide on further patient management. Therefore, a study following patients’ lung 
function prior to diagnosis using handheld spirometry and subsequently relating these 

 
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data to levels of activity would provide useful and early information on disease 
progression. 
This study will look into disease behavior in patients with suspected IPF/ILD. The study 
is meant to characterize the disease behavior of IPF and ILD and to detect potential 
differences in FVC decline between IPF and ILD. 
By receiving data from daily handheld spirometry measurements, treating physicians 
may have an improved chance of detecting early a decline in lung function. Improving 
the ability of clinicians to detect early declines could potentially lead to improvements in 
both diagnosis and treatment for patients with IPF/ILD. 
3.3.1 Rationale for Disease Response–based Endpoints 
The primary objective for this study is to evaluate the change in pulmonary function 
(FVC measured in mL by daily handheld spirometry) from study inclusion to 6 months 
follow-up after a diagnosis of IPF or from study inclusion to the start of IPF drug 
treatment, chosen independently by the Investigator (whichever occurs sooner; see 
Section 2). Changes in FVC have been examined in several different clinical studies 
which enrolled patients with both IPF (du Bois et al. 2011a; Reichmann et al. 2015; 
Zappala et al. 2010) and non-IPF ILD (Solomon et al. 2013; Swigris et al. 2006; Zamora 
et al. 2008) and are generally accepted as a valid measure of disease course in patients 
with IPF/ILD. Moreover, in the single center study using handheld spirometry in 50 
patients with IPF (Russell et al. 2016), the rate of decline in FVC following the use of 
handheld spirometers was highly predictive of outcome and subsequent mortality when 
measured at 3, 6, and 12 months. The conclusion of the study was that daily home 
spirometry measurements in patients with IPF are clinically highly informative and, for 
the majority of patients, quite easy to perform. 
Other disease response-based parameters that will be examined in this study include 
accelerometry, 6MWT, and various PRO measures (K-BILD, mMRC, EQ-5D-5L, FAS 
and cough, urge to cough, and fatigue VAS). Some of these assessments have been 
used as disease response-based parameters in studies involving patients with IPF and 
ILD (Atkins et al. 2016; du Bois et al. 2011b; Nakayama et al. 2015; Nishiyama et al. 
2010; Patel et al. 2012; Shulgina et al. 2013). 
The PRO measures selected are short, easy to complete, covering various aspects of 
the disease. Moreover, fatigue has not been assessed by PROs in major IPF trials so far, 
despite the fact that fatigue is common and one of most limiting symptoms for patients. 
Thus, assessing fatigue by FAS in this trial will generate evidence that may be relevant 
for patients with IPF/ILD.  

 
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As diagnosis may influence health-related quality of life, the study will ensure that all 
PROs are repeated at the time of diagnosis and then analyzed separately for the time 
periods pre and post diagnosis. 
4 
MATERIALS AND METHODS  
4.1 Patients 
Approximately 180 patients will be enrolled at about 50 study centers in seven countries 
(Canada, Russia and Europe).  
It is assumed that approximately 40% of the patients will be diagnosed with IPF and the 
remaining 60% of patients will either be diagnosed with a non-IPF ILD (approximately 
50%) or with a disease other than ILD or no diagnosis (approximately 10%, i.e. 
approximately 18 patients). Thus, approximately 72 patients with IPF and 90 patients 
with non-IPF ILD are planned to have data available for the evaluation of the primary 
and secondary objectives of the study.  
Patients leaving the study prematurely will not be replaced. 
At least one tertiary center will be included in every participating country. 
4.1.1 Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. Signed Informed Consent Form 
2. Able to comply with the study protocol, in the Investigator’s judgment – for example, 
the ability to use the provided spirometer and tablet and the ability to fill in the 
required patient reported outcomes questionnaires 
3. Age ≥50 years 
4. Suspicion of IPF/ILD: radiological evidence of IPF/ILD in symptomatic patients 
(unexplained dyspnea on exertion and/or cough). 
 
4.1.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Participation in any investigational study within 28 days prior to inclusion 
2. History of clinically significant cardiac disease that could explain the patient’s 
symptomatology in the opinion of the Investigator 

 
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3. Known history of any connective tissue disease, including, but not limited to, 
rheumatoid arthritis, scleroderma, systemic lupus erythematosus, or mixed 
connective tissue disease. 
4.2 Method of Treatment Assignment and Blinding  
No investigational drug is involved in the study and therefore no treatment blinding will 
occur during the study. 
4.3 Study Treatment  
No investigational drug is involved in the study. During the study, patients will be 
managed according to the standard of care at the discretion of the Investigator. 
4.4 Concomitant Therapy 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient from inclusion until the end of the study. All such medications should be 
reported to the Investigator and recorded on the Concomitant Medications eCRF.  
4.4.1 Permitted Therapy  
All medications taken by the patient for concomitant disease(s) should be continued as 
necessary during the study and be recorded on the eCRF.  
4.5 Study Assessments  
The schedule of activities to be performed during the study is provided in Appendix 1. All 
activities must be performed and documented for each patient.  
4.5.1 Informed Consent Forms and Enrollment Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures. Signed Informed Consent Forms for enrolled 
patients will be maintained at the study site file. 
All evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before enrollment. The Investigator will maintain an enrollment log to 
record details of all patients screened and to confirm eligibility or record reasons for 
enrollment failure, as applicable. 
4.5.2 Medical History, Concomitant Medication, and Demographic Data 
Medical history, including clinically significant respiratory diseases, (asthma, chronic 
obstructive pulmonary disease, and pneumonia), reproductive status, smoking 

 
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history, and use of alcohol and drugs of abuse, will be recorded at baseline. In addition, 
all medications will be recorded as described in section 4.4.  
Demographic data will include age, gender, and self-reported race/ethnicity (if country 
appropriate). 
4.5.3 Physical Examinations (including vital signs) 
Physical examinations will be conducted as per the schedule of activities (see Appendix 
1). The directed physical examination should be based on signs and symptoms of the 
patient. Physicians should pay particular attention to the signs and symptoms that are 
characteristic of IPF or ILD. Additional physical examinations may be performed only if 
clinically indicated.  
Physical examinations will include weight (kg); in addition, at baseline, the examination 
will include height (cm), and body mass index (BMI) will be calculated. 
Physical examination is the responsibility of the principal Investigator or medically 
qualified designee.  
4.5.4 Disease-relevant Assessments  
Disease-relevant data potentially collected may include, but are not limited to, pulmonary 
function tests (FVC and DLCO), physical functional capacity (6MWT and accelerometry 
data), and results from bronchoalveolar lavage (BAL), HRCTs, radiographs, and lung 
biopsy. 
FVC will be conducted on site at each patient visit.  
The 6MWT will be conducted at each patient visit, only at sites where a formalized 
process is available and the test can be performed under safe conditions. 
Patients will visit the site for assessment at baseline, diagnosis and end-of-study as well 
as at least once during each study period (pre- and post-diagnosis). During these visits 
HRCTs, radiographs, DLCO, and lung biopsies may also be conducted and the results 
will be recorded. 
Further information on the assessments (e.g., FVC, 6MWD, PROs) that will be 
conducted as part of this study can be found in the Procedure Manual. 

 
F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol  M A 3 9 2 9 7, V er si o n 1, 2 6 A pril 2 0 1 7  
3 4  
4. 5. 5  H o m e -b a s e d A s s e s s m e nt s  
A s d e s cri b e d i n s e cti o n 3. 1 , at t h e e nr oll m e nt vi sit, p ati e nt s will r e c ei v e tr ai ni n g o n t h e 
u s e of t h e c o m p o n e nt s of t h e st u d y kit – t h e s pir o m et er, t h e a c c el er o m et er a n d t h e t a bl et 
c o m p ut er.  
T h e p ati e nt s will b e a bl e t o s e e t h e r e s ult s of t h eir d ail y s pir o m etr y a n d a c c el er o m et er 
r e a di n g s pr e s e nt e d gr a p hi c all y o n t h e t a bl et c o m p ut er. D at a fr o m t h e t a bl et will b e 
a ut o m ati c all y s e nt t o t h e c oll a b or ati o n pl atf or m a n d e C R F s.  
T h e y will al s o r e c ei v e s et s of p a p er -b a s e d P R O q u e sti o n n air e s a n d s c al e s f or 
c o m pl eti o n pri or t o sit e vi sit s. T h e s e q u e sti o n n air e s c a n h o w e v er al s o b e c o m pl et e d o n 
sit e, if t h e  p ati e nt f or g et s t o, or i s ot h er wi s e u n a bl e t o c o m pl et e t h e m at h o m e b ef or e t h e 
vi sit.  
4. 5. 5. 1  D ail y S pir o m etr y  
T hr o u g h o ut t h e st u d y, p ati e nt s will p erf or m a s pir o m etr y r e a di n g of F V C [ m L ] at 
a p pr o xi m at el y t h e s a m e ti m e e a c h d a y. F or t hi s p ur p o s e, st u d y p arti ci p a nt s will b e 
pr o vi d e d wit h a p ort a bl e h a n d h el d s pir o m et er a n d a t a bl et c o m p ut er. E a c h s pir o m et er 
will b e f a ct or y c ali br at e d.  
4. 5. 5. 2  D ail y P h y si c al F u n cti o n al C a p a cit y A s s e s s m e nt s  
P ati e nt will b e a s k e d t o w e ar a n a c c el er o m et er w hi c h pr o vi d e s i nf or m ati o n o n t h eir 
p h y si c al a cti vit y, s u c h a s st e p s p er d a y a n d c al ori e e x p e n dit ur e.  
4. 5. 6  L a b or at or y a n d Ot h er Bi ol o gi c al S a m pl e s  
N o s a m pl e s will b e c oll e ct e d d uri n g t hi s st u d y f or m a n d at or y a s s e s s m e nt of l a b or at or y 
p ar a m et er s or m a n d at or y bi o m ar k er s.  
4. 5. 7  O pti o n al Bi o m ar k er S a m pl e s  
T h e st u d y i s ai mi n g t o c oll e ct t w o o pti o n al  b a s eli n e s a m pl e s, o nl y at sit e s w h er e 
a p pr o pri at e i nfr a str u ct ur e i s a v ail a bl e . T h e f oll o wi n g o pti o n al bi o m ar k er s a m pl e s will 
b e c oll e ct e d a s p er t h e S c h e d ul e of A s s e s s m e nt s ( s e e A p p e n di x 1) a n d s e nt t o t h e 
S p o n s or or a d e si g n e e f or a n al y si s:  
•  
o n e s er u m s a m pl e ( pr e p ar e d fr o m 8 m L of w h ol e bl o o d)  
•  
o n e w h ol e bl o o d s a m pl e ( 6 m L)  
T h e s er u m s a m pl e at b a s eli n e will b e a v ail a bl e f or a n al y si s of bi o m ar k er s t h at m a y b e 
i n v ol v e d i n t h e d e v el o p m e nt a n d pr o gr e s si o n of I P F/I L D. 
 
 
 

 
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 Baseline protein biomarkers will also be 
examined to look for differences between patients with suspected IPF who later become 
diagnosed with IPF versus those who do not. Additionally, baseline protein biomarkers 
may be examined for correlations with other clinical outcomes measured such as activity 
and quality of life.  
 
 
 
 
 
 
 
The whole blood sample will be collected at baseline for deoxyribonucleic acid (DNA) 
extraction to examine genetic polymorphisms and their potential role in the pathogenesis 
and associated clinical outcomes of IPF.  
 
 
 
 
 
 
 
  
Patient participation for this assessment is voluntary, and declining participation to 
collect biomarker samples will not influence eligibility for this trial. Any samples 
remaining after analyses have been conducted will be destroyed no later than five years 
after the end of the study (see definition for End of Study in Section 3.2). 
The above whole blood sample may be sent to one or more laboratories for analysis of 
germline or somatic mutations via whole genome sequencing (WGS), whole exome 
sequencing (WES), next-generation sequencing (NGS), or other genomic analysis 
methods.  
Genomics is increasingly informing researcher's understanding of disease 
pathobiology. WGS and WES provide a comprehensive characterization of the genome 

 
F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol  M A 3 9 2 9 7, V er si o n 1, 2 6 A pril 2 0 1 7  
3 6  
a n d e x o m e, r e s p e cti v el y, a n d, al o n g wit h cli ni c al d at a c oll e ct e d i n t hi s st u d y, m a y 
i n cr e a s e t h e o p p ort u nit y f or d e v el o pi n g n e w t h er a p e uti c a p pr o a c h e s. D at a will b e 
a n al y z e d i n t h e c o nt e xt of t hi s st u d y b ut will al s o b e e x pl or e d i n a g gr e g at e wit h d at a fr o m 
ot h er st u di e s.  T h e a v ail a bilit y of a l ar g er d at a s et will a s si st i n i d e ntifi c ati o n of i m p ort a nt 
p at h w a y s, g ui di n g t h e d e v el o p m e nt of n e w t ar g et e d a g e nt s.  
F or s a m pli n g pr o c e d ur e s, st or a g e c o n diti o n s, a n d s hi p m e nt i n str u cti o n s, s e e t h e 
l a b or at or y m a n u al. 
W h e n a p ati e nt wit h dr a w s fr o m t h e st u d y, s a m pl e s c oll e ct e d pri or t o t h e d at e of 
wit h dr a w al  m a y still b e a n al y z e d, u nl e s s t h e p ati e nt s p e cifi c all y r e q u e st s t h at t h e 
s a m pl e s b e d e str o y e d or l o c al l a w s r e q uir e d e str u cti o n of t h e s a m pl e s.  
D at a ari si n g fr o m s a m pl e a n al y si s, i n cl u di n g g e n e pr o m ot er p ol y m or p hi s m s, will b e 
s u bj e ct t o t h e c o nfi d e nti alit y st a n d ar d s d e s cri b e d i n S e cti o n  8. 4 . 
4. 5. 8  P ati e nt -R e p ort e d O ut c o m e s ( P R O)  
V ari o u s p a p er -b a s e d P R O q u e sti o n n air e s a n d vi s u al a n al o g s c al e s will b e u s e d t o 
m o nit or t h e p ati e nt s’ h e alt h st at u s a n d w ell -b ei n g d uri n g t h e st u d y:  
•  
Ki n g' s Bri ef I nt er stiti al L u n g Di s e a s e  ( K-BI L D) Q u e sti o n n air e.  T hi s 
q u e sti o n n air e w a s s p e cifi c all y d e v el o p e d t o a n al y z e t h e h e alt h st at u s of p ati e nt s 
wit h I L D ( P at el et al. 2 0 1 2). T h e q u e sti o n n air e c o n si st s of 1 5 it e m s t h at ar e 
c o m pil e d i nt o t hr e e d o m ai n s of br e at hl e s s n e s s a n d a cti viti e s, p s y c h ol o gi c al, a n d 
c h e st s y m pt o m s.  
•  
M o difi e d M e di c al R e s e ar c h C o u n cil  ( m M R C) D y s p n e a S c al e. T h e m M R C 
c hr o ni c d y s p n e a s c al e i s si m pl e t o a d mi ni st er a n d h a s b e e n u s e d f or m a n y y e ar s 
t o gr a d e t h e eff e ct s of br e at hl e s s n e s s o n d ail y a cti viti e s ( P a piri s et al. 2 0 0 5). T h e 
s c al e c o n si st s of si x c at e g ori e s a b o ut p er c ei v e d br e at hl e s s n e s s w hi c h r a n g e fr o m 
n o d y s p n e a ( C at e g or y 0) t o a v er y s e v er e d e gr e e of d y s p n e a ( C at e g or y 5).  
•  
T h e E ur o Q ol 5 -Di m e n si o n Q u e sti o n n air e  (E Q -5 D -5 L). T h e 5 -l e v el v er si o n ( E Q-
5 D -5 L) i s a v ali d at e d s elf -r e p ort h e alt h st at u s q u e sti o n n air e ( Br o o k s 1 9 9 6; E ur o Q ol 
Gr o u p 1 9 9 0; H er d m a n et al. 2 0 1 1; J a n s s e n et al. 2 0 1 3) . T h er e ar e t w o 
c o m p o n e nt s t o t h e E Q -5 D -5 L:  
o  a fi v e -it e m h e alt h st at e pr ofil e t h at a s s e s s e s m o bilit y, s elf-c ar e, u s u al a cti viti e s, 
p ai n/ di s c o mf ort, a n d a n xi et y/ d e pr e s si o n  
o  a V A S t h at  m e a s ur e s h e alt h st at e.  

 
F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol  M A 3 9 2 9 7, V er si o n 1, 2 6 A pril 2 0 1 7  
3 7  
•  
F ati g u e A s s e s s m e nt S c al e ( F A S) . T h e F A S i s a f ati g u e q u e sti o n n air e c o n si sti n g 
of 1 0 it e m s; fi v e q u e sti o n s r efl e ct p h y si c al f ati g u e a n d fi v e q u e sti o n s a n al y z e 
m e nt al f ati g u e ( D e Vri e s et al. 2 0 0 4). A fi v e -p oi nt s c al e ( o n e f or n e v er t o  fi v e f or 
al w a y s) i s u s e d f or p ati e nt r e s p o n s e s a n d t h er ef or e F A S s c or e s c a n r a n g e fr o m 1 0 
t o 5 0. 
•  
C o u g h / Ur g e t o c o u g h / F ati g u e Vi s u al A n al o g u e S c al e s ( V A S). T h e V A S ar e 
1 0 0  m m s c al e s o n w hi c h p ati e nt s i n di c at e t h e s e v erit y of t h eir c o u g h, t h e ur g e t o 
c o u g h a n d t h eir f ati g u e ( M ori c e et al. 2 0 0 7). 
T h e a b o v e P R O q u e sti o n n air e s, tr a n sl at e d, v ali d at e d i nt o t h e l o c al l a n g u a g e, will b e 
c o m pl et e d i n t h eir e ntir et y b y t h e p ati e nt s at b a s eli n e at t h e st u d y sit e, a n d t h e n j u st pri or 
t o or d uri n g t h eir n e xt s c h e d ul e d sit e vi sit, f oll o wi n g a r e q u e st fr o m t h e I n v e sti g at or. T o 
e n s ur e i n str u m e nt v ali dit y a n d t h at d at a st a n d ar d s m e et h e alt h a ut h orit y r e q uir e m e nt s, 
q u e sti o n n air e s will b e s elf -a d mi ni st er e d pri or t o t h e p ati e nt r e c ei vi n g a n y i nf or m ati o n o n 
di s e a s e st at u s a n d pri or t o t h e p erf or m a n c e of a n y  n o n -P R O a s s e s s m e nt s. T h e 
q u e sti o n n air e s s h o ul d al w a y s b e c o m pl et e d i n t h e s a m e or d er.  
F urt h er i nf or m ati o n o n t h e s e P R O a s s e s s m e nt s, w hi c h will b e c o n d u ct e d a s p art of t hi s 
st u d y, c a n b e f o u n d i n t h e Pr o c e d ur e M a n u al.  
4. 6  P ati e nt, St u d y, a n d Sit e Di s c o nti n u ati o n  
4. 6. 1  P ati e nt Di s c o nti n u ati o n fr o m St u d y  
P ati e nt s h a v e t h e ri g ht t o v ol u nt aril y wit h dr a w fr o m t h e st u d y at a n y ti m e f or a n y r e a s o n. 
I n a d diti o n, t h e I n v e sti g at or h a s t h e ri g ht t o wit h dr a w a p ati e nt fr o m t h e st u d y at a n y ti m e. 
R e a s o n s f or wit h dr a w al fr o m t h e st u d y m a y i n cl u d e, b ut ar e n ot li mit e d t o, t h e f oll o wi n g:  
•  
P ati e nt wit h dr a w al of c o n s e nt  
•  
St u d y t er mi n ati o n or sit e cl o s ur e  
•  
P ati e nt n o n -c o m pli a n c e, d efi n e d a s f ail ur e t o c o m pl y wit h pr ot o c ol r e q uir e m e nt s a s 
d et er mi n e d b y t h e I n v e sti g at or or S p o n s or  
E v er y eff ort s h o ul d b e m a d e t o o bt ai n i nf or m ati o n o n p ati e nt s w h o wit h dr a w fr o m t h e 
st u d y. T h e pri m ar y r e a s o n f or wit h dr a w al fr o m t h e st u d y s h o ul d b e d o c u m e nt e d o n t h e 
a p pr o pri at e e C R F. If a p ati e nt r e q u e st s t o b e wit h dr a w n fr o m t h e st u d y, t hi s r e q u e st 
m u st b e d o c u m e nt e d i n t h e s o ur c e d o c u m e nt s a n d si g n e d b y t h e I n v e sti g at or. P ati e nt s 
w h o wit h dr a w fr o m t h e st u d y will n ot b e r e pl a c e d.  
4. 6. 2  St u d y Di s c o nti n u ati o n  
T h e S p o n s or h a s t h e ri g ht t o t er mi n at e t hi s st u d y at a n y ti m e. R e a s o n s f or t er mi n ati n g 
t h e st u d y m a y i n cl u d e, b ut ar e n ot li mit e d t o, t h e f oll o wi n g:  

 
F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol  M A 3 9 2 9 7, V er si o n 1, 2 6 A pril 2 0 1 7  
3 8  
•  
P ati e nt e nr oll m e nt i s u n s ati sf a ct or y  
T h e S p o n s or will n otif y t h e i n v e sti g at or if t h e S p o n s or d e ci d e s t o di s c o nti n u e t h e st u d y.  
4. 6. 3  Sit e Di s c o nti n u ati o n  
T h e S p o n s or h a s t h e ri g ht t o cl o s e a sit e at a n y ti m e. R e a s o n s f or cl o si n g a sit e m a y 
i n cl u d e, b ut ar e n ot li mit e d t o, t h e f oll o wi n g: 
•  
P o or pr ot o c ol a d h er e n c e  
•  
N o n -c o m pli a n c e wit h t h e I nt er n ati o n al C o u n cil f or H ar m o ni s ati o n (I C H) g ui d eli n e 
f or G o o d Cli ni c al Pr a cti c e 
•  
N o st u d y a cti vit y (i. e., all p ati e nt s h a v e c o m pl et e d t h e st u d y a n d all o bli g ati o n s 
h a v e b e e n f ulfill e d)  
5 
A S S E S S M E N T O F S A F E T Y  
5. 1  S af et y Pl a n  
T hi s st u d y h a s n o pr ot o c ol m a n d at e d i n v e sti g ati o n al m e di ci n al pr o d u ct (I M P) or 
tr e at m e nt r e q uir e m e nt s.  
P ati e nt s will st o p t h e st u d y pri or t o st arti n g a n y dr u g tr e at m e nt f or I P F/I L D, a s d e s cri b e d 
i n s e cti o n 3. 1 . 
A n y o c c urr e n c e s of n o n -el e cti v e h o s pit ali z ati o n, I n v e sti g at or -r e p ort e d a c ut e 
e x a c er b ati o n s, d e at h s, a n d e v e nt s r el at e d t o st u d y a s s e s s m e nt s s h o ul d b e c oll e ct e d i n 
t h e e C R F o nl y. 
It will b e t h e r e s p o n si bilit y of t h e I n v e sti g at or t o m a n a g e t h e s e e v e nt s a p pr o pri at el y. 
A n y u nt o w ar d o c c urr e n c e s t h o u g ht t o b e d u e t o, or a s s o ci at e d wit h, a c o m m er ci al 
m e di ci n al pr o d u ct u s e d d uri n g t h e c o ur s e of a p ati e nt’ s st a n d ar d m e di c al tr e at m e nt will 
n ot b e r e p ort e d i n t h e e C R F s, b ut s h o ul d b e r e p ort e d t o t h e r e s p e cti v e M ar k et 
A ut h ori z ati o n H ol d er or l o c al H e alt h A ut h orit y a c c or di n g t o l o c al r e g ul at or y r e q uir e m e nt s.  
6 
S T A TI S TI C A L C O N SI D E R A TI O N S A N D A N A L Y SI S P L A N  
6. 1  D et er mi n ati o n of S a m pl e Si z e  
T h e m ai n p ur p o s e of t hi s st u d y i s h y p ot h e si s g e n er ati o n a n d e sti m ati o n r e g ar di n g t h e 
i m p a ct o n p ul m o n ar y f u n cti o n i n t er m s of t h e c h a n g e i n F V C, a s m e a s ur e d b y d ail y 
h a n d h el d s pir o m etr y, i n p ati e nt s s u s p e ct e d t o s uff er  fr o m I P F. 

 
F. Hoffmann-La Roche Ltd 
Protocol MA39297, Version 1, 26 April 2017 
39 
For this study, a total sample size of approximately 180 patients is planned (Table 2). 
The majority of the patients will be enrolled into two study cohorts, i.e., patients with a 
diagnosis of IPF or non-IPF ILD. Due to the uncertainty of the numbers of patients to be 
enrolled into these two cohorts, the sample size cannot be derived for a certain patient 
number. For the purpose of sample size and power calculation, it is assumed that 
approximately 40% of patients will be diagnosed with IPF and 50% of patients will be 
diagnosed with non-IPF ILD. Approximately 10% of patients are expected to suffer from 
a disease other than ILD (non-ILD) or will not have a diagnosis within 12 months of 
enrollment. This assumption is based on published data (Wapenaar-deKorver et al. 
2016). 
Thus, it is expected to enroll approx. 72 patients with a diagnosis of IPF and approx. 90 
patients with a diagnosis of non-IPF ILD. Approximately 18 patients may be diagnosed 
with non-ILD or have no diagnosis within the 12 months period following enrollment. 
Table 2 
Sample Size Scenarios 
Number of 
patients with IPF  
Mean FVC 
decline [mL] 
over 6 months 
Lower Bound 
of 95% CI 
Upper Bound 
of 95% CI 
Total number of 
patients to be 
enrolled 
72 
25 
8.83 
41.17 
180 
72 
50 
33.83 
66.17 
180 
72 
75 
58.83 
91.17 
180 
CI = confidence interval 
In Table 2 point estimates and 95% confidence intervals based on a normal distribution 
are tabulated for a range of possible outcomes, assuming 72 patients analyzed, a 
standard deviation of 70 ml, and a precision of 16.17% (estimates produced using 
nQuery, version 7). A mean semi-annual FVC decline in the IPF group of 50 mL is 
considered being a clinically relevant decline and a reasonable expectation in 
accordance with the literature (Ley et al. 2011). In addition, after inspection of historical 
data, it can be assumed that the common standard deviation in mean FVC decline is 70 
mL as measured by handheld spirometry.  
6.2 Summaries of Conduct of Study 
The number of patients who enroll, discontinue, or complete the study will be 
summarized by diagnosis cohort. Reasons for premature study withdrawal will be listed 
and summarized. Enrollment and major protocol deviations will be listed and evaluated 
for their potential effects on the interpretation of study results.  

 
F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol  M A 3 9 2 9 7, V er si o n 1, 2 6 A pril 2 0 1 7  
4 0  
A c o h ort of p ati e nt s w h o c o ul d n ot b e di a g n o s e d d uri n g t h e fir st y e ar aft er i n cl u si o n i nt o 
t h e st u d y will b e a n al y z e d s e p ar at el y a s w ell. 
6. 3  S u m m ari e s of D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s  
D e m o gr a p hi c  a n d b a s eli n e c h ar a ct eri sti c s s u c h a s a g e, s e x a n d r a c e ( w h er e p er mi s si bl e) 
will b e s u m m ari z e d u si n g m e a n s, st a n d ar d d e vi ati o n s, m e di a n s, a n d r a n g e s f or 
c o nti n u o u s v ari a bl e s a n d pr o p orti o n s f or c at e g ori c al v ari a bl e s, a s a p pr o pri at e. 
S u m m ari e s will b e pr e s e nt e d b y di a g n o si s c o h ort.  
A s u m m ar y of c o n c o mit a nt m e di c ati o n s will b e di s pl a y e d i n fr e q u e n c y t a bl e s.  
6. 4  Pri m ar y a n d S e c o n d ar y A n al y s e s  
T h e m ai n p ur p o s e of t hi s st u d y i s h y p ot h e si s g e n er ati o n  a n d e sti m ati o n  r e g ar di n g t h e 
i m p a ct o n p ul m o n ar y f u n cti o n i n t er m s of t h e c h a n g e i n F V C, a s m e a s ur e d b y d ail y 
h a n d h el d s pir o m etr y, i n p ati e nt s wit h s u s p e ct e d t o s uff er fr o m I P F. 
6. 4. 1  Pri m ar y E n d p oi nt  
T h e pri m ar y e n d p oi nt of t h e st u d y i s t h e ti m e -a dj u st e d s e mi -a n n u al F V C d e cli n e  (i n m L) 
i n p ati e nt s wit h I P F d uri n g t h e p eri-di a g n o sti c p eri o d.  
F or t h e c o h ort u n d er o b s er v ati o n (i. e. p ati e nt s di a g n o s e d wit h I F P), t h e e sti m at e d ti m e -
a dj u st e d F V C d e cli n e ( m L) will b e pr e s e nt e d d e s cri pti v el y, al o n g wit h t h e c orr e s p o n di n g 
t w o-si d e d 9 5 % c o nfi d e n c e i nt er v al.  
T h e st ati sti c al a n al y si s of t h e pri m ar y e n d p oi nt will b e p erf or m e d b y c al c ul ati n g t h e m e a n 
F V C d e cli n e i n t h e c orr e s p o n di n g st u d y c o h ort (i. e., p ati e nt s di a g n o s e d wit h I P F). T h e 
m e a n F V C d e cli n e s will b e c al c ul at e d u si n g t h e e sti m at e d F V C d e cli n e f or e a c h 
i n di vi d u al p ati e nt. T h e i n di vi d u al F V C d e cli n e will b e e sti m at e d b y a p pl yi n g a li n e ar 
r e gr e s si o n m o d el t o all d at a p oi nt s c oll e ct e d d uri n g t h e e ntir e st u d y p eri o d. I n a d diti o n, a 
si n gl e ar m r e p e at e d m e a s ur e s mi x e d m o d el will b e a p pli e d t o e sti m at e t h e F V C d e cli n e 
o v er 6 m o nt h s a s a s e n siti vit y a n al y si s . 
T h e m e a n F V C d e cli n e ( m L) will al s o b e pr o vi d e d f or pr e -s p e cifi e d ti m e p eri o d s  at  3, 6 or 
1 2 m o nt h s, t o g et h er wit h c orr e s p o n di n g 9 5 % c o nfi d e n c e i nt er v al s.  
6. 4. 2  S e c o n d ar y E n d p oi nt s  
•  
T h e c h a n g e i n p ul m o n ar y f u n cti o n t e st s ( F V C m e a s ur e d i n m L b y  d ail y h o m e 
s pir o m etr y ) i n p ati e nt s wit h n o n-I P F I L D will b e a n al y z e d i n t h e s a m e f a s hi o n a s t h e 
pri m ar y e n d p oi nt . 

 
F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol  M A 3 9 2 9 7, V er si o n 1, 2 6 A pril 2 0 1 7  
4 1  
•  
T h e c h a n g e i n p ul m o n ar y f u n cti o n t e st s ( m L a n d % pr e di ct e d F V C) b y sit e 
s pir o m etr y will b e a n al y z e d i n t h e s a m e f a s hi o n a s t h e pri m ar y e n d p oi n t. Ti m e 
a dj u st e d m e a n c h a n g e s a n d c orr e s p o n di n g 9 5 % c o nfi d e n c e i nt er v al s will b e 
pr o vi d e d f or e a c h di a g n o si s c o h ort.  
•  
T h e c h a n g e i n 6 M W T will b e a n al y z e d d e s cri pti v el y o v er ti m e f or e a c h di a g n o si s 
c o h ort  
•  
T h e c h a n g e i n p h y si c al f u n cti o n al c a p a cit y ( m e a s ur e d b y d ail y h o m e a c c el er o m etr y, 
e. g. n u m b er of f o ot st e p s p er d a y a n d c al ori e e x p e n dit ur e) will b e a n al y z e d 
d e s cri pti v el y o v er ti m e f or e a c h di a g n o si s c o h ort  
•  
T h e c h a n g e i n P R O m e a s ur e s will b e a n al y z e d d e s cri pti v el y o v er ti m e f or e a c h 
di a g n o si s c o h ort  
•  
T h e c orr el ati o n of F V C ( m L) b et w e e n h o m e a n d sit e s pir o m etr y will b e a n al y z e d b y 
c al c ul ati n g P e ar s o n’ s c orr el ati o n c o effi ci e nt t a ki n g t h e i n di vi d u al m e a n F V C d e cli n e s 
f or e a c h p ati e nt i nt o a c c o u nt  
•  
T h e c orr el ati o n b et w e e n p h y si c al f u n cti o n al c a p a cit y a s s e s s e d at h o m e i n t er m s of 
t h e d e cli n e i n t h e n u m b er of f o ot st e p s a n d o n sit e i n t er m s of t h e d e cli n e i n di st a n c e 
of t h e 6 M W T will b e a n al y z e d b y c al c ul ati n g P e ar s o n’ s c orr el ati o n c o effi ci e nt t a ki n g 
t h e i n di vi d u al v al u e s f or e a c h p ati e nt i nt o a c c o u nt 
•  
A c o m p ari s o n of di s e a s e b e h a vi or i n I P F a n d n o n -I P F I L D p ati e nt s will b e 
s u m m ari z e d d e s cri pti v el y  
•  
E v al u at e t h e b a s eli n e c h ar a ct eri sti c s of pr o gr e s si n g v s n o n -pr o gr e s si n g p ati e nt s, 
p ati e nt s r e q uiri n g r e s pir at or y -r el at e d h o s pit ali z ati o n s 
•  
T h e i n ci d e n c e r at e of n o n -el e cti v e h o s pit ali z ati o n, b ot h r e s pir at or y a n d all c a u s e will 
b e s u m m ari z e d d e s cri pti v el y b y di a g n o si s c o h ort  
•  
T h e i n ci d e n c e of I n v e sti g at or -r e p ort e d a c ut e e x a c er b ati o n s will b e s u m m ari z e d 
d e s cri pti v el y b y di a g n o si s c o h ort  
•  
I n ci d e n c e of d e at h, all c a u s e a n d r e s pir at or y-r el at e d d e at h s will b e s u m m ari z e d 
d e s cri pti v el y b y di a g n o si s c o h ort  
•  
T h e i n ci d e n c e of e v e nt s r el at e d t o t h e st u d y a s s e s s m e nt s will b e s u m m ari z e d 
d e s cri pti v el y b y di a g n o si s c o h ort  
6. 4. 3  E x pl or at or y Effi c a c y E n d p oi nt s  
•  
Diff er e nt I L D s u b gr o u p s, e. g. c o n n e cti v e ti s s u e di s e a s e a s s o ci at e d I L D, c hr o ni c 
h y p er s e n siti vit y p n e u m o niti s  I L D, will b e a n al y z e d i n t er m s of b a s eli n e 
c h ar a ct eri sti c s a n d c h a n g e i n F V C ( ml) d uri n g t h e e ntir e st u d y p eri o d d e p e n di n g o n 
t h e a v ail a bl e d at a 

 
F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol  M A 3 9 2 9 7, V er si o n 1, 2 6 A pril 2 0 1 7  
4 2  
•  
E v al u at e t h e c h ar a ct eri sti c s ( b a s eli n e c h ar a ct eri sti c s, c h a n g e s i n p ul m o n ar y 
f u n cti o n a n d p h y si c al a cti vit y) of p ati e nt s wit h n o di a g n o si s m a d e 1 2 m o nt h s aft er 
i n cl u si o n i nt o t h e st u d y 
•  
E v al u ati o n of t h e diff er e n c e s i n F V C v al u e s at b e gi n ni n g of tr e at m e nt, d e p e n di n g o n 
r ei m b ur s e m e nt r e stri cti o n s  
•  
E v al u ati o n of t h e c oll a b or ati o n pl atf or m b y I n v e sti g at or s  
•  
E v al u ati o n of t h e di git al s ol uti o n s et u p f or p ati e nt s  
F urt h er d et ail s o n t h e a n al y s e s o n st u d y c o h ort s a n d e x pl or at or y effi c a c y e n d p oi nt s will 
b e pr o vi d e d i n t h e St ati sti c al A n al y si s Pl a n.  
 
6. 5  Bi o m ar k er  A n al y s e s  
Bi o m ar k er v ari a bl e s will b e s u m m ari z e d u si n g d e s cri pti v e st ati sti c s: m e a n s/ m e di a n s, 
st a n d ar d d e vi ati o n a n d r a n g e f or c o nti n u o u s v ari a bl e s a n d fr e q u e n c y t a bl e s f or 
c at e g ori c al v ari a bl e s. It s r el ati o n s hi p t o pri m ar y a n d s e c o n d ar y e n d p oi nt s m a y  b e 
e x pl or e d . D et ail s o n t h e s e st ati sti c al m et h o d s will b e  pr o vi d e d i n a s e p ar at e st ati sti c al 
a n al y si s pl a n.  
6. 6  I nt eri m A n al y s e s 
I nt eri m a n al y s e s will b e p erf or m e d at l e a st o n c e p er y e ar. T h e fir st i nt eri m a n al y si s i s 
pl a n n e d w h e n 2 0 p ati e nt s e nr oll e d ar e di a g n o s e d wit h I P F a n d c a n b e f ull y e v al u at e d 
wit h r e g ar d t o t h e pr e -di a g n o sti c p eri o d.  
7 
D A T A C O L L E C TI O N A N D M A N A G E M E N T  
7. 1  D at a Q u alit y A s s ur a n c e  
A c o ntr a ct r e s e ar c h or g a ni z ati o n ( C R O) will b e r e s p o n si bl e f or t h e d at a m a n a g e m e nt of 
t hi s st u d y, i n cl u di n g q u alit y c h e c ki n g of t h e d at a. D at a e nt er e d m a n u all y will b e c oll e ct e d 
vi a el e ctr o ni c d at a c a pt ur e  ( E D C) t hr o u g h t h e u s e of e C R F s ( el e ctr o ni c c a s e r e c or d 
f or m s). Sit e s will b e r e s p o n si bl e f or d at a e ntr y i nt o t h e E D C s y st e m. I n t h e e v e nt of 
di s cr e p a nt d at a, t h e C R O will r e q u e st d at a cl arifi c ati o n fr o m t h e sit e s, w hi c h t h e sit e s will 
r e s ol v e el e ctr o ni c all y i n t h e E D C s y st e m.  
T h e S p o n s or will p erf or m o v er si g ht of t h e d at a m a n a g e m e nt of t hi s st u d y. T h e S p o n s or 
will pr o d u c e a n E D C St u d y S p e cifi c ati o n d o c u m e nt t h at d e s cr i b e s t h e q u alit y c h e c ki n g t o 
b e p erf or m e d o n t h e d at a.  

 
F. Hoffmann-La Roche Ltd 
Protocol MA39297, Version 1, 26 April 2017 
43 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail. 
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
7.2 Electronic Case Report Forms  
eCRFs are to be completed through use of a Sponsor-designated EDC system. Sites will 
receive training and have access to a manual for appropriate eCRF completion. eCRFs 
will be submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the Investigator or a designee. 
At the end of the study, the Investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required. 
7.3 Patient-Reported Outcome Data 
PRO data will be collected on paper questionnaires. The data from the questionnaires 
will be entered into the EDC system.  
The electronic data will be available for view access only, via a secure method. Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail. The Sponsor will have view access only. System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor’s standard procedures. 
Once the study is complete, the data, audit trail, and study and system documentation 
will be archived. The Investigator will keep all PRO forms completed by the patient in the 
study records as source data. In addition, the site will receive all data in a machine-
readable format on a compact disc. Acknowledgement of receipt of the compact disc is 
required. 
7.4 Source Data Documentation 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 

 
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clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medicotechnical departments involved 
in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be entered 
directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification and review, the Investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for trial-
related monitoring, Sponsor audits, and Institutional Review Board (IRB)/Ethics 
Committee (EC) review. The study site must also allow inspection by applicable health 
authorities. 
7.5 Use of Computerized Systems 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research. An 
acceptable computerized data collection system allows preservation of the original entry 
of data. If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.6 Retention of Records 
Records and documents pertaining to the conduct of this study, including but not limited 
to eCRFs, paper PRO data, Informed Consent Forms, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer. After that period of time, the documents may be destroyed, subject to local 
regulations.  

 
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No records may be disposed of without the written approval of the Sponsor. Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8 
ETHICAL CONSIDERATIONS 
8.1 Compliance with Laws and Regulations 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). 
8.2 Informed Consent 
The Sponsor’s sample Informed Consent Form will be provided to each site in a certified 
translation of the local language. The Sponsor or its designee must review and approve 
any proposed deviations from the Sponsor's sample Informed Consent Forms or any 
alternate consent forms proposed by the site (collectively, the "Consent Forms") before 
IRB/EC submission. The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures. The Investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure. 
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason. A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures. Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 

 
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Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 Institutional Review Board or Ethics Committee 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated. 
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
8.4 Confidentiality 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study Investigators or 
patients unless required by law. The aggregate results of any conducted research will be 

 
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available in accordance with the effective Roche policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
9 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION 
9.1 Study Documentation 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval. In addition, at the end of the study, the Investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 Protocol Deviations 
The Investigator should document and explain any protocol deviations. The Investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 Site Inspections 
Site visits may be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs. The Investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 Administrative Structure 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd. The Sponsor 
will provide clinical operations management, data management, and medical monitoring. 
Approximately 50 sites globally will participate to enroll approximately 180 patients.  
Central facilities will be used for biomarker analyses of baseline samples as specified in 
Section 4.5.  

 
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The study will be conducted under the leadership of a Steering Committee. The Steering 
Committee is composed of experts in the ILD field and members representing the 
Sponsor. The Steering Committee, together with the Sponsor, developed the study 
protocol and has overall responsibility for the study conduct and publication. A separate 
charter describing roles and responsibilities of the members of the committee will be 
maintained by the Sponsor. 
9.5 Publication of Data and Protection of Trade Secrets 
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results. For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
www.roche.com/roche global policy on sharing of clinical study information.pdf  
The results of this study may be published or presented at scientific congresses. The 
Investigator must agree to submit all manuscripts or abstracts to the Sponsor prior to 
submission for publication or presentation. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the Investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. Any formal publication of 
the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the Investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 Protocol Amendments 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 

 
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Appendix 1 
 
Schedule of Activities 
 
 
Enrollment 
(Suspicion of 
IPF/ILD) 
[Baseline 
visit] 
Pre-diagnosis 
Assessment period 
(max 12 months) a 
[Visit 1] 
Day of 
initial 
Diagnosis 
[Visit 2] 
Post-diagnosis 
Assessment period 
(max. 6 months) a 
[Visit 3] 
End of study 
/ Early 
termination b 
[End of 
Study visit] 
 
Informed consent c 
x 
 
 
 
 
Review of inclusion/exclusion criteria 
x 
 
 
 
 
Demographic data 
x 
 
 
 
 
General medical history and baseline conditions 
x 
 
 
 
 
Physical examination: 
 
 
 
 
 
Vital signs and weight 
x 
x 
x 
x 
x 
Height and body mass index (BMI) 
x 
 
 
 
 
Disease-relevant data, as available d 
x 
x 
x 
x 
x 
Home-based assessments: 
 
 
 
 
 
Daily spirometry e 
x 
x 
x 
x 
x 
Daily physical functional capacity assessments f 
x 
x 
x 
x 
x 
PRO g 
x 
x 
x 
x 
x 
Site assessments: 
 
 
 
 
 
FVC 
x 
x 
x 
x 
x 
6MWT h 
x 
x 
x 
x 
x 
Serum sample for biomarker assessment (optional) i 
x 
 
 
 
 
Whole blood sample for biomarker assessment 
(optional) i 
x 
 
 
 
 
Concomitant medications j 
x 
x 
x 
x 
x 

 
F.  H off m a n n -L a R o c h e Lt d  
Pr ot o c ol  M A 3 9 2 9 7, V er si o n 1, 2 6 A pril 2 0 1 7  
5 5  
 
E nr oll m e nt 
( S u s pi ci o n of 
I P F/I L D) 
[B a s eli n e 
vi sit ] 
Pr e -di a g n o si s 
A s s e s s m e nt p eri o d  
( m a x 1 2 m o nt h s) a 
[ Vi sit 1] 
D a y of 
i niti al 
Di a g n o si s  
[ Vi sit 2] 
P o st -di a g n o si s 
A s s e s s m e nt p eri o d 
( m a x. 6 m o nt h s) a 
[ Vi sit 3] 
E n d of st u d y 
/ E arl y 
t er mi n ati o n b 
[ E n d of 
St u d y vi sit]  
 
I n v e sti g at or / P ati e nt s ur v e y 
 
 
 
 
x 
N o n -el e cti v e h o s pit ali z ati o n s, a c ut e e x a c er b ati o n s, 
d e at h s, e v e nt s r el at e d t o st u d y -a s s e s s m e nt s  
 
x 
x 
x 
x 
6 M W T = 6 -mi n ut e w al k t e st; E Q -5 D = E ur o Q o L Fi v e -Di m e n si o n  5-l e v el v er si o n; F A S = F ati g u e A s s e s s m e nt S c al e; F V C =f or c e d vit al c a p a cit y; 
I L D =i nt er stiti al l u n g di s e a s e; I P F =i di o p at hi c p ul m o n ar y fi br o si s; K- BI L D = Ki n g’ s Bri ef I nt er stiti al L u n g Di s e a s e; m M R C = m o difi e d M e di c al R e s e ar c h 
C o u n cil . P R O = p ati e nt -r e p ort e d o ut c o m e; V A S = Vi s u al A n al og u e S c al e . 
a  T h e l e n gt h of t hi s p eri o d m a y v ar y o n a n i n di vi d u al b a si s. D uri n g t h e s e a s s e s s m e nt p eri o d s, l o c al cli ni c al pr a cti c e s h o ul d b e  f oll o w e d; h o w e v er, 
at l e a st 1 sit e vi sit h a s t o b e p erf or m e d.  
b E n d of st u d y f or a n i n di vi d u al p ati e nt:  
•  S h o ul d n o di a g n o si s b e m a d e 1 2 m o nt h s aft er i n cl u si o n i nt o t h e st u d y, t h e p ati e nt will l e a v e t h e st u d y.  
•  P ati e nt s di a g n o s e d wit h a n o n -I L D c o n diti o n will l e a v e t h e st u d y o n t h e d at e of di a g n o si s. 
•  P ati e nt s di a g n o s e d wit h I P F or I L D will r e m ai n a n d b e f oll o w e d i n t h e st u d y u p t o t h e st art of dr u g tr e at m e nt ( wit hi n si x m o nt h s) or a 
m a xi m u m of si x m o nt h s if n o dr u g tr e at m e nt i s pr e s cri b e d  
c I nf or m e d c o n s e nt m u st b e d o c u m e nt e d b ef or e a n y st u d y-s p e cifi c pr o c e d ur e s ar e p erf or m e d.  
d D at a t o b e c oll e ct e d i n cl u d e, b ut ar e n ot li mit e d t o, p ul m o n ar y f u n cti o n t e st s ( e. g., F E V 1 , D LC O ), br o n c h o al v e ol ar l a v a g e, a n d l u n g bi o p s y r e s ult s 
( a s a v ail a bl e). 
e D ail y s pir o m etr y will b e c o n d u ct e d b y t h e p ati e nt at h o m e u si n g t h e st u d y kit pr o vi d e d. S pir o m etr y a s s e s s m e nt s ( F V C)  will b e c o n d u ct e d at 
a p pr o xi m at el y t h e s a m e ti m e e a c h d a y  wit h t h e p ati e nt i n a s e at e d p o siti o n.  
f D ail y p h y si c al f u n cti o n al c a p a cit y a s s e s s m e nt s ( e. g., st e p s p er d a y, c al ori e e x p e n dit ur e) will b e m e a s ur e d o n a n o n g oi n g b a si s u si n g t h e 
a c c el er o m etr y d e vi c e pr o vi d e d.  
g  P ati e nt s will c o m pl et e s p e cifi c q u e sti o n n air e s ( K -BI L D, m M R C, E Q -5 D -5 L, a n d F A S) a n d vi s u al a n al o g u e s c al e s ( c o u g h, ur g e t o c o u g h, a n d 
f ati g u e) u p o n r e q u e st fr o m t h e I n v e sti g at or. 
h  T h e 6 M W T will b e p erf or m e d o nl y at sit e s w h er e a f or m ali z e d pr o c e s s i s a v ail a bl e a n d t h e t e st c a n b e p erf or m e d u n d er s af e c o n diti o n s  
i Pr o vi di n g a s er u m s a m pl e a n d a b l o o d s a m pl e f or bi o m ar k er a s s e s s m e nt i s o pti o n al f or p ati e nt s. S am pli n g will o nl y b e c o n d u ct e d at sit e s wit h 
a p pr o pri at e i nfr a str u ct ur e f or bl o o d pr o c e s si n g.  
j  In cl u d e s a n y m e di c ati o n ( e. g., pr e s cri pti o n dr u g s, o v er -t h e-c o u nt er dr u g s, v a c ci n e s, h er b al or h o m e o p at hi c r e m e di e s, n utriti o n al s u p pl e m e nt s) 
u s e d b y a p ati e nt fr o m i n cl u si o n u ntil t h e e n d of t h e st u d y.  
 

 
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Appendix 2 
 
Hand-Held Spirometry: Example of Disease Behavior in an 
Individual Patient 
Figure 4 shows the results of daily FVC measurements in a patient suffering a sudden 
and rapid decrease in FVC (Russell et al. 2016). This decrease may not have been 
detected the patient only been assessed using longer intervals between measurements. 
Figure 4 
Daily FVC Measurements over Time