Conditions: Lung Diseases, Interstitial
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 663
Healthy volunteers: no

Brief summary:
The aim of the current study is to investigate the efficacy and safety of nintedanib over 52 weeks in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD) defined as patients who present with features of diffuse fibrosing lung disease of \>10% extent on high-resolution computed tomography (HRCT) and whose lung function and respiratory symptoms or chest imaging have worsened despite treatment with unapproved medications used in clinical practice to treat ILD. There is currently no efficacious treatment available for PF-ILD. Based on its efficacy and safety in Idiopathic Pulmonary Fibrosis (IPF), it is anticipated that Nintedanib will be a new treatment option for patients with PF-ILD.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Nintedanib intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c03736471-03
EudraCT No.:
2015-003360-37
BI Trial No.:
1199.247 (INBUILD®)
BI Investigational 
Product(s):
Nintedanib
Title:
A double blind, randomized, placebo-controlled trial evaluating 
the efficacy and safety of nintedanib over 52 weeks in patients 
with Progressive Fibrosing Interstitial Lung Disease (PF-ILD)
Brief Title:
Efficacy and safety of nintedanib in patients with Progressive 
Fibrosing Interstitial Lung Disease (PF-ILD)
Clinical Phase:
Phase III
Trial Clinical 
Monitor:
Boehringer Ingelheim Pharma GmbH & Co. KG
Birkendorfer Straße 65
88397 Biberach an der Riss, Germany
Phone: 
Fax: 
Coordinating 
Investigator:
.
University of Michigan Health System
1500 E. Medical Center Drive, 3916 Taubman Center
Ann Arbor, MI 48109-0360, USA
Phone:
Fax:
Status:
Final Protocol (Revised Protocol based on global amendment 2)
Version and Date:
Version: 3.0
Date: 08 Jun 2018
Page 1 of 132
Proprietary confidential information.
! 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 2 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Nintedanib
Name of active ingredient:
Nintedanib
Protocol date:
13 Sep 2016
Trial number:
1199.247
Revision date:
08 Jun 2018
Title of trial:
A double blind, randomized, placebo-controlled trial evaluating the 
efficacy and safety of nintedanib over 52 weeks in patients with 
Progressive Fibrosing Interstitial Lung Disease (PF-ILD)
Coordinating
Investigator:
Trial site(s):
Multi-centre trial; approximately 14 participating countries
Worldwide
Clinical phase:
Phase III
Objective:
To investigate the efficacy and safety of 150 mg bid nintedanib over 
52 weeks in patients with Progressive Fibrosing Interstitial Lung 
Disease (PF-ILD).
Methodology:
Placebo controlled, randomized, double-blind, parallel design trial 
comparing 150 mg nintedanib bid to placebo over a 52 week 
treatment period (Part A). Patients will continue on blinded 
randomized treatment (i.e. nintedanib or placebo) until the end of the 
trial (Part B).
The primary assessment of benefit- risk of nintedanib in PF-ILD will 
be based on the efficacy and safety data over 52 weeks. Additional
data beyond the 52 week treatment period will provide supportive 
longer term information on secondary time to event efficacy 
endpoints and on safety.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 3 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Nintedanib
Name of active ingredient:
Nintedanib
Protocol date:
13 Sep 2016
Trial number:
1199.247
Revision date:
08 Jun 2018
Methodology continued: The study population will be enriched for patients with PF-ILD with 
Usual Interstitial Pneumonia (UIP) pattern. UIP pattern will be 
defined based on High Resolution Computed Tomography (HRCT)
using the same HRCT criteria as in the Phase III IPF trials with 
nintedanib. Since these criteria differ slightly from the current 
definition of radiologic UIP provided in the American Thoracic 
Society/European Respiratory Society (ATS/ERS) guidelines, 
screening HRCT meeting the protocol criteria for UIP as confirmed 
by central review will be referred to as ”HRCT with UIP-like fibrotic 
pattern only”
No. of patients: 
total entered:
600
each treatment:
Nintedanib: 300
Placebo: 300
Diagnosis :
Physician diagnosis of PF-ILD
Main criteria
for inclusion:
Patients aged ≥ 18 years with PF-ILD, defined as patients who 
present with features of diffuse fibrosing lung disease of >10% 
extent on HRCT and whose lung function and respiratory symptoms 
or chest imaging have worsened despite treatment with unapproved 
medications used in clinical practice to treat ILD.
Test product(s):
Nintedanib
dose:
150 mg bid (300 mg daily)
with optional dose reduction to 100 mg bid (200 mg daily) to 
manage adverse events
mode of 
administration:
Per os


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 4 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Nintedanib
Name of active ingredient:
Nintedanib
Protocol date:
13 Sep 2016
Trial number:
1199.247
Revision date:
08 Jun 2018
Comparator products:
Placebo matching nintedanib soft gelatine capsules
dose:
N/A
mode of 
administration:
Per os
Duration of treatment:
For each patient, the study will consist of two parts: Part A and Part 
B. Part A will be of 52 weeks duration. Part B will be a variable 
treatment period beyond 52 weeks. 
In Part B, patients will continue on blinded randomized treatment 
(nintedanib or placebo) until the end of the trial or until a reason for 
treatment withdrawal is met. The trial will end once the last 
randomized patient completes the EOTB or Follow- up Visit, as 
applicable.
Endpoints:
Primary:
∀
Annual rate of decline in Forced Vital Capacity (FVC; in 
mL) over 52 weeks
Main secondary: 
∀
Absolute change from baseline in King's Brief Interstitial 
Lung Disease Questionnaire (K-BILD) total score at week 52
∀
Time to first acute ILD exacerbation or death over 52 weeks
∀
Time to death over 52 weeks
Other secondary:
∀
Time to death due to respiratory cause over 52 weeks
∀
Time to progression or death over 52 weeks 
∀
Proportion of patients with a relative decline from baseline in 
FVC % pred of >10% at week 52
∀
Proportion of patients with a relative decline from baseline in 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 5 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Nintedanib
Name of active ingredient:
Nintedanib
Protocol date:
13 Sep 2016
Trial number:
1199.247
Revision date:
08 Jun 2018
Endpoints continued:
FVC % pred of >5% at week 52
∀
Absolute change from baseline in Living with Pulmonary 
Fibrosis (L-PF) Symptoms dyspnea domain score at week 52
∀
Absolute change from baseline in Living with Pulmonary 
Fibrosis (L-PF) Symptoms cough domain score at week 52
Safety criteria:
∀
Vital signs, physical examination, body weight
∀
Clinical laboratory tests (haematology, clinical chemistry and 
urinalysis)
∀
Reporting of adverse events 
∀
Others, e.g. 12 lead electrocardiogram
Statistical methods:
There will be two co-primary analysis populations: the first will 
comprise all patients (the overall population); the second will 
comprise PF-ILD patients with HRCT with UIP-like fibrotic pattern 
only. A Hochberg procedure will be used to adjust the significance 
level for the multiple testing. For the primary endpoint, statistical 
significance will be declared if the analyses in both co-primary 
populations are significant at the two-sided 5% level, or if the 
analyses in either co-primary population are statistically significant 
at the two-sided 2.5% level.
Random coefficient regression (random slopes and intercepts) model 
for the primary endpoint, Mixed Effects Models for Repeated 
Measures (MMRM) for all other continuous secondary endpoints, 
Cox proportional hazards models as well as Kaplan-Meier plots for 
time to event secondary endpoints, and logistic regressions for binary 
secondary endpoints.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 6 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
FLOW CHART PART A: 52 WEEKS TREATMENT PERIOD
Visit
1
2
3
4
5
6
6a
7
7a
8
8a
9
EOTA
1
FU1
Screening*
Treatment#
FU
Weeks of treatment
0
2
4
6
12
18
24
30
36
44
52
+4
Day
Time window
Before or 
at the latest at 
visit 1
≥ 4d 
before 
V 2
1
15
±3
29
±3
43
±3
85
±3
127
±7
169
±7
211
±7
253
±7
309
±7
365
±7
+28
+7
Informed consent
X*
HRCT sent to central review2
X
Demographics
X
Medical history 
X
X
Adverse events, concomitant medication
X
X
X
X
X
X
X
X
X
X
X
In-/exclusion criteria
X
X
Physical examination, vital signs
X
X
X
X
X
X
X
X
X
X
X
Safety Laboratory (blood and urine)
X3
X
X
X
X
X
X4
X
X4
X
X4
X
X
Pregnancy test5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sample6
X
X
Serum and plasma biomarker samples7
X
X
X
X
X
X
RNA sample7
X
X
X
X
Serum banking samples (optional)7, 8
X
X
X
X
X
X
DNA banking sample (optional)8
X
HCRU assessments
X
X
X
X
X
X
X
X
X
Non-elective hospitalization
X
X
X
X
X
X
X
X
X
Spirometry (FVC)9
X
X
X
X
X
X
X
X
X
X
X
SpO2 (earlobe or forehead, resting)
X
X
X
X
DLCO
9
X
X
X
X
X
HRCT (optional)10
X
X
X
X11
Resting 12-lead ECG12
X
X
X
X
X
Questionnaires: K-BILD, L-PF Symptoms & 
Impact, EQ-5D, PF-IQOLS13
X
X
X
X
X
X


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 7 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
FLOW CHART PART A: 52 WEEKS TREATMENT PERIOD (CONT.)
Visit
1
2
3
4
5
6
6a
7
7a
8
8a
9
EOTA
1
FU1
Screening*
Treatment#
FU
Weeks of treatment
0
2
4
6
12
18
24
30
36
44
52
+4
Day
Time window
Before or
at the latest 
at visit 1
≥ 4d before 
V 2
1
15
±3
29
±3
43
±3
85
±3
127
±7
169
±7
211
±7
253
±7
309
±7
365
±7
+28
+7
Review questionnaires for completeness
X
X
X
X
X
X
Acute ILD Exacerbations
X
X
X
X
X
X
X
X
X
Randomization
X
IRT call/notification
X14
X
X
X
X
X
X
(X)
Administer 1st  trial medication at the clinic
X
Dispense trial medication
X
X
X
X
X
X
Collect trial drug
X
X
X
X
X
X
Compliance / drug accountability
X17
X
X17
X
X
X
X
X
Trial medication termination
X
Vital status assessment15
X
Conclude subject participation
X16
* Informed consent needs to be signed before any procedure related to the study. When it is signed before visit 1, e.g. to allow shipment of images for central review, all AEs and 
Concomitant Treatments occurring after the informed consent have to be recorded. The Screening period (informed consent to Visit 2) must not be longer than 12 weeks. Upon 
obtaining informed consent, the patient will be instructed on the medication wash-out and other restrictions needed.
# In case of dose change (reduction or re-escalation) additional visits have to be included (refer to Section 6.2.4). In case of premature discontinuation of trial medication, the 
patient will be expected to attend all visits (Part A and Part B visits) as originally planned until the end of the trial (except for the laboratory visits 6a, 7a, 8a) (see Section 6.2.3).
1 EOTA should be done in cases of premature trial medication discontinuation during Part A of the study with a follow-up Visit (FU) 4 weeks later. A scheduled visit (V3-V9) can 
be skipped if EOTA or Follow-up Visit occurs within 4 weeks prior to scheduled visits.
2 Review of high resolution computed tomography (HRCT) for meeting the HRCT criteria for fibrosing lung disease, for extent of ILD in the lung (10% or more), and for HRCT 
pattern. Central review HRCT not older than 12 months should be sent. If the patient does not have a HRCT within 12 months of Visit 1 or the available HRCT scan fails to meet 
the required image acquisition specification, a new HRCT can be performed for the purposes of participation in the trial, provided the patient meets all other inclusion and no 
exclusion criteria.
3 The safety lab of Visit 1 must be repeated if screening is longer than 6 weeks.
4 Intermediate lab tests (a-Visit) to be done as needed for additional safety monitoring (see Section 4.2.2.2) at the discretion of the investigator. 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 8 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
5 ß-HCG will be performed at Visit 2 only, at central laboratory. Urine dipstick pregnancy tests will be provided by central laboratory and should be performed in all women of 
childbearing potential every 4-6 weeks, i.e. at least at every visit and if necessary, additionally at home or at a local laboratory / local doctor. If urine test is not acceptable to 
local authorities, a blood test can be done at a local laboratory. Documentation will be done in patient’s notes. 
6 PK samples will be taken at Visits 4 and 7 just before drug administration. Date and exact clock time of drug administration and blood sampling must be recorded on the eCRF. 
Patients will be provided (Visits 3 and 6) with a PK-card to support the record of the exact clock time of medication intake three days preceding PK sampling.
7 Biomarker samples will be taken just before drug administration.
8 Deoxyribonucleic Acid (DNA) and serum banking samples: will be taken from eligible patients who signed a separate informed consent at Visit 2, at the timepoints indicated in 
the Flowchart; participation is voluntary and is not a prerequisite for participation in the trial. DNA samples can be taken at Visit 2 or any subsequent visit.
9 Order of lung function measurements: 1. FVC followed by patients rest; 2. DLCO. Measurements at approximately the same time each visit, reference time at Visit 2.
10 High resolution CT scan will be done at baseline, 24 and 52 weeks in patients who agree as part of the informed consent. Participation is voluntary and is not a prerequisite for 
participating in the trial. Baseline scan will not be performed in patients where eligibility scan was performed during screening. 
11 If EOT takes place before Visit 7, HRCT should not be performed at EOT. 
12 Resting ECG will be performed (if possible prior to blood draw) at Visit 2 prior to randomization (only if abnormal at Visit 1).
13 Self-reported outcomes / Questionnaires must always be done by the patients in a quiet place prior to any other visit procedure. Order of questionnaires: 1. K-BILD, 2. L-PF 
Symptoms and Impact, 3. EQ-5D, 4.PF- IQOLS.
14 IRT needs to be notified at the latest at Visit 1 but can be notified upon informed consent’s signature.
15 Vital status at 52 weeks (Visit 9) should be available for all randomized patients. Consent for a vital status call at 52 weeks in case of premature discontinuation of trial 
participation will be requested for all patients as part of the informed consent.
16 Conclusion of participation is only applicable for subjects who withdraw consent for trial participation.
17 Compliance / drug accountability only in case of dose reduction / increase.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 9 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
FLOW CHART PART B1: VARIABLE TREATMENT PERIOD 
BEYOND 52 WEEKS
Visit
Xa2
X3
EOTB
4
FU4
Treatment#
Weeks of treatment from V9
8 +
Every 16wk
16 +
Every 16wk
+4wk past 
EOTB
Day
Time window
+7
+7
+28
+7
Physical examination, vital signs
X
X
X
Adverse events, concomitant medication
X
X
X
Safety Laboratory (blood and urine)
X
X
X
Pregnancy test5
X
X
X
X
Resting 12-lead ECG6
X
X
Spirometry (FVC)7
X
X
X
DLCO7
X
X
HCRU assessments
X
X
Non-elective hospitalization
X
X
X
Acute ILD Exacerbations
X
X
X
Dispense trial medication
X
Collect trial drug
X
X
Compliance / drug accountability
X
X
IRT call/notification
X
X
Trial medication termination
X
Vital status assessment8
X
Conclude subject participation
X
# In case of dose change (reduction or re-escalation) additional visits have to be included (refer to Section 6.2.4).
Termination of trial medication data needs to be collected any time trial medication is permanently discontinued.
1 After completion of the 52 weeks treatment period (V9), patients will continue on blinded treatment (nintedanib or placebo) 
until the end of the trial or until a reason for treatment withdrawal is met. In case of premature discontinuation of trial 
medication,  the patient will be expected to attend all visits (Part B visits) as originally planned until the end of the trial 
(except for the laboratory visits Xa) (see Section 6.2.3).
2 Intermediate lab tests (“a”-Visits) to be done as needed for additional safety monitoring (see Section 4.2.2.2) at the 
discretion of the investigator. 
3 Visit X stands for V10, 11 etc. Visits should occur every 16 weeks until the end of the trial. Same visit procedures should 
be repeated at every visit.
4 In case of premature discontinuation of study medication, EOTB should be done as soon as possible after last drug intake 
and a Follow-up Visit should be completed 4 weeks after EOTB. A scheduled visit can be skipped if EOTB or Follow-up 
Visit occurs within 4 weeks prior to scheduled visits. For patients who complete the study regularly, EOTB should be 
scheduled after the Sponsor’s communication of the end of the trial. Only in case the patient does not roll-over in the 
separate open-label study a Follow-up Visit should be completed 4 weeks after EOTB.
5 Urine dipstick pregnancy tests will be provided by central laboratory and should be performed in all women of childbearing 
potential at least at every visit and if necessary; additionally at home or at a local laboratory / local doctor every 4-6 weeks. 
If urine test is not acceptable to local authorities, a blood test can be done at a local laboratory. Documentation will be 
done in patient’s notes.
6 Resting ECG should be done at every other scheduled visit (i.e. Visit X)
7 Order of lung function measurements: 1. FVC followed by patients rest; 2. DLCO. Measurements at approximately the 
same time each visit, reference time at Visit 2.
8 Vital status at the time of the data cut-off for the primary analysis and at the end of the trial should be available for all 
randomized patients. Consent for a vital status call at respective time points in case of premature discontinuation of trial 
participation will be requested for all patients as part of the informed consent.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 10 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART PART A: 52 WEEKS TREATMENT PERIOD.......................................6
FLOW CHART PART B1: VARIABLE TREATMENT PERIOD BEYOND 52 WEEKS
.................................................................................................................................9
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1.
INTRODUCTION...............................................................................................17
MEDICAL BACKGROUND.............................................................................17
1.1
1.1.1
ILD Overview......................................................................................................17
1.1.2
PF-ILD disease concept ......................................................................................19
1.1.3
Patient population to be studied in the current trial .......................................20
DRUG PROFILE................................................................................................21
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....26
RATIONALE FOR PERFORMING THE TRIAL.........................................26
2.1
TRIAL OBJECTIVES........................................................................................26
2.2
BENEFIT - RISK ASSESSMENT.....................................................................26
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................29
OVERALL TRIAL DESIGN AND PLAN .......................................................29
3.1
3.1.1
Administrative structure of the trial .................................................................31
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................32
SELECTION OF TRIAL POPULATION .......................................................34
3.3
3.3.1
Main diagnosis for trial entry ............................................................................34
3.3.2
Inclusion criteria .................................................................................................35
3.3.3
Exclusion criteria ................................................................................................35
3.3.4
Imaging criteria...................................................................................................37
3.3.5
Removal of patients from therapy or assessments...........................................38
Removal of individual patients from therapy .......................................................38
3.3.5.1
Removal of individual patients from trial.............................................................39
3.3.5.2
Discontinuation of the trial by the Sponsor ..........................................................40
3.3.5.3
4.
TREATMENTS...................................................................................................41
TREATMENTS TO BE ADMINISTERED.....................................................41
4.1
4.1.1
Identity of BI investigational product(s)...........................................................41
4.1.2
Method of assigning patients to treatment groups...........................................41
4.1.3
Selection of doses in the trial..............................................................................41


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 11 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
4.1.4
Drug assignment and administration of doses for each patient......................42
4.1.5
Blinding and procedures for unblinding...........................................................43
Blinding.................................................................................................................43
4.1.5.1
Unblinding and breaking the code ........................................................................43
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................44
4.1.7
Storage conditions...............................................................................................44
4.1.8
Drug accountability.............................................................................................45
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................45
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....45
4.2.1.1
Management of diarrhoea .....................................................................................46
4.2.1.2
Management of liver enzyme elevation................................................................48
4.2.1.3
Management of acute ILD exacerbations .............................................................49
4.2.2
Restrictions ..........................................................................................................49
Restrictions regarding concomitant treatment ......................................................49
4.2.2.1
Cautionary notes ...................................................................................................51
4.2.2.2
Restrictions on diet and life style..........................................................................52
4.2.2.3
Restrictions regarding women of childbearing potential......................................52
4.2.2.4
TREATMENT COMPLIANCE........................................................................52
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................53
TRIAL ENDPOINTS..........................................................................................53
5.1
5.1.1
Primary Endpoint ...............................................................................................53
5.1.2
Secondary Endpoints..........................................................................................53
5.1.3
Further Endpoints...............................................................................................53
Further Endpoints over 52 weeks (Part A)............................................................53
5.1.3.1
Further Endpoints over the whole trial (Part A and Part B)..................................54
5.1.3.2
ASSESSMENT OF EFFICACY........................................................................54
5.2
5.2.1
Assessment of FVC..............................................................................................54
5.2.2
Time to progression or death.............................................................................55
5.2.3
Time to death.......................................................................................................55
5.2.4
Acute ILD exacerbations....................................................................................55
5.2.5
Assessment of DLCO ..........................................................................................56
5.2.6
Time to hospitalization .......................................................................................56
5.2.7
Assessment of PRO questionnaires ...................................................................56
King's Brief Interstitial Lung Disease Questionnaire (K-BILD) ..........................57
5.2.7.1
Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (L-PF)...57
5.2.7.2
EuroQol 5-Dimensional quality of life Questionnaire (EQ-5D)...........................57
5.2.7.3
Pulmonary Fibrosis Impact on Quality of Life Scale (PF-IQOLS) ......................58
5.2.7.4
ASSESSMENT OF SAFETY.............................................................................58
5.3
5.3.1
Physical examination ..........................................................................................58
5.3.2
Vital Signs............................................................................................................59
5.3.3
Safety laboratory parameters ............................................................................59
5.3.4
Electrocardiogram ..............................................................................................60
5.3.5
Other safety parameters.....................................................................................61
5.3.6
Assessment of adverse events.............................................................................61


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 12 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Definitions of AEs ................................................................................................61
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................64
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................66
5.4.1
Assessment of Pharmacokinetics.......................................................................66
5.4.2
Methods of sample collection .............................................................................66
5.4.3
Analytical determinations ..................................................................................67
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................67
ASSESSMENT OF EXPLORATORY BIOMARKER(S)..............................67
5.5
5.5.1
Methods and timing of sample collection..........................................................68
5.5.2
Analytical determinations ..................................................................................68
5.5.3
Biobanking...........................................................................................................68
OTHER ASSESSMENTS...................................................................................70
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................71
5.7
6.
INVESTIGATIONAL PLAN.............................................................................72
VISIT SCHEDULE.............................................................................................72
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................73
6.2
6.2.1
Screening..............................................................................................................73
6.2.2
Treatment phase..................................................................................................74
6.2.3
Follow-up Visit and trial completion.................................................................78
6.2.4
Dose reduction visit / dose increase visit...........................................................79
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................81
STATISTICAL DESIGN - MODEL.................................................................81
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................81
7.2
PLANNED ANALYSES.....................................................................................82
7.3
7.3.1
Primary endpoint analyses.................................................................................82
7.3.2
Secondary endpoint analyses .............................................................................83
7.3.3
Further endpoint analyses..................................................................................84
7.3.4
Safety analyses.....................................................................................................85
7.3.5
Pharmacokinetic analyses ..................................................................................86
INTERIM ANALYSES ......................................................................................86
7.4
HANDLING OF MISSING DATA ...................................................................86
7.5
7.5.1
Efficacy Endpoints..............................................................................................86
7.5.2
Safety....................................................................................................................88
7.5.3
Plasma concentrations........................................................................................88
RANDOMIZATION...........................................................................................88
7.6
DETERMINATION OF SAMPLE SIZE .........................................................88
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................93
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................93
DATA QUALITY ASSURANCE ......................................................................94
8.2
RECORDS...........................................................................................................94
8.3


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 13 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
8.3.1
Source documents ...............................................................................................94
8.3.2
Direct access to source data and documents.....................................................95
8.3.3
Storage period of records ...................................................................................95
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS95
8.4
8.4.1
Listedness.............................................................................................................95
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................95
STATEMENT OF CONFIDENTIALITY........................................................95
8.5
END OF TRIAL..................................................................................................96
8.6
PROTOCOL VIOLATIONS .............................................................................96
8.7
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY..............................................................................96
9.
REFERENCES....................................................................................................97
PUBLISHED REFERENCES............................................................................97
9.1
UNPUBLISHED REFERENCES....................................................................102
9.2
10.
APPENDICES...................................................................................................104
LUNG FUNCTION CRITERIA......................................................................104
10.1
CREATININE CLEARANCE.........................................................................104
10.2
PATIENT REPORTED OUTCOME QUESTIONNAIRES ........................105
10.3
10.3.1
K-BILD ..............................................................................................................105
10.3.2
L-PF Symptoms and Impact Questionnaire...................................................108
10.3.3
EQ-5D.................................................................................................................118
10.3.4
PF-IQOLS..........................................................................................................121
HANDLING AND DERIVATION OF PHARMACOKINETIC 
10.4
PARAMETERS.................................................................................................123
10.4.1
Pharmacokinetic Methods................................................................................123
FVC DECLINE RESULTS IN IPF TRIALS .................................................124
10.5
SAS CODE FOR SAMPLE SIZE CALCULATION ....................................125
10.6
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................127


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 14 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
ABBREVIATIONS
AC
Adjudication Committee
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALK
Alkaline Phosphatase
ALT
Alanine Aminotransferase
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
ATP
Adenosine Triphosphate
ATS / ERS
American Thoracic Society / European Respiratory Society
AUC
Area under the Curve
AZA
Azathioprine
BI
Boehringer Ingelheim
bid
bis in die (twice a day)
BLQ
Below Limit of Quantification
BNP
Brain natriuretic peptide
CA
Competent Authority
CHP
Chronic fibrosing Hypersensitivity Pneumonitis
CK
Creatine Kinase
Cmax
Maximum measured concentration of the analyte in plasma
CML
Local Clinical Monitor 
CNS
Central Nervous System
CRA
Clinical Research Associate
CrCL
Creatinine Clearance
CRF
Case Report Form
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CTD 
Connective Tissue Disease
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DDI
Drug-Drug Interaction
DEDP
Drug Exposure During Pregnancy
DILI
Drug-Induced Liver Injury
DLCO
Carbon Monoxide Diffusion Capacity
DLT
Dose Limiting Toxicity
DMARD
Disease-Modifying Anti-Rheumatic Drug
DMC
Data Monitoring Committee
DNA
Desoxyribo Nucleic Acid
DPLD
Diffuse Parenchymal Lung Diseases
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDTA
Ethylenediamine-Tetraacetic Acid
EOT
End of Treatment
ePRO
Electronic Patient Reported Outcome
EudraCT
European Clinical Trials Database


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 15 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
EQ5D
EuroQol 5-Dimensional quality of life Questionnaire
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 second
FGFR
Fibroblast Growth Factor Receptor
FU
Follow-up
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GI
Gastro Intestinal
GLI
Global Lung Initiative
GP
General Practitioner
Hb
Haemoglobin
HCG
Human Chorionic Gonadotropin
HCRU
Health Care Resource Utilization
HCT
Haematocrit
HP
Hypersensitivity Pneumonitis
HR
Hazard Ratio
HRCT
High Resolution Computed Tomography
IEC
Independent Ethics Committee
IIPs
Idiopathic Interstitial Pneumonias
ILD
Interstitial Lung Disease
INR
International Normalized Ratio
iNSIP
Idiopathic Nonspecific Interstitial Pneumonia
IPAF
Interstitial Pneumonia with Autoimmune Features
IPF
Idiopathic Pulmonary Fibrosis
IQOLS
Impact on Quality of Life Scale
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
K-BILD
King's Brief Interstitial Lung Disease Questionnaire
Lck
Lymphocyte-specific Tyrosine-protein Kinase
LDH
Lactate Dehydrogenase
L-PF
Living with Pulmonary Fibrosis Scale
LPLVPE
Last Patient Last Visit Primary Endpoint
Lyn
Lymphocyte antigen receptor-associated tyrosine kinases
MACE
Major Adverse Cardiovascular Events
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMF
Mycophenolate Mofetil
MMRM
Mixed Effects Models for Repeated Measures
NAC
N-Acetylcysteine 
NOA
Not Analyzed
NOR
No Valid Result
NOS
No Sample
OCS
Oral Corticosteroides
PD
Pharmacodynamics
PDGFR
Platelet-derived Growth Factor Receptor


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 16 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
P-gp
P-glycoprotein
PF-ILD
Progressive Fibrosing Interstitial Lung Disease
PF-IQOLS
Pulmonary Fibrosis Impact on Quality of Life Scale
PIT
Partial Thromboplastin Time
PK
Pharmacokinetics
PRO
Patient Reported Outcome
PT
Prothrombin Time
QoL
Quality of Life
QOLS
Quality of Life Scale
RA-ILD
Rheumatoid Arthritis-associated ILD
RBC
Red Blood cell Count
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
REML
Restricted Maximum Likelihood
RNA
Ribo Nucleic Acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
s.c.
Subcutaneous
SD
Standard Deviation
SGRQ
Saint George's Respiratory Questionnaire
SMQ
Standard MedDRA Query
SOP
BI Standard Operating Procedures
SpO2
Saturation of oxygen
Src
proto-oncogene tyrosine-protein kinase src
SSc-ILD
Systemic Sclerosis-associated ILD
STPD
Standard Temperature and Pressure, Dry
SUSAR
Suspected Unexpected Serious Adverse Reactions
TOEP
Toeplitz
TOEPH
Heterogeneous Toeplitz
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UIP
Usual Interstitial Pneumonia
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
VEGF / R
Vascular Endothelial Growth Factor / Receptor
wk
Week


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 17 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
The aim of the current study is to investigate the efficacy and safety of 150 mg bid nintedanib 
over 52 weeks in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD) 
defined as patients who present with features of diffuse fibrosing lung disease of >10% extent 
on high-resolution computed tomography (HRCT) and whose lung function and respiratory 
symptoms or chest imaging have worsened despite treatment with unapproved medications 
used in clinical practice to treat ILD. Section 1.1.1 below provides background information 
on ILDs in general, Section 1.1.2 on the concept of PF-ILD and Section 1.1.3 on the target 
study population of the current study.
1.1.1
ILD Overview
ILDs, also referred to as diffuse parenchymal lung diseases (DPLD), encompasses a large 
group of over 200 pulmonary disorders. The clinical assessment of a patient with ILD 
requires a multidisciplinary approach: medical history including occupational, environmental, 
medication, smoking and family history, physical examination, laboratory investigation, lung 
function testing together with chest imaging studies and histologic/Bronchial Alveolar 
Lavage examinations are necessary to establish the diagnosis. Achieving a correct diagnosis 
is a dynamic process requiring close communication between clinician, radiologist and 
pathologist (R13-4145).
Classification
There is no universally accepted single classification of ILDs. Figure 1.1: 1 shows one of the 
many classifications to illustrate the complex nature of ILDs. This classification uses five 
categories:
∀
idiopathic interstitial pneumonias (IIPs) which includes the most studied idiopathic 
pulmonary fibrosis (IPF), 
∀
hypersensitivity pneumonitis (HP), 
∀
autoimmune ILD that includes systemic sclerosis-associated ILD (SSc-ILD) and 
rheumatoid arthritis-associated ILD (RA-ILD), 
∀
sarcoidosis and 
∀
the group of “other ILDs”.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 18 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Figure 1.1: 1
Classification of interstitial lung disease
Pathomechanism
Overall, the major abnormality in ILDs is the disruption of the distal lung parenchyma. 
Although the pathogenesis, especially of the IIPs, remains unknown, it is generally agreed 
that some form of injury of the alveolar epithelial cells initiates an inflammatory response 
coupled with repair mechanisms. The initiating injury can be introduced via the airways (e.g. 
inhalation of mineral fibres or dust as in occupational diseases or sensitization to inhaled 
allergens as in hypersensitivity pneumonitis) or via the circulation (e.g. Connective Tissue 
Disease (CTD) and drug-induced ILDs). The injury-repair process is reflected pathologically
as inflammation, fibrosis or a combination of both. However, irrespective of the underlying 
pathophysiology, the resulting alteration of the interstitial space leads to clinical symptoms 
such as dyspnoea and cough and physiologic abnormalities such as restrictive ventilatory 
deficit on pulmonary function testing (R16-0722).
Prognosis
Of all ILDs, IPF accounts for 20% to 30% and has the worst prognosis. IPF is a progressive, 
severely debilitating disease characterized by decline in lung function leading to respiratory 
failure and death. The median survival of IPF is 2.5–3.5 years from diagnosis (P11-07084).
The natural history of other ILDs is less well characterized because no large, prospective, 
controlled clinical trials have been performed in ILDs other than IPF and SSc-ILD.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 19 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
The currently available data in different ILDs collectively suggest that the ILD injury pattern, 
and severity of lung involvement i.e. extent of fibrosis and longitudinal behaviour of lung 
function have major impact on prognosis. (P11-07084, R16-0557, R15-3264, R16-0553, 
R10-6539, R06-4127, R10-2727, P12-09611, R14-1149, R12-3648, R14-1150). The 
prognosis and clinical behaviour of fibrosing ILDs, particularly those with a Usual Interstitial 
Pneumonia (UIP) pattern, seem to be similar to that of IPF (R06-4129, R15-3262, R16-0553, 
R16-0496).
1.1.2
PF-ILD disease concept
Based on clinical experience, there is a group of patients who, independent from the ILD
classification, at some point in time, develop a progressive fibrosing phenotype. In this group 
of patients, the natural history appears to follow a course similar to IPF with worsening of 
respiratory symptoms, lung function, QoL and functional status, as well as early mortality 
despite treatment with currently available non-approved immunomodulatory therapies. The 
proposed terminology for describing this group is progressive fibrosing interstitial lung 
disease (PF-ILD).
Based on expert consensus, the main fibrosing ILDs in which progressive behaviour is 
present include:
∀
Idiopathic Interstitial Pneumonias (IIPs): mainly IPF, idiopathic non-specific 
interstitial pneumonia (iNSIP) and unclassifiable IIP
∀
Chronic fibrosing hypersensitivity pneumonitis (CHP)
∀
Autoimmune ILDs: connective tissue disease- ILD (CTD-ILD)
(mainly RA-ILD and SSc-ILD) and interstitial pneumonia with autoimmune features 
∀
Environmental/occupational fibrosing lung disease
The scientific working hypothesis is that the response to lung injury in these ILDs includes 
the development of fibrosis which becomes progressive, self-sustaining and independent of 
the original clinical association or trigger. It is postulated that, at this stage, targeted anti-
fibrotic therapy is required to slow the progression of the disease. 
Based on the similarity in both, the biologic and clinical behaviours i.e. self-sustaining 
fibrosis and progressive decline in lung function and early mortality, it is considered justified 
to group patients with PF- ILDs together regardless of their original ILD diagnosis.
Nintedanib is a kinase inhibitor indicated for the treatment of IPF, which has been shown to 
slow the progression of IPF. Based on the similarity in both the underlying pathophysiology 
and clinical course of PF-ILD and IPF, it is anticipated that nintedanib will elicit similar 
effects in PF-ILD as it demonstrated in IPF. This assumption is supported by the pre-clinical 
data indicating that nintedanib impacts fundamental processes of lung fibrosis and that the 
anti-fibrotic activity of nintedanib is independent of the cause of the fibrosing lung disease 
(P14-02860, P14-17410, P15-02392, P15-06100).


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 20 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
1.1.3
Patient population to be studied in the current trial
The current clinical trial will include patients with PF-ILD defined as patients who present 
with features of diffuse fibrosing lung disease of >10% extent on high-resolution computed 
tomography (HRCT) and whose lung function and respiratory symptoms or chest imaging 
have worsened despite treatment with unapproved medications used in clinical practice to 
treat ILD (see Section 3.3.2). 
The selection criteria (see Section 3.3) mirror the physicians’ assessment in the clinical 
practice as they are based on a composite of the three dimensions of the disease activity i.e. 
worsening of symptoms, worsening of lung function and increasing fibrosis on chest images. 
Patients with physician diagnosis of ILD who fulfil at least one of the following criteria for 
PF-ILD within 24 months of the screening visit as assessed by the investigator will be
eligible:
∀
clinically significant decline in FVC % predicted (%pred) based on ≥10% relative 
decline
∀
marginal decline in FVC %pred based on ≥5 – <10% relative decline in FVC 
combined with worsening of respiratory symptoms 
∀
marginal decline in FVC %pred based on ≥5 – <10% relative decline in FVC 
combined with increasing extent of fibrotic changes on chest imaging
∀
worsening of respiratory symptoms as well as increasing extent of fibrotic changes on 
chest imaging
Further, the following additional inclusion criteria will be used to ensure that patients with 
progressive fibrosing phenotype are selected for the study:
∀
Features of fibrosing lung disease with >10% extent on HRCT as confirmed by 
central review
∀
Baseline diffusing capacity of the lungs for carbon monoxide (DLCO) (%pred) <80%
Although patients with IPF exhibit a progressive phenotype, patients with clinical diagnoses 
of IPF will be excluded from the study (see Section 3.3). The rationale for this is based on the 
fact that the efficacy and safety of nintedanib has already been established in IPF. The current 
study will focus on patients with PF-ILD in whom the effects of nintedanib have not yet been 
assessed or demonstrated.
Nintedanib is hypothesized to have the same relative effect in all patients with PF-ILD i.e. an 
approximately 50% reduction in the annual rate of decline in FVC. However, it is expected 
that the absolute effect difference between groups will be the largest in the patients with PF-
ILD with UIP pattern since these patients are assumed to have a larger annual rate of decline 
in FVC than patients with other fibrotic patterns. Based on this, the study will be enriched for 
patients with UIP pattern to maintain a high statistical power to detect a clinically meaningful
effect of nintedanib in the rare disease of PF-ILD (see Section 3.2).
UIP pattern can be assessed either by surgical biopsy or HRCT. However, given the 
challenges associated with surgical sampling in clinical practice in patients with impaired 
lung function, availability of surgical biopsy is often limited. In contrast, HRCT assessment 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 21 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
of extent of fibrosis and fibrotic pattern has become an essential part of the evaluation and 
diagnosis of patients with ILDs. Since HRCT diagnosis of UIP has been shown to correlate 
with both histologic UIP (P11-07084) and prognosis in patients with ILDs (R16-0560, R16-
0756, R14-3529), the proposed Phase III study will be enriched for patients with UIP pattern 
based on HRCT.
As described in the 2011 ATS/ERS Guidelines for IPF (P11-07084), the HRCT pattern of 
“definite UIP” requires the presence of honeycombing. However, recent evidence suggests 
that an HRCT pattern of fibrosing ILD defined by the presence of traction bronchiectasis is 
independently correlated with histologic UIP as well as prognosis in patients with IPF, CTD-
ILD and CHP (R16-1567, R14-3529, R16-0752, R16-1568). These data are also supported by 
findings from the nintedanib Phase III studies in IPF. In a post-hoc pooled analysis, patients 
with traction bronchiectasis without evidence of honeycombing (“possible UIP” in the 
guidelines) were found to have similar lung function decline and response to therapy  
compared to those with “definite UIP” pattern on HRCT (P15-04977, P15-05695). These data 
suggest that both honeycombing and traction bronchiectasis may predict the presence of
histologic UIP and have similar prognostic value.
Accordingly, the same HRCT criteria for UIP pattern as the Phase III IPF trials for nintedanib 
(P15-04977, P15-05695) will be used and the study will be enriched for patients meeting 
either criteria A, B and C, or criteria A and C, or criteria B and C as described below:
A. Definite honeycomb lung destruction with basal and peripheral predominance
B. Presence of reticular abnormality AND traction bronchiectasis consistent with fibrosis 
with basal and peripheral predominance
C. Atypical features are ABSENT, specifically: nodules and consolidation. Ground glass 
opacity, if present, is less extensive than reticular opacity pattern
Since these criteria differ slightly from the current definition of radiologic UIP provided in 
the ATS/ERS guidelines (P11-07084), screening HRCT meeting the above criteria will be 
referred to as “HRCT with UIP-like fibrotic pattern only”. Patients with HRCT patterns not 
meeting the above criteria will be referred to as “patients with other HRCT fibrotic patterns”. 
DRUG PROFILE
1.2
Mechanism of Action
Nintedanib is a small molecule tyrosine kinase inhibitor including the receptors platelet-
derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-
3, and vascular endothelial growth factor receptor (VEGFR) 1-3. Nintedanib binds 
competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and 
blocks the intracellular signalling. In addition nintedanib inhibits Fms-like tyrosine-protein 
kinase 3 (Flt 3), lymphocyte-specific tyrosine-protein kinase (Lck), tyrosine-protein kinase 
lyn (Lyn) and proto-oncogene tyrosine-protein kinase src (Src).
These growth factor pathways and their down-stream signal cascades have been 
demonstrated to be involved in the pathogenesis of fibrotic tissue remodelling.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 22 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Nintedanib inhibited the proliferation and migration of human lung fibroblasts from patients 
with IPF. It demonstrated anti-fibrotic and anti-inflammatory activity in three animal models 
of lung fibrosis and in more specific models of systemic sclerosis-associated interstitial lung 
disease (SSc-ILD) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD). 
Although the initiation of the fibrotic lung pathology in these model systems is different, 
progressive fibrotic lung pathology with proliferation, migration and transformation of 
fibroblasts to the pathogenic myofibroblast is the final common pathway. These similarities 
and the mode of action of nintedanib directed against the proliferation, migration and 
transformation of fibroblasts strongly support the rationale for the use of nintedanib in the 
treatment of patients with PF-ILD (U06-1451, U06-1479, U12-2437-01, U12-2066-01, 
n00239669, n00247887).
Pharmacokinetics
A soft gelatine capsule formulation of nintedanib is used in humans. Maximum plasma 
concentrations (Cmax) occur between 2 to 4 hours after oral administration. Steady state is 
reached at the latest within one week of dosing. After food intake, a trend towards an 
increased systemic exposure (around 20%) and a delayed absorption is observed compared to 
administration under fasted conditions. Nintedanib is preferentially distributed in plasma with 
a blood to plasma ratio of 0.87 and the terminal half-life is in the range of 7 to 19 h. The 
absolute bioavailability of nintedanib is slightly below 5%. Nintedanib is recommended to be 
taken with food and is mainly eliminated via faeces.
Co-administration of nintedanib with the P-glycoprotein (P-gp) inhibitor ketoconazole 
increased exposure to nintedanib by 60-70% based on area under the curve (AUC) and by 
80% based on Cmax in a dedicated drug-drug interaction (DDI) study. Patients taking potent 
P-gp inhibitors (e.g. ketoconazole, erythromycin or cyclosporine) should be monitored 
closely for tolerability of nintedanib.
In a DDI study with the P-gp inducer rifampicin, exposure to nintedanib decreased to 50.3% 
based on AUC and to 60.3% based on Cmax upon co-administration with rifampicin compared 
to administration of nintedanib alone.
Based on population pharmacokinetic (PK) analysis, age and body weight were correlated 
with nintedanib exposure. However, their effects on exposure are not sufficient to warrant an 
a priori dose adjustment. There was no influence of sex or mild and moderate renal 
impairment (creatinine clearance (CrCL) > 30 mL/min) on the exposure of nintedanib. In a 
dedicated single dose phase I study and compared to healthy subjects, exposure to nintedanib 
was approximately 2-fold higher in volunteers with mild hepatic impairment (Child Pugh A) 
and approximately 8-fold higher in volunteers with moderate hepatic impairment (Child Pugh 
B). Subjects with severe hepatic impairment (Child Pugh C) have not been studied.
Clinical experience
Nintedanib (trade name: Ofev) was approved for the treatment of IPF in the US, EU, Japan 
and a large number of additional countries. Nintedanib has been in clinical development for 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 23 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
the treatment of several types of cancer. It is currently being evaluated for the treatment of 
systemic sclerosis in patients with SSc-ILD as part of a separate study.
Summary of the efficacy results in IPF
The main evidence of the efficacy of nintedanib in IPF is provided by the 2 randomized, 
double-blind, placebo-controlled confirmatory phase III trials 1199.32 (U13-2381-01) and 
1199.34 (U13-2382-01), which were of identical design and investigated the efficacy and 
safety of nintedanib 150 mg bid versus placebo over 52 weeks. Patients were randomized at 
2:3 ratio (placebo: nintedanib). The primary endpoint in these trials was the annual rate of 
decline in Forced Vital Capacity (FVC) expressed in mL over 52 weeks and the key 
secondary endpoints were the change from baseline in Saint George's Respiratory 
Questionnaire (SGRQ) total score at 52 weeks and the time to first acute IPF exacerbation 
over 52 weeks. Additional evidence of efficacy is provided by the 52-week randomized, 
double-blind, placebo-controlled, proof-of-concept phase II trial 1199.30. The primary 
endpoint in this trial was the same as the phase III trials; the annual rate of decline in FVC 
(expressed in L over 52 weeks). Change from baseline in SGRQ total score at 52 weeks and 
time to first acute IPF exacerbation over 52 weeks were also investigated as secondary 
endpoints in trial 1199.30 (U11-1225-02).
In both phase III trials, nintedanib significantly reduced the annual rate of decline in FVC 
compared with placebo. The adjusted difference in the annual rate of decline between 
nintedanib and placebo in the 2 trials was similar: 125 mL (95% CI 78, 173; p <0.0001) in 
trial 1199.32 and 94 mL (95% CI 45, 143; p=0.0002) in trial 1199.34. Of note, the consistent 
phase III results for the primary endpoint are further supported by the results of the phase II 
trial 1199.30. In this trial, the difference in the annual rate of decline in FVC between 
nintedanib 150 mg and placebo was 0.131 L/year (95% CI 0.027, 0.235; nominal p=0.0136).
The difference in the adjusted mean change in SGRQ total score at 52 weeks was statistically 
significant and in favour of nintedanib in trial 1199.34 (-2.69; 95% CI -4.95, -0.43; p = 
0.0197); there was no treatment difference in trial 1199.32 (-0.05; 95% CI -2.50, 2.40; p = 
0.9657). In the phase II trial 1199.30, the difference in the adjusted mean change from 
baseline in SGRQ total score at 52 weeks was -6.12 (95% CI -10.57, -1.67; p=0.0071) in 
favour of nintedanib.
In trial 1199.34, the frequency of patients with at least 1 acute IPF exacerbation over 
52 weeks based on Investigator reporting was lower in the nintedanib group (3.6%) than in 
the placebo group (9.6%). The hazard ratio (HR) of 0.38 (95% CI 0.19, 0.77) indicated a 
significantly lower risk of having a first acute IPF exacerbation in the nintedanib group than 
in the placebo group at any time point over 52 weeks. In trial 1199.32, the frequency of 
patients with at least 1 acute IPF exacerbation based on Investigator reported adverse events 
was 6.1% in the nintedanib group and 5.4% in the placebo group; the HR was 1.15 (95% CI 
0.54, 2.42), indicating no significant difference in the risk of first acute IPF exacerbation 
between the treatment groups. In the phase II trial 1199.30, the number of patients with acute 
IPF exacerbations over 52 weeks was lower in the nintedanib group (2.3%) compared to 
placebo (13.8%). The estimated HR of nintedanib versus placebo was 0.16 (95% CI 0.04, 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 24 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
0.71; p=0.0054) indicating a significantly lower risk of having an acute IPF exacerbation in 
the nintedanib group than in the placebo group.
In the pre-specified pooled analysis of the Phase III studies 1199.32 and 1199.34, consistent 
with the effect of nintedanib on the decline in lung function, overall mortality over 52 weeks 
was numerically lower in the nintedanib group (5.5%) than in the placebo group (7.8%). The 
analysis of the time to death resulted in a hazard ratio (HR) of 0.70 (95% CI 0.43, 1.12; 
p=0.1399) indicating a 30% reduction in the risk of death in the nintedanib group compared 
with placebo. The results of all survival endpoints (such as on-treatment mortality and 
respiratory mortality) showed a consistent numerical difference in favour of nintedanib.
A post-hoc time to progression analysis, defined as time to ≥10% absolute decline of FVC % 
predicted (% pred) or death was performed on data from the phase III trials, 1199.32 and 
1199.34. This showed that the risk of progression was statistically significantly reduced for 
patients treated with nintedanib compared with placebo in both trials. The results were 
consistent across the 2 Phase III trials with a HR of 0.53 (95% CI 0.39, 0.72; p=0.0001) in 
study 1199.32 and a HR of 0.67 (95% CI 0.51, 0.89; p=0.0054) in 1199.34. In the pooled 
analysis of the Phase III trials, there was a 40% reduction in the risk of progression for 
patients treated with nintedanib compared to placebo (HR: 0.60; 95% CI 0.49, 0.74; 
p<0.0001).
In conclusion: nintedanib has shown robust, reproducible, statistically significant, and 
clinically meaningful effects on the decline in lung function as measured by FVC. In 2 large, 
international, placebo controlled phase III trials of identical design, nintedanib statistically 
and clinically significantly reduced the annual rate of decline in FVC over 52 weeks 
compared with placebo, with a similar treatment effect, about 100 mL/year, i.e. a relative 
difference of 50% between nintedanib and placebo, in both trials. These consistent phase III 
results are further supported by 1-year data from the phase II trial 1199.30, which showed 
comparable results for nintedanib 150 mg bid in regard to annual rate of decline in FVC.
As the natural history of IPF has been described as a progressive decline in pulmonary 
function until eventual death from respiratory failure or complicating comorbidity (P11-
07084), the effects of nintedanib are considered consistent with slowing disease progression.
Summary of the safety results in IPF
The safety profile of nintedanib has been investigated comprehensively based on the pooled 
data of the two phase III studies 1199.32 and 1199.34. The proportion of patients with 
Adverse Events (AEs) and Serious Adverse Events (SAEs) was comparable between the
nintedanib and placebo groups.
During the nintedanib trials 1199.32 and 1199.34, the most commonly reported adverse 
events (≥ 10% and ≥1.5 times placebo) experienced with nintedanib were diarrhoea
(nintedanib 62.4% vs placebo 18.4%) , nausea (24.5% vs 6.6%), abdominal pain (15.0% vs 
6.1%), vomiting (11.6% vs 2.6%) and decreased appetite (10.7% vs 5.7%). Most of these 
AEs were of mild or moderate intensity, reported as non-serious, and were managed by 
symptomatic treatment and/or temporary interruption and/or reduction of the nintedanib 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 25 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
dosage. 19% of patients treated with nintedanib had an adverse event leading to treatment 
discontinuation (compared to 13% in the placebo treatment group). The most commonly 
reported adverse events (≥ 1% and more than for placebo) leading to nintedanib 
discontinuation were diarrhoea (4.4%), nausea (2.0%) and decreased appetite (1.4%).
Liver enzyme elevations (AST and/or ALT ≥3 x ULN) were experienced by 5.0% of patients 
treated with nintedanib in the phase III trials (versus 0.7% of patients treated with placebo).
Arterial thromboembolic events were infrequently reported: in 0.7% of patients in the 
placebo and 2.5% in the nintedanib treated group. While adverse events reflecting ischemic
heart disease were overall balanced between the nintedanib and placebo groups, within this 
group of terms a higher percentage of patients experienced myocardial infarctions in the 
nintedanib group (1.6%) compared to the placebo group (0.5%).
For further details refer to the current version of the Investigators Brochure 
In conclusion: the most frequent AEs were gastrointestinal events which were manageable by 
the proposed dose regimen that includes dose reduction and dosing interruption. This dosing 
regimen was also effective in the management of liver enzyme and bilirubin elevations that 
are associated with nintedanib treatment. 
Overall, the evidence available from the clinical development programme demonstrates a 
favourable benefit-risk balance for nintedanib in the treatment of patients with IPF.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 26 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Nintedanib is a kinase inhibitor indicated for the treatment of IPF. Based on the similarity in 
both the underlying pathophysiology and clinical course of PF-ILD and IPF, the established 
efficacy and safety profile of nintedanib in IPF is considered Proof of Concept for PF-ILD. 
As nintedanib is expected to impact the final common pathogenic mechanisms of progressive 
fibrosis similarly as in IPF, it is anticipated that nintedanib will elicit similar effects in PF-
ILD as it demonstrated in IPF.
Based on data suggesting that the HRCT pattern has a major impact on prognosis, the study 
population will be enriched for patients with HRCT with UIP-like fibrotic pattern only (see 
Section 1.1.3).
TRIAL OBJECTIVES
2.2
The objective of the trial is to investigate the efficacy and safety of 150 mg bid nintedanib in 
patients with PF-ILD compared to placebo over 52 weeks (Part A).
The primary objective is to demonstrate a reduction in lung function decline, as measured by 
the annual rate of decline in FVC for nintedanib compared to placebo over 52 weeks.
The main secondary objectives of the trial are to investigate the effect of treatment on quality 
of life using the King's Brief Interstitial Lung Disease Questionnaire (K-BILD), and to assess 
the effect of nintedanib on time to first acute ILD exacerbation and overall survival over 52 
weeks. Other objectives include the assessment of other lung function parameters and other 
symptoms of the disease such as dyspnea and cough (L-PF) over 52 weeks.
PK, safety and tolerability of nintedanib and biomarkers (e.g. serologic and imaging) will 
also be assessed.
The objectives of Part B (variable treatment period beyond 52 weeks) will be to collect 
supportive, longer term efficacy (time to event endpoints) and safety data on the effect of 
nintedanib compared to placebo.
BENEFIT - RISK ASSESSMENT
2.3
In the group of patients with PF-ILD the natural history of the disease appears to follow a 
course similar to IPF with worsening of respiratory symptoms, lung function, quality of life 
(QoL) and functional status, as well as early mortality. With the exception of nintedanib and 
pirfenidone which are available for patients with IPF, there is no approved therapy for PF-
ILD.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 27 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
In patients with IPF, a typical example of PF-ILD, nintedanib has shown robust, 
reproducible, statistically significant, and clinically meaningful effects on the decline in lung 
function consistent with slowing disease progression. The safety profile of nintedanib has 
been investigated comprehensively. The most frequent AEs were gastrointestinal events 
(nausea, vomiting, diarrhoea, abdominal pain) which were manageable by symptomatic 
treatment or adjustment of the dose regimen that includes dose reduction and dosing 
interruption. This dosing regimen adjustment was also effective in the management of liver 
enzyme and bilirubin elevations that are associated with nintedanib treatment (see Section 
4.2.1). Cases of drug-induced liver injury (DILI) have been observed with nintedanib 
treatment. The majority of patients presented with mild to moderate liver enzyme elevation, 
which was in most cases transient upon dose reduction or treatment discontinuation. 
However, severe DILI with fatal outcome has also been reported.
Based on data from clinical trials and post-marketing experience and supported by population 
pharmacokinetic models, patients with low body weight (<65 kg), Asian and female patients 
have a higher risk of liver enzyme elevations with nintedanib treatment.
Risks of nintedanib treatment also include hypertension, bleeding, thrombocytopenia, 
gastrointestinal perforations, thrombo-embolism and bleeding, pancreatitis, decreased 
appetite and decreased weight.
The safety assessments and evaluation plan in the current protocol are based on the 
information available to date from the IPF program. Important identified risks and important 
potential risks described for nintedanib in IPF are taken into account by the definition of 
eligibility criteria and will be closely monitored during the conduct of the study. No effect of 
nintedanib is expected on the underlying conditions e.g. RA. Hence potential changes in the 
course of the underlying diseases will be captured via AE reporting and safety laboratory 
assessments; no specific monitoring tools will be applied.
A placebo arm is needed to allow for a true assessment of the effects of nintedanib on the rate 
of decline in FVC. Treatment with unapproved anti-inflammatory/immunomodulatory 
treatment for ILD will be required to be discontinued and a wash-out period will be observed, 
if applicable, before randomization of the patient to either placebo or to nintedanib. The use 
of placebo comparator is justified by the following: there is no approved treatment for ILD 
except for IPF. The management of ILD has been based on the suppression of inflammation 
with corticosteroids and immunomodulator/steroid-sparing agents or both. However, there 
are no controlled clinical trials to support the efficacy and safety of these therapies. It is 
hypothesized that in PF-ILD the response to lung injury includes fibrosis which becomes 
self-sustaining and the current unapproved medications used in clinical practice to treat ILD 
are not / are no longer effective at this stage. In the proposed study, patients whose fibrosing 
ILD has worsened despite use of unapproved treatment of ILD will be eligible (see Section 
3.3). In case of clinically significant deterioration, initiation of additional therapy for ILD is 
allowed after 6 months (see Section 4.2.2). 
Based on the similarity in both the underlying pathophysiology and clinical course of PF-ILD 
and IPF, it is anticipated that nintedanib will elicit comparable efficacy in PF-ILD as 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 28 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
demonstrated in IPF. To achieve a positive benefit-risk profile, a similar safety profile in PF-
ILD to that in IPF will be required.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 29 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a multi-centre, multi-national, prospective, randomized, placebo-controlled, double 
blind clinical trial to investigate the efficacy and safety of nintedanib at a dose of 150 mg bid, 
in patients with PF-ILD over 52 weeks.
A total of approximately 600 patients will be randomized, 300 in the active treatment arm and 
300 in the placebo group. The study population will be enriched for patients with HRCT with 
UIP-like fibrotic pattern only applying the criteria used in the Phase III IPF studies for 
nintedanib, and as determined by the central reviewers (see Section 3.3.4). It is planned to 
enrol 400 patients with PF-ILD with HRCT with UIP-like fibrotic pattern only, i.e. two thirds 
(66.7%) of the randomized patients and 200 patients with PF-ILD with other HRCT fibrotic 
patterns.
After signing informed consent (IC), the initial screening visit (Visit 1) will be performed to 
determine eligibility. Following completion of Visit 1, patients with established PF-ILD, as 
assessed by the Investigator, will enter a screening period of maximum 12 weeks to confirm 
HRCT eligibility and determine HRCT pattern for randomization (see Section 3.3.4), and to 
allow for wash-out of treatment for ILD, if applicable (see Section 4.2.2).
Written confirmation by the central readers that the protocol criteria for qualifying HRCT are 
met will be mandatory for randomization. For detailed procedural assessments of patient’s 
eligibility, please refer to the Flowchart Part A and Section 6.2.1.
Once HRCT eligibility is confirmed, Visit 2 will be scheduled to collect all clinical and safety
information, and review all inclusion and exclusion criteria.  Patients will be randomized in
1:1 ratio to either nintedanib or placebo and then enter the treatment phase for a minimum of 
52 weeks. Randomization (stratified by HRCT pattern: “UIP-like fibrotic pattern only”, or 
“Other fibrotic patterns”) will be performed by phone or Internet, using an Interactive 
phone/web Response System (IRT).
Part A of the study will consist of Visits 2 through 9, which will occur within one year of 
randomization. Following completion of the week 52 visit (Visit 9), patients will continue to 
have study visits every 16 weeks (Part B) until the end of the trial. Intermediate laboratory
tests for safety monitoring will be performed as needed for additional safety monitoring until 
the end of the trial.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 30 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Figure 3.1: 1
Study design schematic of study 1199.247 followed by a separate 
open label trial (optional): Part A (Visit 1 through 9 over 52 weeks) 
and Part B (Visit 10 through EOT Visit over variable period for each 
patient)
The primary assessment of benefit-risk of nintedanib in patients with PF-ILD will be based 
on efficacy and safety data over 52 weeks. 
The primary analysis of this study will therefore be performed once the last randomized 
patient reaches the Week 52 Visit (Visit 9 at the end of Part A). At that time, a first database 
lock will occur and all the data will be unblinded. Efficacy and safety analyses will be 
performed on the data from Part A of the trial to assess the benefit-risk of nintedanib over 52 
weeks. In addition, data collected in Part B of the trial (after 52 weeks) and available at the 
time of data cut-off for the primary analysis will be reported together with data from Part A 
(i.e. over the whole trial) (see Section 5.1).
After review of the efficacy and safety data available after the first data base lock, the 
Sponsor will communicate the end of the trial and an EOTB visit has to be performed in all 
ongoing patients. Depending on the results of the evaluation, patients receiving trial 
medication until the end of Part B will be eligible for open-label treatment with nintedanib in 
a separate study.
Trial 1199.247 i.e. Part B will continue until all patients have completed the EOTB visit and 
the Follow-up Visit as applicable. A final database lock will then occur and Part B data 
collected between the data cut off for the primary analysis and the final database lock will be 
reported together with data from Part A i.e. over the whole trial (see Section 5.1).
Concomitant treatment rules, dose reduction procedures and short term drug interruptions in 
case of adverse events are described in Section 4.2.
For each patient, the study period is from the signature of the Informed Consent until their 
last visit. Adverse events are collected during the entire study period and are considered 
treatment-emergent from first study drug intake until 28 days after drug discontinuation.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 31 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
All patients who prematurely discontinue trial medication will need to complete an End of 
Treatment (EOT) visit and a Follow-up (FU) visit 4 weeks later. Patients who prematurely
discontinue trial medication will be asked to remain in the study and to return to all regularly 
scheduled visits until the end of the trial. This request will be outlined in the patient 
information / informed consent procedure prior to randomization.
For those patients who are unable to complete the scheduled visits, every attempt will be 
made to get information on vital status at 52 weeks after randomization, as well as at the time 
of the data cut-off for the primary analysis and at the end of the trial. The need for vital status 
information will be explained to patients prior to their participation in the trial and will be 
part of the patient information / informed consent procedure prior to randomization.
3.1.1
Administrative structure of the trial
Study sites will consist of specialized referral centres experienced in the management of ILD.
A Coordinating Investigator, chosen among experts in the field of ILD, will be nominated 
and will be responsible for providing expert medical support for Investigators at different 
centres participating in this multicentre trial. Tasks and responsibilities of the Coordinating 
Investigator will be defined in a contract. Relevant documentation on all participating 
(Principal) Investigators and other important study personnel, including their curricula vitae, 
will be filed in Investigator Site File (ISF).
For Japan:
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons and relevant local information 
(as protocol reference, if applicable) can be found in the ISF.
HRCT eligibility criteria and HRCT pattern will be confirmed by central review prior to 
randomization (see Section 3.3.4). Central review of the HRCT images will be performed by 
two independent specialists in thoracic radiology with extensive expertise in the 
interpretation of HRCT. The reviewers will be blinded to demographic and clinical data of 
the patient. Cases of disagreement will be adjudicated by a third reviewer.
An independent blinded Adjudication Committee (AC) will review all fatal cases and 
adjudicate all deaths to either cardiac, respiratory or other causes (see Section 5.3.7). The AC
will also review all adverse events categorized as major adverse cardiovascular events 
(MACE) (see Section 5.3.7).
A Data-Monitoring Committee (DMC), independent of the Sponsor will be in place until the 
database lock for the primary analysis after the last patient reaches the Week 52 visit (Part A: 
Visit 9) and will assess the progress of the clinical trial, including safety assessment at 
specified intervals, to recommend to the Sponsor whether to continue, modify, or stop the 
trial (see Section 5.3.7). The tasks and responsibilities of the DMC will be specified in a 
charter. The DMC will maintain written records of all its meetings.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 32 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Central laboratory facilities will handle all laboratory analyses of the trial. Samples for 
intermediate measurements (liver enzymes, creatinine) and pregnancy tests may be collected 
at the office of a local doctor using trial specific lab kits that will be sent to a central 
laboratory for analyses. These kits will be provided at each study visits as applicable to 
women of childbearing age.
An IRT (interactive response technology) vendor will be used in this trial.
The Sponsor has appointed a Trial Clinical Monitor, responsible for coordinating all required
activities, in order to
∀
manage the trial in accordance with applicable regulations and internal SOPs,
∀
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
∀
order the materials as needed for the trial,
∀
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical Evaluation will be done by Boehringer Ingelheim (BI)
according to BI SOPs.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
Placebo control
There is no approved treatment for ILD except for IPF. The management of ILD has been 
based on the suppression of inflammation with corticosteroids and immunomodulator/steroid-
sparing agents or both. However, there are no controlled clinical trials to support the efficacy 
and safety of these therapies. In the current study, patients whose fibrosing ILD has worsened 
despite use of unapproved treatment for ILD will be eligible (see Section 3.3.2). To minimize 
potential impact on efficacy and safety assessments, treatment with unapproved anti-
inflammatory/immunomodulatory treatment for ILD will be required to be discontinued and a 
wash-out period will be observed, if applicable, before randomization of the patient to either 
placebo or to nintedanib (see Section 4.2.2). As there is no targeted antifibrotic therapy 
currently indicated for the treatment of ILD in these patients, the use of placebo comparison 
in PF-ILD is considered justified. However, similar to the Phase III IPF studies, initiation of 
concomitant immunomodulatory treatment as medically indicated will be allowed for the 
management of worsening of the disease after the first six months of the trial (see Section
4.2.2).
Dose regimen
The dosing regimen to be investigated is the same as approved for IPF indication, i.e. 150 mg 
bid with the option of dose reduction to 100 mg and/or interruptions to manage adverse 
events (AEs). Exploration of higher dose(s) is not regarded feasible due to dose-limiting 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 33 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
toxicities (DLTs) observed in the oncology development program; testing of lower dose(s) is 
not considered based on lack of efficacy in IPF.
12 months treatment duration for primary assessment of benefit-risk of nintedanib in PF-ILD
The primary assessment of benefit-risk of nintedanib in patients with PF-ILD will be based 
on efficacy and safety data over 52 weeks (12 months) of study treatment. This is based on 
the assumptions that PF-ILD is similar to IPF and the treatment effect of nintedanib 
demonstrated in IPF will be reproduced in PF-ILD. 
In IPF, the association between decline in FVC over one year and clinical outcome has been 
examined in the scientific literature (R10-6539, R06-4127, P12-10347, R14-1150, P14-
06844, R14-1149). While these publications do not, by stringent statistical criteria, prove that 
reduction in the annual rate of FVC decline is a surrogate for improved survival, they do 
strongly suggest that an increased rate and extent of decline in FVC at 12 months is 
associated with an increased risk of death. Due to the expected similarity in disease 
progression, especially for FVC decline and mortality, between PF-ILD patients and IPF 
patients, the proposed benefit-risk assessment over12 months is regarded as the most 
appropriate period to detect a difference in the reduction of FVC decline between nintedanib 
and placebo in PF-ILD patients.
Additional data beyond 12 months will be collected while patients remain on blinded 
treatment to provide supportive longer term efficacy and safety data on the effect of 
nintedanib in a controlled manner, especially for the early enrollers to the study. Due to the 
varying length of follow-up in Part B of the trial, the efficacy measures incorporating data 
from Part A and Part B will focus on time to event endpoints.
The use of placebo control for this extended period is justified by the lack of approved ILD 
treatments and by the provision of the protocol that allows for the use of any of the 
unapproved  medications utilized in the clinical practice to treat ILD, in case of worsening of 
the patient’s ILD as assessed by the investigator (see Section 4.2.2.1).
Primary and main secondary endpoints
The primary endpoint of the study is the annual rate of decline in forced vital capacity (FVC). 
In clinical trials in IPF, FVC is an established efficacy parameter; mean changes in FVC over 
time are considered relevant to assess the effect of a pharmacologic intervention at population 
level (P11-13635, P12-10347, R06-4126, R06-4127). FVC as primary endpoint has served as 
basis for worldwide regulatory approvals for nintedanib and pirfenidone in IPF (P14-07514, 
P10-13367).
Similar to IPF, in other interstitial lung diseases (ILDs) the accelerated decline in lung 
function over time is considered consistent with disease progression and is thought to be 
associated with mortality (R10-6539, R06-4127, P12-10347, R14-1150, P14-06844, R14-
1149). In PF-ILD, and even more so for patients with PF-ILD with histologic usual interstitial 
pneumonia (UIP) pattern, it is expected that the placebo decline in FVC is similar to the 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 34 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
decline observed in patients with IPF and that nintedanib will slow the decline in FVC in a
similar way as it does in IPF.
The main secondary endpoints are the absolute change from baseline in King’s Brief 
Interstitial Lung Disease (K-BILD) total score at week 52, time to first acute ILD 
exacerbation or death over 52 weeks and time to death over 52 weeks. These endpoints are 
considered relevant to the assessment of the effect of nintedanib in PF-ILD and will provide 
the main supportive evidence to the primary endpoint assessment.
Enrichment design
Based on data suggesting that the HRCT pattern has a major impact on prognosis (see 
Section 1.1), the study population will be enriched for patients with HRCT with UIP-like 
fibrotic pattern only (see Section 3.3.4). An enrichment design will be used in order to 
increase the likelihood of detecting a clinically meaningful effect of nintedanib with the 
greatest statistical efficiency, therefore ensuring feasibility of the enrolment of patients with 
this rare disease. This enrichment design is consistent with the considerations for prognostic 
enrichment strategies in the Food and Drug Administration (FDA) Draft Guidance for
Industry on Enrichment Strategies for Clinical Trials to Support Approval of Human Drug 
and Biological Products (R13-0580).
SELECTION OF TRIAL POPULATION
3.3
A total of approximately 600 patients with PF-ILD will be randomized (300 in the active 
dose group and 300 in placebo) in approximately 14 countries. Approximately 100 sites are 
each expected to include a minimum of 4-5 patients.
The study population will be enriched for patients with HRCT with UIP-like fibrotic pattern 
only: about 400 patients with PF-ILD with HRCT with UIP-like fibrotic pattern only and 
about 200 patients with PF-ILD with other HRCT fibrotic patterns will be randomized.
Patients with clinical diagnosis of IPF will be excluded from the current study (see Section 
1.1.3). 
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Outpatients aged ≥ 18 years with PF-ILD, defined as patients who present with features of 
diffuse fibrosing lung disease of >10% extent on HRCT and whose lung function and 
respiratory symptoms or chest imaging have worsened despite treatment with unapproved 
medications used in clinical practice to treat ILD, are eligible for inclusion if they fulfil all 
the inclusion criteria (Section 3.3.2) and do not present any of the exclusion criteria (Section 
3.3.3).


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 35 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Written Informed Consent consistent with ICH-GCP and local laws signed prior to 
entry into the study (and prior to any study procedure including shipment of HRCT to 
reviewer).
2. Male or female patients aged ≥ 18 years at Visit 1.
3. Patients with physician diagnosed ILD who fulfil at least one of the following criteria 
for PF-ILD within 24 months of screening visit (Visit 1) despite treatment with 
unapproved medications used in clinical practice to treat ILD, as assessed by the 
investigator (refer to Exclusion Criteria):
a. Clinically significant decline in FVC % pred based on a relative decline of ≥10%
b. Marginal decline in FVC % pred based on a relative decline of ≥5-<10% 
combined with worsening of respiratory symptoms 
c. Marginal decline in FVC % pred based on a relative decline of ≥5-<10% 
combined with increasing extent of fibrotic changes on chest imaging
d. Worsening of respiratory symptoms as well as increasing extent of fibrotic 
changes on chest imaging
[Note: Changes attributable to comorbidities e.g. infection, heart failure must be 
excluded. Unapproved medications used in the clinical practice to treat ILD
include but are not limited to corticosteroid, azathioprine, mycophenolate mofetil 
(MMF), n-acetylcysteine (NAC), rituximab, cyclophosphamide, cyclosporine, 
tacrolimus].
4. Fibrosing lung disease on HRCT, defined as reticular abnormality with traction 
bronchiectasis with or without honeycombing, with disease extent of >10%, performed 
within 12 months of Visit 1 as confirmed by central readers.
5. For patients with underlying CTD: stable CTD as defined by no initiation of new 
therapy or withdrawal of therapy for CTD within 6 weeks prior to Visit 1.
6. DLCO corrected for Haemoglobin (Hb) [visit 1] ≥ 30% and <80% predicted of normal
at Visit 2 (refer to Appendix 10.1).
7. FVC ≥ 45% predicted at Visit 2 (refer to Appendix 10.1).
3.3.3
Exclusion criteria
1. AST, ALT > 1.5 x ULN at Visit 1
2. Bilirubin > 1.5 x ULN at Visit 1
3. Creatinine clearance <30 mL/min calculated by Cockcroft–Gault formula at Visit 1 
(refer to Appendix 10.2).
[Note: Laboratory parameters from Visit 1 have to satisfy the laboratory threshold 
values as shown above. Visit 2 laboratory results will be available only after 
randomization. In case at Visit 2 the results do no longer satisfy the entry criteria, the 
Investigator has to decide whether it is justified that the patient remains on study drug. 
The justification for decision needs to be documented. Laboratory parameters that are 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 36 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
found to be abnormal at Visit 1 are allowed to be re-tested (once) if it is thought to be a 
measurement error (i.e. there was no abnormal result of this test in the recent history of 
the patient and there is no related clinical sign) or the result of a temporary and 
reversible medical condition, once that condition is resolved].
4. Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic 
impairment).
5. Previous treatment with nintedanib or pirfenidone.
6. Other investigational therapy received within 1 month or 6 half-lives (whichever was 
greater) prior to screening visit (Visit 1).
7. Use of any of the following medications for the treatment of ILD: azathioprine (AZA), 
cyclosporine, MMF, tacrolimus, oral corticosteroids (OCS) >20mg/day and the 
combination of OCS+AZA+NAC within 4 weeks of Visit 2, cyclophosphamide within 
8 weeks of Visit 2, rituximab within 6 months of Visit 2.
Note: Patients whose RA/CTD is managed by these medications should not be 
considered for participation in the current study unless change in RA/CTD medication 
is medically indicated (refer to Inclusion Criterion #5)
8. Diagnosis of IPF based on ATS/ERS/JRS/ALAT 2011 Guidelines (P11-07084).
9. Significant Pulmonary Arterial Hypertension (PAH) defined by any of the following:
a. Previous clinical or echocardiographic evidence of significant right heart failure
b. History of right heart catheterization showing a cardiac index ≤ 2 l/min/m²
c. PAH requiring parenteral therapy with epoprostenol/treprostinil
10. Primary obstructive airway physiology (pre-bronchodilator FEV1/FVC < 0.7 at 
Visit 1).
11. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
12. Major extrapulmonary physiological restriction (e.g. chest wall abnormality, large 
pleural effusion)
13. Cardiovascular diseases, any of the following:
a.
Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 
6 month of Visit 1
b. Myocardial infarction within 6 months of Visit 1
c.
Unstable cardiac angina within 6 months of Visit 1
14. Bleeding risk, any of the following:
a.
Known genetic predisposition to bleeding.
b. Patients who require 
i. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, 
direct thrombin inhibitors, heparin, hirudin)
ii. High dose antiplatelet therapy. 
[Note: Prophylactic low dose heparin or heparin flush as needed for 
maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. 
per day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic 
acid up to 325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other 
antiplatelet therapy) are not prohibited].
c.
History of haemorrhagic central nervous system (CNS) event within 12 months of 
Visit 1.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 37 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
d. Any of the following within 3 months of Visit 1:
i. Haemoptysis or haematuria
ii. Active gastro-intestinal (GI) bleeding or GI – ulcers
iii. Major injury or surgery (Investigators judgment).
e.
Coagulation parameters: International normalized ratio (INR) >2, prolongation of 
prothrombin time (PT) and activated partial thromboplastin time (aPTT) by >1.5 x 
ULN at Visit 1.
15. History of thrombotic event (including stroke and transient ischemic attack) within 12 
months of Visit 1.
16. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin)
17. Patients with peanut allergy.
18. Other disease that may interfere with testing procedures or in the judgment of the 
Investigator may interfere with trial participation or may put the patient at risk when 
participating in this trial.
19. Life expectancy for disease other than ILD < 2.5 years (Investigator assessment).
20. Planned major surgical procedures.
21. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
22. Women of childbearing potential* not willing or able to use highly effective methods of 
birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year 
when used consistently and correctly as well as one barrier method for 28 days prior to 
and 3 months after nintedanib administration. A list of contraception methods meeting 
these criteria is provided in the patient information.
23. In the opinion of the Investigator, active alcohol or drug abuse.
24. Patients not able to understand or follow trial procedures including completion of self-
administered questionnaires without help.
*A woman is considered of childbearing potential, i.e. fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilisation methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
3.3.4
Imaging criteria
Patients with original physician diagnosis of different fibrosing ILDs, i.e. CTD-ILD, chronic 
fibrosing HP, iNSIP, unclassifiable IIP and environmental/ occupational fibrosing lung 
disease will be included if they meet the protocol criteria for PF-ILD. While the clinical ILD 
diagnosis will not be verified, central review of the screening HRCT images will ensure that 
relevant lung fibrosis is present and the HRCT pattern is not indicative of other causes of 
progression. 
At screening the most recent (not older than 12 months at screening) HRCT image of the 
patient will be evaluated; previous HRCT images will not be collected or reviewed. Hence 
inclusion based on increasing extent of fibrotic changes on chest imaging within 24 months 
will reflect the investigator’s judgement. 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 38 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Eligible patients will have fibrosing lung disease on HRCT, defined as reticular abnormality 
with traction bronchiectasis with or without honeycombing with disease extent of >10%.
The following co-existing features will be accepted:
∀
ground glass opacity
∀
upper lung or peribronchovascular predominance
∀
mosaic attenuation
∀
air trapping
∀
centrilobular nodules
The following co-existing features will not be allowed:
∀
widespread consolidation
∀
progressive massive fibrosis
In addition, determination of the HRCT pattern will also be done by central review and will 
be used for randomization stratification. The study will be enriched for patients meeting 
either criteria A, B and C, criteria A and C, or criteria B and C as described below. These 
patients will be referred to as “patients with HRCT with UIP-like fibrotic pattern only”. 
Patients with PF-ILD who do not meet these criteria will be referred to as “patients with other 
HRCT fibrotic patterns”.
A=Definite honeycomb lung destruction with basal and peripheral predominance
B=Presence of reticular abnormality AND traction bronchiectasis consistent with fibrosis 
with basal and peripheral predominance
C=Atypical features are ABSENT, specifically: nodules and consolidation. Ground glass 
opacity, if present, is less extensive than reticular opacity pattern
Specifications for the HRCT acquisition will be provided in the ISF. Screening HRCT can be 
performed as part of the study in case the available HRCT does not meet the required image 
acquisition specifications.
3.3.5
Removal of patients from therapy or assessments
Removal of individual patients from therapy
3.3.5.1
The trial medication has to be permanently discontinued in the following circumstances:
∀
The patient experiences signs of hepatic injury, defined in Section 5.3.6.1.
∀
In the opinion of the Investigator, the patient experiences unacceptable adverse events 
despite dose adjustments and supportive care.
∀
Use of restricted concomitant treatment: as defined in Section 4.2.2 “restrictions”.
∀
Pregnancy: If a patient becomes pregnant during the trial the investigational product 
needs to be stopped and the patient should be followed up until birth or otherwise 
termination of the pregnancy. The data of the patient will be collected and reported in 
the clinical trial report (CTR) until patient´s last visit and any events thereafter will be 
reported in the BI drug safety database. Refer to Section 5.3.6 for detailed information 
on event reporting in case of pregnancy.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 39 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Premature discontinuation: in case the patient discontinues study drug, it is of utmost 
importance for the robustness and integrity of the trial results that his/her lung function 
parameters and safety data are recorded until the end of the 52 weeks period. Thus all patients 
will be asked to follow their visit schedule until the end of the trial (refer to Section 6.2.3).
For patients who prematurely discontinue trial medication and are unable to complete the 
scheduled visits, every attempt will be made to get information on vital status at 52 weeks 
after randomization, as well as at the time of the data cut-off for the primary analysis and at 
the end of the trial.
In the following cases discontinuation of trial medication is highly recommended. Only in 
special circumstances, the Investigator, upon thorough assessment of all available clinical 
data and taking into consideration the potential risks associated with administration of 
nintedanib, may decide not to withdraw the trial medication, even though one or more of the 
below mentioned criteria are fulfilled. In such a case, continuation of treatment with trial 
medication should be discussed with the patient, and the decision and reasoning documented 
in the source data.
∀
Major surgery, including any abdominal or intestinal surgery.
∀
Anti-coagulation. Patients who require full-dose therapeutic anticoagulation (e.g. 
vitamin K antagonists, heparin, hirudin, direct thrombin inhibitors, etc.), or high-dose 
antiplatelet therapy. (Prophylactic low dose heparin or heparin flush as needed for 
maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. per 
day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 
325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other antiplatelet 
therapy is allowed.).
∀
Major thrombo-embolic events e.g. stroke, deep vein thrombosis, pulmonary 
embolism, myocardial infarction.
∀
Increased risk of bleeding e.g. haemorrhagic CNS event, gross / frank haemoptysis or 
haematuria, active gastro-intestinal bleeding or GI-ulcers.
For conditions that allow treatment interruption please refer to Section 4.2.1.
Removal of individual patients from trial
3.3.5.2
All efforts should be made to continue to record safety data and lung function parameters for 
patients who withdraw study medication prematurely. Patients, will be asked to follow their 
original visit schedule (except the laboratory ‘a-Visits’; refer to Section 6.2.2).
Participation in the trial must be stopped if the patient withdraws his consent for all 
procedures of the study. There is no other pre-specified criterion to withdraw from the trial.
Attempts to collect vital status will be made at Week 52, at the time of data cut-off for the 
primary analysis and at the end of trial for patients who have withdrawn consent as applicable
(see Section 5.3.2). 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 40 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
For all patients, the reason for withdrawal (e.g. adverse events) must be recorded in the 
electronic Case Report Form (eCRF). These data will be included in the trial database and 
will be reported.
For final assessment and safety follow-up, please refer to Section 6.2.3.
Discontinuation of the trial by the Sponsor
3.3.5.3
The Sponsor reserves the right to discontinue the trial overall or at a particular trial site at any 
time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of Good Clinical Practice (GCP), the Clinical Trial Protocol (CTP), or the 
contract disturbing the appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 41 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
4.1.1
Identity of BI investigational product(s)
Table 4.1.1: 1
Identity of BI investigational products
Nintedanib 
Placebo 
Substance:
Nintedanib
-
Pharmaceutical formulation: Soft gelatine capsule
Soft gelatine capsule
Source:
BI Pharma GmbH # Co. KG
BI Pharma GmbH # Co. KG
Unit strength:
150 mg, 100 mg
Placebo to 150 mg, 100 mg
Posology:
bid
bid
Route of administration:
Oral (swallowed)
Oral (swallowed)
4.1.2
Method of assigning patients to treatment groups
During Visit 2 after eligibility has been confirmed including the criterion of presence of 
features of fibrosing lung disease with >10% extent on HRCT and the HRCT pattern has 
been determined by central review, patients will be randomized to receive nintedanib or 
placebo in a 1:1 ratio according to a randomization plan. The randomization list will be 
generated using a validated system. The assignment will occur in a blinded fashion via 
Interactive Response Technology (IRT). Access to the codes will be controlled and 
documented.
Technical and statistical features of the process of treatment allocation are described in 
Section 7.6.
To facilitate the use of the IRT, the Investigator will receive all necessary instructions.
Dose reductions or re-escalation (refer to Section 6.2.4) will need to be assigned through IRT 
and require a patient visit.
4.1.3
Selection of doses in the trial
Based on the efficacy, safety and dose-finding from trials investigating nintedanib in IPF, a 
dose of 150 mg bid is selected for the PF-ILD program. With 150 mg bid, acceptable 
tolerability in PF-ILD patients is expected based on the risk profile seen in IPF patients. 
Lower starting doses are not expected to demonstrate efficacy based on the dose ranging trial 
in IPF. However, to manage adverse events, the dose may be reduced to 100 mg bid 
temporarily or permanently (see Section 4.2.1 and Section 6.2.4).


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 42 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
4.1.4
Drug assignment and administration of doses for each patient
The treatment for an individual patient will be assigned by means of an IRT contact during 
Visits 2, 4, 6, 7, 8, 9 to X. Patient will receive either active drug at a dosage of 150 mg bid or 
placebo bid.
Trial medication will consist of 1 capsule twice daily (bid) administered orally throughout the 
study. Wallets covering 4 weeks + 1 week reserve treatment will be dispensed to the patient:
∀
1 wallet at Day 1 (randomization = Visit 2) (30 days plus 5 days reserve)
∀
2 wallets at Visit 4 (60 days plus 10 days reserve)
∀
3 wallets at Visit 6 and Visit 7 (90 days plus 15 days reserve)
∀
4 wallets at Visit 8 (120 days plus 20 days reserve)
∀
4 wallets at Visit 9 (120 days plus 20 days reserve)
∀
4 wallets at Visit X (120 days plus 20 days reserve) 
Trial medication will be administered orally on a twice daily basis (bid). The patients should 
swallow the trial medication, without chewing, together with a glass of water (~250 mL), and 
should observe a dose interval of 12 hours. Trial medication needs to be taken at the same 
time every day (between 06:00 and 11:00 in the morning, and between 18:00 and 23:00 in the 
evening). Because nintedanib may cause stomach discomfort, it is recommended to take the 
trial medication after food intake.
A forgotten dose should be skipped if the time window to the next dose is less than 8 hours. 
The following dose should be taken according to the protocol. No catch up of missed doses is 
permitted.
The investigational product should only be dispensed to participating patients according to 
the protocol by authorized personnel as documented in the form “Investigator’s Trial Staff”.
In case of adverse events requiring dose reduction between planned visits, an additional site 
visit is required. 100 mg bid (or matching placebo) will be assigned by means of an IRT call 
from the Investigator (see Section 6.2.4). The colour of capsules (100 mg capsule or 
corresponding placebo) will be slightly different but the packaging will remain the same 
(same number of capsules per blister and same number of blisters per wallet).
The dose can be reduced without prior interruption, i.e., immediately stepping down from 
150 mg bid to 100 mg bid if necessary due to adverse events which require a special trial visit 
according to procedures described in Section 4.2.1.
If the reduced dose is well tolerated, re-escalation is possible within 4 weeks (after the dose 
reduction visit) or 8 weeks in case of AEs not considered drug related, which if it occurs 
between scheduled trial visits will also require a special trial visit according to procedures 
described in Section 4.2.1.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 43 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Patients experiencing adverse events requiring temporary interruption of trial medication may 
re-start trial medication according to procedures described in Section 4.2.1.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
This trial is a double-blind trial.
Trial medication is identified by a medication code number. Packaging and labelling is
otherwise identical. Colour, size and shape of nintedanib and placebo capsules are 
indistinguishable within dose strength, but are different between dose strengths.
Patients, Investigators and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial (apart from the DMC) will remain blinded with regard to the 
randomized treatment assignments until after database lock.
When the last randomized patient reaches the Week 52 Visit (Part A: Visit 9), the trial data 
base will be locked and unblinded by the sponsor for the primary assessment of benefit-risk
of nintedanib over 52 weeks in patients with PF-ILD. With exception of the sponsor, the trial 
conduct will continue blinded until the end of the trial when the final database lock occurs.
The randomization codes will be provided to Bioanalytics prior to last patient out to allow for 
the exclusion from the analyses of PK samples taken from placebo patients. Bioanalytics will 
not disclose the randomization code or the PK analysis results until after the final database 
lock.
The DMC may review unblinded data upon request, and only under conditions that ensure 
that patients, Investigators and everyone involved in trial conduct or analysis or with any 
other interest in this double-blind trial will remain blinded.
Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the Investigator / Pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the Investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and/or appropriate CRF page along with the date and 
the initials of the person who broke the code.
To avoid unblinding of the study team through drug safety reports which are to be unblinded 
as per regulatory requirements, a procedure will be maintained to keep code-breaking in these 
cases invisible to study team.
The independent statistician of the DMC will receive the randomization code to allow the 
required analyses on unblinded data upon request of DMC. 
 will ensure that all unblinded 
information remains within the DMC.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 44 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
For Japan:
In this blinded trial, an emergency code break will be available to the Investigator / the sub-
Investigators via the IRT system. This code break may only be accessed in emergency 
situations when the identity of the trial drug must be known to the Investigator /the sub-
Investigators in order to provide appropriate medical treatment or if required to assure the 
safety of trial participants. Each site receives a manual from the IRT provider that contains 
instructions on how to unblind the treatment of a patient via the IRT (via 24-hour Emergency 
helpline). If the code break for a patient is accessed, the Sponsor must be informed 
immediately. The reason for accessing the code break, together with the date, must be 
documented on the appropriate eCRF page. In case third party needs to break the code, 
however, when the Investigator cannot be reached, the code can be opened by calling 
emergency code manager.
4.1.6
Packaging, labelling, and re-supply
Primary study material will be capsules containing 150 mg of nintedanib (or 100 mg of 
nintedanib if dose is reduced due to intolerability), and matching placebo. All trial medication 
will be packaged in blister cards. Each blister card will contain 10 capsules. Seven blisters 
cards will be packaged into one child-resistant tamper-evident wallet (i.e. 70 capsules/
wallet). Each wallet will be labelled with a multi-language booklet according to the 
requirements of the participating countries.
One wallet covers for one month of treatment.
For details of packaging and the description of the label, refer to the ISF.
Initial supply and further re-supplies will be managed by IRT. The IRT will assign an 
appropriate kit to each patient according to the randomization list that are generated by the 
Sponsor and not known by the study personnel.
Re-supplies of trial medication are planned due to the short expiry date and the long duration 
of the trial. The medication for re-supply will be packaged in an identical manner as the
medication for initial supply.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
All unused trial medication must be returned to the Sponsor or appointed Contract Research 
Organization (CRO). Receipt, usage and return must be documented on the respective 
forms/IRT system. Account must be given for any discrepancies.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 45 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
4.1.8
Drug accountability
The Investigator will receive the investigational drugs delivered by the Sponsor when the 
following requirements are fulfilled:
∀
Approval of the trial protocol by the Institutional Review Board (IRB) / ethics 
committee, 
∀
Availability of a signed and dated clinical trial contract between the Sponsor and the 
head of the investigational site,
∀
Approval/notification of the regulatory authority, e.g. competent authority,
∀
Availability of the curriculum vitae of the principal Investigator,
∀
Availability of a signed and dated clinical trial protocol,
∀
Investigational site must be trained to perform site-related procedures,
∀
In countries where it is required, availability of the proof of a medical license for the 
Principal Investigator,
∀
In the US, availability of Form 1572.
The Investigator must maintain records of the product’s delivery to the trial site, the 
inventory at the site, the use by each patient, and the return to the Sponsor or alternative 
disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator will maintain records that document adequately that the patients were provided 
the doses specified in Section 4.1.4 and reconcile all investigational products received from 
the Sponsor. At the time of return to the Sponsor or appointed CRO, the Investigator must 
verify that all unused or partially used drug supplies have been returned by the clinical trial 
patient and that no remaining supplies are in the Investigator’s possession.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Rescue medication to reverse the action of nintedanib is not available.
Dose reduction from 150 mg bid to 100 mg bid or treatment interruption should be 
considered to manage adverse events. No further dose reduction is possible for patients on the 
100 mg bid regimen. In case of persistent adverse events observed at this dose, or severe 
effects at 150 mg bid, permanent treatment discontinuation should be considered.
Treatment interruption, reduction and re-increase are allowed at multiple occasions.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 46 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 4.2.1: 1 Allowed treatment reduction / interruption periods:
AEs considered related to 
study drug 
AEs not considered related to 
study drug
Maximum interruption
4 weeks
8 weeks
Recommended restart
with reduced dose (100 mg bid)
with the same dose as before 
interruption 
(100 mg bid or 150 mg bid)
Re-escalation
within 4 weeks to 150 mg bid
N/A
4.2.1.1
Management of diarrhoea
Diarrhoea is a known side effect of nintedanib treatment (see Section 1.2). However, 
potential causes for diarrhoea other than study medication should always be considered and 
treated accordingly (e.g. viral infections, bacterial overgrowth, antibiotic treatment).
Diarrhoea should be managed as early as possible after onset of first symptoms with standard 
antidiarrheal symptomatic treatment, e.g. loperamide.
If diarrhoea persists despite optimal symptomatic treatment, treatment interruption and/or
dose reduction of nintedanib to 100 mg bid should be considered according to the 
recommendations described in Table 4.2.1.1: 1.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 47 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 4.2.1.1: 1 Management of diarrhoea (considered related to trial medication)
Description
Symptomatic Treatment*
Action with trial medication
Diarrhoea with 
increase of <4 stools 
per day over baseline1.
Initiate anti-diarrheal medicines at 
first signs of symptoms (e.g. 4 mg 
loperamide followed by 2 mg after 
each loose stool or every 2-4 hours 
to a maximum of 16 mg/day) until 
bowel movements cease for 12 
hours.
Continue same trial medication dose.
Diarrhoea with 
increase of 4 to 6 
stools per day over 
baseline1.
Initiate/continue anti-diarrheal
medicines;
If diarrhoea of this severity persists 
for ≥48 to 72 hours assess for 
dehydration and electrolyte 
imbalance; 
In addition, consider IV fluids and 
electrolyte replacement as 
clinically indicated.
If diarrhoea persists for ≥48 to 72 
hours despite optimal symptomatic 
care:
1.
Interrupt trial medication until 
recovery.
2.
Reduce dose to 100 mg bid after 
recovery. 
3.
Re-escalate to 150 mg bid within 
4 weeks if deemed clinically 
appropriate.
Diarrhoea with 
increase of ≥7 stools 
per day over baseline1; 
stool incontinence, 
or
life threatening 
consequences.
Follow recommendations above.
In addition, consider stool work-up 
to exclude infectious colitis; 
adequate IV fluid replacement ≥24 
hours, hospitalization as clinically 
indicated; consider referral to a GI 
specialist to rule out potential 
differential diagnoses.
1.
Interrupt trial medication until 
recovery.
2.
Reduce dose to 100 mg bid after 
recovery.
3.
Consider re-escalation within 4 
weeks to 150 mg bid if deemed 
clinically appropriate.
In case of reoccurrence of diarrhoea
of this severity despite optimal 
symptomatic treatment and dose 
reduction, treatment with trial 
medication should be permanently 
discontinued.
Footnotes:
* Other potential causes for diarrhoea should always be considered and treated accordingly (e.g. viral infections, SSc related 
diarrhoea, bacterial overgrowth, antibiotic treatment)
1 Baseline defined as usual stools/day prior randomization.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 48 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
4.2.1.2
Management of liver enzyme elevation
Nintedanib can be associated with increased liver enzymes (see Section 1.2). Concomitant 
use of other drugs known to cause liver enzyme elevations should be evaluated. For a detailed 
guidance on how to manage liver enzyme elevations, please refer to Table 4.2.1.2: 1.
Table 4.2.1.2: 1 Recommendations for managing liver enzyme elevations
AST or ALT increase to
Signs of hepatic injury* 
(Section 5.3.6)
>1.5x to <3x
ULN
≥3x to <5x
ULN and no 
signs of  hepatic 
injury
(see Section 
5.3.6)
≥5x to <8x
ULN and no 
signs of  hepatic 
injury
(see Section 
5.3.6)
Visit 2
(randomization)
Withdraw trial 
medication or 
justify 
continuation1
Withdraw trial 
medication 
Withdraw trial 
medication 
Withdraw trial medication 
Any other Visit
Continue as 
planned2
Reduce dose or 
interrupt trial 
medication 3
Interrupt trial 
medication 
Withdraw trial medication
CLINICAL 
EVALUATION OF 
HEPATIC INJURY
(Section 5.3.6) 
Close 
observation4
After 2 weeks or 
any time later
Close 
observation4
After 2 weeks 
or any time later
<3x ULN
≥3x ULN
< 3x ULN
≥3x ULN
Reduced: 
return to initial 
dose.
Interrupted: 
restart at 
reduced dose.
Monitor bi-
weekly for at 
least 8 weeks
Permanently 
discontinue trial 
medication
Close 
observation4
Restart at 
reduced dose
Monitor weekly 
for 4 weeks, 
then bi-weekly
for at least 8 
weeks
Permanently discontinue 
trial medication.
Close observation4
Footnotes:
*Signs of hepatic injury are defined as
∀
ALT and/or AST ≥8 fold ULN
∀
ALT and/or AST ≥3 fold ULN and total bilirubin ≥2 fold ULN 
∀
ALT and/or AST ≥3 fold ULN and unexplained INR >1.5
∀
ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%)
∀
ALT and/or AST ≥3 fold ULN and appearance of fatigue, nausea, vomiting, right upper abdominal quadrant pain 
or tenderness, fever and/or rash
1 Investigator to confirm in writing that continuation is justified (e.g. intermittent fluctuation of transaminases).
2 According to visit schedule. Consider additional control visits as adequate.
3 To be decided by Investigator, based on individual risk assessment.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 49 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
4 Close observation: Re-test ALT and AST, alkaline phosphatase, total bilirubin, and eosinophils within 48 to 72 hours, then 
approximately 7 days, then approximately 2 weeks by using intermediate visit lab kit.
Initial assessment of liver enzyme elevation should be performed at the investigational site. 
Blood samples for additional monitoring may be collected at the investigational site, primary 
care physician or external laboratory with specific trial lab kits and sent to the central 
laboratory for analysis.
4.2.1.3
Management of acute ILD exacerbations 
In case of acute ILD exacerbation (see Section 5.2.4), all treatment options considered 
adequate by the Investigator are allowed. The patient may interrupt study treatment for up to 
8 weeks, if necessary (e.g. if short-term full anticoagulation is performed).
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
The aim of the study is to investigate the efficacy and safety of nintedanib in patients whose 
progressive lung disease is the main contributor to morbidity.
Treatment of ILD
Immunomodulatory medications i.e. Azathioprine, cyclosporine, tacrolimus, Rituximab, 
Cyclophosphamide, mycophenolate mofetil, OCS have been utilized in the clinical practice 
for the treatment of ILD although their benefit-risk profiles in ILD have not been established 
and they are not approved for the treatment of ILD in most countries. In order to avoid the 
potential impact of these drugs on the assessment of the efficacy and safety of nintedanib in 
PF-ILD, their use will not be allowed at randomization and during the first six months of the 
treatment period. 
Patients who receive any of these medications for the treatment of their ILD will have to 
discontinue these drugs prior to randomization. As the protocol requires that eligible patients 
progress despite treatment with these medications (i.e. do not or no longer benefit from these 
drugs), prohibition of these medications is considered justified. In case of acute worsening of 
PF-ILD during the treatment period, the use of any of these drugs after six months of study 
treatment will be allowed if judged necessary by the investigator.
Treatment of the underlying diseases associated with ILD
The largest group of patients with PF-ILD that has an underlying disease associated with ILD 
is the group of patients with CTD. Eligible patients with underlying CTD should have stable
CTD defined as no initiation or withdrawal of therapy for CTD within six weeks prior to 
screening. In addition, investigators are encouraged to maintain the baseline treatment of 
CTD during the entire study unless change is medically indicated.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 50 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
The majority of the eligible patients with CTD is expected to have RA and to be receiving 
disease-modifying anti-rheumatic drug (DMARD) e.g. methotrexate or TNF inhibitors. All 
approved RA/CTD medications are allowed at stable doses at Baseline (Visit 2) and during 
the study with the exceptions of the following, less frequently used medications: 
Azathioprine, cyclosporine, tacrolimus, high dose steroids, and Rituximab. The use of these 
medications will not be allowed in this study. In addition, the following drugs used off-label 
for the treatment of RA/CTD will not be allowed throughout the study: Cyclophosphamide 
and MMF.
The rationale for these limitations is that, as described above, these drugs have also been 
utilized in the clinical practice for the treatment of ILD. In order to avoid the potential impact 
of these drugs on the assessment of the efficacy and safety of nintedanib in PF-ILD, their use 
will not be allowed. 
Patients whose RA/CTD is well managed by these medications should not be considered for 
participation in the current study. In case a change in the RA/CTD treatment to another non-
restricted medication is indicated, the patient’s disease has to be stable (i.e. no initiation of 
new therapy or withdrawal of therapy for CTD within 6 weeks prior to Visit 1) before 
entering in the current trial.
Table 4.2.2.1: 1 Medication restrictions
Restricted medications: 
Azathioprine, cyclosporine, tacrolimus, Rituximab, Cyclophosphamide, mycophenolate 
mofetil, OCS >20mg/day, investigational drugs
For ILD
For CTD
Baseline
Not allowed at V2* 
Not allowed 
Within first 6 months 
of study treatment
Not allowed
Not allowed
After 6 months of 
study treatment
Allowed in case of significant 
deterioration#
Allowed case of significant 
deterioration #
After EOT
Allowed
Allowed 
* Wash-out periods to be observed as described in Table 4.2.2.1: 2 below
# All can be used in case of clinically significant deterioration of PF-ILD or worsening CTD at the discretion of the 
Investigator, except for investigational drugs. Introduction of new therapy for CTD should be minimized.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 51 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 4.2.2.1: 2 Wash-out schedule. Wash-out rules apply only for medications used for ILD
treatment.
Medication
Wash-out period
Azathioprine
Cyclosporine
Tacrolimus
Mycophenolate mofetil
OCS >20mg/day
4 weeks prior to Visit 2
Rituximab
6 months prior to Visit 2
Cyclophosphamide
8 weeks prior to Visit 2
Investigational drug(s)
4 weeks or 6 half-lives (whichever is 
longer) prior to Visit 1
In case of clinically significant deterioration, initiation of additional therapy for ILD i.e. on 
top of the study medication is allowed after completion of the 6-month study visit (Visit 7) as 
described in Table 4.2.2.1:1, as determined by the Investigator. For example, introduction of 
additional therapy may be considered if the patient experiences ≥ 10% relative decline in 
FVC% pred from baseline that is not attributed to a reversible process (i.e. respiratory 
infection). Detailed (S)AE information following such events should be recorded in the 
eCRF. Please also refer to cautionary notes (Section 4.2.2.2).
Prohibited medications
As detailed in the exclusion criteria, patients receiving pirfenidone, nintedanib, full dose 
therapeutic anticoagulation or high dose antiplatelet therapy (e.g. acetyl salicylic acid >325 
mg/day, or clopidogrel >75 mg/day, or equivalent doses of other antiplatelet therapy) are not 
eligible for participation in the study. 
The use of pirfenidone and nintedanib are prohibited throughout the study, including the 
Follow-up period. 
Cautionary notes
4.2.2.2
Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Co-administration with 
oral doses of a potent P-gp and CYP3A4 inhibitors, e.g. ketoconazole, erythromycin, may 
increase exposure to nintedanib. In such cases, patients should be monitored closely. 
Management of adverse reactions may require interruption, dose reduction, or 
discontinuation of therapy with nintedanib.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 52 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Co-administration with oral doses of a potent P-gp and CYP3A4 inducers, e.g. rifampicin, 
carbamazepine, phenytoin, and St. John’s wort may decrease exposure to nintedanib and 
should be avoided.
As the most common side effects known for nintedanib are GI effects i.e. diarrhoea, nausea 
and vomiting (see Section 4.2.1.1) the concomitant use of medication with an overlapping 
safety profile (e.g. mycophenolate mofetil) should be carefully considered.
Nintedanib is also associated with increases in liver enzymes and bilirubin. If in addition to 
the trial medication, a treatment is introduced that is known to induce AST/ALT elevations 
(e.g. methotrexate, bosentan), additional measurements of liver enzymes (ALT and AST, 
alkaline phosphatase, total bilirubin, and eosinophils) every 2 weeks for approximately 6 
weeks, by using intermediate (a-visit) trial lab kit are recommended.
Restrictions on diet and life style
4.2.2.3
There are no restrictions on diet and life style.
Restrictions regarding women of childbearing potential
4.2.2.4
The anti-angiogenic properties of nintedanib indicate a high potential for teratogenicity and 
embryotoxicity, including fetotoxicity and lethality. In women of childbearing potential 
receiving nintedanib, contraceptive measures must be employed 28 days before treatment 
initiation, during the trial and for a period of 3 months after last drug intake.
TREATMENT COMPLIANCE
4.3
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on capsule counts, treatment compliance will be calculated as the number of capsules 
taken, divided by the number of capsules which should have been taken according to the 
scheduled period, multiplied by 100. Compliance will be verified by the on-site monitor 
authorized by the Sponsor.
Treatment compliance (%) =
Number of capsules actually taken ∃100
Number of capsules which should have been taken
If the number of doses taken is not between 80-120%, site staff will explain to the patient the 
importance of treatment compliance.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 53 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint
The primary efficacy endpoint is the annual rate of decline in Forced Vital Capacity (FVC; 
expressed in mL over 52 weeks).
5.1.2
Secondary Endpoints
The main secondary efficacy endpoints are:
∀
Absolute change from baseline in King's Brief Interstitial Lung Disease Questionnaire 
(K-BILD) total score at week 52
∀
Time to first acute ILD exacerbation or death over 52 weeks
∀
Time to death over 52 weeks
The other secondary efficacy endpoints are:
∀
Time to death due to respiratory cause over 52 weeks
∀
Time to progression (defined as a ≥ 10% absolute decline in FVC % pred) or death 
over 52 weeks 
∀
Proportion of patients with a relative decline from baseline in FVC % pred of >10% at 
week 52
∀
Proportion of patients with a relative decline from baseline in FVC % pred of >5% at 
week 52
∀
Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms 
dyspnea domain score at week 52
∀
Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms 
cough domain score at week 52
5.1.3
Further Endpoints
Further Endpoints over 52 weeks (Part A)
5.1.3.1
Further efficacy endpoints over 52 weeks are:
∀
Time to first non-elective hospitalization or death over 52 weeks
∀
Absolute change from baseline in FVC (mL) at week 52
∀
Absolute change from baseline in FVC % pred at week 52
∀
Proportion of patients with an absolute decline from baseline in FVC % pred of >10% 
at week 52
∀
Proportion of patients with an absolute decline from baseline in FVC % pred of >5% 
at week 52


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 54 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
∀
Absolute change from baseline in DLCO % pred at week 52
∀
Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Total score 
at week 52
∀
Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Impact 
score at week 52
∀
Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms 
total score at week 52
∀
Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms 
Fatigue domain score at week 52
∀
Absolute change from baseline in Pulmonary Fibrosis Impact on Quality of Life Scale 
(PF-IQOLS) summary score at week 52
Further Endpoints over the whole trial (Part A and Part B)
5.1.3.2
Part B of the trial (variable treatment period beyond 52 weeks) will be conducted in order to 
collect supportive longer term data on the effect of nintedanib in patients with PF-ILD in a 
controlled manner, especially for the early enrollers. Due to the varying length of follow-up 
in Part B of the trial, the efficacy measures incorporating data from Part A and Part B will 
focus on time to event endpoints and will be referred to as time to event endpoints over the 
whole trial.
Those further efficacy endpoints are:
∀
Time to first acute ILD exacerbation or death over the whole trial
∀
Time to death over the whole trial
∀
Time to death due to respiratory cause over the whole trial
∀
Time to progression (defined as a ≥ 10% absolute decline in FVC % pred) or death 
over the whole trial
∀
Time to first non-elective hospitalization or death over the whole trial
More details will be provided and additional further endpoints may be defined in the trial 
statistical analysis plan (TSAP).
ASSESSMENT OF EFFICACY
5.2
5.2.1
Assessment of FVC
FVC will be assessed with the FlowScreen® spirometer which will be supplied to all 
participating sites. 
Spirometry measurements must be performed according to ATS/ERS 2005 guideline (P05-
12782), including daily calibration of the spirometer, and regular calibration of the calibration 
pump. Spirometry will be conducted while the patient is in a seated position. The test will be 
done in triplicate (three curves to be provided), and the best result selected according to the 
guidelines. The best of three efforts will be defined as the highest FVC, obtained on any of 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 55 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
the three blows meeting the ATS/ERS criteria with preferably a maximum of five 
manoeuvres.
Efforts should be made, to schedule the spirometric measurements at approximately the same 
time of the day, with reference to baseline measurement (Visit 2). On days of clinic visits, 
patients must refrain from strenuous activity at least 12 hours prior to pulmonary function 
testing. Smoking should be discouraged throughout the visit days (clinic visit) and will not be 
permitted in the 30-minute period prior to spirometry. Patients should also avoid cold 
temperatures, environmental smoke, dust, or areas with strong odours (e.g. perfumes). If 
treated with bronchodilators, wash-out of 24 hours for long acting and 8 hours for short 
acting bronchodilators should be observed before spirometry.
Spirometry results will be electronically transmitted. To ensure the quality of primary 
endpoint measurement a central spirometry review is put in place to provide feedback to the 
investigational site and the CRA on the quality of the data received from the site.
Further instructions regarding FVC measurements will be provided in the ISF.
5.2.2
Time to progression or death
Time to progression or death is based on the time of death as defined in section 5.2.3 and 
based on time to progression. Progression is defined as a ≥10% absolute decline in FVC % 
predicted.
5.2.3
Time to death
Time to death will be based either on the date of death on the AE report for patients with AEs 
leading to death or will be based on the information from the vital status assessment.
Analysis of time to death due to respiratory cause will be based on the adjudicated cause of 
death as determined by the Adjudication Committee.
5.2.4
Acute ILD exacerbations
Exacerbation of ILD has not been previously studied. Based on the similarity between IPF 
and PF-ILD, in the current study, the most recent definition of acute IPF exacerbation will be 
adapted for use as described below (P16-06899). For the endpoints evaluating the effect of 
nintedanib on these events, AEs reported by the Investigator will be used; the AEs will not be 
adjudicated. 
Acute exacerbation will be defined as an acute, clinically significant, respiratory deterioration 
characterized by evidence of new widespread alveolar abnormality with all of the following:
∀
Previous or concurrent diagnosis of ILD
∀
Acute worsening or development of dyspnea typically less than one month duration
∀
Computed tomography with new bilateral ground-glass opacity and/or consolidation 
superimposed on a background pattern consistent with fibrosing ILD
∀
Deterioration not fully explained by cardiac failure or fluid overload


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 56 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Events that are clinically considered to meet the definition of acute exacerbation but fail to 
meet all four diagnostic criteria due to missing CT data should be termed “suspected acute 
exacerbations”.
5.2.5
Assessment of DLCO
The site will use its own carbon monoxide diffusion capacity (DLCO) equipment and 
conduct all measurements with the same DLCO equipment in case that several devices are 
available at the site. Single-breath DLCO measurement will be carried out according to the 
ATS/ERS guideline on DLCO measurements (R06-2002). DLCO and the corresponding 
alveolar volume will be measured at time points given in the Flowcharts Part A and B. Before 
beginning the test, the manoeuvres should be demonstrated and the subject carefully 
instructed.
DLCO values will be adjusted for altitude, carboxyhaemoglobin (COHb) and the most recent 
haemoglobin value (Appendix 10.1). For predicted normal values, different sites may use 
different prediction formulas, based on the method used to measure DLCO. In any case, the 
calculation method used must be in compliance with the ATS/ERS guideline on DLCO 
measurements (R06-2002) and the prediction formula appropriate for that method. Raw data 
(gas mixture, equation used for prediction of normal, further adjustments made if so) must be 
traced.
The DLCO assessment should always be performed after the FVC measurement and should 
always be started approximately the same time a day.
Further instructions regarding DLCO measurements will be provided in the ISF.
5.2.6
Time to hospitalization
Time to non-elective hospitalization assessment will be based on the date of hospitalization 
collected on a specific hospitalization CRF page. The CRF page will capture whether the 
non-elective hospitalization was due to respiratory cause, and the primary admission 
diagnosis.
5.2.7
Assessment of PRO questionnaires 
The patient should complete patient reported outcome (PROs) questionnaires on his/her own 
in the pre-specified order defined in the Flowchart Part A in a quiet area/room prior to any 
other trial-related examination. Site personnel will check the answers of the patients in the 
questionnaires for completeness prior to the patient leaving the site, but the response to each 
item should not be scrutinized. In instances where a patient cannot give or decide upon a 
response, no response should be recorded. The scores will be transcribed into the eCRF by 
designated site-personnel.
The PRO questionnaires should be presented and filled out in the following order:
1. King's Brief Interstitial Lung Disease Questionnaire (K-BILD)


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 57 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
2. Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (L-PF)
3. EuroQol 5-Dimensional quality of life Questionnaire (EQ-5D) 
4. Pulmonary Fibrosis Impact on Quality of Life Scale (PF-IQOLS) 
King's Brief Interstitial Lung Disease Questionnaire (K-BILD)
5.2.7.1
The K-BILD is a self-administered health status questionnaire that was developed and 
validated specifically for patients with ILD (R12-4171). The questionnaire development and 
validation included a range of ILDs, including the ILD disease types that encompass the 
observed study population.
The questionnaire consists of 15 items and 3 domains: breathlessness and activities, 
psychological and chest symptoms. Possible score ranges from 0-100, with a score of 100 
representing the best health status. The K-BILD (Appendix 10.3.1) will be self-administered 
by the patient and will be administered at study visits as indicated in the Flowchart Part A
and in Section 6.
Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (L-PF)
5.2.7.2
The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44 item questionnaire with two 
modules: 1) symptoms (23 items) and 2) impacts (21 items). L-PF was developed with the 
input of patients with pulmonary fibrosis (PF) and thus is intended to capture perceptions 
specific to PF patients. The Symptoms module yields three domain scores: 1) dyspnea, 2) 
cough and 3) fatigue as well as a total Symptoms score. The Impacts module yields a single 
Impacts score. Symptoms and Impacts scores are summed to yield a total L-PF score. Scoring 
is performed as a summary score, the mean of the dimension ratings multiplied by 100. 
Summary score range from 0-100, the higher the score the greater the impairment.
The L-PF Symptoms and Impact Questionnaire (Appendix 10.3.2) will be self-administered 
by the patient at visits indicated in the Flowchart Part A and in Section 6.
EuroQol 5-Dimensional quality of life Questionnaire (EQ-5D)
5.2.7.3
The EQ-5D was developed by the European Quality of Life Group (EuroQol Group) and is a 
standardized instrument for use as a measure of health outcome (R96-2382). The version 
used in this trial is the new five-level version (EQ-5D-5L).
The questionnaire essentially consists of 2 pages. The first page is the descriptive system with 
5 questions to the patient´s health state today. Each question captures one dimension of health 
(e.g. mobility, self-care) and has five levels to answer. The second page records the patient´s 
self-rated health status of today on a vertical graduated (0 to 100) visual analogue scale.
The EQ-5D-5L (Appendix 10.3.3) will be self-administered by the patient at visits indicated 
in the Flowchart Part A and Section 6.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 58 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Pulmonary Fibrosis Impact on Quality of Life Scale (PF-IQOLS)
5.2.7.4
The impact on quality of life scale (IQOLS) is based on the Quality of Life Scale (QOLS) 
that was developed by John Flanagan to measure current the quality of life of individuals. 
The IQOLS scale was developed to measure the impact of a disease and its treatment on the 
patient’s quality of life. The quality of life dimensions used in the Flanagan IQOLS were 
identified using the critical incident methodology, and the QOLS was administered initially 
to a purposive sample of 3,000 American adults by personal interview (R16-2064, R16-
2404). The questionnaire was subsequently adapted for use in chronic illness groups by 
addition of a 16th dimension (R16-2065), but that adaptation also used a response scale that 
differed from the Flanagan version and had problematic anchor descriptions. The IQOLS 
includes all 16 dimensions and a 5-point standard Likert-type response scale on which 
patients rate the impact of the disease on their quality of life (R16-2387, R16-2388). Unlike 
the most common disease-related quality of life instruments that measure only health/disease-
related aspects of QoL (largely symptoms and physical and emotional functioning), the 
IQOLS measures the impact of a given disease on the full range of domains that are 
important to an individuals’ life such as material and physical well-being, relationships with 
other people, work, social, community and civic activities, personal development, recreation 
and independence. The IQOLS approach has been used most extensively, to date, to study the 
quality of life impact of asthma and its treatment (the A-IQOLS). Versions have been 
developed to study the impact of other conditions as well (e.g., pulmonary fibrosis, breast 
cancer, heart failure), as well as the impact of a child’s asthma on their parent’s quality of 
life).
Scoring of IQOLS is performed as a summary score, the mean of the dimension ratings.
Summary score range from 1-5 with greater scores meaning the worse quality of life.
The PF-IQOLS (Appendix 10.3.4) will be self-administered by the patient at visits indicated 
in the Flowchart Part A and Section 6.
ASSESSMENT OF SAFETY
5.3
The primary assessment of benefit-risk of nintedanib in patients with PF-ILD will be based 
on efficacy and safety data over 52 weeks. In addition to the assessment of safety after 52 
weeks of treatment, selected safety analyses will be repeated to include data collected beyond 
12 months, especially for the early enrollers to the study.
5.3.1
Physical examination
Physical examination will be performed at time points indicated in the Flowcharts Part A and 
B. All abnormal findings at baseline will be recorded on the Baseline Condition eCRF page. 
New abnormal findings or worsening of baseline conditions detected at the subsequent 
physical examinations, if judged clinically relevant, will be recorded as adverse events on the 
appropriate eCRF page.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 59 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
5.3.2
Vital Signs
Systolic and diastolic blood pressure and pulse rate will be measured with the patient seated 
after having rested. All abnormal findings at baseline will be recorded on the baseline 
condition eCRF page. New abnormal findings or worsening of baseline conditions detected at 
the subsequent physical examinations, if judged clinically relevant, will be recorded as 
adverse events on the appropriate eCRF page.
5.3.3
Safety laboratory parameters
The laboratory tests at regular site visits will include:
Category
Laboratory test 
Haematology
Red blood cell count (RBC)
Haemoglobin (Hb)
Haematocrit (Hct)
Mean corpuscular volume
White blood cell count including differential
Platelet count
Biochemistry 
Aspartate aminotransferase (AST)
Alanine transaminase (ALT)
Gamma-glutamyl transferase (GGT)
Alkaline phosphatase (ALK)
Creatine kinase (CK)
Lactate dehydrogenase (LDH)
Total protein
Total bilirubin
Brain natriuretic peptide (BNP at V2, V7, V9 and EOT)
Creatinine
Glucose (non fasting)
Uric acid
Thyroid stimulating hormone (only at V2, V7, V9, and EOT)
ß-HCG (at Visit 2 only)
Electrolytes
Sodium
Potassium
Calcium
Chloride
Inorganic phosphorus
Coagulation
International normalized ratio (INR)
Activated partial thromboplastin time (aPTT)
Prothrombin time (PT)
Urinalysis 
pH, glucose, erythrocytes, leukocytes, protein, nitrite (semi-quantitative 
measurements; -, +, ++, +++)
Local Urine dipstick pregnancy test in all women of childbearing potential. If urine test is not 
acceptable to local authorities, a blood test must be done at a local laboratory.
The laboratory tests at intermediate ‘a’ visits will include:


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 60 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Category
Laboratory test 
Biochemistry
Total protein, creatinine, electrolytes and liver function (AST, ALT, GGT, 
alkaline phosphatase, and total bilirubin)
Urinalysis 
pH, glucose, erythrocytes, leukocytes, protein, nitrite (semi-quantitative 
measurements; -, +, ++, +++)
Local Urine dipstick pregnancy test in all women of childbearing potential. If urine test is not 
acceptable to local authorities, a blood test must be done at a local laboratory.
At ‘a-Visits’, safety blood, pregnancy tests and urine samples will be collected and submitted 
to the central laboratory if needed for additional safety monitoring at the discretion of the 
Investigator (see Section 4.2.2.2 for additional safety monitoring).
The samples and pregnancy tests may be collected at the office of a local doctor using trial 
specific lab kits that will be sent to a central laboratory for analyses. These kits will be 
provided to patients at study visits as applicable.
A maximum total amount of approximately 100 mL blood will be taken for standard safety 
laboratory during the course of Part A. In Part B, a maximum total amount of approximately 
90 mL blood will be taken for standard laboratory depending of the time the patient will stay 
in Part B.
Creatinine clearance will be calculated based on serum creatinine according to Cockcroft and 
Gault (R96-0690, Appendix 10.2).
If laboratory values indicate abnormality, adequate and more frequent blood sampling may be 
performed at the discretion of the Investigator.
In case of liver function value elevations, close monitoring must be ensured by the 
Investigator. Refer to Section 4.2.1.2 for monitoring elevations and Section 3.3.4 for 
withdrawal criteria.
Laboratory analysis will be done using central laboratory services. Venous whole blood will 
be collected in appropriate syringes provided by the Sponsor through the assigned central 
laboratory. Details regarding centrifuge, processing, storage and shipment of samples will be 
determined by the central laboratory in accordance with the Sponsor. The Investigators will 
be informed and instructed by the central laboratory and detailed documentation will be 
included in the ISF.
5.3.4
Electrocardiogram
Resting 12 lead Electrocardiograms (ECGs) are conducted during the trial with site’s own 
equipment. Rate, rhythm and repolarization changes have to be evaluated, compared to 
previous tracings, and assessed for clinical relevance.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 61 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Clinically relevant findings must be entered as adverse events.
5.3.5
Other safety parameters
Worsening of underlying CTD (if applicable) will be assessed via evaluation of adverse 
events / serious adverse events.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorization or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:
∀
results in death,
∀
is life-threatening,
∀
requires inpatient hospitalization or prolongation of existing hospitalization,
∀
results in persistent or significant disability or incapacity,
∀
is a congenital anomaly/birth defect,
or
∀
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 62 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
For Japan: 
The following events will be handled as “deemed serious for any other reason”. An AE which 
possibly leads to disability will be reported as an SAE.
AEs considered “Always Serious”
Every new occurrence of cancer of new histology must be reported as a serious event 
regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the RDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
Adverse events relating to gastrointestinal perforation and hepatic injury will be considered 
AESIs.
Hepatic injury
In this trial protocol, signs of hepatic injury are defined as:
∀
ALT and/or AST ≥8 fold ULN
∀
ALT and/or AST ≥3 fold ULN and total bilirubin ≥ 2 fold ULN* 
∀
ALT and/or AST ≥3 fold ULN and unexplained INR > 1.5*
∀
ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%)*
∀
ALT and/or AST ≥3 fold ULN and appearance of fatigue, nausea, vomiting, right 
upper abdominal quadrant pain or tenderness, fever and/or rash
* in the same blood draw sample.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 63 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to immediately stop the trial medication and need to be followed up 
according to the “drug-induced liver injury (DILI) checklist” provided in the ISF. The 
investigator is asked to collect requested information within 48 hours upon laboratory hepatic 
injury alert/notification.
Potential DILI cases are defined as AESIs, and are reported and processed following the SAE 
process on the respective SAE form.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST and total bilirubin) available, the Investigator should make sure these parameters 
are analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
In addition the intensity of diarrhoea adverse events should be classified and recorded in the 
eCRF according to the Common Terminology Criteria for adverse events (CTCAE) version 4 
(R10-4848, Table 5.3.6.1:1).
Table 5.3.6.1:1
CTCAE Categorization for diarrhoea
CTCAE Grade
Diarrhoea
1
Increase of <4 stools per day over baseline
2
Increase of 4 to 6 stools per day over baseline
3
Increase of ≥7 stools per day over baseline; incontinence
4 
Life threatening consequences
5
Death
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 64 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug 
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced.
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction, weeks after discontinuation of the drug 
concerned).
∀
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∀
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
∀
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
5.3.7
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
∀
From signing the informed consent onwards until the end of treatment (including the 
Residual Effect Period, REP): 
- all AEs (non-serious and serious) and all AESIs.
After the end of treatment (including the REP) until the individual patient’s end of trial: 
- all AEs (non-serious and serious) and all AESIs should be collected.
∀
After the individual patient’s end of the trial: 
the Investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs and relevant AESIs of which the Investigator may become aware of. 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 65 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
The end of treatment will occur during Part B of the study, except in case of premature trial 
medication discontinuation during Part A.
The REP is defined as 28 days after the last trial medication intake. All AEs which occurred 
through the treatment phase and throughout the REP will be considered as on-treatment
(please see Section 7.3.4). Events which occurred after the REP will be considered as post-
treatment events.
AE reporting to Sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
For Japan: 
All SAEs and AESIs must be reported immediately to the head of the trial site.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication.
The following should also be recorded as an (S)AE in the CRF and SAE form (if applicable):
∀
Worsening of the underlying disease e.g. RA, other CTD or of other pre-existing 
conditions e.g. hypertension, diabetes.
∀Changes in vital signs, resting ECG, physical examination and laboratory test results, 
if they are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the Sponsor’s unique entry point (country-


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 66 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
specific contact details will be provided in the ISF). The Pregnancy Monitoring Form for 
Clinical Trials (Part A) should be used. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
Safety monitoring and adverse events with additional information collection:
∀
An independent Data Monitoring Committee (DMC) will conduct regular reviews of 
the trial safety data as detailed in Section 3.1.1 and in the DMC charter.
∀
An independent Adjudication Committee (AC) will review all fatal cases and 
adjudicate all deaths to either cardiac, respiratory or other causes and will review all 
adverse events categorized as major adverse cardiovascular events (MACE). MACE 
is defined as non-fatal myocardial infarction, non-fatal stroke and cardiac death.
∀
Additional details (on top of standard AE and SAE reporting) will be collected in the 
eCRF for the adverse event ‘Diarrhoea’ and the adverse events in the subordinate 
Standard MedDRA Query (SMQ) ‘Haemorrhage terms, excluding laboratory terms’.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
Plasma concentration monitoring of nintedanib (BIBF 1120) will be performed in order to 
assess drug exposure in the PF-ILD patient population. PK plasma sampling will be 
conducted at Visits 4 and 7, just before drug administration and, hence, the pharmacokinetic 
parameter Cpre,ss will be determined at these time points. The pharmacokinetic parameter 
will be included in the clinical trial report.
5.4.2
Methods of sample collection
A detailed description of sample collection and handling is provided in the ISF. For 
quantification of drug plasma concentrations of nintedanib (BIBF 1120), venous blood will 
be collected using a pre-labelled potassium ethylenediamine-tetraacetic acid (EDTA) 
containing blood drawing tube. Overall, about 7 mL blood will be taken for pharmacokinetic 
measurement during the course of the trial.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 67 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
No morning administration of nintedanib should be performed on Visits 4 and 7 before the 
pre-dose PK sample has been collected. Date and exact clock time of drug administration and 
blood sampling must be recorded on the eCRF. Additionally, the date and exact clock time of 
drug administration for the three days preceding the visit where blood sampling for PK is 
performed must be recorded by the patient on a PK-card.
5.4.3
Analytical determinations
Nintedanib (in form of its free base BIBF 1120 BS) plasma concentrations will be determined 
by a validated assay based on liquid chromatography-tandem-mass spectrometry (LC-MS / 
MS).
The procedures and specifications of the analytical method are available at the bioanalytical
site (Nuvisan GmbH & Co KG, Wegenerstraße 13, 89231 Neu-Ulm, Germany).
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
Exposure-response relationships will be explored. In case of a negative outcome of the trial,
formal exposure-response analyses might be omitted. In addition, pharmacokinetic / 
pharmacodynamic (PK / PD) relationships might be explored with selected exploratory 
biomarkers and reported separately.
ASSESSMENT OF EXPLORATORY BIOMARKER(S)
5.5
The scientific working hypothesis is that the response to lung injury in PF-ILD includes the 
development of fibrosis which becomes progressive, self-sustaining and independent of the 
original clinical association or trigger. Due to the clinical and mechanistic parallels between 
PF-ILD and IPF, it is anticipated that nintedanib will elicit similar effects in PF-ILD as it 
demonstrated in IPF (see Section 1.1.2). The aim of the biomarker analyses is to provide 
further support of the scientific hypothesis of the protocol. In addition, these analyses may 
contribute to identification and validation of pharmacodynamic (PD) and patient selection 
biomarkers which may support future drug development.
Planned assessments include but are not limited to:
∀
determining the correlation between biomarkers and selected clinical parameters
∀
identifying potential predictors of disease progression 
∀
characterizing similarities and differences between patient subgroups within the study 
and across patients in ILD projects 
Accordingly, the following biomarkers related to lung fibrosis will be explored before and 
after treatment with the study medication and will be correlated with clinical endpoints. All 
biomarker analyses are considered exploratory.
Serum/plasma samples:
Biomarkers that will be evaluated will include but are not limited to:


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 68 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
∀
CRP, IL-8 , KL6, SP-D, ECM turnover biomarkers (such as BGM, C1M, C3M, C5M, 
C6M, CRPM, EL-NE), s-ICAM, MMP7
In addition, a metabolite panel and miRNAs related to lung fibrosis such as miR-29b may 
also be evaluated contingent upon availability of validated assays.
Ribonucleic Acid (RNA) samples:
Blood will be sampled for RNA extraction and subsequent gene expression analyses.
5.5.1
Methods and timing of sample collection
Serum and plasma collection:
Whole blood (approx. 16 mL) will be collected for the preparation of serum and plasma 
analysis. Collection time points are outlined in the Flowchart Part A. Correct, complete and 
legible documentation of drug administration and blood sampling times is mandatory to 
obtain data of adequate quality for biomarker analysis. A detailed description of biomarker 
sample collection and sample handling is provided in the ISF.
RNA sample collection:
Whole blood will be collected for transcriptome-wide expression analyses. Collection time 
points are outlined in the Flowchart Part A. Approximately 2.5 mL blood will be collected 
per PAXgene Blood RNA Tubes. Samples in PAXgene Blood RNA Tubes must be stored at
approximately -20°C/4°F or below.
Overall, a maximum total amount of approximately 90 mL blood will be taken for 
explorative biomarker assessment during the course of the trial.
5.5.2
Analytical determinations
Biomarkers will be analysed in EDTA plasma or serum using validated assays. The analytical 
methods of plasma, serum and RNA biomarkers will be given in detail in an analytical report.
All biomarkers will be analysed by the sponsor or by a contractor of the sponsor.
5.5.3
Biobanking
As scientific understanding of fibrosing lung diseases is expected to develop over time, all 
patients will be asked to provide additional samples to enable further biomarker analyses.
Only if a separate, optional biobanking informed consent is given in accordance with local 
ethical and regulatory requirements, Desoxyribo Nucleic Acid (DNA) and serum banking 
samples will be taken, processed and stored. Patients will be informed about the purpose of 
banking serum and DNA samples and the procedures during the informed consent process.
Participation in the biobanking part is voluntary and not a prerequisite for participation in the 
study.
The current study in patients with PF-ILD provides a unique opportunity to investigate 
exploratory biomarkers of disease progression in a large group of patients with physician 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 69 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
diagnoses of different fibrosing ILDs but the same clinical phenotype i.e. PF-ILD. Since the 
biomarker area has been rapidly evolving not all biomarker analyses can be pre-specified at 
this time. Banking serum samples will enable future analyses that may contribute to 
identification and validation of new biomarkers. Thereby future analyses of banked samples 
may, for example, contribute to better understanding of your and other lung diseases and to 
optimizing treatment of patients.
Banking of serum and DNA samples at BI is compliant with principles of Good Clinical 
Practice (GCP) as outlined in the guidance by the “International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human 
Use” (CPMP/ICH/135/95) 
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC
500002874.pdf) which ensure oversight and that full compliance for the protection of patient 
data and interests are observed. This encompasses a tight standard operation procedure 
scheme including a sound scientific review/evaluation of any projects done with banked 
DNA samples and regular audits by a quality assurance unit.
BI’s business model is the development of new innovative drugs; it does not include 
commercial trade of samples. Samples can be transferred to third party only for the purposes 
clearly stated in the Informed Consent Form.  
The banking samples will be stored for up to 30 years after the final study report has been 
signed. Biomarker analyses of banked samples will be restricted to biomarkers relevant to the 
area of respiratory diseases.
DNA banking:
Only if a the separate, optional biobanking informed consent is given in accordance with 
local ethical and regulatory requirements, Desoxyribo Nucleic Acid (DNA) banking samples 
will be taken, processed and stored. Participation in the biobanking part is voluntary and is 
not a prerequisite for participation in the study.
One 8.5 mL blood sample for DNA banking will be collected in PAXgene blood DNA tube 
at or after Visit 2 for those patients who signed a separate informed consent for DNA banking
(see Flowchart). Blood samples collected in PAXgene blood DNA tubes should be stored and 
shipped at a temperature of about -20°C/4°F or below.
The stored DNA may be analysed and assessed to retrospectively identify e.g. whether there 
are genetic factors that could contribute to a better therapeutic outcome or to a higher risk of 
developing treatment-related adverse drug reactions.
Serum banking:
All randomized patients who signed the separate, optional biobanking informed consent will 
be requested to provide blood samples for serum banking.
Approximately 10 ml additional blood will be collected in serum collection tubes according 
to the Flowchart Part A. Details on sample collection and processing will be given in the ISF.
For serum banking the maximum total amount of blood taken during the course of the trial 
will be approximately 50mL.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 70 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Samples may be used for further biomarker investigations as the science of lung diseases 
evolves.
OTHER ASSESSMENTS
5.6
Health care resource utilization (HCRU)
For the purpose of a separate health economic analysis (such as cost-utility analysis), health 
care resource utilization (HCRU) data will be collected throughout the trial. Resource use 
data collected for calculating direct costs will include unscheduled hospitalizations, 
healthcare provider visits, and emergency room/intensive care unit use. Non-medical resource 
use data will include changes in work productivity.
The economic evaluation of the HCRU data will not be part of the clinical trial report but 
reported separately.
HRCT assessment
HRCT assessment of extent of fibrosis and fibrotic pattern has become an essential part of the 
evaluation and diagnosis of patients with ILDs. HRCT diagnosis of UIP has been shown to 
correlate with both histologic UIP (P11-07084) and prognosis in patients with ILDs (R16-
0560, R16-0756, R14-3529). However, as the majority of the data currently available in the 
literature pertains to IPF, the present study provides an opportunity to explore the impact of 
extent of fibrosis and HRCT patterns on clinical makers of disease progression and response 
to treatment in other progressive fibrotic ILDs (i.e. patients with PF-ILD). In addition, 
exploratory HRCT analyses from this study may help identify prognostic imaging biomarkers 
to support future drug development and patient characterization.
Screening HRCT will be used in all patients to determine study eligibility and randomization 
stratification. In addition to confirmation of the presence of relevant fibrosis (>10% extent) 
and determination of the HRCT pattern for randomization stratification (see Section 3.3.4),
visual and quantitative analyses of the screening HRCTs will be performed to explore 
potential predictors of clinical outcomes e.g. FVC decline, progression, exacerbation. 
In patients who provide consent to optional longitudinal HRCT, HRCT scans will be 
performed at baseline, 6 months and/or 12 months (see Flowchart A). The planned 
assessments of the optional longitudinal HRCT include but are not limited to:
∀
identifying potential predictors of progression 
∀
determining the correlation between HRCT-derived imaging biomarkers and selected 
clinical parameters
∀
investigating the performance of the computer aided analysis for the characterization 
and monitoring of ILDs
Details of the planned HRCT analyses and endpoints will be described in a specific SAP and 
are considered exploratory.  All results will be reported separately. 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 71 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
The same acquisition protocol specifications will be used for all HRCT scans. Whenever 
possible, HRCT scans should be completed on the same scanner and by the same technician
to minimize variability. Scans will be digitally transferred for central review. HRCT scans 
will be stored for up to 15 years at the sponsor facilities or by an external vendor for future 
scientific research.
APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements conducted for primary and secondary endpoints are using standard 
methods. Refer to Section 3.2 for the discussion of the choice of FVC as primary endpoint. 
The pharmacokinetic parameters and measurements outlined in Section 5.5 are generally used 
as measurements to assess drug exposure. Measures conducted for exploratory further 
endpoints might be new methodologies already used in clinical trials but not yet validated for 
this rare disease.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 72 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
The trial consists of two parts: Part A and Part B. Part A will consist of Visits 2 through 9, 
which will occur within one year of randomization. Following completion of the week 52 
visit (Visit 9), patients will continue to have study visits every 16 weeks (Part B) until the end 
of the trial. Intermediate lab tests for safety monitoring will be performed as needed until the 
end of the trial.
There is one screening visit (Visit 1; which may be preceded by a separate informed consent 
visit) and 8 visits (Visits 2 to 9) planned within the 52 weeks treatment period (Part A). 
Additional visits will occur every 16 weeks until the end of the trial. Furthermore, there are 
intermediate scheduled blood analyses and a follow-up Visit.
The trial will last until all patients completed the EOTB visit and the Follow-up Visit as 
applicable. (see Figure 3.1: 1).
After giving his/her informed consent, the patient will be screened for inclusion (see Section 
3.3.2) and exclusion criteria (see Section 3.3.3) for the trial at Visit 1 and Visit 2 (refer to 
Flowchart Part A).
Visit 2 can be performed once the results from central laboratory of Visit 1 and central HRCT 
review are obtained. If for any reason the screening phase for an individual patient lasts for 
more than 6 weeks, then the laboratory examination for Visit 1 has to be repeated before 
randomization. The screening phase must be no longer than 12 weeks. The patient will be 
randomized at Visit 2 if all inclusion and none of the exclusion criteria are fulfilled.
The results of laboratory parameters from Visit 2 will become available only after Visit 2. 
Therefore, laboratory results from Visit 2 cannot qualify as exclusion criteria; laboratory 
results from Visit 1 will be used instead. In case laboratory results of Visit 2 would 
retrospectively fulfil an exclusion criterion, the patient should not continue receiving trial 
medication unless continuation is justified in writing by the Investigator.
Visits 2, 3, 4 and 5 will occur every 2 weeks. Visit 6 will be scheduled 6 weeks later, Visits 7 
and 8 are planned every 12 weeks and Visits 9 is planned after further 16 weeks. Visits 6a, 
7a, and 8a are intermediate laboratory control visits.
After Visit 9, study visits will occur every 16 weeks (Part B) until the end of the trial. Visit 
numbers will continue with Visit 10, Visit 11, etc.
The samples for the ‘a-Visits’ may be drawn locally (i.e. local general practitioner [GP]). The 
Investigator would in that case give the required documentation to the patient, with the 
corresponding trial kit for the respective ‘a-Visit’ to be sent to the central laboratory even if 
not at the trial site. Information, agreement and training of the respective local GP for blood 
draw will be ensured on an individual site basis consulting the Sponsor’s local monitor.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 73 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Pregnancy test will be performed in women of childbearing potential every 4-6 weeks. Urine 
dipstick test will be done at every visit and will be provided for at home pregnancy testing as 
soon as visit intervals are > 6 weeks (2 to 3 pregnancy test dipsticks to take home at Visit 7
and 8). Documentation will be done in patient’s notes.
The primary endpoint Visit 9 is scheduled 52 weeks after randomization and occurs 16 weeks 
after Visit 8.
A window of ±3 days for Visits 3 to 6, ±7 days for Visits 6a to 9 is allowed to accommodate 
scheduling problems. If a delay is observed for a particular visit, the original calendar 
schedule should be kept for subsequent visits (delays should not accumulate). For visits in 
Part B, a window of ±7 days is allowed.
If treatment is discontinued, an end of treatment visit (EOT) will be performed in all patients.
A follow-up Visit has to be organized 28 days (+ 7 days) after the end of treatment visit
except for patients being transferred into the separate open-label extension study.
In case of a missed visit, the investigator should contact the local clinical monitor, these will
be addressed on a case by case basis.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening
All trial procedures at selected visits will be done according to Flowchart Part A and 
footnotes and the CTP.
Informed consent (before or at the latest at Visit1)
∀
Informed consent will be obtained prior to patient participation in the trial, which 
includes any medication wash-out procedures or restrictions as well as HRCT transfer 
to central review. Upon obtaining informed consent, the patient will be instructed on 
the medication washout and other restrictions needed.
∀
Patients will be asked to give informed consent to the DNA banking sample (please 
note: the DNA banking sample must not be taken prior to Visit 2). Participation is 
voluntary and is not a prerequisite for participation in the trial.
∀
A preliminary check of in-/exclusion criteria is recommended at time of informed 
consent to avoid unnecessary wash-out procedures in non-eligible patients.
∀
An HRCT not older than 12 months will be sent for central review, after the 
Investigator’s evaluation, 
o
to confirm that the extent of features of fibrosis is >10% is in accordance with the
inclusion criteria (see Section 3.3.4),
o
to assess HRCT pattern for stratification.
Provided the patient meets all other eligibility criteria, the HRCT can be performed 
for the purposes of participation in the trial if the patient does not have a HRCT within 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 74 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
12 months at the time of the scheduled Visit 1 or the HRCT available does not meet 
the image acquisition specifications of the study.
∀
Site personnel will perform a screening call in IRT to ensure in-time trial medication 
shipment.
∀
Upon obtaining informed consent the patient will receive a trial identification card.
Observations and procedures at Visit 1
∀
If a separate informed consent Visit was not done, obtaining informed consent and the 
above mentioned procedures will be done prior to any further procedure at this visit.
∀
Demographics will be recorded.
∀
Medical history including pre-existing conditions will be recorded.
∀
Concomitant therapy including previous medications will be recorded.
∀
Any adverse events (since consent, if applicable) will be recorded.
∀
Local urine pregnancy test (dipstick) will be done, if applicable (see Section 5.3.3).
∀
Physical examination including vital signs will be performed.
∀
A resting 12-lead electrocardiogram using site’s own equipment will be performed 
and evaluated by the Investigator (if possible prior to blood draw).
∀
FVC measurement will be conducted with the FlowScreen® spirometer.
∀
DLCO measurement will be conducted. FVC measurement has to be done first, 
followed by patient’s rest and subsequent DLCO measurement.
∀
Blood and urine samples (safety lab) will be collected and submitted to the central 
laboratory (for details refer to Section 5.3.3). Prior to blood draw a pre-assessment of 
all inclusion and exclusion criteria is highly recommended.
∀
Site personnel will send HRCT to central review (if not already done at time of 
informed consent).
∀
For patients qualified to enter the screening period, Visit 2 will be scheduled.
6.2.2
Treatment phase
At the beginning of each visit during treatment phase, Investigator and site personnel should 
ensure the well-being of the patient as well as prepare all requirements for conduct of the 
visits that are necessary.
The order of the different trial procedures should follow the protocol and should be planned
for taking into account the specific structure of the investigational site and following the 
mandatory needs outlined in the clinical trial protocol.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 75 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Mandatory needs: the following has to be ensured during trial visits according to the study
Flowchart:
∀
Patient reported outcome questionnaires have to be filled out always prior to any other 
procedures by the patient in a quiet area and in the following order:
1.
K-BILD
2.
L-PF Symptoms and Impact Questionnaire
3.
EQ-5D
4.
PF-IQOLS
∀
Urine pregnancy test and any laboratory sample collection must be performed prior 
trial medication administration.
∀
FVC and DLCO measurement at all visits should be performed approximately at the 
same time of the day to reference time point at Visit 2.
∀
Order of pulmonary function tests must always be
1. FlowScreen® spirometry (FVC) followed by patient’s rest
2. DLCO with site’s own equipment.
Baseline Visit 2 (randomization) 
The following prerequisites must be available for randomization:
∀
Eligibility confirmation and HRCT pattern from central HRCT review.
∀
Safety laboratory results including haemoglobin and creatinine from Visit 1.
Procedures: 
∀
All patients will be asked to fill out the patient reported outcome questionnaires prior 
to any other visit procedure. The order of the questionnaires will always be: 1. K-
BILD, 2. L-PF Symptoms and Impact Questionnaire, 4. EQ-5D, 5. PF-IQOLS.
∀
Site personnel will review questionnaires for completeness.
∀
Physical examination including vital signs and HCRU interview will be performed.
∀
Adverse events and concomitant therapy since last visit will be reviewed and 
recorded.
∀
Medical history will be reviewed.
∀
Repeated resting 12-lead electrocardiogram using site’s own equipment will be 
performed and evaluated if resting ECG was abnormal at Visit 1 (if possible prior to 
blood draw).
∀
SpO2 will be recorded (earlobe or forehead, resting).
∀
FVC measurement will be conducted with the FlowScreen® spirometer.
∀
DLCO measurement with sites own equipment will be conducted.
∀
All in/exclusion criteria will be assessed based on Visit 1 laboratory and Visit 2 
measures.
∀
HRCT will be performed in patients who agree to have follow-up HRCT done as part 
of the trial, unless a screening HRCT was done as part of the study to determine 
eligibility. 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 76 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
∀
Safety blood and urine samples will be collected and submitted to the central 
laboratory. 
∀
Biomarker samples will be collected and submitted to the central laboratory. 
∀
The time of blood collection for biomarker samples will be recorded in the eCRF. 
Note: blood samples should always be collected prior to drug administration.
∀
One blood sample for DNA banking will be collected in eligible patients and only 
after obtaining a separate informed consent.
∀
Local urine dipstick pregnancy test (if applicable).
∀
If a patient is eligible for the trial, randomization will be performed by using the IRT 
system.
∀
Treatment will be dispensed.
∀
The next visit will be scheduled and prepared.
Visit 7, Visit 9 and EOTA (‘big visits’) procedures
At Visit 7, Visit 9 and EOTA (primary endpoint visit), the same procedures will be performed 
as done at baseline Visit 2. Exceptions are the typical randomization measures, e.g. eligibility 
review, medical history assessment and randomization as well as DNA banking sample 
which is only taken once. In addition, if EOT takes place before Visit 7, HRCT should not be 
repeated. For Visit 7, Visit 9 and EOTA always refer to the Flowchart Part A.
General rules
∀
Treatment compliance will be reviewed by site personal.
∀
Trial medication will be collected and/or dispensed according to Flowcharts Part A.
∀
Visit 9 and end of treatment visit (EOTA) are identical visits. EOTA is to be used in 
eCRF at any time a patient ends trial medication (scheduled or prematurely).
∀
Patient who prematurely discontinued trial medication will attend all originally 
planned visits until the end of the trial (except for the laboratory visits 6a, 7a and 8a).
∀
IRT should always be notified on end of treatment (EOT).
∀
Vital status will be collected for patients who prematurely discontinued trial 
medication and failed to attend future visits as planned, as well as for those who did 
not attend scheduled visits as planned at week 52 (scheduled Visit 9/EOTA).
∀
PROs will always be scheduled prior to any other procedure and in the above 
described order and will be reviewed for completeness by site personal.
∀
Drug intake at visit days should always be performed at site and after blood and urine 
sample collection and pregnancy test.
∀
FlowScreen® spirometry (FVC) and DLCO measurements will always be in the 
allowed time window and the described order (reference visit = Visit 2).
∀
Non-elective hospitalization will be recorded.
∀
Acute ILD exacerbations will be recorded.
∀
Resting 12-lead electrocardiogram using site’s own equipment will be performed and 
evaluated (if possible prior to blood draw).
∀
At Visit 7, a PK sample will be collected. The patient needs to record exact date and 
clock time of medication intake the preceding three days on a PK-card provided at 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 77 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Visit 6. The date and time of blood collection for PK and drug administration at the 
site will be recorded.
∀
Biomarker blood sampling will be done. The date and time of blood collection for 
biomarker samples will be recorded in the eCRF.
∀
For patients who agreed to the optional HRCT-follow-up, HRCT should be done at 
V7 and V9.
Visit 3, 4, 5, 6, and 8 (‘medium visits’) procedures
Please note that not all medium visits are drug dispensation visits (please always refer to 
Flowchart Part A). However, compliance of patients regarding drug intake should always be 
reviewed (see also treatment compliance in Section 4.3).
∀
Physical examination including vital signs and HCRU interview will be performed.
∀
Adverse events and concomitant therapy since last visit will be reviewed and 
recorded.
∀
PROs will be scheduled prior to any other procedure and in the above described order 
and will be reviewed for completeness by site personal at Visits 6 and 8.
∀
Local dipstick pregnancy test (if applicable).
∀
Safety blood and urine samples will be collected and submitted to the central 
laboratory.
∀
At medium Visits 6 and 8, biomarker samples will be collected. The date and time of 
blood collection for biomarker samples will be recorded in the eCRF.
∀
At medium Visit 4, a PK sample will be collected. The patient needs to record exact 
date and clock time of medication intake the preceding three days on a PK-card
provided at Visit 3. The date and time of blood collection and drug administration at 
the site will be recorded.
∀
At medium Visit 6, a PK-card will be provided to record exact date and clock time of 
medication intake three days preceding PK sampling at Visit 7.
∀
FlowScreen® spirometry (FVC) in the allowed time window will be performed.
∀
Non-elective hospitalization will be recorded.
∀
Acute ILD exacerbations will be recorded.
∀
2 to 3 take home pregnancy tests (dipsticks) at Visit 8 will be dispensed.
∀
Treatment compliance will be reviewed by site personal at every visit (except at 
randomization visit and at ‘a-Visits’).
∀
Trial medication will be collected and/or dispensed according to Flowchart Part A.
Visit X and EOTB procedures
∀
Physical examination including vital signs and HCRU interview will be performed.
∀
Adverse events and concomitant therapy since last visit will be reviewed and 
recorded.
∀
Local dipstick pregnancy test (if applicable).
∀
Safety blood and urine samples will be collected and submitted to the central 
laboratory.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 78 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
∀
Resting 12-lead electrocardiogram using site’s own equipment will be performed and 
evaluated (if possible prior to blood draw) at every other visit and EOT.
∀
The date and time of blood collection and drug administration at the site will be 
recorded.
∀
FlowScreen® spirometry (FVC) and DLCO measurements in the allowed time 
window will be performed.
∀
Non-elective hospitalization will be recorded.
∀
Acute ILD exacerbations will be recorded.
∀
Home pregnancy tests (dipsticks) will be dispensed.
∀
Treatment compliance will be reviewed by site personal at every visit.
∀
Trial medication will be collected and/or dispensed according to Flowchart Part B.
∀
Assessment of vital status at EOTB visit
Intermediate ‘a-Visit’ procedures
∀
Safety blood, pregnancy tests and urine samples will be collected and submitted to the 
central laboratory if needed for additional safety monitoring at the discretion of the 
Investigator (see Section 4.2.2.2).
6.2.3
Follow-up Visit and trial completion
A Follow-up Visit has to be scheduled 28 days after End of Treatment Visit for all patients 
except for patients transferred into a separate open-label extension study. This Follow-up 
Visit is the safety follow-up after treatment discontinuation.
∀
Physical examination including vital signs.
∀
Adverse events and concomitant therapy will be assessment since last visit.
∀
Local dipstick pregnancy test (if applicable).
∀
FlowScreen® spirometry (FVC) in the allowed time window will be performed.
∀
Non-elective hospitalization will be recorded.
∀
Acute ILD exacerbations will be recorded.
∀
Patient’s participation will be concluded for patients who withdraw consent and do
not attend future visits.
Trial completion
The trial completion eCRF page has to be filled-in when the patient has terminated the trial. 
The end of the trial for the individual patient is:
∀
For patients who complete all study visits, end of trial is EOTB. A follow-up visit is 
only required for those who do not roll-over in the separate open-label study
∀
For patients who withdraw consent
%
at time of trial medication discontinuation, end of trial is an EOT visit followed by 
a follow-up visit.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 79 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
%
after EOT was already completed, then the patient should have a final visit based 
on their scheduled study visit.
Patients who prematurely discontinued trial medication
In case a patient has to permanently discontinue trial medication, for whatever reason, he/she 
will be encouraged to attend all future visits up to end of trial as originally planned (except 
for the laboratory ‘a-Visits’).
∀
During these visits, the patient will undergo all planned examinations according to 
Flowcharts A and B, especially FlowScreen® spirometry (FVC) and will fill in the 
PRO questionnaires (only Part A); however he/she will not have to do the resting 
ECG, safety laboratory, biomarker laboratory and PK blood draw. 
∀
These visits will be regarded as part of the trial despite the patient having 
discontinued trial medication.
The need for coming to future visits in case of prematurely discontinuation of trial medication 
will be explained to patients prior to their participation in the trial.
Vital status information
In case of premature discontinuation of trial medication, if the patient does not attend future 
visits as planned, every attempt will be made to get information on vital status at 52 weeks 
after his/her randomization, at the time of data cut-off for the primary analysis and at the end 
of the trial for patients who have withdrawn consent.
Patients will be asked to agree to be contacted by the site personnel, which could be by 
telephone calls, to allow collection of the vital status.
If death occurs, the Investigator will review the circumstances, including the relevant medical 
records to ascertain the most likely primary and secondary causes of death. The cause of 
death will be adjudicated by the AC.
Collection of vital status will be performed in accordance with national ethical and regulatory 
guidelines.
6.2.4
Dose reduction visit / dose increase visit
If a patient experiences a drug related adverse event, the dose can be reduced and the dose 
can be re-increased after recovery as described in Section 4.2.1. In both cases, the patient will 
have to come back to a visit where the following will be performed:
∀
Physical examination including vital signs.
∀
Adverse events and concomitant therapy will be assessment since last visit.
∀
Local dipstick pregnancy test (if applicable).


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 80 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
∀
Safety blood and urine samples will be collected and submitted to the central 
laboratory.
∀
FlowScreen® spirometry (FVC) in the allowed time window will be performed.
∀
Trial medication will be collected and treatment compliance will be reviewed.
∀
IRT call for reduction or increase of the dose and trial medication dispensation.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 81 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is a multi-centre, multi-national, prospective, randomized, placebo-controlled, double 
blind trial to investigate the efficacy and safety of nintedanib 150 mg bid over 52 weeks in 
patients with PF-ILD.
The primary endpoint is the annual rate of decline in FVC estimated from readings taken over 
52 weeks. The annual rate of decline in FVC will be analysed using a random coefficient 
regression (random slopes and intercepts) model including baseline FVC in mL and HRCT 
pattern (except for the analyses on the co-primary population assessing only patients with 
HRCT with UIP-like fibrotic pattern only) as covariates.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The superiority of nintedanib 150 mg bid compared to placebo will be tested for the annual 
rate of decline in FVC in mL.
For the overall population, the null hypothesis is:
H0: There is no difference in the annual rate of decline in FVC in mL between nintedanib 150 
mg bid and placebo in the overall population.
The alternative hypothesis is:
Ha: There is a difference in the annual rate of decline in FVC in mL between nintedanib 150 
mg bid and placebo in the overall population.
For the co-primary population of patients with HRCT with UIP-like fibrotic pattern only, the 
null hypothesis is:
H0: There is no difference in the annual rate of decline in FVC in mL between nintedanib 150 
mg bid and placebo in the patients with HRCT with UIP-like fibrotic pattern only.
The alternative hypothesis is:
Ha: There is a difference in the annual rate of decline in FVC in mL between nintedanib 150 
mg bid and placebo in patients with HRCT with UIP-like fibrotic pattern only.
In order to maintain an overall type 1 error rate of 5%, a Hochberg procedure will be used 
(R97-1003). For the primary endpoint, statistical significance will be declared if the analyses 
in both co-primary populations are significant at the two-sided 5% level, or if the analyses in 
either co-primary population are statistically significant at the two-sided 2.5% level.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 82 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Overall population p<0.05
Overall population p<0.025
AND
OR
OR
Patients with HRCT with UIP-
like fibrotic pattern only p<0.05
Patients with HRCT with UIP-
like fibrotic pattern only 
p<0.025
Figure 7.2: 1
Scenarios for statistical significance using Hochberg procedure
PLANNED ANALYSES
7.3
The efficacy and safety analyses will be conducted on the treated set (TS), which consists of 
patients who are randomized to a treatment group and receive at least one dose of study 
medication. There will be two co-primary analysis populations: the first will comprise all 
patients from the treated set (the overall population); the second will comprise all patients
from the treated set with HRCT with UIP-like fibrotic pattern only.
The primary assessment of benefit-risk of nintedanib in patients with PF-ILD will be based 
on efficacy and safety data over 52 weeks (including data from part A only); assessments
performed within the first 52 weeks (time-windowing rules will be defined in the TSAP) will 
be used.
The primary analysis is a random coefficient regression (random slopes and intercepts) model 
including baseline FVC (mL) and HRCT pattern (except for the analyses on the co-primary 
analysis population assessing only patients with HRCT with UIP-like fibrotic pattern only) as 
covariates.
Efficacy and safety data over the whole trial (including data from part A and part B) will be 
reported descriptively only. Data collected in Part B of the trial and available at the time of 
the primary analysis data cut-off will be reported after the first database lock. Selected
analyses will be repeated after the final database lock and will include data collected until the 
end of the trial.
All analyses will be based on the treatment group (nintedanib 150 mg bid or placebo) as 
randomized by IRT.
Although there is no per protocol data set in the study, reasons for important protocol 
violations will be specified in the Trial Statistical Analysis Plan (TSAP). Patients with 
important protocol violations will be identified at Blinded Review Planning Meetings and 
listed in the CTR.
7.3.1
Primary endpoint analyses
The primary endpoint is defined in Section 5.1.1.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 83 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Baseline FVC in mL will be included as a covariate in the analysis model. Baseline FVC is 
defined as the FVC result recorded at Visit 2, unless missing in which case the screening 
result will be used. The HRCT pattern (“UIP-like fibrotic pattern only” or “Other fibrotic 
patterns”) will also be used as a covariate for the analysis performed on the overall 
population and will not be a covariate for the analysis on the co-primary population assessing 
only patients with HRCT with UIP-like fibrotic pattern only. The primary analysis will also 
be performed on the complementary population of patients with other HRCT fibrotic 
patterns. A forest plot will present the three placebo-corrected, adjusted annual rates of 
decline in FVC with 95% confidence intervals from the analyses on the co-primary 
populations and on the complementary subgroup population.
The decrease in FVC is assumed to be linear within each subject over 52 weeks; this was also 
assumed in the IPF trials INPULSIS-1 and INPULSIS-2 (P14-07514). The intercepts and 
slopes will be assumed to be normally distributed with arbitrary covariance matrix. The 
within patient error will be assumed to be independent and normally distributed with mean 
zero and a common variance. The Kenward-Roger approximation will be used to estimate 
denominators degrees of freedom. Significant tests will be based on least-squares means; p-
values and two-sided 95% confidence intervals for the difference between the treatment 
groups will be presented. An intent-to-treat principle will be used (i.e. all available data from 
the treated set within the first 52 weeks will be used, including baseline and data retrieved 
post treatment discontinuation for patients who prematurely discontinued randomized
treatment). Analyses will be implemented using SAS® Version 9.4 or higher. 
The assumptions for the primary analysis of decline in FVC will be tested; details will be 
provided in the TSAP. The primary analysis will be based on observed data (but including 
retrieved drop out measurements) and will assume remaining missing data are missing at 
random. The effect of missing data will be investigated using multiple imputation methods 
which assume that patients who discontinue treatment will no longer benefit from it in the 
future. See Section 7.5.1 for further details of these sensitivity analyses.
Subgroup analyses will be specified in the TSAP and will include:
∀
Age
∀
Gender
∀
Original diagnosis (e.g. IIP; CTD-ILD; other ILDs)
A cumulative distribution plot will be provided, showing the percentage of patients by the 
change from baseline in FVC in mL at Week 52.
Data will be summarized graphically and using summary statistics.
7.3.2
Secondary endpoint analyses
Secondary endpoints are defined in Section 5.1.2.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 84 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
For all secondary endpoints, an intent-to-treat principle will be used (i.e. all available data
from the treated set within the first 52 weeks will be used, including data for patients who 
prematurely discontinued randomized treatment).
Continuous endpoints will be analysed using a restricted maximum likelihood (REML) based 
repeated measures approach. Analyses will include the fixed, categorical effects of HRCT 
pattern (except for the analyses on the co-primary analysis population assessing only patients 
with HRCT with UIP-like fibrotic pattern only), treatment, visit, and treatment-by-visit 
interaction, as well as the continuous, fixed covariates of baseline and baseline-by-visit 
interaction. An unstructured (co)variance structure will be used to model the within-patient 
measurements.
If this analysis fails to converge, the following covariance structures will be tested in order: 
heterogeneous toeplitz (TOEPH), toeplitz (TOEP) and autoregressive 1 (AR[1]). The first 
model to converge will be used. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. Significance tests will be based on least-squares means 
using a two-sided α = 0.05 (two-sided 95% confidence intervals). In case the model fails to 
converge under PROC MIXED, the “singular” option will be considered. The treatment 
comparisons will be the contrast between treatments at week 52. 
Time-to-event endpoints will be analysed using a Cox proportional hazards model. The 
equality of the hazard rates will be tested by the Wald test for the treatment effect at the two-
sided 5% significance level. The model will include the treatment effect and HRCT pattern
(except for the analyses on the co-primary analysis population assessing only patients with 
HRCT with UIP-like fibrotic pattern only) as covariates. Breslow’s method for handling ties 
will be used. Kaplan-Meier plots by treatment group will also be presented. If the proportion 
of patients experiencing at least 1 acute ILD exacerbation over 52 weeks is less than 2%, then 
only frequencies of exacerbations by treatment group will be provided for the main secondary 
endpoint of time to first acute ILD exacerbation or death over 52 weeks and no statistical 
analysis will be performed. 
Comparisons between treatment groups regarding the binary endpoint variables based on 
categorical declines in FVC % predicted (% pred) will be performed using a logistic 
regression model adjusting for the continuous covariate baseline FVC % pred and the binary 
covariate HRCT pattern (except for the analyses on the co-primary analysis population 
assessing only patients with HRCT with UIP-like fibrotic pattern only). The likelihood-ratio 
test will be used to test for differences between treatments. Adjusted odds ratios together with 
95% confidence intervals will be used to quantify the effect of treatment, comparing 
nintedanib 150 mg bid to placebo as the reference.
Any p-values presented for the secondary endpoints will be considered nominal in nature and 
no adjustment for multiplicity will be made.
7.3.3
Further endpoint analyses
All further endpoints will be considered exploratory in nature.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 85 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
The analysis of further endpoints over 52 weeks will be performed with the same models and 
procedures as described for the secondary endpoints in Section 7.3.2.
Further time to event endpoints over the whole trial will be analysed in a descriptive manner. 
Frequency tables and Kaplan-Meier plots will be produced.
7.3.4
Safety analyses
The primary assessment of benefit-risk of nintedanib in patients with PF-ILD will be based 
on efficacy and safety data over 52 weeks (using data from Part A of the trial). All safety 
assessments described below will focus on data collected within the first 52 weeks of the 
study. In addition, selected safety analyses will be repeated to include data collected beyond 
52 weeks (during Part B of the trial); further details will be specified in the TSAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. 
All treated patients will be included in the safety analysis for the overall population and the 
safety analysis will be repeated for the co-primary population of patients with HRCT with 
UIP-like fibrotic pattern only. In general, safety analyses will be descriptive in nature and 
will be based on BI standards. No hypothesis testing is planned.
Kaplan-Meier plots will be produced for the time to premature treatment discontinuation, for 
the time to first dose reduction and for the time to first treatment interruption.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’. The residual effect 
period is defined as the 28 days after the date of the last dose of trial medication. Adverse 
events that start before first drug intake and deteriorate under treatment will also be 
considered ‘treatment-emergent’. Based on the half-life of the study drug, the medical 
residual effect period is 7 days after the last dose of trial medication. Therefore, additional 
analysis of safety data will be made for adverse events that occur between the start of 
treatment and up to 7 days after the date of the last dose of trial medication will be analysed 
in addition.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of MedDRA.
Summary tables will be produced for the adjudication results of MACE and deaths.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 86 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the treatment and at the end-of-treatment evaluation will be 
assessed with regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic analyses
Pre-dose plasma concentrations (Cpre,ss) of nintedanib will be tabulated with descriptive 
statistics in the CTR. For pharmacokinetic analysis and displays, concentrations will be used 
in the same format as reported in the bio-analytical report. Only concentrations within the 
validated concentration range will be used and these will be reported using actual sampling 
times.
INTERIM ANALYSES
7.4
No interim analysis is planned but the conduct of the trial will be monitored by a DMC until 
the primary analysis is performed. The purpose, scope and tasks of the DMC are described in 
Section 3.1.1.
The primary assessment of benefit-risk of nintedanib in patients with PF-ILD will be based 
on efficacy and safety data over 52 weeks. The primary analysis will therefore be performed 
once the last patient reaches the Week 52 Visit (Part A: Visit 9).
HANDLING OF MISSING DATA
7.5
7.5.1
Efficacy Endpoints
The effect of missing data on the primary endpoint will be investigated using multiple 
imputation techniques.
For the primary endpoint, for each co-primary analysis population, the following subsets of 
patients will be defined:
1. Patients with an FVC result at week 52 who received trial medication until week 52.
2. Patients with an FVC result at week 52 who prematurely discontinued trial medication 
prior to week 52.
3. Patients without an FVC result at week 52 who were alive at week 52.
4. Patients without an FVC result at week 52 who died prior to week 52.
These four subsets of patients will be used in sensitivity analyses to estimate the treatment 
effect under differing assumptions around the persistence of efficacy after withdrawal of trial 
medication. Table 7.5.1: 1 describes the planned sensitivity analyses for handling missing 
primary endpoint data. Sensitivity analyses 1 and 2 will only be performed if there are at least 
10 patients included in patient subset 2 in each treatment group.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 87 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 7.5.1: 1
Sensitivity analyses for handling missing primary endpoint data
Analysis
Patient subset 3: No FVC result but 
alive at Week 52
Patient subset 4: No FVC result and 
died prior to Week 52
Handling of 
missing 
FVC result
Underlying 
assumption
Handling of 
missing 
FVC result
Underlying assumption
Primary 
analysis
Missing data 
handled by 
model.
Assumes missing at 
random. Discontinued 
patients would have 
behaved similarly to 
patients who did not 
discontinue.
Missing data 
handled by 
model.
Assumes missing at 
random. Discontinued 
patients would have 
behaved similarly to 
patients who did not 
discontinue.
Sensitivity 
analysis 1
Based on the 
slope 
estimates for 
drug and 
placebo in 
patient 
subset 2.
Patients without a result 
would have behaved 
similarly to 
discontinued patients 
with a result who are in 
the same treatment 
group.
Based on the 
slope 
estimates for 
placebo 
patients in 
patient 
subset 2, but 
truncated so 
that those 
who died are 
more severe.
Patients who died before 
week 52 would have 
behaved in a similar or 
worse way to a placebo 
patient who prematurely 
discontinued.
Sensitivity 
analysis 2
Based on the 
slope 
estimates for 
placebo in 
patient 
subset 2.
Patients without a result 
would have behaved 
similarly to 
discontinued placebo 
patients with a result.
Sensitivity 
analysis 3
Based on the 
slope 
estimates for 
placebo in 
patient 
subsets 1 and 
2.
Patients without a result 
would have behaved 
similarly to placebo 
patients with a result 
regardless of whether 
they prematurely 
discontinued treatment 
or not.
Based on 
slope 
estimates for 
placebo 
patients in 
subsets 1 and 
2, but 
truncated so 
those who 
died are 
more severe.
Patients who died before 
week 52 would have 
behaved in a similar or 
worse way to a placebo 
patient regardless of 
whether they prematurely 
discontinued treatment or 
not.
Further sensitivity analyses will be described in detail in the TSAP.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 88 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
In the analysis of all other continuous endpoints, missing data will not be imputed. The mixed 
effect model will handle missing data based on a likelihood method under the "missing at 
random assumption".
In the analysis of time-to-event endpoints, missing or incomplete data will be handled using 
standard survival analysis techniques (i.e. censoring). Efficacy time-to-event endpoints will 
be calculated from the randomization date. 
In the analyses of the categorical endpoints, missing data will be imputed using the worst 
case.
7.5.2
Safety
Missing or incomplete AE dates will be imputed according to BI standards. Other missing 
safety data will not be imputed.
7.5.3
Plasma concentrations
Descriptive statistics of concentrations at specific time points will be calculated only when at 
least 2/3 of the individuals have concentrations within the validated concentration range. The 
overall sample size to decide whether the “2/3 rule” is fulfilled will be based on the total 
number of samples intended to be drawn for that time point (i.e. BLQ, NOR, NOS, and NOA 
are included).
RANDOMIZATION
7.6
Within each randomization HRCT pattern stratum (“UIP-like fibrotic pattern only” or “Other 
fibrotic patterns”), patients will be randomized in blocks to double-blind treatment in a 1:1 
ratio. Approximately equal numbers of patients will be randomized to each treatment group. 
The randomization system will include caps for the two HRCT pattern strata so that 
approximately two thirds of the patients are randomized to the “UIP-like fibrotic pattern
only” stratum and one third is randomized to the “Other fibrotic patterns” stratum (i.e.
approximately 400 and 200 patients to each stratum, respectively). As a consequence of these 
caps randomization might be put on hold in one stratum temporarily and may mean that 
screened patients cannot be randomized immediately.
The Sponsor will arrange for the randomization and the packaging and labelling of trial
medication. The randomization list will be generated using a validated system, which 
involves a pseudo-random number generator so that the resulting treatment will be both 
reproducible and non-predictable. The block size will be documented in the CTR. Access to 
the codes will be controlled and documented.
DETERMINATION OF SAMPLE SIZE
7.7
Lack of published data from randomized clinical trials in patients with PF-ILD leads to 
uncertainty both on the rate of forced vital capacity (FVC) decline and on its variability in the 
planned study population.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 89 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
The main assumption of the study is that patients with PF-ILD, independent from their 
original ILD classification, at some point in time, exhibit a progressive fibrosing phenotype. 
In this group of patients with PF-ILD, the disease behaviour over time (e.g. lung function, 
mortality) appears to follow a course similar to IPF, a typical example of PF-ILD.
Based on the existing literature for IPF, the observed mean values for the annual rate of 
decline in FVC or the FVC change from baseline to 45–52 weeks in patients treated with 
placebo was approximately between 140 mL and 250 mL (see Section 10.5).
The currently available data in different ILDs show that the ILD injury pattern, in particular
the presence of UIP, is associated with worse prognosis (P11-07084, R10-6539, R16-0554, 
R15-3264, R16-1567, R14-3529, R16-0752, R16-1568). Based on this, the study will be 
enriched for patients with UIP pattern. UIP pattern will be defined based on HRCT using the 
same HRCT criteria as in the Phase III IPF trials for nintedanib (P15-04977, P15-05695) and 
described in Section 1.1. Since these criteria differ slightly from the current definition of 
radiologic UIP provided in the ATS/ERS guidelines (P11-07084), patients with screening 
HRCT meeting the protocol criteria for UIP will be referred to as “patients with HRCT with 
UIP-like fibrotic pattern only”. Patients with HRCT patterns not meeting the protocol criteria 
for UIP will be referred to as “patients with other HRCT fibrotic patterns”. 
For scenario planning for the sample size calculation, a rate of decline of 150-200 mL/year 
has been assumed for PF-ILD patients with HRCT with UIP-like fibrotic pattern only. For the 
patients with other HRCT fibrotic patterns, the FVC rate of decline is assumed to be slightly 
lower than in PF-ILD patients with HRCT with UIP-like fibrotic pattern only: between 120 
and 150 mL/year.
Nintedanib is hypothesized to have the same relative effect on all patients with PF-ILD (an 
approximate 50% reduction in the annual rate of decline in FVC). However it is expected that 
the absolute effect difference between groups will be the largest in the patients with HRCT 
with UIP-like fibrotic pattern only since these patients are assumed to have a larger annual 
rate of decline than patients with other HRCT fibrotic patterns.
The treatment effect to detect is therefore in the range of 75-100 mL/year for the PF-ILD 
patients with HRCT with UIP-like fibrotic pattern only and of 60-75 mL/year in the PF-ILD 
patients with other HRCT fibrotic patterns.
Given some expected heterogeneity in the rate of decline across the PF-ILD subpopulations, 
the variability is assumed to be larger than in IPF for patients with other HRCT fibrotic 
patterns with a standard deviation (SD) of 400 mL/year. For patients with HRCT with UIP-
like fibrotic pattern only, a more homogeneous group of patients, the variability is assumed to 
be the same as observed in IPF with a SD of 300 mL/year.
By enrichment, it is planned to recruit 400 PF-ILD patients with HRCT with UIP-like fibrotic 
pattern only, making up two thirds (66.7%) of the study population. This design will be used 
in order to maintain a high power to detect a clinically meaningful effect of nintedanib in the 
rare disease of PF-ILD.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 90 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
There will be two co-primary analysis populations: the first will comprise all patients (the 
overall population); the second will comprise all patients with HRCT with UIP-like fibrotic 
pattern only. Since establishing an effect in either of these two populations is considered 
clinically relevant, the trial will be considered positive if it establishes efficacy in either one 
of the two populations or in both.
In order to maintain an overall type 1 error rate of 5%, a Hochberg procedure will be used 
(R97-1003). This multiplicity adjustment strongly controls the overall Type I error rate in 
clinical trials with a targeted subpopulation (R16-1041). For the primary endpoint, statistical 
significance will be declared if the analyses in both co-primary populations are significant at 
the two-sided 5% level, or if the analyses in either co-primary population are statistically 
significant at the two-sided 2.5% level. Given the proposed design properties it is calculated 
that applying this procedure, the overall alpha spent will be 4.35% so the overall Type I error 
control is below 5%. This is based upon the summation of the probabilities of rejecting H0
under various combinations of results for the co-primary populations within the Hochberg 
procedure (calculated using SAS® Version 9.4, see Appendix 10.6 for details).
Table 7.7: 1 below presents the power properties of this study for several scenarios for the 
treatment effect in the two co-primary populations.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 91 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 7.7: 1:
Power properties for several scenarios for the treatment effect in the 
two co-primary populations 
Patients with 
HRCT with UIP-
like fibrotic 
pattern only 
Co-primary
Patients with 
other HRCT
fibrotic patterns
Overall patient 
population
Co-primary
Scenario 1
Assumed treatment difference in absolute 
change in FVC in mL/year (SD)
100 (300)
75 (400)
92 (337)
Individual test power
90.2%
90.3%
Overall Power*
92.6%
Scenario 2
Assumed treatment difference in absolute 
change in FVC in mL/year (SD)
75 (300)
60 (400)
70 (337)
Individual test power
67.2%
68.2%
Overall Power*
72.4%
Scenario 3
Assumed treatment difference in absolute 
change in FVC in mL/year (SD)
75 (300)
75 (400)
75 (337)
Individual test power
68.2%
73.4%
Overall Power*
75.8%
FVC, forced vital capacity; SD, standard deviation.
Power calculations are based on Hochberg procedure at the overall type 1 error rate of 5% (two-sided), with 200 patients with HRCT with 
UIP-like fibrotic pattern only and 100 patients with other HRCT fibrotic patterns per treatment group.
*The overall power is the probability of concluding statistical significance for either of the co-primary populations.
Power calculated using SAS® Version 9.4 (see Appendix 10.6 for details)
Drop-out is not accounted for in the sample size calculation since all patients from the treated 
set are expected to have sufficient data to be included in the primary analysis.
With a sample size of 300 patients randomized per treatment group, and 600 patients in total 
including 400 patients with HRCT with UIP-like fibrotic pattern only and using a Hochberg 
procedure, there will be:
∀
more than 90% power to detect a treatment effect of 100 mL/year assuming a standard 
deviation of 300 mL/year in the patients with HRCT with UIP-like fibrotic pattern 
only ,
∀
more than 90% power to detect a treatment effect of 92mL/year  assuming a standard 
deviation of 337 mL/year in the overall population, and


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 92 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
∀
more than 90% overall power (probability to conclude significance for the overall 
population or for the patients with HRCT with UIP-like fibrotic pattern only )
In fact with this sample size and study design, even in the scenario assuming the lowest rate 
of FVC declines for the patients with HRCT with UIP-like fibrotic pattern only and for the 
patients with other HRCT fibrotic patterns (scenario 2), there will be almost  80% overall 
power to detect an effect of nintedanib.
The proposed sample size will therefore provide adequate power to demonstrate a clinically 
important treatment benefit on the primary endpoint even in scenarios where the annual rate 
of decline in both PF-ILD co-primary patient populations is much lower than observed for 
IPF patients in the Phase III IPF trials.
In general, no key secondary endpoints are planned for the trial since there is no data in the 
published ILD literature on which to base assumptions for treatment effect and power for the 
proposed main secondary endpoints. However, the endpoints defined as main secondary are 
those which are considered most relevant to the assessment of the effect of nintedanib in PF-
ILD. These endpoints will provide the main supportive evidence to the primary endpoint 
assessment.
The mortality rate in PF-ILD is anticipated to be similar to IPF (R15-3264, R16-0554). Power 
calculations based on the mortality rate expected and later observed in the IPF trials with
nintedanib indicated that for demonstrating a statistically significant treatment benefit for 
nintedanib in all-cause mortality approximately 6,000 patients would be required for a 
placebo-controlled trial of 52-week duration in IPF (P14-06844). The current study in PF-
ILD is powered for the primary endpoint, annual rate of decline in FVC with a total sample 
size of 600 patients. The study is therefore not powered to demonstrate a statistically 
significant reduction in mortality over 52 weeks. However, all-cause mortality as a main 
secondary endpoint will provide further clinically meaningful information on the effect of 
nintedanib in PF-ILD.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 93 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) 
and the harmonized standards for Medical Devices (ISO 14155-01 and ISO 14155-02).
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), and 
relevant regulations
and the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, 
March 27, 1997).
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP
and the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28,
March 27, 1997).
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the Sponsor
with regard to publication of the results of this trial are described in the Investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
For Japan:
The rights of the Investigator / trial site and of the Sponsor with regard to publication of the 
results of this trial are described in the Investigator contract / trial site’s contract. As a 
general rule, no trial results should be published prior to finalization of the Clinical Trial 
Report.
The certificate of insurance cover is made available to the Investigator and the patients, and 
is stored in the ISF (Investigator Site File).”
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 94 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
For Japan:
The Investigator must give a full explanation to trial patients based on the patient 
information form. A language understandable to the patient should be chosen, technical 
terms and expressions avoided, if possible. The patient must be given sufficient time to 
consider participation in the trial. The Investigator obtains written consent of the patient’s 
own free will with the informed consent form after confirming that the patient understands 
the contents. 
The Investigator must sign (or place a seal on) and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
RECORDS
8.3
eCRF for individual patients will be provided by the Sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
All data must be derived from source documents.
Source documents in addition to the patient file are:


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 95 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
∀
Originals or copies of HRCT results
∀
Lung function test results
∀
Laboratory reports
∀
Resting ECG results (original or copies of printouts)
∀
DLCO results
∀
Patient reported outcome forms 
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all eCRF, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
the national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For nintedanib this is the current version of the Investigator’s Brochure nintedanib in IPF for 
more details.
8.4.2
Expedited reporting to health authorities and IEC / IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IEC / IRB, will be done according to local 
regulatory requirements.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 96 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
END OF TRIAL
8.6
The end of the trial is defined as last patient out. The Last Patient Last Visit Primary 
Endpoint (LPLVPE) is defined as the date when the last randomized patient reaches the 
Week 52 Visit (Visit 9 at the end of Part A). 
For EU member states:
The IEC / competent authority in each participating EU member state needs to be notified 
about the end of the trial or early termination of the trial.
For Japan:
When the trial is completed, the Investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
Sponsor of the completion in writing.
PROTOCOL VIOLATIONS
8.7
Mandatory in Japan:
The Investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reason, the principal Investigator should prepare 
and submit the records explaining the reasons thereof to the Sponsor, and retain a copy of 
the records.
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY
Mandatory in Japan:
In the event of health injury associated with this trial, the Sponsor is responsible for 
compensation based on the contract signed by the trial site.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 97 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
9.
REFERENCES
PUBLISHED REFERENCES
9.1
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, 
Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, Johnson 
DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi 
G, Wanger J. Standardisation of spirometry. Eur Respir J 2005. 26(2):319-
338.
P10-13367
Overview of the FDA background materials for New Drug Application 
(NDA) 22-535, Esbriet (pirfenidone) for the treatment of patients with 
idiopathic pulmonary fibrosis (IPF) to reduce the decline in lung function.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMa
terials/Drugs /Pulmonary-
AllergyDrugsAdvisoryCommittee/UCM203081.pdf (access date: 19 
November 2010) (2010).
P11-07084
Raghu G, et al, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary 
Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary 
fibrosis: evidence-based guidelines for diagnosis and management. Am J 
Respir Crit Care Med 183 (6), 788 - 824 (2011).
P11-13635
Bois RM du, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, 
Lancaster L, Noble PW, Raghu G, Sahn SA, Szwarcberg J, Thomeer M, 
Valeyre D, King TE. Ascertainment of individual risk of mortality for 
patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 184 
(4), 459 - 466 (2011)
P12-09611
Bois RM du, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, 
King TE, Lancaster L, Noble PW, Sahn SA, Thomeer M, Valeyre D, Wells 
AU. Forced vital capacity in patients with idiopathic pulmonary fibrosis: test 
properties and minimal clinically important difference. Am J Respir Crit 
Care Med 184, 1382 - 1389 (2011)
P12-10347
Bois RM du, Nathan SD, Richeldi L, Schwarz MI, Noble PW. Idiopathic 
pulmonary fibrosis: lung function is a clinically meaningful endpoint for 
phase 3 trials. Am J Respir Crit Care Med 186 (8), 712 - 715 (2012)
P14-02860
Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Anti-fibrotic and 
anti-inflammatory activity of the tyrosine kinase inhibitor, nintedanib, in 
experimental models of lung fibrosis. J Pharmacol Exp Ther 349, 209 - 220 
(2014)
P14-06844
Richeldi L, Cottin V, Flaherty KR, Kolb M, Inoue Y, Raghu G, Taniguchi H, 
Hansell DM, Nicholson AG, Maulf F le, Stowasser S, Collard HR. Design of 
the Inpulsis trials: two phase 3 trials of nintedanib in patients with idiopathic 
pulmonary fibrosis. Respir Med 108 (7), 1023 - 1030 (2014)


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 98 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
P14-07514
Richeldi L, et al, INPULSIS Trial Investigators. Efficacy and safety of 
nintedanib in idiopathic pulmonary fibrosis. New England Journal of 
Medicine, published on May 18, 2014, doi: 10.1056/NEJMoa1402584 N 
Engl J Med 2014. 370(22):2071-2082.
P14-07665
Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J 
Med 2014; 370: 2093–2101.
P14-17410
Hostettler KE, Zhong J, Papakonstantinou E, Karakiulakis G, Tamm M, 
Seidel P, Sun Q, Mandal J, Lardinois D, Lambers C, Roth M. Anti-fibrotic 
effects of nintedanib in lung fibroblasts derived from patients with idiopathic 
pulmonary fibrosis. Respir Res (Lond) 15, 157 (2014)
P15-02392
Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, Kolb 
M. Mode of action of nintedanib in the treatment of idiopathic pulmonary 
fibrosis. Eur Respir J 45 (5), 1434 - 1445 (2015)
P15-04977
Raghu G, Wells A, Nicholson AG, Richeldi L, Flaherty KR, Maulf F le, 
Stowasser S, Schlenker-Herceg R, Hansell DM. Consistent effect of 
nintedanib on decline in FVC in patients across subgroups based on HRCT 
diagnostic criteria: results from the INPULSIS trials in IPF. ATS 2015, 111th 
Int Conf of the American Thoracic Society (ATS), Denver, 15 - 20 May 2015 
(Poster)
P15-05695
Raghu G, Wells A, Nicholson AG, Richeldi L, Flaherty KR, Maulf F le, 
Stowasser S, Schlenker-Herceg R, Hansell DM. Consistent effect of 
nintedanib on decline in FVC in patients across subgroups based on HRCT 
diagnostic criteria: results from the INPULSIS trials in IPF. ATS 2015, 111th 
Int Conf of the American Thoracic Society (ATS), Denver, 15 - 20 May 2015 
(Oral Presentation)
P15-06100
Huang J, Beyer C, Palumbo-Zerr K, Zhang Y, Ramming A, Distler A, Gelse 
K, Distler O, Schett G, Wollin L, Distler JHW. Nintedanib inhibits fibroblast 
activation and ameliorates fibrosis in preclinical models of systemic 
sclerosis. Ann Rheum Dis 75 (5), 883 - 890 (2016)
P15-06701
Hansell DM, Goldin JG, King TE, Lynch DA, Richeldi L, Wells AU. CT 
staging and monitoring of fibrotic interstitial lung diseases in clinical practice 
and treatment trials: a position paper from the Fleischner Society. Lancet 
Respir Med 3, 483 - 496 (2015)
P16-06899
Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, et al. 
Acute exacerbation of idiopathic pulmonary fibrosis: an international 
working group report. Am J Respir Crit Care Med, (2016)
R06-2002
Macintyre N, Crapo RO, Viegi G, Johnson DC, Grinten CPM van der, 
Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, Gustafsson P, 
Hankinson J, Jensen R, McKay R, Miller MR, Navajas D, Pedersen OF, 
Pellegrino R, Wanger J. Standardisation of the single-breath determination of 
carbon monoxide uptake in the lung. Eur Respir J 2005. 26(4):720-735.
R06-4126
Latsi PI, Bois RM du, Nicholson AG, Colby TV, Bisirtzoglou D, 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 99 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Nikolakopoulou A, Veeraraghavan S, Hansell DM, Wells AU. Fibrotic 
idiopathic interstitial pneumonia: the prognostic value of longitudinal 
functional trends. Am J Respir Crit Care Med 168, 531 - 537 (2003)
R06-4127
Collard HR, King TE, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. 
Changes in clinical and physiologic variables predict survival in idiopathic 
pulmonary fibrosis. Am J Respir Crit Care Med 168, 538 - 542 (2003)
R06-4129
Jegal Y, Kim DS, Shim TS, Lim CM, Lee SD, Koh Y, Kim WS, Kim WD, 
Lee JS, Travis WD, Kitaichi M, Colby TV. Physiology is a stronger predictor 
of survival than pathology in fibrotic interstitial pneumonia. Am J Respir Crit 
Care Med 171, 639 - 644 (2005).
R10-2727
Zappala CJ, Latsi PI, Nicholson AG, Colby TV, Cramer D, Renzoni EA, 
Hansell DM, Bois RM du, Wells AU. Marginal decline in forced vital 
capacity is associated with a poor outcome in idiopathic pulmonary fibrosis. 
Eur Respir J 35 (4), 830 - 835 (2010)
R10-4848
Common terminology criteria for adverse events (CTCAE): version 4.0 (NIH 
publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 2010), 
revised June 2010, reprinted June 2010). 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pd f 2010.
R10-6539
Flaherty KR, Mumford JA, Murray S, Kazerooni EA, Gross BH, Colby TV, 
Travis WD, Flint A, Toews GB, Lynch JP, Martinez FJ. Prognostic 
implications of physiologic and radiographic changes in idiopathic interstitial 
pneumonia. Am J Respir Crit Care Med 168, 543 - 548 (2003).
R12-3648
Richeldi L, Ryerson CJ, Lee JS, Wolters PJ, Koth LL, Ley BM, Elicker B, 
Jones KD, King TE, Ryu JH, Collard HR. Relative versus absolute change in 
forced vital capacity in idiopathic pulmonary fibrosis. Thorax 67, 407 - 411 
(2012)
R12-4171
Patel AS, Siegert RJ, Brignall K, Gordon P, Steer S, Desai SR, Maher TM, 
Renzoni EA, Wells AU, Higginson IJ, Birring SS. The development and 
validation of the King's Brief Interstitial Lung Disease (K-BILD) health 
status questionnaire. Thorax 67, 804 - 810 (2012).
R13-0580
Guidance for industry: enrichment strategies for clinical trials to support 
approval of human drugs and biological products (draft guidance (this 
guidance document is being distributed for comment purposes only), 
December 2012, clinical medical). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor
mation/Guida nces/UCM332181.pdf (access date: 11 February 2013) ; 
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER), Center for Devices and 
Radiological Health (CDRH) (2012)
R13-4145
Travis WD, et al, ATS/ERS Committee on Idiopathic Interstitial 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 100 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Pneumonias. An official American Thoracic Society/European Respiratory 
Society statement: update of the international multidisciplinary classification 
of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 188 (6), 
733 - 748 (2013)
R14-1149
Schmidt SL, Nambiar AM, Tayob N, Sundaram B, Han MK, Gross BH, 
Kazerooni EA, Chughtai AR, Lagstein A, Myers JL, Murray S, Toews GB, 
Martinez FJ, Flaherty KR. Pulmonary function measures predict mortality 
differently in IPF versus combined pulmonary fibrosis and emphysema. Eur 
Respir J 38 (1), 176 - 183 (2011)
R14-1150
Schmidt SL, Tayob N, Han MK, Zappala C, Kervitsky D, Murray S, Wells 
AU, Brown KK, Martinez FJ, Flaherty KR. Predicting pulmonary fibrosis 
disease course from past trends in pulmonary function. Chest, (2014)
R14-2103
King TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, 
Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer 
DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW, 
ASCEND Study Group. A Phase 3 Trial of Pirfenidone in Patients with 
Idiopathic Pulmonary Fibrosis. N Engl J Med 370 (22), 2083 - 2092 (2014).
R14-3529
Walsh SLF, Sverzellati N, Devaraj A, Keir GJ, Wells AU, Hansell DM. 
Connective tissue disease related fibrotic lung disease: high resolution 
computed tomographic and pulmonary function indices as prognostic 
determinants. Thorax 69 (3), 216 - 222 (2014)
R15-0845
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright 
PL, Hankinson JL, Ip MSM, Zheng J, Janet Stocks on behalf of the ERS 
Global Lung Function Initiative. Multi-ethnic reference values for spirometry 
for the 3 - 95 year age range: the global lung function 2012 equations: report 
of the Global Lung Function Initiative (GLI), ERS task force to establish 
improved lung function reference values. Eur Respir J 2012. 40(6):1324-
1343.
R15-1725
Lederer DJ, Bradford WZ, Fagan EA, Glaspole I, Glassberg MK, Glasscock 
KF, Kardatzke D, King TE, Lancaster LH, Nathan SD, Pereira CA, Sahn SA, 
Swigris JJ, Noble PW. Sensitivity analyses of the change in forced vital 
capacity in a phase 3 trial of pirfenidone for idiopathic pulmonary fibrosis. 
Chest, (2015).
R15-2073
Kubota M, Kobayashi H, Quanjer PH, Omori H, Tatsumi K, Kanazawa M, 
Clinical Pulmonary Functions Committee of the Japanese Respiratory 
Society. Reference values for spirometry, including vital capacity, in 
Japanese adults calculated with the LMS method and compared with 
previous values. Respir Invest 2014. 52(4):242-250.
R15-3262
Strand MJ, Sprunger D, Cosgrove GP, Fernandez-Perez ER, Frankel SK, 
Huie TJ, Olson AL, Solomon J, Brown KK, Swigris JJ. Pulmonary function 
and survival in idiopathic vs secondary usual interstitial pneumonia. Chest 
146 (3), 775 - 785 (2014).


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 101 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
R15-3264
Kim EJ, Elicker BM, Maldonado F, Webb WR, Ryu JH, Uden JH van, Lee 
JS, King TE, Collard HR. Usual interstitial pneumonia in rheumatoid 
arthritis-associated interstitial lung disease. Eur Respir J 35 (6), 1322 - 1328 
(2010)
R16-0496
Fernandez Perez ER, Swigris JJ, Forssen AV, Tourin O, Solomon JJ, Huie 
TJ, Oslon AL, Brown KK. Identifying an inciting antigen is associated with 
improved survival in patients with chronic hypersensitivity pneumonitis. 
Chest 144 (5), 1644 - 1651 (2013).
R16-0553
Hanak V, Golbin JM, Hartman TE, Ryu JH. High-resolution CT findings of 
parenchymal fibrosis correlate with prognosis in hypersensitivity 
pneumonitis. Chest 134 (1), 133 - 138 (2008).
R16-0554
Moua T, Zamora Martinez AC, Baqir M, Vassallo R, Limper AH, Ryu JH. 
Predictors of diagnosis and survival in idiopathic pulmonary fibrosis and 
connective tissue disease-related usual interstitial pneumonia. Respir Res 
(Lond) 15, 154 (2014).
R16-0557
Vourlekis JS, Schwarz MI, Cherniack RM, Curran-Everett D, Cool CD, 
Tuder RM, King TE, Brown KK. The effect of pulmonary fibrosis on 
survival in patients with hypersensitivity pneumonitis. Am J Med 116 (10), 
662 - 668 (2004)
R16-0560
Lynch DA, Godwin JD, Safrin S, Starko KM, Hormel P, Brown KK, Raghu 
G, King TE, Bradford WZ, Schwartz DA, Webb WR, Idiopathic Pulmonary 
Fibrosis Study Group. High-resolution computed tomography in idiopathic 
pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med 172 
(4), 488 - 493 (2005)
R16-0722
Schwartz MI, King TE, Interstitial lung disease. 5th ed. Shelton: People’s 
Medical Publishing House (2011).
R16-0752
Edey AJ, Davaraj AA, Barker RP, Nicholson AG, Wells AU, Hansell DM. 
Fibrotic idiopathic interstitial pneumonias: HRCT findings that predict 
mortality. EurRadiol 21 (8), 1586 - 1593 (2011)
R16-0756
Moguloc N, Brutsche MH, Bishop PW, Greaves SM, Horrocks AW, Egan JJ, 
Greater Manchester Pulmonary Fibrosis Consortium. Pulmonary function in 
idiopathic pulmonary fibrosis and referral for lung transplantation. Am J 
Respir Crit Care Med 164, 103 - 108 (2001)
R16-0818
Fischer A, et al, ERS/ATS Task Force on Undifferentiated Forms of CTD-
ILD. Anofficial European Respiratory Society/American Thoracic Society 
research statement: interstitial pneumonia with autoimmune features. Eur 
Respir J 46 (4), 976 - 987 (2015)
R16-1041
Wang SJ, O'Neill RT, Hung HMJ. Approaches to evaluation of treatment 
effect in randomized clinical trials with genomic subset. Pharm Stat 6 (3), 
227 - 244 (2007)
R16-1567
Walsh SLF, Wells AU, Sverzellati N, Devaraj A, Thusen J von der, Yousem 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 102 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
SA, Colby TV, Nicholson AG, Hansell DM. Relationship between 
fibroblastic foci profusion and high resolution CT morphology in fibrotic 
lung disease. BMC Med 13, 241 (2015)
R16-1568
Sumikawa H, Johkoh T, Colby TV, Ichikado K, Suga M, Taniguchi H, 
Kondoh Y, Ogura T, Arakawa H, Fujimoto K, Inoue A, Mihara N, Honda O, 
Tomiyama N, Nakamura H, Muller NL. Computed tomography findings in 
pathological usual interstitial pneumonia: relationship to survival. 
AmJRespirCritCareMed 177 (4), 433 - 439 (2008)
R16-2064
Flanagan JC. A research approach to improving our quality of life. Am 
Psychol 33, 138 - 147 (1978)
R16-2065
Burckhardt CS, Woods SL, Schultz AA, Ziebarth DM. Quality of life of 
adults with chronic illness: a psychometric study. Res Nurs Health 12, 347 -
354 (1989)
R16-2387
Wilson SR, Knowles SB, Mulligan M, Chausow A, Ayala E, Wise RA, et 
al. Relative and absolute reliability and other properties of the Asthma 
Impact on Quality of Life Scale (A-IQOLS) and Flanagan QOLS: results of 
the AQOLIS test-retest study. ATS 2016, 112th Int Conf of the American 
Thoracic Society (ATS), San Francisco, 13 - 18 May 2016
Am J Respir Crit Care Med 193, A2679, Abstr (2016)
R16-2388
Wilson S, Wise RA, Knowles SB, Huang Q, Wei CY, Castro M. 
Psychometric properties of the Asthma Impact on Quality of Life Scale (A-
IQOLS) and the Flanagan QOLS in adults with well-controlled 
asthma:baseline results in the LASST trial. ATS 2015, 111th Int Conf of the 
American Thoracic Society (ATS), Denver, 15 - 20 May 2015
Am J Respir Crit Care Med 191, A5189, Abstr (2015)
R16-2404
Flanagan JC. Measurement of quality of life: current state of the art. Arch 
Phys Med Rehabil 63 (2), 56 - 59 (1982)
R96-0690
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976. 16(1):31-41.
R96-2382
EuroQol - a new facility for the measurement of health-related quality of life. 
Health Policy 1990. 16:199-208.
R97-1003
Hochberg Y. A sharper bonferroni procedure for multiple tests of 
significance. Biometrika 75 (4), 800 - 802 (1988).
UNPUBLISHED REFERENCES
9.2
n00239669
 Evaluation of Nintedanib in preclinical model systems of 
systemic sclerosis. Study number Dist-GvHD-Tsk-1-Fra-2. 26 September 
2014. This was submitted to IND 124707 on January 15, 2015 (Sequence 
0001/Serial Number Not Applicable), Module 4.2.1.1.
n00247887
. Evaluation of the therapeutic efficacy of 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 103 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Nintedanib in a model of rheumatoid arthritis-associated intersitial lung 
disease. 11 Feb 2016.
U06-1451
 Dose-dependent effects of BIBF 1120 ES on bleomycininduced 
lung fibrosis in rats. 1 Jun 2006.
U06-1479
 Effect of 50 mg/kg BIBF 1120 ES on bleomycin-induced lung 
fibrosis in rats using a delayed treatment model. 14 Jun 2006.
U11-1225-02
: A 52 week, 
doubleblind, randomized, placebo-controlled trial evaluating the effect of 
BIBF 1120 administered at oral doses of 50 mg qd, 50 mg bid, 100 mg bid 
and 150 mg bid on Forced Vital Capacity decline during one year, in 
patients with Idiopathic Pulmonary Fibrosis, with optional active treatment 
extension until last patient out. Study 1199.30. 03 January 2012
U12-2066-01
 Effect of nintedanib (BIBF 1120) on silica-induced lung 
inflammation and fibrosis. 31 July 2012.
U12-2437-01
 Effect of nintedanib (BIBF 1120) on bleomycin-induced lung 
inflammation and fibrosis. 19 October 2012.
U13-2381-01
c02098775
: A 52 weeks, double blind,
randomized, placebo-controlled trial evaluating the effect of oral BIBF 
1120, 150 mg twice daily, on annual Forced Vital Capacity decline, in 
patients with Idiopathic Pulmonary Fibrosis (IPF). Study 1199.32. 08
April 2014
U13-2382-01
c02155574
: A 52 weeks, double blind,
randomized, placebo-controlled trial evaluating the effect of oral BIBF 
1120, 150 mg twice daily, on annual Forced Vital Capacity decline, in 
patients with Idiopathic Pulmonary Fibrosis (IPF). Study 1199.34. 08 
April 2014CTR 1199.34


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 104 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
10.
APPENDICES
LUNG FUNCTION CRITERIA
10.1
At Visit 2, FVC must fulfil the following criteria:
∀
≥ 45% of predicted normal
Predicted normal values will be calculated according to GLI (Global Lung Initiative) (R15-
0845, R15-2073). FVC % predicted is a key inclusion criterion and a secondary endpoint 
using the following demographic information: race, age, gender and height.
At Visit 2, DLCO must fulfil the following criteria:
∀
≥ 30% and <80% of predicted normal; corrected for Hb
For predicted normal values, different sites may use different prediction formulas, based on 
the method used to measure DLCO. In any case, the method used must be in compliance with 
the ATS/ERS guideline on DLCO measurements (R06-2002), and the prediction formula 
appropriate for that method. DLCO values will be adjusted for altitude, COHb (if applicable) 
and the most recent haemoglobin value. Raw data (gas mixture, equation used for prediction 
of normal, further adjustments made if so) must be traced.
Percent predicted DLCO corrected for haemoglobin (Hb) expressed in g·dL-1 (R06-2002) 
can be calculated as:
∀
Percent predicted DLCO corrected for Hb = Percent predicted DLCO x 
(10.22+Hb)/(1.7Hb) for males 
∀
Percent predicted DLCO corrected for Hb = Percent predicted DLCO x 
(9.38+Hb)/(1.7Hb) for females 
For decision on inclusion / exclusion, percent predicted DLCO results from Visit 2 will be 
corrected for haemoglobin (value obtained at Visit 1) by the site.
For analysis of the trial data, percent predicted DLCO results will be corrected for 
haemoglobin by central data management. This means that the site has to enter the DLCO 
results without haemoglobin correction in the eCRF, at all visits.
There should be at least two acceptable tests that meet the repeatability requirement of either 
being within 3 mL CO (Standard Temperature and Pressure, Dry - STPD)•min-1 •mmHg-1 
(or 1 mmol•min-1•kPa-1) of each other or within 10% of the highest value.
CREATININE CLEARANCE
10.2
Creatinine clearance calculation is done according to Cockroft and Gault (R96-0690).
∀
Creatinine clearance = (140 - age) x (Weight in kg) x (0.85 if female) / (72 x serum 
creatinine in mg/dL)


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 105 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
PATIENT REPORTED OUTCOME QUESTIONNAIRES
10.3
10.3.1
K-BILD


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 106 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 107 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 108 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
10.3.2
L-PF Symptoms and Impact Questionnaire


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 109 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 110 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 111 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 112 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 113 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 114 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 115 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 116 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 117 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 118 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
10.3.3
EQ-5D


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 119 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 120 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 121 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
10.3.4
PF-IQOLS


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 122 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 123 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
HANDLING AND DERIVATION OF PHARMACOKINETIC 
10.4
PARAMETERS
10.4.1
Pharmacokinetic Methods
Concentrations will be used for calculations in the format that is reported in the bioanalytical 
report. The data format for descriptive statistics of concentrations will be identical with the 
data format of the respective concentrations. For the calculation of PK parameters, actual 
sampling times and only concentrations within the validated concentration range will be used. 
The descriptive statistics of PK parameters will be calculated using the individual values with 
the number of decimal places as provided by the evaluation program. Then, the individual 
values, as well as the descriptive statistics, will be reported with three significant digits in the 
clinical trial report. For pre-dose samples, the actual sampling time will be set to zero. 
Descriptive PK analyses will be carried out using Phoenix® WinNonlin® 6.3 (or later) 
and/or SAS® software, version 9.4 (or later).
Analyte plasma concentrations will be plotted graphically versus time for all subjects as listed 
in the analyte plasma concentration-time tables. For the presentation of the mean profiles, the 
geometric mean and the planned blood sampling times will be used.


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 124 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
FVC DECLINE RESULTS IN IPF TRIALS
10.5
Study
N treated 
placebo
FVC% pred 
at baseline 
Mean absolute change from 
baseline in FVC
Acetylcysteine
PANTHER (P14-07665)
131
73 % pred
Week 45 (observed):
-0.15 L 
Week 60 (MMRM):
-0.19 L (SD=0.31 L*)
Week 60 (observed):
-0.15 L
Pirfenidone
CAPACITY 004 (P10-
13367)
174
76 %pred
Week 48 (without imputation):
-179 mL
Pirfenidone
CAPACITY 006 (P10-
13367)
173
73 %pred
Week 48 (without imputation):
-141 mL
Pirfenidone
ASCEND (R15-1725, R14-
2103)
277
69 % pred
Week 52 (without imputation):
-256 mL
Nintedanib 
1199.30b (U11-1225-02)
85
82 % pred
Week 52 (observed cases):
-188 mL (SD = 365 mL)**
Nintedanib 
1199.32 (U13-2381-01)
204
81% pred
Week 52 (observed cases):
-202 mL (SD = 306 mL)
Nintedanib 
1199.34 (U13-2382-01)
219
78% pred
Week 52 (observed cases):
-204 mL (SD = 280 mL)
*SD was estimated based on the confidence interval
**FVC data were converted from L to mL by multiplying raw data by 1000


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 125 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
SAS CODE FOR SAMPLE SIZE CALCULATION
10.6
%MACRO PRBHOCH(a,b,d1,d2,sd1,sd2,f,n,dat);
**************************************************************************;
** a
= 1-sided Type 1 error used in powering                  
  **;
** b   = Type II error used in powering                              
  **;
** d1  = hypothesized overall treatment effect                   
  **;
** d2  = hypothesized subpopulation treatment effect       
  **;
** sd1 = assumed SD overall                                              
  **;
** sd2 = assumed SD subpopulation                                   
  **;
** f   = fraction in subpopulation                                        
**;
** n   = Planned sample size per treatment group                
  **; 
** dat = dataset name                                                          
**;
**************************************************************************; 
       
DATA x;
a=&a;  
b=&b;  
f=&f;  
d1=&d1;
sd1=&sd1;
d2=&d2;
sd2=&sd2;
n=&n;
ns=round(f*n,1);
r=sqrt(f);   ** correlation between subpopulation and overall population test statistics **; 
** under null using Hochberg**;
zhoc1= probit(1-0.025);       
zhoc2= probit(1-0.025/2);
** critical values for Hochberg**;
choc1025=   zhoc1*sd1*sqrt(2/n);
choc10125=  zhoc2*sd1*sqrt(2/n);
choc2025=   zhoc1*sd2*sqrt(2/ns);
choc20125=  zhoc2*sd2*sqrt(2/ns);
  
**under alternative Hochberg**;   
t1025=(choc1025-d1)/(sd1*sqrt(2/n));
t10125=(choc10125-d1)/(sd1*sqrt(2/n));
t2025=(choc2025-d2)/(sd2*sqrt(2/ns));
t20125=(choc20125-d2)/(sd2*sqrt(2/ns)); 
       
** Hochberg overall type 1 error**;    
phoc1025= PROBBNRM(-zhoc1,50000,r);
phoc10125= PROBBNRM(-zhoc2,50000,r);


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 126 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
phoc2025= PROBBNRM(-zhoc1,50000,r);
phoc20125= PROBBNRM(-zhoc2,50000,r);
phoc1025nphoc2025= PROBBNRM(-zhoc1,-zhoc1,r);
phoc10125nphoc2025= PROBBNRM(-zhoc2,-zhoc1,r); 
phoc20125nphoc1025= PROBBNRM(-zhoc1,-zhoc2,r); 
pp1 = phoc10125 - phoc10125nphoc2025;
pp2 = phoc20125 - phoc20125nphoc1025;
phoc1sig = phoc1025nphoc2025 + pp1;
phoc2sig = phoc1025nphoc2025 + pp2;
HocTy1 = phoc1sig + phoc2sig - phoc1025nphoc2025; * 1-sided Type 1 error;
       
** Hochberg overall power **;    
xhoc1025= PROBBNRM(-t1025,50000,r);
xhoc10125= PROBBNRM(-t10125,50000,r);
xhoc2025= PROBBNRM(-t2025,50000,r);
xhoc20125= PROBBNRM(-t20125,50000,r);
xhoc1025nxhoc2025= PROBBNRM(-t1025,-t2025,r);
xhoc10125nxhoc2025= PROBBNRM(-t10125,-t2025,r);
xhoc20125nxhoc1025= PROBBNRM(-t20125,-t1025,r); 
xx1 = xhoc10125 - xhoc10125nxhoc2025;
xx2 = xhoc20125 - xhoc20125nxhoc1025;
xhoc1sig = xhoc1025nxhoc2025 + xx1;  * Power for overall population test; 
xhoc2sig = xhoc1025nxhoc2025 + xx2;  * Power for sub-population test; 
HocPow = (xhoc1sig + xhoc2sig - xhoc1025nxhoc2025); * Overall power; 
       
run;   
       
PROC PRINT;      
RUN;   
       
data &dat;set x;
Dat="&dat";      
run;   
       
%MEND; 
          
%prbhoch(0.025,0.10,92,100,337,300,0.667,300 ,d1);
%prbhoch(0.025,0.10,70,75,337,300,0.667,300,d2);
%prbhoch(0.025,0.10,75,75,337,300,0.667,300,d3);
     
data all;set d1 d2 d3;
run;   
       
proc print data = all;   
run;


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 127 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
2.0
Date of CTP revision
08 Jun 2018
EudraCT number
2015-003360-37
BI Trial number
1199.247
BI Investigational Product(s)
Nintedanib 
Title of protocol
A double blind, randomized, placebo-controlled 
trial evaluating the efficacy and safety of 
nintedanib over 52 weeks in patients with 
Progressive Fibrosing Interstitial Lung Disease 
(PF-ILD)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Synopsis
Description of change
Administrative changes, corrections and 
clarification.
Rationale for change
Add trial name ‘INBUILD®’
Section to be changed
I
II
Synopsis
Section 6.1(Visit Schedule)
Description of change
The trial will last until all patients completed the 
EOTB visit and the Follow-up Visit as applicable
Rationale for change
Clarification of end of trial
Section to be changed
Flowchart – Part A (Footnotes)
Description of change
EOTA should be done in cases of premature trial 
medication discontinuation during Part A of the 
study with a follow-up Visit (FU) 4 weeks later. A 
scheduled visit (V3-V9) can be skipped if EOTA or 
Follow-up Visit occurs within 4 weeks prior to 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 128 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
scheduled visits
Rationale for change
Clarification of visit conduct in case of premature 
medication discontinuation 
Section to be changed
Flowchart – Part A (Footnotes)
Description of change
Compliance / drug accountability at Visit 3 and 
Visit 5 to be performed only in case of dose 
reduction / increase
Rationale for change
Clarification what needs to be documented in 
regards of compliance / drug accountability
Section to be changed
Flowchart – Part A (Footnotes)
Description of change
For biomarker sampling, date and exact clock time 
of drug administration and blood sampling needs
not be recorded on the eCRF
Rationale for change
Clarification of inconsistency between CTP and 
eCRF
Section to be changed
Flowchart – Part B
Description of change
In case of premature discontinuation of study 
medication, EOTB should be done as soon as 
possible after last drug intake and a Follow-up 
Visit should be completed 4 weeks after EOTB. A 
scheduled visit can be skipped if EOTB or Follow-
up Visit occurs within 4 weeks prior to scheduled 
visits. For patients who complete the study 
regularly, EOTB should be scheduled after the 
Sponsor’s communication of the end of the trial. 
Only in case the patient does not roll-over in the 
separate open-label study a Follow-up Visit should 
be completed 4 weeks after EOTB. 
The specific time window for EOTB was removed, 
the time intervals for Visits X and Xa  corrected 
and the need for an IRT call included
Rationale for change
Clarification of conduct and timing of EOTB
Section to be changed
Section 1.1.1 (ILD Overview), Figure 1.1: 1
Description of change
IPAF stands for Interstitial Pneumonia with 
Autoimmune Features
Rationale for change
Correction 
Section to be changed
2.3 (Benefit risk assessment)
Description of change
According to changes in the recent IB versions, 
adverse drug reactions and risks of nintedanib 
treatment have been added. Patients with low body 
weight (<65 kg), Asian and female patients have a 


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 129 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
higher risk of elevations in liver enzymes. It was 
clarified that cases of drug-induced liver injury 
(DILI) have been observed with nintedanib 
treatment. The majority of patients presented with 
mild to moderate liver enzyme elevation, which 
was in most cases transient upon dose reduction or 
treatment discontinuation. However, severe DILI 
with fatal outcome has also been reported
Rationale for change
Clarification of inconsistency between IB and CTP
Section to be changed
Section 3.1 (Overall Trial Design and Plan)
Description of change
After the Sponsor has communicated the end of 
the trial, an EOTB visit has to be performed in all 
ongoing patients. Depending on the findings, 
patients receiving trial medication until the end of 
Part B will be eligible for open-label treatment 
with nintedanib in a separate study
Rationale for change
Clarification of the end of trial and roll-over into 
an open-label treatment
Section to be changed
Section 5.3.6.1 (Definitions of AEs)
Description of change
Potential DILI cases are defined as AESIs and a 
DILI checklist has to be worked off
Rationale for change
More detailed description of DILI handling
Section to be changed
Section 5.3.7 (Adverse event collection and 
reporting)
Description of change
All AEs (non-serious and serious) and all AESIs 
should be collected after the end of treatment
(including the Residual Effect Period until the 
individual patient’s end of trial. Figure 5.3.7: 1will 
be deleted as no longer applicable
Rationale for change
Clarification of AE documentation after end of 
treatment, with the goal to have all patients coming 
to the regular visits afterwards
Section to be changed
6.2.1 (Screening)
Description of change
Correct reference time point for historical HRCT 
within 12 month to Visit 1
Rationale for change
Correction for clarification and consistency with
Inclusion criterion
Section to be changed
Section 6.2.3 (Follow-up Visit and trial 
completion)
Description of change
A follow-up visit is only required for those 
patients who do not roll-over in the separate open-


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 130 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
label study
Rationale for change
To clarify by including new wording
Section to be changed
7.3.4 (Safety analyses)
Description of change
Clarification that based on the half-life of the trial 
drug, adverse events that occur between the start of 
treatment and up to 7 days after the date of the last 
dose of trial medication will be analysed in 
addition
Rationale for change
Specification of an additional adverse event 
analyses to take the half-life of the trial drug into 
account


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 131 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Number of global amendment
1.0
Date of CTP revision
21 Dec 2016
EudraCT number
2015-003360-37
BI Trial number
1199.247
BI Investigational Product(s)
Nintedanib 
Title of protocol
A double blind, randomized, placebo-controlled 
trial evaluating the efficacy and safety of 
nintedanib over 52 weeks in patients with 
Progressive Fibrosing Interstitial Lung Disease 
(PF-ILD)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flowchart A and footnote 
Section 5.5.3
Description of change
Serum banking changed from mandatory to 
optional
Rationale for change
To ensure that the trial can be conducted according 
to regulatory and ethical requirements in the 
participating countries 
Section to be changed
Flowchart B
Description of change
ECG will also be performed at EOT in Part B 
Rationale for change
To make sure that respective safety assessment is 
performed in Part B of the trial
Section to be changed
Appendix 10.1
Description of change
Correct criterion for FVC to >45% of predicted 
normal and delete <90%
Rationale for change
To align with inclusion criterion in Synopsis and 
Section 3.3.2
Section to be changed
Section 5.2.7.2


Boehringer Ingelheim
08 Jun 2018
BI Trial No.: 1199.247
c03736471-03
Trial Protocol
Page 132 of 132
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Description of change
Adapt scoring information for the different L-PF
domains
Rationale for change
Scoring instructions update for L-PF
Section to be changed
Section 5.3.7
Description of change
Update role of Adjudication Committee under AE 
reporting an collection
Rationale for change
To correct information provided for MACE 
Section to be changed
Section 7.3.1 
Description of change
The primary analysis will also be performed on the 
complementary population of patients with other 
HRCT fibrotic patterns
Rationale for change
To address FDA requirement
Section to be changed
Section 8.1
Description of change
Information highlighted in cursive for Japan 
regarding ICF procedures
Rationale for change
To adapt ICF handling for specific regulatory 
requirements in Japan
Section to be changed
Whole document
Description of change
Change naming of HRCT to high resolution 
computed tomography
Rationale for change
To use correct wording “computed” instead of 
“computer”


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03736471
3.0
clinical-trial-protocol-version-03
A double blind, randomized, placebo-controlled trial evaluating the efficacy and
safety of nintedanib over 52 weeks in patients with Progressive Fibrosing Interstitial
Lung Disease (PF-ILD)
Author-Trial Clinical Monitor
15 Jun 2018 08:48 CEST
Author-Trial Clinical
Pharmacokineticist
15 Jun 2018 10:26 CEST
Approval-Team Member Medicine
15 Jun 2018 16:10 CEST
Author-Trial Statistician
18 Jun 2018 10:53 CEST
Approval-Therapeutic Area 
20 Jun 2018 14:13 CEST
Verification-Paper Signature
Completion
22 Jun 2018 07:09 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03736471
3.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c11935728-03 
BI Trial No.: 
1199.247
Title:
A double blind, randomized, placebo-controlled trial evaluating the 
efficacy and safety of nintedanib over 52 weeks in patients with 
Progressive Fibrosing Interstitial Lung Disease (PF-ILD)
Including Protocol Amendment 2 [c03736471-03] 
Investigational 
Product: 
Nintedanib 
Responsible trial 
statisticians: 
Boehringer Ingelheim Pharma GmbH & Co. KG
Global BDS
Birkendorfer Straße 65 
88397 Biberach an der Riss 
Germany
Phone: 
+
Fax:  
+
Date of statistical 
analysis plan: 
14 DEC 2018 SIGNED
Version:
Final
Page 1 of 106 
Proprietary confidential information
¤ 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 2 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.
TABLE OF CONTENTS
TITLE PAGE ........................................................................................................................... 1 
1. 
TABLE OF CONTENTS...................................................................................... 2 
LIST OF TABLES ................................................................................................................... 7 
LIST OF FIGURES ................................................................................................................. 9 
2. 
LIST OF ABBREVIATIONS ............................................................................ 10 
3. 
INTRODUCTION ............................................................................................... 13 
4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY .................... 16 
4.1 
ADDITIONS / NEW ANALYSES ..................................................................... 16 
4.2 
CHANGES ........................................................................................................... 16 
4.3 
CLARIFICATIONS............................................................................................ 16 
5. 
ENDPOINTS ....................................................................................................... 20 
5.1 
PRIMARY ENDPOINT ..................................................................................... 20 
5.2 
SECONDARY ENDPOINTS ............................................................................. 20 
5.2.1 
Key secondary endpoints .................................................................................... 20 
5.2.2 
Secondary endpoints ........................................................................................... 20 
5.2.2.1 
Main secondary efficacy endpoints ....................................................................... 21 
5.2.2.1.1 
Absolute change from baseline in King’s Brief Interstitial Lung Disease 
Questionnaire (K-BILD) Total Score at 52 weeks ............................................... 21 
5.2.2.1.2 
Time to death over 52 weeks ................................................................................ 21 
5.2.2.1.3 
Time to first acute ILD exacerbation or death over 52 weeks .............................. 22 
5.2.2.2 
Other secondary efficacy endpoints ...................................................................... 23 
5.2.2.2.1 
Time to death due to respiratory cause over 52 weeks ......................................... 23 
5.2.2.2.2 
Time to progression or death over 52 weeks ........................................................ 24 
5.2.2.2.3 
Relative decline from baseline in FVC % pred at 52 weeks ................................. 25 
5.2.2.2.4 
Change from baseline in Living with Pulmonary Fibrosis Symptoms and 
Impact Questionnaire (L-PF) Dyspnea and Cough Domain Scores at week 52 ... 25 
5.3 
FURTHER ENDPOINTS ................................................................................... 26 
5.3.1 
Endpoints over 52 weeks .................................................................................... 26 
5.3.1.1 
Time to first non-elective hospitalisation or death over 52 weeks ....................... 26 
5.3.1.2 
Absolute change from baseline in FVC at week 52 .............................................. 27 
5.3.1.3 
Absolute decline from baseline in FVC % pred at week 52 ................................. 27 
5.3.1.4 
Absolute change from baseline in Carbon Monoxide Diffusion Capacity 
(DLCO) % pred over 52 weeks ............................................................................ 27 
5.3.1.5 
Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (L-PF) ... 28 
5.3.1.6 
Change from baseline in Pulmonary Fibrosis Impact on Quality of Life Scale 
(PF-IQOLS) summary score at week 52 ............................................................... 28 
5.3.2 
Endpoints over the whole trial ........................................................................... 29 
5.3.2.1 
Time to death over the whole trial ........................................................................ 29 
5.3.2.2 
Time to first acute ILD exacerbation or death over the whole trial ...................... 29 
5.3.2.3 
Time to first non-elective hospitalisation or death over the whole trial ............... 30 
5.3.2.4 
Time to death due to respiratory cause over the whole trial ................................. 31 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 3 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.3.2.5 
Time to progression or death over the whole trial ................................................ 32 
5.4 
OTHER VARIABLES ........................................................................................ 32 
5.4.1 
Demographics and baseline characteristics ...................................................... 32 
5.4.1.1 
Demographic data ................................................................................................. 32 
5.4.1.2 
Trial indication ...................................................................................................... 33 
5.4.1.3 
Baseline characteristics for lung function ............................................................. 34 
5.4.1.4 
Baseline characteristics for questionnaires and derived outcomes ....................... 34 
5.4.2 
Compliance .......................................................................................................... 34 
5.4.2.1 
Over 52 weeks ....................................................................................................... 34 
5.4.2.2 
Over the whole trial............................................................................................... 35 
5.4.3 
Exposure .............................................................................................................. 35 
5.4.3.1 
Over 52 weeks ....................................................................................................... 35 
5.4.3.2 
Over the whole trial............................................................................................... 38 
5.4.4 
Liver enzyme and bilirubin elevations .............................................................. 41 
5.4.5 
Marked changes in vital signs ............................................................................ 43 
6. 
GENERAL ANALYSIS DEFINITIONS .......................................................... 44 
6.1 
TREATMENTS ................................................................................................... 44 
6.1.1 
Over 52 weeks ...................................................................................................... 44 
6.1.2 
Over the whole trial ............................................................................................ 46 
6.2 
IMPORTANT PROTOCOL DEVIATIONS.................................................... 47 
6.3 
PATIENT SETS ANALYSED ........................................................................... 53 
6.4 
SUBGROUPS ...................................................................................................... 53 
6.5 
POOLING OF CENTRES ................................................................................. 54 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS .................................... 54 
6.6.1 
Primary endpoint ................................................................................................ 55 
6.6.2 
Secondary and further endpoints ...................................................................... 55 
6.6.2.1 
Change from baseline endpoints ........................................................................... 55 
6.6.2.1.1 
K-BILD ................................................................................................................. 55 
6.6.2.1.2 
L-PF ...................................................................................................................... 55 
6.6.2.1.3 
PF-IQOLS ............................................................................................................. 56 
6.6.2.2 
Time-to-event endpoints ....................................................................................... 56 
6.6.2.3 
Categorical endpoints ............................................................................................ 56 
6.6.3 
Other variables .................................................................................................... 56 
6.6.3.1 
Concomitant therapies........................................................................................... 56 
6.6.3.2 
Safety endpoints .................................................................................................... 56 
6.6.3.3 
Trial diagnosis date ............................................................................................... 56 
6.6.3.4 
Pharmacokinetic endpoints ................................................................................... 57 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS ................... 57 
7. 
PLANNED ANALYSIS ...................................................................................... 61 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......... 62 
7.2 
CONCOMITANT DISEASES AND MEDICATION ..................................... 62 
7.2.1 
Baseline conditions and cardiovascular medical history ................................. 62 
7.2.2 
Concomitant therapies ........................................................................................ 62 
7.3 
TREATMENT COMPLIANCE ........................................................................ 64 
7.4 
PRIMARY ENDPOINT ..................................................................................... 65 
7.4.1 
Primary analysis .................................................................................................. 65 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 4 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.4.2 
Sensitivity analyses .............................................................................................. 67 
7.4.2.1 
Sensitivity to data handling assumptions .............................................................. 68 
7.4.2.1.1 
Statistical model using on-treatment measurements only ..................................... 68 
7.4.2.1.2 
Sensitivity to missing data handling ..................................................................... 68 
7.4.2.2 
Sensitivity to the analysis model ........................................................................... 71 
7.4.2.2.1 
Sensitivity to linearity assumption ........................................................................ 71 
7.4.2.2.2 
Sensitivity to mis-stratification ............................................................................. 71 
7.4.3 
Subgroup analyses............................................................................................... 72 
7.5 
SECONDARY ENDPOINTS ............................................................................. 74 
7.5.1 
Key secondary endpoints .................................................................................... 74 
7.5.2 
Secondary endpoints ........................................................................................... 74 
7.5.2.1 
Main secondary efficacy endpoints ....................................................................... 74 
7.5.2.1.1 
King’s Brief Interstitial Lung Disease Questionnaire (K-BILD) Total Score ...... 74 
7.5.2.1.2 
Time to death ........................................................................................................ 74 
7.5.2.1.3 
Time to first acute ILD exacerbation or death ...................................................... 75 
7.5.2.2 
Other secondary efficacy endpoints ...................................................................... 75 
7.5.2.2.1 
Time to death due to respiratory cause ................................................................. 75 
7.5.2.2.2 
Time to progression or death ................................................................................ 75 
7.5.2.2.3 
Relative decline from baseline in FVC % pred..................................................... 75 
7.5.2.2.4 
Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (L-PF) ... 75 
7.6 
FURTHER ENDPOINTS ................................................................................... 76 
7.6.1 
Over 52 weeks ...................................................................................................... 76 
7.6.1.1 
Time to first non-elective hospitalisation or death ................................................ 76 
7.6.1.2 
Absolute change from baseline in FVC ................................................................ 76 
7.6.1.3 
Absolute decline from baseline in FVC % pred ................................................... 77 
7.6.1.4 
Carbon Monoxide Diffusion Capacity (DLCO) % pred ....................................... 77 
7.6.1.5 
Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (L-PF) ... 77 
7.6.1.6 
Pulmonary Fibrosis Impact on Quality of Life Scale (PF-IQOLS) ...................... 78 
7.6.2 
Over the whole trial ............................................................................................ 78 
7.6.2.1 
Time to first acute ILD exacerbation or death ...................................................... 78 
7.6.2.2 
Time to death ........................................................................................................ 78 
7.6.2.3 
Time to death due to respiratory cause ................................................................. 78 
7.6.2.4 
Time to progression or death ................................................................................ 78 
7.6.2.5 
Time to first non-elective hospitalisation or death ................................................ 79 
7.6.2.6 
Descriptive evaluations of lung function parameters ............................................ 79 
7.6.3 
Pharmacokinetics ................................................................................................ 79 
7.6.4 
Biomarkers .......................................................................................................... 79 
7.6.5 
Longitudinal HRCT assessments ....................................................................... 79 
7.7 
EXTENT OF EXPOSURE ................................................................................. 79 
7.7.1 
Over 52 weeks ...................................................................................................... 79 
7.7.2 
Over the whole trial ............................................................................................ 80 
7.8 
SAFETY ANALYSIS .......................................................................................... 80 
7.8.1 
Adverse events ..................................................................................................... 80 
7.8.1.1 
Over 52 weeks ....................................................................................................... 81 
7.8.1.2 
Over the whole trial............................................................................................... 82 
7.8.1.3 
Adjudicated adverse events ................................................................................... 83 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 5 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.8.1.4 
Adverse events with additional information collection ........................................ 83 
7.8.1.5 
Exposure adjusted analysis of adverse events ....................................................... 83 
7.8.2 
Laboratory data .................................................................................................. 84 
7.8.2.1 
Over 52 weeks ....................................................................................................... 84 
7.8.2.2 
Over the whole trial............................................................................................... 85 
7.8.3 
Vital signs ............................................................................................................. 85 
7.8.3.1 
Over 52 weeks ....................................................................................................... 85 
7.8.3.2 
Over the whole trial............................................................................................... 85 
7.8.4 
ECG ...................................................................................................................... 85 
7.8.5 
Others ................................................................................................................... 85 
8. 
REFERENCES .................................................................................................... 86 
9. 
ADDITIONAL SECTIONS ............................................................................... 88 
9.1 
K-BILD SCORING INSTRUCTIONS ............................................................. 88 
9.1.1 
Overview .............................................................................................................. 88 
9.1.2 
Scoring Algorithm ............................................................................................... 88 
9.2 
L-PF SCORING INSTRUCTIONS ................................................................... 91 
9.2.1 
Symptoms ............................................................................................................. 91 
9.2.1.1 
Dyspnea (items 1-12) ............................................................................................ 91 
9.2.1.2 
Cough (items 13-18) ............................................................................................. 91 
9.2.1.3 
Energy (items 19-23) ............................................................................................ 91 
9.2.1.4 
Symptoms Total Score .......................................................................................... 92 
9.2.2 
Impacts ................................................................................................................. 92 
9.2.2.1 
Dyspnea (items 1-6) .............................................................................................. 92 
9.2.2.2 
Cough (items 7-11) ............................................................................................... 92 
9.2.2.3 
Energy (items 13-14) ............................................................................................ 92 
9.2.2.4 
Global (items 12, 15-21) ....................................................................................... 92 
9.2.2.5 
Impacts Total Score .............................................................................................. 92 
9.3 
PF-IQOLS SCORING INSTRUCTIONS ......................................................... 92 
9.3.1 
Summary score .................................................................................................... 92 
9.4 
ADDITIONAL ANALYSES FOR REGIONAL SUBMISSIONS .................. 95 
9.5 
PROGRAMMING CODE FOR INFERENTIAL ANALYSIS ...................... 95 
9.5.1 
Primary endpoint model ..................................................................................... 95 
9.5.2 
Primary endpoint subgroup analysis model:.................................................... 96 
9.5.3 
Implementation of multiple imputation:........................................................... 96 
9.6 
SPECIAL ADAM COMPOSITION INSTRUCTIONS .................................. 97 
9.6.1 
ADEX ................................................................................................................... 97 
9.7 
LIST OF BI CUSTOMISED DRUG GROUPINGS OF INTEREST ............ 98 
9.8 
SPECIFICATION OF RESTRICTED AND FORBIDDEN 
CONCOMITANT THERAPIES ....................................................................... 99 
9.9 
LIST OF POTENTIAL TERMS FOR HEPATIC INJURY 
DERIVATION ..................................................................................................... 99 
9.10 
LIST OF PREFERRED TERMS INCLUDED IN STROKE 
PHARMACOVIGILANCE ENDPOINT ....................................................... 100 
9.11 
LIST OF TERMS FOR THE CATEGORISATION OF BLEEDING
EVENTS ............................................................................................................. 101 
9.12 
ADDITIONAL SENSITIVITY ANALYSES.................................................. 101 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 6 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.12.1 
Tipping point analysis ....................................................................................... 101 
9.13 
LIST OF UNDERLYING ILD GROUPINGS FOR “OTHER 
FIBROSING ILD” ENTRIES ......................................................................... 103 
10. 
HISTORY TABLE ............................................................................................ 106 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 7 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
LIST OF TABLES
Table 5.2.2.1.2: 1 Censoring Rules for Time to death over 52 weeks .................................. 21 
Table 5.2.2.1.3: 1 Censoring Rules for Time to first acute ILD exacerbation or death over 
52 weeks ........................................................................................................... 23 
Table 5.2.2.2.1: 1 Censoring Rules for Time to death due to respiratory cause over 52 
weeks ................................................................................................................ 24 
Table 5.2.2.2.2: 1 Censoring Rules for Time to progression or death over 52 weeks .......... 25 
Table 5.3.1.1: 1 
Censoring Rules for Time to first non-elective hospitalisation or death 
over 52 weeks ................................................................................................... 26 
Table 5.3.2.1: 1 
Censoring Rules for Time to death over the whole trial .......................... 29 
Table 5.3.2.2: 1 
Censoring Rules for Time to first acute ILD exacerbation or death over 
the whole trial ................................................................................................... 30 
Table 5.3.2.3: 1 
Censoring Rules for Time to first non-elective hospitalisation or death 
over the whole trial ........................................................................................... 31 
Table 5.3.2.4: 1 
Censoring Rules for Time to death due to respiratory cause over the 
whole trial ......................................................................................................... 31 
Table 5.3.2.5: 1 
Censoring Rules for Time to progression or death over the whole trial .. 32 
Table 5.4.3.1: 1 
Censoring Rules for Time to first dose reduction over 52 weeks ............ 36 
Table 5.4.3.1: 2 
Censoring Rules for Time to first treatment interruption over 52 weeks . 37 
Table 5.4.3.1: 3 
Censoring Rules for Time to premature treatment discontinuation over 
52 weeks ........................................................................................................... 38 
Table 5.4.3.2: 1 
Censoring Rules for Time to first dose reduction over the whole trial .... 39 
Table 5.4.3.2: 2 
Censoring Rules for Time to first treatment interruption over the whole 
trial 40 
Table 5.4.3.2: 3 
Censoring Rules for Time to premature treatment discontinuation over 
the whole trial ................................................................................................... 41 
Table 5.4.4: 1 Censoring Rules for Time to first liver enzyme elevation over 52 weeks ....... 42 
Table 5.4.4: 2 Censoring Rules for Time to first liver enzyme elevation over the whole 
trial .................................................................................................................... 43 
Table 6.1.1: 1 Summary of analysis periods over 52 weeks (Part A) according to the type 
of endpoint or analysis ...................................................................................... 45 
Table 6.1.2: 1 Summary of analysis periods over the whole trial (Part A and Part B) 
according to the type of endpoint or analysis ................................................... 46 
Table 6.2: 1 
Important protocol deviations ........................................................................... 47 
Table 6.4: 1 
Subgroup analyses – List of subgroups ............................................................ 54 
Table 6.7: 1 
Time windowing rules for spirometry (FVC), physical exam, vital signs ....... 58 
Table 6.7: 2 
Time windowing rules for K-BILD, L-PF, PF-IQOLs, SpO2 .......................... 58 
Table 6.7: 3 
Time windowing rules for DLCO .................................................................... 59 
Table 6.7: 4 
Time windowing rules for laboratory measurements (and pregnancy test) ..... 59 
Table 7.2.2: 1 Concomitant therapy outputs over 52 weeks. ................................................... 63 
Table 7.2.2: 2 Concomitant therapy outputs over the whole trial. ........................................... 64 
Table 7.4.2.1.2: 1 Primary and sensitivity analyses for handling of missing data ................ 70 
Table 7.4.3: 1 Subgroup analyses – List of analyses ............................................................... 73 
Table 7.8.1: 1 Protocol-specified AESI ................................................................................... 81 
Table 9.1.2: 1 K-BILD Response Option Weightings ............................................................. 88 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 8 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 9.1.2: 2 K-BILD Score Transformations ....................................................................... 89 
Table 9.4: 1 
Patient subset definitions for local regulatory submission in Asia ................... 95 
Table 9.7: 1 
Concomitant Therapy groupings ...................................................................... 98 
Table 9.7: 2 
DMARDS with known hepatotoxic or gastrointestinal effects ........................ 98 
Table 9.8: 1 
Prohibited or restricted concomitant therapies ................................................. 99 
Table 9.9: 1 
List of potentially relevant MedDRA preferred terms ..................................... 99 
Table 9.12.1: 1 Overview of the median adjustment in imputed FVC (mL) at week 52 .... 103 
Table 9.13: 1 Other Fibrosing ILD grouping ........................................................................ 104 
Table 10: 1 
History table ................................................................................................... 106 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 9 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
LIST OF FIGURES
Figure 3: 1 
Study design schematic of study 1199.247 followed by a separate open label 
extension trial 1199_0248 (optional): Part A is a fixed duration period of 52 
weeks, and Part B has variable duration for each patient. ................................ 14 
Figure 3: 2 
Patient level example of study design and trial part duration for an 
individual patient – including the time point when the benefit-risk analysis 
occurs (BRA). The blue area represents Part A of the study on patient level, 
and the subsequent part in the black area Part B. ............................................. 14 
Figure 9.3.1: 1 Part I of the PF-IQOLS Questionnaire. ............................................................ 93 
Figure 9.3.1: 2 Part II of the PF-IQOLS Questionnaire ............................................................ 94 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 10 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
2.
LIST OF ABBREVIATIONS 
Term
Definition / description
AC
Adjudication Committee
AE
Adverse event
ALK
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATS
American Thoracic Society
AZA
Azathioprine
BI
Boehringer Ingelheim
BicDQ
BI Customised Drug Queries
bid
bis in die
BRA
Benefit-Risk Assessment
BRPM
Blinded Report Planning Meeting
CDG
Customized Drug Groupings
COHb
Carboxyhaemoglobin
CT
Computed Tomography
CTD
Connective Tissue Disease
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DLCO
Carbon Monoxide Diffusion Capacity
DMARDs
Disease-Modifying Anti-Rheumatic Drugs
DNA
Desoxyribo Nucleic Acid
eCRF
electronic Case Report Form
EMA
European Medicines Agency
EOT
End of Treatment
ERS
European Respiratory Society (ERS)
FPI
First patient in (= first patient randomised)
FVC
Forced Vital Capacity
g
Gramm
Hb
Haemoglobin
HLT
High Level Term


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 11 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Term
Definition / description
HRCT
High-Resolution Computer Tomography
ICH
International Conference on Harmonisation
IIP
Idiopathic Interstitial Pneumonia
ILD
Interstitial Lung Disease
INR
International Normalized Ratio
IPD
Important Protocol Deviation
IPF
Idiopathic Pulmonary Fibrosis
IRT
Interactive Response Technology
K-BILD
King’s Brief Interstitial Lung Disease Questionnaire
kPa
Kilopascal
L-PF
Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire
LPI
Last patient in (= last patient randomised)
LPLVPE
Last Patient Last Visit Primary Endpoint
m
Meter
MAR
Missing at Random
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligramm
min
Minute
ml
Milliliter
MMF
Mycophenolate Mofetil
mmHg
Millimeters of Mercury
mmol
Millimol
MAR
Missing at random
MCMC
Markov Chain Monte Carlo
MMRM
Mixed effect Model Repeat Measurement
MNAR
Missing not at random
MQRM
Medical Quality Review Meeting
N
Number
NAC
N-Acetylcysteine
OCS
Oral Corticosteroids
PD
Protocol Deviation
PF
Pulmonary Fibrosis


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 12 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Term
Definition / description
PF-ILD
Progressive Fibrosing Interstitial Lung Disease
PF-IQOLS
Pulmonary Fibrosis Impact on Quality of Life Scale
PK
Pharmacokinetics
pred
Predicted
PT
Preferred Term
REML
Restricted Maximum Likelihood
REP
Residual Effect Period
RS
Randomised Set
SCS
Screened Set
SD
Standard deviation
SE
Standard Error
SEM
Standard Error of the Mean
SMQ
Standardised MedDRA Query
SOC
System organ class
SpO2
Saturation of oxygen
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TTE
Time-to-event
UIP
Usual Interstitial Pneumonia
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 13 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size as well as
randomization. This TSAP follows Boehringer Ingelheims (BI) internal references (2, 3). To 
support the reader with the understanding of this document, please find a brief summary of 
the trial setup below. 
This placebo-controlled, double-blind clinical trial 1199.247 investigates the efficacy and 
safety of nintedanib at a dose of 150 mg bid, in patients with Progressive Fibrosing Interstitial 
Lung Disease (PF-ILD) over 52 weeks. A total of approximately 600 patients will be 
randomised in a 1:1 ratio between the active treatment arm and the placebo arm. The study 
population will be enriched for patients with High-Resolution Computer Tomography 
(HRCT) with Usual Interstitial Pneumonia (UIP)-like fibrotic pattern only (referred to as 
“HRCT with UIP-like fibrotic pattern only” within this document), applying the HRCT 
criteria used in the Phase III Idiopathic Pulmonary Fibrosis (IPF) studies for nintedanib and 
confirmed by independent and blinded central readers, with the aim to have at least 400 
patients with “HRCT with UIP-like fibrotic pattern only” and approximately 200 patients with 
“other HRCT fibrotic patterns”.
The overall population and the subpopulation of patients with “HRCT with UIP-like fibrotic 
pattern only” are considered as co-primary populations. The subpopulation of patients with 
“other HRCT fibrotic patterns” is referred to as complementary population. The primary 
endpoint of the study – the annual rate of decline in Forced Vital Capacity (FVC) expressed in 
mL over 52 weeks – will be evaluated in both co-primary populations in a confirmatory 
manner. Secondary and further endpoints, as well as safety parameters, will also be shown 
and evaluated in both co-primary populations. For the primary endpoint a Hochberg 
procedure will be used in order to maintain an overall type 1 error rate of 5%. Statistical 
significance will be declared if the primary endpoint analyses in both co-primary populations 
are significant at the two-sided 5% level, or if the analyses in either co-primary population are 
statistically significant at the two-sided 2.5% level. No other endpoints i.e. secondary or 
further endpoints will be evaluated in a confirmatory manner. 
For each patient, the study will consist of two parts: Part A and Part B. Part A of the study 
will consist of Visits 2 through 9, which will occur within 52 weeks of randomisation. 
Following completion of the week 52 visit (Visit 9), patients will continue receiving blinded 
study medication and have study visits every 16 weeks (Part B) until the end of the trial. See 
Figure 3: 1. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 14 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Figure 3: 1 
Study design schematic of study 1199.247 followed by a separate open label 
extension trial 1199_0248 (optional): Part A is a fixed duration period of 52 
weeks, and Part B has variable duration for each patient.
FPI: First Patient In / LPI: Last Patient In / DBL1: Primary Database Lock / BRA: Benefit-Risk Assessment / DBL2: Final Database Lock
Figure 3: 2 
Patient level example of study design and trial part duration for an individual 
patient – including the time point when the benefit-risk analysis occurs (BRA).
The blue area represents Part A of the study on patient level, and the 
subsequent part in the black area Part B. 
Figure 3: 2 depicts Part A and Part B of the trial on patient level, and shows that the 
assessment of benefit-risk (BRA) of nintedanib in PF-ILD will occur when the last 
randomised patient (LPI) reaches the end of Part A. At that time a database lock will occur 
(DBL1), and the data will be unblinded. Efficacy and safety analyses will be performed on the 
data from Part A of the trial to assess the benefit-risk of nintedanib over 52 weeks. In 
addition, data collected in Part B of the trial (after 52 weeks) and available at the time of data 
cut-off for DBL1 will provide supportive longer term information for further endpoints and 
on safety. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 15 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Patients who stopped the trial medication prematurely (before week 52) are asked to continue 
following the visit schedule and come to the sites for assessments, in order to have a dataset 
for the confirmatory primary analyses that is as complete as possible. Per study design, 
patients will have a different amount of data collected in Part B of the trial, as the duration of 
study participation for each patient is different depending on their entry date into the study. 
This is the reason why evaluations over the whole trial (Part A and B combined) include only
descriptive analyses of efficacy parameters, assessments of time-to-event endpoints and safety 
analyses.
Analyses over the whole trial (Part A and Part B) will be repeated after the final database lock 
(DBL2) to include newly emerging data in the descriptive analyses of efficacy parameters and 
to assess further time-to-event efficacy endpoints and selected safety outputs over the whole 
trial. An overview of all trial endpoints can be found in Section 4.3.
Unless stated otherwise, SAS® Version 9.4 or later will be used for all analyses. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 16 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
4.1
ADDITIONS / NEW ANALYSES
In addition to the evaluations depicted in the CTP, the following evaluations will be added: 
x
Sensitivity Analyses for the primary endpoint 
o
A tipping point analysis for the primary endpoint in both co-primary 
populations will be implemented. Details can be found in Section 9.12.1.
4.2
CHANGES
The following changes compared to the plans outlined in the CTP will be implemented: 
x
In Section 7.3.2 (Secondary endpoint analyses) of the CTP it is written that 
convergence issues observed in the analysis of continuous endpoints via a restricted 
maximum likelihood (REML) based repeated measures approach would be tackled by 
applying different covariance structures. The exact wording is: “If this analysis fails to 
converge, the following covariance structures will be tested in order: heterogeneous 
toeplitz (TOEPH), toeplitz (TOEP) and autoregressive 1 (AR[1]). The first model to 
converge will be used.” It is not intuitive why a different approach should be used for 
a secondary or further endpoint compared to what is done when the primary analysis 
shows similar issues. Hence, the analysis approach for convergence issues for 
continuous secondary or further endpoints will be modified to follow the one used for 
the primary analysis.
x
In Section 7.3.2 (Secondary endpoint analyses) of the CTP it is written that 
Time-to-event (TTE) endpoints will be analysed using a Cox proportional hazards 
model. The exact wording is: “Time-to-event endpoints will be analysed using a Cox 
proportional hazards model. The equality of the hazard rates will be tested by the 
Wald test for the treatment effect at the two-sided 5% significance level. The model 
will include the treatment effect and HRCT pattern (except for the analyses on the co-
primary analysis population assessing only patients with HRCT with UIP-like fibrotic 
pattern only) as covariates. Breslow’s method for handling ties will be used. Kaplan-
Meier plots by treatment group will also be presented. If the proportion of patients 
experiencing at least 1 acute ILD exacerbation over 52 weeks is less than 2%, then 
only frequencies of exacerbations by treatment group will be provided for the main 
secondary endpoint of time to first acute ILD exacerbation or death over 52 weeks and 
no statistical analysis will be performed.” While the Cox Model is still employed to 
compute the effect size, i.e. the hazard ratio, a stratified log-rank test will be used to 
evaluate the effect of nintedanib on TTE endpoints compared to placebo. 
4.3
CLARIFICATIONS
The following points warrant further clarification: 
x
Within this document, “drug intake” refers to the intake of the trial medication – either 
placebo or nintedanib. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 17 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
x
This study comprises of the following “populations”: The “overall” population and the 
subpopulation of patients with “HRCT with UIP-like fibrotic pattern only” are 
considered to be co-primary populations. The subpopulation of patients with “other 
HRCT fibrotic patterns” is considered to be the complementary population. Unless 
stated otherwise in the TSAP, evaluations are only done for the co-primary 
populations. 
x
In order to determine whether the results for the primary endpoint are consistent 
between the subpopulation of patients with “HRCT with UIP-like fibrotic pattern 
only” and the subpopulation of patients with “other HRCT fibrotic patterns” the 
following steps will be taken
o
The numerical results, including the 95% CI will be inspected visually 
o
HRCT pattern will be treated as a subgroup in one sensitivity analysis, and the 
obtained interaction p-value will be depicted on a forest plot in addition to the 
results of the “overall” population, the subpopulation of patients with “HRCT 
with UIP-like fibrotic pattern only” and the subpopulation of patients with 
“other HRCT fibrotic patterns”. See Section 7.4.3 for additional details.
x
Due to the possible occurrence of mis-stratifications during the randomisation process, 
the HRCT pattern as reported in the eCRF will be used in all analyses. In case this 
occurs in more than 3% of all randomised patients, an additional sensitivity analysis is 
implemented utilising the values used during the randomisation process in the 
Interactive Response Technology (IRT) system. See Section 7.4.2.2.2 for additional 
details.
x
Two patients were randomised by mistake, whose disease extent was ≤ 10% and 
whose HRCT pattern was not determined by the central readers. Both patients were 
randomised under “other HRCT fibrotic patterns”. Given that the HRCT pattern was 
actually not determined, those patients do not have an entry for this variable in the 
eCRF. They will be counted in the subpopulation of patients with “other HRCT 
fibrotic patterns” in all analyses within the CTR except for the sensitivity analysis 
implemented to evaluate the mis-stratifications – there they will be counted in the 
subpopulation of patients with “HRCT with UIP-like fibrotic pattern only”. See 
Section 6.6 for further details.
x
This study is only powered and adequately sized to evaluate the efficacy of nintedanib 
as determined by the primary endpoint
analysis. To avoid confusion and 
misinterpretation, the depiction of p-values in the outputs will be limited to the 
following evaluations: 
o
Primary analysis performed in the “overall population” and the co-primary 
population of patients with “HRCT with UIP-like fibrotic pattern only” 
o
Sensitivity analyses of the primary endpoint analysis in both co-primary 
populations 
o
Nominal p-values for the evaluation of the main secondary endpoints, 
evaluated in both co-primary populations 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 18 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
o
Interaction p-values for the efficacy evaluations in the subgroup analyses (see 
Section 6.4 for information about the devised subgroups) 
x
In Section 5.1.3 of the CTP, the following statement was made: “More details will be 
provided and additional further endpoints may be defined in the trial statistical 
analysis plan (TSAP)”
o
Details about further endpoints over the whole trial can be found in Section 
5.3.2.
o
No additional endpoints apart from those already mentioned in the CTP were 
defined for this trial. 
x
Due to the layout of this document, it may not be as straight forward to determine the 
different endpoints. To help with this and show the order of endpoints for CTR 
creation, below is an overview of the endpoints as depicted in Sections 5.1.1, 5.1.2 and 
5.1.3 of the CTP: 
o
Primary Endpoint 

The primary efficacy endpoint is the annual rate of decline in FVC 
(expressed in mL over 52 weeks).
o
Secondary Endpoints 

Main secondary efficacy endpoints 
x
Absolute change from baseline in King's Brief Interstitial Lung 
Disease Questionnaire (K-BILD) total score at week 52
x
Time to first acute Interstitial Lung Disease (ILD) exacerbation 
or death over 52 weeks 
x
Time to death over 52 weeks 

Other secondary efficacy endpoints 
x
Time to death due to respiratory cause over 52 weeks 
x
Time to progression (defined as a ≥ 10% absolute decline in 
FVC % predicted (pred)) or death over 52 weeks 
x
Proportion of patients with a relative decline from baseline in 
FVC % pred of >10% at week 52 
x
Proportion of patients with a relative decline from baseline in 
FVC % pred of >5% at week 52 
x
Absolute change from baseline in Living with Pulmonary 
Fibrosis (L-PF) Symptoms dyspnea domain score at week 52 
x
Absolute change from baseline in Living with Pulmonary 
Fibrosis (L-PF) Symptoms cough domain score at week 52 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 19 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
o
Further Endpoints 

Further efficacy endpoints over 52 weeks (Part A)
x
Time to first non-elective hospitalization or death over 52 
weeks
x
Absolute change from baseline in FVC (mL) at week 52 
x
Absolute change from baseline in FVC % pred at week 52 
x
Proportion of patients with an absolute decline from baseline in 
FVC % pred of >10% at week 52 
x
Proportion of patients with an absolute decline from baseline in 
FVC % pred of >5% at week 52
x
Absolute change from baseline in DLCO % pred at week 52 
x
Absolute change from baseline in Living with Pulmonary 
Fibrosis (L-PF) Total score at week 52
x
Absolute change from baseline in Living with Pulmonary 
Fibrosis (L-PF) Impact score at week 52
x
Absolute change from baseline in Living with Pulmonary 
Fibrosis (L-PF) Symptoms total score at week 52
x
Absolute change from baseline in Living with Pulmonary 
Fibrosis (L-PF) Symptoms Fatigue domain score at week 52
x
Absolute change from baseline in Pulmonary Fibrosis Impact 
on Quality of Life Scale (PF-IQOLS) summary score at week 
52

Further efficacy endpoints over the whole trial (Part A and Part B)
x
Time to first acute ILD exacerbation or death over the whole 
trial
x
Time to death over the whole trial 
x
Time to death due to respiratory cause over the whole trial
x
Time to progression (defined as a ≥ 10% absolute decline in 
FVC % pred) or death over the whole trial 
x
Time to first non-elective hospitalization or death over the 
whole trial


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 20 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.
ENDPOINTS
In this section, more details are given regarding endpoints. Note that for all endpoints and 
analyses, Section 6.7 should be consulted for baseline value definition. For analyses that are 
specified over 52 weeks (Part A), unless otherwise specified, all data (including baseline) up 
to week 52 (inclusive – as defined in Section 6.1) will be taken into account, including 
follow-up visits before week 52 for patients who discontinue the trial medication prematurely.
Analyses over the whole trial (Part A and Part B) reported at the time of the benefit-risk
analysis will be based on all data collected until the data cut-off for DBL1. Analyses over the 
whole trial (Part A and Part B) reported after the final database lock (DBL2) will be based on 
all data collected within the trial.
Handling of missing data points is described in Section 6.6.
For endpoints where the “date of last contact” is utilised, the following will apply:
x
The last contact date when the patient was known to be alive is defined as the latest 
date recorded in the electronic Case Report Form (eCRF) from the dates listed below
(in case a date is planned to be imputed for the analysis, the imputed date will also be 
used for the definition of “date of last contact”): 
o
Date of last visit (e.g. for spirometry), data of last reported Adverse Event 
(AE) (excluding censored dates), date of last reported concomitant treatment, 
date of last laboratory sample, date of last drug intake, date of last reported 
dose change / interruption, last contact date (as documented on the termination 
of trial eCRF page if the reason for not completing the planned observation 
period is NOT “Death”), vital status date (from the vital status eCRF page if 
the patient is known to be alive) and the latest of vital status date / last 
successful contact date (from the vital status eCRF page if the patient was lost 
to follow-up). 
5.1
PRIMARY ENDPOINT
The primary efficacy endpoint is the annual rate of decline in Forced Vital Capacity (FVC) 
over 52 weeks expressed in ml. The analysis will be based on FVC values obtained at 
pre-specified visits over 52 weeks (Part A). Handling of missing data points is described in 
Section 6.6.1.
5.2
SECONDARY ENDPOINTS
5.2.1 
Key secondary endpoints 
This section is not applicable as no key secondary endpoint has been specified in the CTP.
5.2.2
Secondary endpoints
The secondary endpoints include change from baseline and time-to-event endpoints at or over 
52 weeks. Please note: Additional information about the 52 weeks analysis period can be 
found in Section 6.1.1, according to the type of endpoint. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 21 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.2.2.1 Main secondary efficacy endpoints 
5.2.2.1.1 
Absolute change from baseline in King’s Brief Interstitial Lung Disease 
Questionnaire (K-BILD) Total Score at 52 weeks
The K-BILD is a self-administered health status questionnaire that was developed and 
validated specifically for patients with ILD (12). The questionnaire consists of 15 items and 3 
domains: breathlessness and activities, psychological, and chest symptoms. Possible score 
ranges from 0-100, with a score of 100 representing the best health status. 
The K-BILD evaluation will primarily focus on the absolute change from baseline in the total 
score at week 52. To score the K-BILD, the Likert response scale weightings for individual 
items are combined, if necessary for certain items, to ensure they detect progressive change in 
health status. Then the scores are transformed to a range of 0–100 by using logit values and a 
look-up table to yield interval-level scores, where higher scores indicate better health status. 
The specific instructions for deriving the K-BILD total score are provided in Section 9.1.
Specific rules of handling of missing items are detailed in Section 6.6.2.1.1.
5.2.2.1.2
Time to death over 52 weeks  
Date of death for an individual patient will be obtained from either the AE reporting page for 
patients with AEs leading to death or from the vital status assessment eCRF page.
For patients with known date of death (regardless of the cause of death) within the first 52 
weeks the derivation will be as follows: 
x
Time to death [days] = Date of death – date of first drug intake + 1
Patients who did not experience any event within the first 52 weeks will be censored 
according to the mechanism for censoring as described in Table 5.2.2.1.2: 1 below. 
Table 5.2.2.1.2: 1 
Censoring Rules for Time to death over 52 weeks
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring 
1
Patient died within the first 
52 weeks and date of Death 
is known
Event 
Date of event
2
Patient died within the first 
52 weeks and date of Death 
is unknown
Event 
Imputed date of event 
3
Patient is alive after 52 
weeks
Censored
Day 373
(372 days after 
first drug intake)
4
Patient status is unknown 
Censored
Date of last contact when 
the patient was known to be 
alive


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 22 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.2.2.1.3
Time to first acute ILD exacerbation or death over 52 weeks 
Acute ILD exacerbation is defined in the CTP as an acute, clinically significant, respiratory 
deterioration characterized by evidence of new widespread alveolar abnormality with all of 
the following: 
x
Previous or concurrent diagnosis of ILD
x
Acute worsening or development of dyspnoea typically less than one month 
duration 
x
Computed tomography with new bilateral ground-glass opacity and/or 
consolidation superimposed on a background pattern consistent with fibrosing ILD 
x
Deterioration not fully explained by cardiac failure or fluid overload 
Events that are clinically considered to meet the definition of acute exacerbation but fail to 
meet all four diagnostic criteria due to missing CT data should be termed “suspected acute 
exacerbations”. Please note that only acute ILD exacerbations that fulfil all the criteria 
depicted above will be taken into account and contribute to the endpoint. Information on acute 
ILD exacerbations will be obtained from the Adverse Events page. 
For those patients who either experience acute ILD exacerbations or who die due to any cause
within the first 52 weeks, time to first acute ILD exacerbation or death [days] will be 
computed as: 
x
Earliest of date of first documented acute ILD exacerbation or death – date of first
drug intake + 1
Patients who did not experience any ILD exacerbation event within the first 52 weeks will be 
censored according to the mechanism for censoring as described in Table 5.2.2.1.3: 1.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 23 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 5.2.2.1.3: 1 
Censoring Rules for Time to first acute ILD exacerbation or death over 
52 weeks 
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring 
1
Patient had a documented 
acute ILD exacerbation or 
died within the first 52 
weeks and the date of the
event is known
Event 
Earliest Date of event
2
Patient had a documented 
acute ILD exacerbation or 
died within the first 52 
weeks and the date of the 
event is unknown
Event 
Imputed date of event 
3
Patient did not have a
documented acute ILD 
exacerbation and is alive 
after 52 weeks
Censored
Day 373 
(372 days after 
first drug intake) 
4
Patient status is unknown 
Censored
Date of last contact when 
the patient was known to be 
alive and event free
5.2.2.2 Other secondary efficacy endpoints 
5.2.2.2.1
Time to death due to respiratory cause over 52 weeks 
Analysis of time to death due to respiratory cause will be based on the adjudicated cause of 
death as determined by an independent Adjudication Committee (AC). The AC will review all 
fatal cases and adjudicate all deaths to either cardiovascular, respiratory or other causes.
For those patients who died, and whose death is attributed to respiratory causes within the 
first 52 weeks by the AC, time to death due to respiratory cause [days] will be computed as: 
x
Date of death – date of first drug intake + 1
Patients who did not experience any event within the first 52 weeks will be censored 
according to the mechanism for censoring as described in Table 5.2.2.2.1: 1.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 24 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 5.2.2.2.1: 1 
Censoring Rules for Time to death due to respiratory cause over 52 
weeks
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient died within the first 
52 weeks due to respiratory 
cause and the date of the 
event is known
Event 
Date of event
2
Patient died within the first 
52 weeks due to respiratory 
cause and the date of the 
event is unknown
Event 
Imputed date of event 
3
Patient is alive after 52 
weeks
Censored
Day 373
(372 days after
first drug intake)
4
Patient status is unknown 
Censored
Date of last contact when 
the patient was known to be 
alive
5.2.2.2.2 
Time to progression or death over 52 weeks 
Progression is defined as the date when ≥ 10% of absolute decline in FVC % pred compared 
to baseline occurs for the first time.
For those patients who fulfil the criteria for progression or death due to any cause within the 
first 52 weeks, time to progression or death due to any cause [days] will be computed as: 
x
Earliest of date of documented progression event or death – date of first drug 
intake + 1
Patients who did not experience any event within the first 52 weeks will be censored 
according to the mechanism for censoring as described in Table 5.2.2.2.2: 1.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 25 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 5.2.2.2.2: 1 
Censoring Rules for Time to progression or death over 52 weeks 
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
progression or died within 
the first 52 weeks and the 
date of the event is known
Event 
Earliest Date of event
2
Patient had a documented 
progression or died within 
the first 52 weeks and the 
date of the event is 
unknown
Event 
Imputed date of event 
3
Patient did not have a 
documented progression 
and is alive after 52 weeks
Censored
Day 373
(372 days after 
first drug intake)
4
Patient status is unknown 
Censored
Date of last contact when 
the patient was known to be 
alive and event free
5.2.2.2.3
Relative decline from baseline in FVC % pred at 52 weeks 
Patients will be categorised based on the relative decline from baseline in FVC % pred greater 
than 5% or greater than 10% at week 52. The categorisations will be handled as separate 
endpoints, and the proportion of patients with a decline of greater than 5% as well as the 
proportion of patients with a decline of greater than 10% will be evaluated separately between 
the two treatment groups. Please note that patients who fulfil the criterion of a relative decline 
of greater than 10% also automatically fulfil the criterion of a relative decline of greater than 
5%, and will therefore be counted in both endpoint evaluations. Specific rules of handling of 
missing items are detailed in Section 6.6.2.3.
5.2.2.2.4 
Change from baseline in Living with Pulmonary Fibrosis Symptoms and Impact 
Questionnaire (L-PF) Dyspnea and Cough Domain Scores at week 52  
The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44 item questionnaire with two 
modules: 1) symptoms (23 items) and 2) impacts (21 items). L-PF was developed with the 
input of patients with pulmonary fibrosis (PF) and thus is intended to capture perceptions 
specific to PF patients. The Symptoms module yields three domain scores: 1) dyspnea, 2) 
cough and 3) fatigue as well as a total Symptoms score. The Impacts module yields a single 
Impacts score. Symptoms and Impacts scores are summed to yield a total L-PF score. Scoring 
is performed as a summary score, the mean of the dimension ratings multiplied by 100. 
Summary score range from 0-100, the higher the score the greater the impairment. 
The absolute change from baseline in the L-PF symptoms dyspnea domain score at week 52 
as well as the absolute change from baseline in the L-PF symptoms cough domain score at 
week 52 will be computed and evaluated separately. Scoring instructions for L-PF are 
described in Section 9.2. Specific rules of handling of missing items are detailed in Section 
6.6.2.1.2.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 26 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.3
FURTHER ENDPOINTS
This section includes endpoints over 52 weeks (Part A) as well as further endpoints over the 
whole trial (Part A and Part B).
5.3.1
Endpoints over 52 weeks
Please note: Additional information about the 52 weeks analysis period can be found in 
Section 6.1.1, according to the type of endpoint. 
5.3.1.1
Time to first non-elective hospitalisation or death over 52 weeks 
Time to non-elective hospitalization assessment will be based on the date of hospitalization 
collected on a specific hospitalization eCRF page. The eCRF page will capture whether the 
non-elective hospitalization was due to respiratory cause, and the primary admission 
diagnosis according to the investigator. Cause of non-elective hospitalizations will not be 
adjudicated by the AC.
For those patients who either experience a non-elective hospitalisation or who die due to any 
cause within the first 52 weeks, time to first non-elective hospitalisation or death [days] will 
be computed as: 
x
Earliest of date of first non-elective hospitalisation or death – date of first drug 
intake + 1
Patients who did not experience any event within the first 52 weeks will be censored 
according to the mechanism for censoring as described in Table 5.3.1.1: 1. 
Table 5.3.1.1: 1 
Censoring Rules for Time to first non-elective hospitalisation or death 
over 52 weeks 
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
non-elective hospitalisation 
or died within the first 52 
weeks and the date of the 
event is known
Event 
Earliest Date of event
2
Patient had a documented 
non-elective hospitalisation 
or died within the first 52 
weeks and the date of the 
event is unknown
Event 
Imputed date of event 
3
Patient did not have a 
documented non-elective 
hospitalisation and is alive 
after 52 weeks
Censored
Day 373 
(372 days after 
first drug intake) 
4
Patient status is unknown 
Censored
Date of last contact when 
the patient was known to be 
alive and event free


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 27 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.3.1.2
Absolute change from baseline in FVC at week 52
The absolute change from baseline in FVC at week 52 will be computed and shown. The 
evaluation will be done by assessing the absolute change in FVC in ml between week 52 and 
baseline; and in addition to that, by assessing the absolute change from baseline in FVC in % 
pred between week 52 and baseline. The changes in these two parameters between the two 
treatment groups will be depicted and described. 
Specific rules of handling of missing items are detailed in Section 6.6.2.1.
5.3.1.3 Absolute decline from baseline in FVC % pred at week 52
Patients will be categorised based on the absolute decline from baseline in FVC % pred
greater than 5% or greater than 10% at week 52. The categorisations will be handled as 
separate endpoints, and the proportion of patients with a decline of greater than 5% as well as 
the proportion of patients with a decline of greater than 10% will be evaluated separately 
between the two treatment groups. Please note that patients who fulfil the criterion of an 
absolute decline of greater than 10% also automatically fulfil the criterion of an absolute 
decline of greater than 5%, und will therefore be counted in both endpoint evaluations.
Specific rules of handling of missing items are detailed in Section 6.6.2.3.
5.3.1.4
Absolute change from baseline in Carbon Monoxide Diffusion Capacity (DLCO) %
pred over 52 weeks 
Single-breath DLCO measurements will be carried out according to the American Thoracic 
Society (ATS) / European Respiratory Society (ERS) guideline on DLCO measurements (13) 
DLCO and the corresponding alveolar volume will be measured at time points given in the 
Flowcharts in the CTP.
DLCO values will be adjusted for altitude, carboxyhaemoglobin (COHb) and the most recent 
haemoglobin value. For predicted normal values of DLCO, different sites may use different 
prediction formulas, based on the method used to measure DLCO. In any case, the calculation 
method used must be in compliance with the ATS/ERS guideline on DLCO measurements 
and the prediction formula appropriate for that method.  
For analyses DLCO % pred at week 52 will be computed as follows: 
x
(mean DLCO) / (DLCO predicted) × 100%, 
where mean DLCO is the mean of the two valid measurements entered in the eCRF (in case 
only one valid measurement then this one will be used) and 
x
DLCO predicted (men) = 
(11.114 × height [m]) – (0.066 × age [years]) – 6.03 
x
DLCO predicted (women) = 
(8.176 × height [m]) – (0.049 × age [years]) – 
2.746


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 28 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
The value of DLCO % pred will always be presented after correction for Haemoglobin.
Percent predicted DLCO corrected for haemoglobin (Hb) expressed in g/dL (13) can be 
calculated as:
x
For men: 
Percent predicted DLCO corrected for Hb = Percent predicted DLCO × (10.22 + ܪܾ)
1.7ܪܾ
x
For women: 
Percent predicted DLCO corrected for Hb = Percent predicted DLCO × (9.38 + ܪܾ)
1.7ܪܾ
Please note that different units for DLCO are dealt with the following way:
x
If unit of DLCO measured value is given as “mmol/min/kPa”, then the value of 
DLCO is used for the computations 
x
If unit of DLCO measured value is given as “ml/min/mmHg”, then the value of 
DLCO is divided by 2.987 before it is used in the computations 
The absolute change from baseline in DLCO % pred at week 52 will be depicted and 
compared between the two treatment groups. 
5.3.1.5 Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (L-PF)
A more detailed description of the L-PF can be found in Section 5.2.2.2.4 or in the CTP. 
The absolute change from baseline in the L-PF total score, the L-PF impact score, the L-PF 
symptoms total score and the L-PF symptoms fatigue domain score all at week 52 will be 
computed and evaluated. Scoring instructions for L-PF are described in Section 9.2. Specific 
rules of handling of missing items are detailed in Section 6.6.2.1.2.
5.3.1.6
Change from baseline in Pulmonary Fibrosis Impact on Quality of Life Scale (PF-
IQOLS) summary score at week 52 
The PF-IQOLS scale was developed to measure the impact of a disease and its treatment on 
the patient’s quality of life. The IQOLS includes 16 dimensions and a 5-point standard Likert-
type response scale on which patients rate the impact of the disease on their quality of life (14,
15). Scoring of IQOLS is performed as a summary score, the average of the individual 
dimension ratings . Summary scores range from 1.0-5.0 with greater scores reflecting a worse 
quality of life.
The absolute change from baseline in the PF-IQOLS summary score at week 52 will be 
computed and evaluated between the two treatment groups. Scoring instructions for PF-
IQOLS are described in Section 9.3. Specific rules of handling of missing items are detailed 
in Section 6.6.2.1.3.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 29 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.3.2
Endpoints over the whole trial
Part B of the trial (a variable treatment period beyond 52 weeks on patient level) will start 
after Part A has concluded, and is conducted in order to collect supportive longer term data on 
the effect of nintedanib in patients with PF-ILD in a controlled manner, especially for the 
early enrollers. Due to the varying length of follow-up in Part B of the trial, the efficacy 
measures incorporating data from Part A and Part B will focus on time-to-event endpoints. 
5.3.2.1
Time to death over the whole trial 
Date of death for an individual patient will be obtained from either the AE reporting page for 
patients with AEs leading to death or the information from the vital status assessment page. 
The start date of time at risk is the date of first drug intake, and, in general, patients who did 
not die during the trial will be censored at the last known date when the patient was alive. 
For patients with known date of death (regardless of the cause of death) at any point within 
the trial, the derivation will be as follows:
x
Time to death = Date of death – date of first drug intake + 1
Patients who did not experience any event during their trial participation will be censored 
according to the mechanism for censoring as described in Table 5.3.2.1: 1. 
Table 5.3.2.1: 1 
Censoring Rules for Time to death over the whole trial 
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient died and date of 
Death is known
Event 
Date of event
2
Patient died and date of 
Death is unknown
Event 
Imputed date of event
3
Patient is alive
Censored
Date of last contact when 
the patient was known to be 
alive
4
Patient status is unknown 
Censored
Date of last contact when 
the patient was known to be 
alive
5.3.2.2
Time to first acute ILD exacerbation or death over the whole trial 
For those patients who either experience acute ILD exacerbations or who die due to any cause 
at any point in the study, time to first acute ILD exacerbation or death [days] will be 
computed as: 
x
Earliest of date of first documented acute ILD exacerbation or death – date of first 
drug intake + 1
Patients who did not experience any event during their trial participation will be censored 
according to the mechanism for censoring as described in Table 5.3.2.2: 1.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 30 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 5.3.2.2: 1 
Censoring Rules for Time to first acute ILD exacerbation or death over 
the whole trial
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
acute ILD exacerbation or 
died and the date of the 
event is known
Event 
Earliest Date of event
2
Patient had a documented 
acute ILD exacerbation or 
died and the date of the 
event is unknown
Event 
Imputed date of event 
3
Patient did not have a 
documented acute ILD 
exacerbation and is alive
Censored
Date of last contact when 
the patient was known to be 
alive and event free
4
Patient status is unknown 
Censored
Date of last contact when 
the patient was known to be 
alive and event free
5.3.2.3
Time to first non-elective hospitalisation or death over the whole trial 
Time to non-elective hospitalization assessment will be based on the date of hospitalization 
collected on a specific hospitalization eCRF page.
For those patients who either experience a non-elective hospitalisation or die due to any cause 
within the trial, time to first non-elective hospitalisation or death [days] will be computed as: 
x
Earliest of date of first non-elective hospitalisation or death – date of first drug 
intake + 1
Patients who did not experience any event during their trial participation will be censored 
according to the mechanism for censoring as described in Table 5.3.2.3: 1.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 31 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 5.3.2.3: 1 
Censoring Rules for Time to first non-elective hospitalisation or death
over the whole trial 
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
non-elective hospitalisation 
or died and the date of the 
event is known
Event 
Earliest Date of event
2
Patient had a documented 
non-elective hospitalisation 
or died and the date of the 
event is unknown
Event 
Imputed date of event 
3
Patient did not have a 
documented non-elective 
hospitalisation and is alive
Censored
Date of last contact when 
the patient was known to be 
alive and event free
4
Patient status is unknown 
Censored
Date of last contact when 
the patient was known to be 
alive and event free
5.3.2.4
Time to death due to respiratory cause over the whole trial
Analysis of time to death due to respiratory cause will be based on the adjudicated cause of 
death as determined by an independent Adjudication Committee (AC). For those patients who 
died, and whose death is attributed by the AC to respiratory causes at any time within the 
trial, time to death due to respiratory cause [days] will be computed as: 
x
Date of death – date of first drug intake + 1
Patients who did not experience any event during their trial participation will be censored 
according to the mechanism for censoring as described in Table 5.3.2.4: 1. 
Table 5.3.2.4: 1 
Censoring Rules for Time to death due to respiratory cause over the 
whole trial
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient died due to 
respiratory cause and the 
date of the event is known
Event 
Date of event
2
Patient died due to 
respiratory cause and the 
date of the event is 
unknown
Event 
Imputed date of event 
3
Patient is alive
Censored
Date of last contact when 
the patient was known to be 
alive
4
Patient status is unknown 
Censored
Date of last contact when 
the patient was known to be 
alive and event free


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 32 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
5.3.2.5 Time to progression or death over the whole trial 
Progression is defined as the date when ≥ 10% of absolute decline in FVC % pred occurs for 
the first time. For those patients who progressed or died due to any causes within the trial, 
time to progression or death due to any cause [days] will be computed as: 
x
Earliest of date of documented progression event or death – date of first drug 
intake + 1
Patients who did not experience any event will be censored at the date of last contact when the 
patient was known to be alive and was known not to have progressed. 
Patients who did not experience any event during their trial participation will be censored 
according to the mechanism for censoring as described in Table 5.3.2.5: 1. 
Table 5.3.2.5: 1 
Censoring Rules for Time to progression or death over the whole trial 
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
progression or died and the 
date of the event is known
Event 
Earliest Date of event
2
Patient had a documented 
progression or died and the 
date of the event is 
unknown
Event 
Imputed date of event 
3
Patient did not have a 
documented progression 
and is alive
Censored
Date of last contact when 
the patient was known to be 
alive and event free
4
Patient status is unknown 
Censored
Date of last contact when 
the patient was known to be 
alive and event free
5.4
OTHER VARIABLES
5.4.1
Demographics and baseline characteristics
5.4.1.1
Demographic data 
x
Gender
x
Ethnicity: overall and by race
x
Race: single race respondents, multiple race respondents (all combinations ticked), 
and all race categories regardless of how many race categories were ticked
x
Age [years] at time of informed consent (transferred by IRT)  
x
Age in categories [years] (<30; ≥30-<45; ≥45 and <60;≥60 and <75; ≥75) 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 33 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
x
Weight [kg] as continuous variable and in classes (<30; ≥30 - <60; ≥60 - <90; 
≥90)
x
Height [cm] 
x
Body mass index [kg/m2]: Weight[kg] / Height [m]*Height[m], as a continuous 
variable and in classes (< 18.5; ≥18.5-<25; ≥25-<30, ≥30) 
x
Tobacco consumption (Never, Current, Former)
x
Pack years (for patients who tick ³&XUUHQW´ RU ³)RUPHU´ in the variable 
“Tobacco consumption”) as continuous variable and in classes (< 20; ≥20-<40; 
≥40)
5.4.1.2 Trial indication
x
Time elapsed since the first diagnosis of ILD [years] will be calculated as: (date of 
randomisation – date of first diagnosis of ILD) / 365.25  
x
Time elapsed since the first diagnosis of ILD will also be coded in classes (≤1
year; > 1 year to ≤3 years; > 3 years to ≤ 5 years; > 5 years)
x
Underlying ILD diagnosis (“,GLRSDWKLF QRQVSHFLILF LQWHUVWLWLDO SQHXPRQLD´
³8QFODVVLILDEOH
LGLRSDWKLF
LQWHUVWLWLDO
SQHXPRQLD´
³+\SHUVHQVLWLYLW\
SQHXPRQLWLV´³5KHXPDWRLG$UWKULWLVDVVRFLDWHG,/'´³0L[HGFRQQHFWLYHWLVVXH
GLVHDVH´
³6\VWHPLF
VFOHURVLV
DVVRFLDWHG
,/'´³([SRVXUHUHODWHG
,/'´
³6DUFRLGRVLV´³2WKHUILEURVLQJ,/'´) 
x
Underlying ILD diagnosis in groups 
o
+\SHUVHQVLWLYLW\SQHXPRQLWLV+3
o
,GLRSDWKLFQRQVSHFLILFLQWHUVWLWLDOSQHXPRQLDL16,3
o
8QFODVVLILDEOHLGLRSDWKLFLQWHUVWLWLDOSQHXPRQLDX,,3
o
$XWRLPPXQH,/'VDXWR
o
Other ILDs (other)
x
Autoimmune ILD (Sub-classification based on the underlying ILD diagnosis 
categories ³5KHXPDWRLG $UWKULWLV DVVRFLDWHG ,/'´ ³0L[HG FRQQHFWLYH WLVVXH
GLVHDVH´DQG³6\VWHPLFVFOHURVLVDVVRFLDWHG,/'´DQGWKHFODVVLILFDWLRQRI³2WKHU
ILEURVLQJ,/'V´VKRZQLQ7DEOHZLWKWKHIODJ³DXWRLPPXQH,/'´) 
x
Exposure-related ILD (Sub classification based on the underlying ILD diagnosis 
category ³([SRVXUHUHODWHG,/'´DQGWKHFODVVLILFDWLRQRI³2WKHUILEURVLQJ,/'V´
VKRZQLQ7DEOHZLWKWKHIODJ³H[SRVXUHUHODWHG,/'´) 
x
Other ILDs (Sub-classification based on the underlying ILD diagnosis category 
“Sarcoidosis”, exposure-related ILDs and the classification of “Other ILEURVLQJ
,/'V´VKRZQLQ7DEOHZLWKWKHIODJ³RWKHU,/'´) 
x
ILD history including:  
o
Time since ILD diagnosis based on imaging [years] 
o
Diagnosis of ILD confirmed by surgical biopsy (Yes, No, Unknown) 
o
Diagnosis of ILD confirmed by transbronchial biopsy (Yes, No, Unknown) 
o
For auto-immune ILD (only): Time since rheumatologic diagnosis [years] 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 34 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
o
For auto-immune ILD (only): Diagnosis confirmed by a rheumatologist? (Yes, 
No, Unknown) 
o
For exposure related ILDs (only): exposure still present (Yes, No) 
x
Criteria for progressive ILD (all combinations of: Decline in FVC % pred ≥10%, 
Decline in FVC % pred ≥5-<10% combined with worsening of respiratory 
symptoms, Decline in FVC % pred ≥5-<10% combined with increasing extent of 
fibrotic changes on chest imaging, Worsening of respiratory symptoms as well as 
increasing extent of fibrotic changes on chest imaging)
x
HRCT assessment results:
o
HRCT pattern (“HRCT with UIP-like fibrotic pattern only”, “Other HRCT 
fibrotic patterns”) 
5.4.1.3
Baseline characteristics for lung function
x
FVC [ml] 
x
FVC [% predicted]
x
FEV1 / FVC
x
Oxygen Saturation on Pulse Oximetry (SpO2) [%] 
x
DLCO (corrected for Hb) [% predicted]: refer to Section 5.3.1.4 for the derivation 
of DLCO % pred. 
5.4.1.4
Baseline characteristics for questionnaires and derived outcomes
x
K-BILD breathlessness and activities score, psychological score, chest symptoms 
score, and total score
x
L-PF
o
Total score
o
Impact score
o
Symptoms dyspnea, cough, and fatigue domain scores and total score 
x
PF-IQOL summary score 
5.4.2
Compliance
5.4.2.1 Over 52 weeks 
Compliance will be calculated over 52 weeks as:
Compliance [%] =
ܰݑܾ݉݁ݎ ݋݂ ܿܽ݌ݏݑ݈݁ݏ ܽܿݐݑ݈݈ܽݕ ݐܽ݇݁݊
݋ݒ݁ݎ ݐ݄݁ 52 െݓ݁݁݇ ݐݎ݁ܽݐ݉݁݊ݐ ݌݁ݎ݅݋݀
ܰݑܾ݉݁ݎ ݋݂ ܿܽ݌ݏݑ݈݁ݏ ݓ݄݄݅ܿ ݏ݄݋ݑ݈݀ ݄ܽݒ݁ ܾ݁݁݊ ݐܽ݇݁݊
݋ݒ݁ݎ ݐ݄݁ 52 െݓ݁݁݇ ݐݎ݁ܽݐ݉݁݊ݐ ݌݁ݎ݅݋݀
ݔ100


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 35 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
The number of capsules which should have been taken over the 52-week treatment period will 
be calculated as:
Number of capsules which should have been taken over the 52-week treatment period
[capsules] = (date of last administration [1] – date of first administration + 1) [days] × 2 [2]
[1] Or Visit 9, if earlier. 
[2] The time of first/ last administration are taken into account, so only one capsule may be expected to be taken 
on some days (calculation is then adapted accordingly).
In case of dose reduction to 100 mg bid, the number of capsules taken per day is still 2, so the 
calculation of compliance remains the same. Only treatment interruptions not due to AE will 
be considered as a compliance issue and will be taken into account in the calculation (duration 
of interruptions due to AE will be subtracted from the duration of the treatment period, as 
defined in Section 6.1).
Compliance will also be categorised into classes: <50%, ≥50% - <80%, ≥80% - ≤ 120%, > 
120%. 
5.4.2.2
Over the whole trial
Similarly, compliance over the whole trial will be calculated and categorised into the same
classes. 
5.4.3
Exposure 
5.4.3.1 Over 52 weeks 
Duration of exposure [months] = (date of last administration[1] – date of first administration 
+1 day) / 30.5  
[1] Or week 52 time-point (372 days after date of first trial drug intake), if earlier.
Duration of exposure in categories: ≤3 months (91 days); >3 months (91 days) to ≤6 months 
(182 days); > 6 months (182 days) to ≤12 months (365 days); > 12 months (365 days)  
Treatment interruptions will not be subtracted from the duration of exposure.  
Duration on actual dose (100 or 150 mg bid) (sum of durations on-treatment for each dose 
effectively taken): in weeks and in categories (≤8 weeks, > 8 weeks)
Total dose [g]: Duration of exposure [days] * actual dose [g] 
Dose intensity [%]: amount of drug actually administered over the study (dose 100mg and 
150mg) divided by the amount of drug that would have been administered had dose 150mg 
bid been administered over all the study (from date of first administration to date of last 
administration, whether or not trial drug was prematurely discontinued). Dose intensity will 
be summarized in percent and in categories (≤30 %, >30% - ≤50%, >50% - ≤90%, >90% - 
<100%, 100%). 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 36 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Time to first dose reduction or time to first treatment interruption in classes : ≤31 days, > 31 
− ≤ 91 days, > 91 - ≤182 days, > 182 days 
Time to first dose reduction, time to first treatment interruption, as well as time to premature 
treatment discontinuation will also be evaluated via survival methods. Censoring rules can be 
found in Table 5.4.3.1: 1, Table 5.4.3.1: 2 and Table 5.4.3.1: 3 respectively. 
Duration of exposure in patient years will also be shown per treatment group. 
Table 5.4.3.1: 1 
Censoring Rules for Time to first dose reduction over 52 weeks 
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
first dose reduction within 
the first 52 weeks or before 
the treatment was 
prematurely[1] discontinued 
and the date of the event is 
known
Event 
Date of event
2
Patient had a documented 
first dose reduction within 
the first 52 weeks or before 
the treatment was 
prematurely[1] discontinued 
and the date of the event is 
unknown
Event 
Imputed date of event 
3
Patient did not have a 
documented first dose 
reduction within the first 52 
weeks or before the 
treatment was 
prematurely[1] discontinued 
Censored
Earliest of
Day 373 
(372 days after 
first drug intake)
or date of permanent 
premature[1] drug 
discontinuation
[1] Prematurely: Discontinuation of the treatment before completion of Visit 9.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 37 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 5.4.3.1: 2 
Censoring Rules for Time to first treatment interruption over 52 weeks
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
first treatment interruption 
within the first 52 weeks or 
before the treatment was 
prematurely[1] discontinued 
and the date of the event is 
known
Event 
Date of event
2
Patient had a documented 
first treatment interruption 
within the first 52 weeks or 
before the treatment was 
prematurely[1] discontinued 
and the date of the event is 
unknown
Event 
Imputed date of event 
3
Patient did not have a 
documented first treatment 
interruption within the first 
52 weeks or before the 
treatment was 
prematurely[1] discontinued 
Censored
Earliest of
Day 373 
(372 days after 
first drug intake)
or date of permanent 
premature[1] drug 
discontinuation
[1] Prematurely: Discontinuation of the treatment before completion of Visit 9.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 38 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 5.4.3.1: 3 
Censoring Rules for Time to premature treatment discontinuation over 
52 weeks 
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
premature treatment 
discontinuation within the 
first 52 weeks and the date 
of the event is known
Event 
Date of event
2
Patient had a documented 
premature treatment 
discontinuation within the 
first 52 weeks and the date 
of the event is unknown
Event 
Imputed date of event 
3
Patient did not have a 
premature treatment 
discontinuation within the 
first 52 weeks
Censored
Day 373 
(372 days after 
first drug intake)
5.4.3.2 Over the whole trial
Similarly, duration of exposure, duration on actual dose, total dose and dose intensity will be 
summarized over the whole trial. Time to first dose reduction and time to first interruption 
will also be computed and shown. 
Over this period, the categories for the duration of exposure will be: ≤3 months (91 days); >3 
months (91 days) to ≤6 months (182 days); > 6 months (182 days) to ≤12 months (365 days); 
> 12 months (365 days) to ≤18 months (547 days); > 18 months (547 days) to ≤ 24 months 
(730 days); > 24 months (730 days) 
Time to first dose reduction, time to first treatment interruption, as well as time to premature 
treatment discontinuation will also be evaluated via survival methods. Censoring rules can be 
found in Table 5.4.3.2: 1, Table 5.4.3.2: 2 and Table 5.4.3.2: 3 respectively.
Duration of exposure in patient years will also be shown per treatment group. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 39 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 5.4.3.2: 1 
Censoring Rules for Time to first dose reduction over the whole trial
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
first dose reduction before 
the treatment was 
permanently discontinued 
or the patient switched into 
the extension trial and the 
date of the event is known
Event 
Date of event
2
Patient had a documented 
first dose reduction before 
the treatment was 
permanently discontinued 
or the patient switched into 
the extension trial and the 
date of the event is 
unknown
Event 
Imputed date of event 
3
Patient did not have a 
documented first dose 
reduction before the 
treatment was permanently 
discontinued or the patient 
switched into the extension 
trial
Censored
Earliest date of permanent 
drug discontinuation, 
database lock or date of 
Informed Consent in 
extension trial[1]
[1] Date of Informed Consent in extension trial is not applicable for the primary analysis. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 40 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 5.4.3.2: 2 
Censoring Rules for Time to first treatment interruption over the whole 
trial
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
first treatment interruption 
before the treatment was 
permanently discontinued 
or the patient switched into 
the extension trial and the 
date of the event is known
Event 
Date of event
2
Patient had a documented 
first treatment interruption 
before the treatment was 
permanently discontinued 
or the patient switched into 
the extension trial and the 
date of the event is 
unknown
Event 
Imputed date of event 
3
Patient did not have a 
documented first treatment 
interruption before the 
treatment was permanently 
discontinued or the patient 
switched into the extension 
trial
Censored
Earliest date of permanent 
drug discontinuation, 
database lock or date of 
Informed Consent in 
extension trial[1]
[1] Date of Informed Consent in extension trial is not applicable for the primary analysis.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 41 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 5.4.3.2: 3 
Censoring Rules for Time to premature treatment discontinuation over 
the whole trial
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
premature treatment 
discontinuation and the date 
of the event is known
Event 
Date of event
2
Patient had a documented 
premature treatment 
discontinuation and the date 
of the event is unknown
Event 
Imputed date of event 
3
Patient did not have a 
documented premature 
treatment discontinuation 
and the patient switched 
into the extension trial 
Censored
Earliest date of database 
lock or date of Informed 
Consent in extension trial[1]
[1] Date of Informed Consent in extension trial is not applicable for the primary analysis.
5.4.4
Liver enzyme and bilirubin elevations
Liver enzyme and bilirubin elevations will be reported using the three following definitions: 
x
(ALT and/or AST ≥ 3xULN) AND bilirubin ≥ 2xULN*
x
ALT ≥ 5xULN and/or AST ≥ 5xULN
x
ALT ≥ 3xULN and/or AST ≥ 3xULN
*These elevations of ALT/AST/bilirubin are defined within a time window of 30 days i.e. the 
elevation of bilirubin should appear within 30 days after the elevation of AST and/or ALT.  
Depending on the number of patients experiencing liver enzyme elevations, other cut-offs 
may be considered.  
Signs of hepatic injury will also be presented based on the following definition: 
x
ALT and/or AST ≥8xULN
x
ALT and/or AST ≥3xULN and unexplained INR > 1.5 in the same sample 
x
ALT and/or AST ≥3xULN and unexplained eosinophilia (>5%) in the same 
sample
x
ALT and/or AST ≥3xULN and presence of fatigue, nausea, vomiting, right upper 
abdominal quadrant pain or tenderness, fever and/or rash (see Section 9.9 for 
details about MedDRA terms used to select relevant AEs) within +/- 7 days of the 
detected ALT or AST increase.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 42 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
In addition, maximum individual elevations based on worst value on treatment will be defined 
as:
x
≥3xULN; ≥5xULN; ≥8xULN for AST and ALT and AST and/or ALT
x
≥1.5xULN; ≥2xULN for Bilirubin
x
≥1.5xULN; ≥2xULN for alkaline phosphatase (ALK)
Time to first liver enzyme elevation will also be evaluated via survival methods. Censoring 
rules can be found in Table 5.4.4: 1 and Table 5.4.4: 2 below. 
Table 5.4.4: 1 Censoring Rules for Time to first liver enzyme elevation over 52 weeks
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
first liver enzyme elevation 
within the first 52 weeks or 
before the treatment was 
prematurely[1] discontinued 
and the end of the residual 
effect period (REP) has been
reached, and the date of the 
event is known
Event 
Date of event
2
Patient had a documented 
first liver enzyme elevation 
within the first 52 weeks or 
before the treatment was 
prematurely[1] discontinued 
and the end of the REP has 
been reached, and the date of 
the event is unknown
Event 
Imputed date of event 
3
Patient did not have a 
documented first liver 
enzyme elevation within the 
first 52 weeks or before the 
treatment was prematurely[1]
discontinued and the end of 
the REP has been reached.
Censored
If day of last drug intake < 
372 days after first drug 
intake:
Date of last drug intake +28 
days or date of death (if 
earlier)[2]
If day of last drug intake ≥ 
373: 
Date of first drug intake + 
372 days
[1] Prematurely: Discontinuation of the treatment before completion of Visit 9.
[2] Patients that die between date of permanent drug discontinuation and the end of the residual effect period will 
be censored at their date of death


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 43 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 5.4.4: 2 Censoring Rules for Time to first liver enzyme elevation over the whole trial
Rule #
Situation
Outcome
(event or censored)
Date of event or censoring
1
Patient had a documented 
first liver enzyme elevation 
before the treatment was 
permanently discontinued 
and the date of the event is 
known
Event 
Date of event
2
Patient had a documented 
first liver enzyme elevation 
before the treatment was 
permanently discontinued 
and the date of the event is 
unknown
Event 
Imputed date of event 
3
Patient did not have a 
documented first liver 
enzyme elevation before the 
treatment was permanently 
discontinued
Censored
Earliest date of database 
lock, date of permanent 
drug discontinuation + 28 
days or date of death[1][2][3]
[1] Date of permanent drug discontinuation may not have been reached when the primary analysis takes place. In 
this case, the date of database lock will be used. 
[2] Patients who switch to the extension study will only be evaluated until date of last drug intake in this study. 
The residual effect period will not apply, as patients will receive continuous treatment
[3] Patients that die between date of permanent drug discontinuation and the end of the residual effect period will 
be censored at their date of death. 
5.4.5 
Marked changes in vital signs 
A marked increase is defined as: 
x
Systolic Blood Pressure >150 mmHg and increase ≥ 25 mmHg above baseline 
x
Diastolic Blood Pressure >90 mmHg and increase ≥ 10 mmHg above baseline 
x
Pulse Rate >100 bpm and increase ≥ 10 bpm above baseline 
A marked decrease is defined as: 
x
Systolic Blood Pressure <100 mmHg and decrease >10 mmHg below baseline 
x
Diastolic Blood Pressure <60 mmHg and decrease >10 mmHg below baseline 
x
Pulse Rate <60 bpm and decrease >10 bpm below baseline 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 44 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For the definition of treatment administered during the trial, see Section 4 of CTP.
Note: the last day of each of the periods is excluded from the respective period. It defines the 
first day of the subsequent period. 
x
Screening: From informed consent to randomisation 
x
Post-randomisation (optional[a]): From randomisation to first trial drug intake in 
treatment period.
x
Treatment period: From first trial drug intake (or re-start of treatment if 
interruption) to last trial drug intake (or the day before start date of interruption if 
interruption) plus one day 
x
Off-treatment (optional[a]): From start date of interruption to re-start of treatment
x
Residual effect period[b]: From the last trial drug intake plus one day to last trial 
drug intake plus 28 days plus one day or to date of first trial drug intake in 
extension trial, whichever occurs earliest
x
Follow-up (optional[a][b]): From last trial drug intake plus 29 days up to the 
beginning of post-study period. This period is only created if last trial drug intake 
took place more than 28 days before trial completion, or for patients having 
prematurely discontinued the treatment and still continuing the trial
x
Post-study[a]: from the latest between last trial drug intake plus 29 days, ‘date of 
trial completion’ (from the Trial Completion page of the eCRF) plus one day and 
‘date of Informed Consent in extension trial’ plus one day (if applicable). This 
period is not created if date of first trial drug intake in extension trial is before last 
trial drug intake plus 28 days 
[a] This period is optional insofar as it does not necessarily exist for all patients.
[b] In addition, a residual effect period of 7 days will be used for safety analyses to more closely reflect the 
period of time after the last trial drug intake when measureable drug levels or pharmacodynamic effects are 
still likely to be present.
All analyses will be based on the planned treatment group (Placebo or Nintedanib 150mg bid) 
as randomised by IRT. 
6.1.1
Over 52 weeks
For efficacy and safety analyses over 52 weeks (Part A), data from first drug intake up to 
≤372 days after first drug intake will be considered. See Table 6.1.1: 1 for details about 
analysis periods for Part A according to the type of endpoint. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 45 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.1.1: 1 Summary of analysis periods over 52 weeks (Part A) according to the type of 
endpoint or analysis
Type of 
analysis
Analyses / Endpoints
Studied period
Start date[2]
End date [1]
Efficacy 
analyses over 
52 Weeks [2]
x
Analyses on all endpoints listed 
in Sections 5.1.1, 5.1.2 and 
5.1.3.1 of the CTP
Date of first 
drug intake
Date of last measurement before or 
at 52 Weeks (≤ 372 days after first 
drug intake)
On-treatment 
efficacy 
analyses over 
52 Weeks
x
Annual rate of decline in FVC in 
ml over 52 weeks, including only 
data until end date of studied 
period
Date of first 
drug intake
Date of last trial drug intake OR 
Week 52 time-point (≤ 372 days 
after first drug intake), whichever 
occurs first
Descriptive 
analyses over 
52 Weeks
Absolute change from baseline in:
x
FVC (ml) 
x
FVC (% of predicted)
x
DLCO (% of predicted )
x
Vital signs
x
K-BILD
x
L-PF
x
PF-IQOLS
Relative change from baseline in :
x
FVC (% of predicted)
Date of first 
drug intake
Date of last measurement before or 
at 52 Weeks (≤ 372 days after first 
drug intake) 
Extent 
of 
exposure 
analysis 
over 
52 weeks
See Section 5.4.3
Date of first 
drug intake
If day of last drug intake < 372
days after first drug intake
x
Date of last drug intake
Else, if day of last drug intake ≥ 
Day 373:
x
Date of first drug intake + 372 
days
Safety survival 
analysis 
Time to 
x
first liver enzyme elevation (for 
all 
definitions 
mentioned 
in 
Section 5.4.4) 
x
first onset of adverse event with 
additional information collection 
(diarrhoea, bleeding, ILD)
Date of first 
drug intake
If day of last drug intake < 372
days after first drug intake: 
x
Date of last drug intake + 28 
days
If day of last drug intake ≥ 373:
Date of first drug intake + 372 days
Time to
x
first dose reduction
x
first treatment interruption
x
premature 
treatment 
discontinuation
Date of first 
drug intake
If day of last drug intake < 372
days after first drug intake: 
x
Date of last drug intake
If day of last drug intake ≥ 373:
x
Date of first drug intake + 372 
days
On-treatment 
safety analysis 
over 52 weeks
x
Adverse events
x
Laboratory data
x
Vital signs
Date of first 
drug intake
If day of last drug intake < 372
days after first drug intake: 
x
Date of last drug intake + 28 
days
If day of last drug intake ≥ 373:
x
Date of first drug intake + 372 
days
[1] End date is included.
[2] Date of randomisation and date of first drug intake should be identical. If there are discordances between 
these dates on patient level, date of first drug intake will be used. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 46 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.1.2
Over the whole trial
For efficacy and safety analyses over the whole trial period (Part A and Part B), data from 
first drug intake up to the last visit in the trial will be considered. Please see Table 6.1.2: 1 for 
details about analysis periods over the whole trial (Part A + Part B) according to the type of 
endpoint. For the main analysis only data collected over the whole trial available at the time 
of data cut-off for DBL1 will be considered, whereas all data collected within the trial will be 
considered and reported for the final analysis. 
Table 6.1.2: 1 Summary of analysis periods over the whole trial (Part A and Part B)
according to the type of endpoint or analysis
Type of 
analysis
Analyses / Endpoints
Studied period
Start date[2]
End date[1][4]
Efficacy 
analyses
Analyses on all endpoints listed in Sections 
5.1.3.2 of the CTP
Date of first 
drug intake
Date of last measurement 
up to the last follow-up 
visit (included) or last 
contact date (as defined in 
Section 5)
Descriptive 
analyses 
over 
the trial period
Absolute change from baseline in:
x
FVC (ml)
x
FVC (% of predicted)
x
DLCO (% of predicted )
x
Vital signs
Relative change from baseline in :
x
FVC (% of predicted)
Date of first 
drug intake
Date of last measurement 
up to last follow-up visit 
(included)
Efficacy 
survival 
analysis
Time to all-cause mortality (over the trial 
period) 
Date of first 
drug intake
Last contact date (as 
defined in Section 5) 
Extent 
of 
exposure 
analysis overall
See Section 5.4.3
Date of first 
drug intake
Date of last drug intake
Safety survival 
analysis [3]
Time to 
x
first liver enzyme elevation (for all 
definitions mentioned in Section 5.4.4) 
x
first onset of adverse event with 
additional 
information 
collection 
(diarrhoea, bleeding, ILD)
Date of first 
drug intake
Date of last drug intake + 
28 days
Time to
x
first dose reduction
x
first treatment interruption
x
premature treatment discontinuation
Date of first 
drug intake
Date of last drug intake
On-treatment 
safety analysis 
overall [3]
x
Adverse events
x
Laboratory data
x
Vital signs
Date of first 
drug intake
Date of last drug intake + 
28 days
[1] End date is included.
[2] Date of randomisation and date of first drug intake should be identical. If there are discordances between 
these dates on patient level, date of first drug intake will be used.
[3] Patients who switch to the extension study will only be evaluated until date of last drug intake in this study. 
The residual effect period will not apply, as patients will receive continuous treatment.
[4] For the main analysis only data collected over the whole trial available at the time of data cut off for DBL1 
will be considered, whereas all data collected within the trial will be considered and reported for the final 
analysis. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 47 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.2
IMPORTANT PROTOCOL DEVIATIONS
No per protocol set analysis will be performed for this study; however, the following list in 
Table 6.2: 1 defines the different categories of potentially important protocol deviations 
(IPD), and it shows whether patients will potentially be excluded from evaluations performed 
in this trial. Potentially important protocol deviations will be handled according to BI 
standards (6), and the proportion of patients with IPDs will be presented for completeness 
purposes and to demonstrate the adherence to the CTP. Several IPDs are defined over 52 
weeks because the primary assessment of benefit-risk of nintedanib in PF-ILD will be based 
on the analysis over 52 weeks (Part A). These IPDs will also be considered over the whole 
trial, and the respective summary will be presented as well in the CTR.
Table 6.2: 1 
Important protocol deviations 
Category/Code
Description
Requirements
Excluded from
A
Entrance Criteria Not Met
A1
Inclusion criteria not met
A1.1
Male or female patients 
aged ≥ 18 years at Visit 1
Inclusion criterion 2 not met (or other age 
restriction specified as per a local 
amendment)
$XWRPDWLF,3'
None
A1.2
At least one criteria for PF-
ILD fulfilled 
within 24 
months of Visit 1 despite 
treatment with unapproved 
medications used in clinical 
practice to treat ILD
Inclusion criteria 3a, 3b, 3c or 3d not met
$XWRPDWLF,3'

$GGLWLRQDOQRWH
5HTXLUHPHQW
IRU
WUHDWPHQW
ZLWK
XQDSSURYHG PHGLFDWLRQV  LV UHODWLYH DQG
GRHVQRWDSSO\IRUDOO,/'V7KHUHIRUHODFN
RI SUHYLRXV WKHUDS\ LV 127 WR EH
FRQVLGHUHGIRUWKLV,3'
None
A1.3
Extent 
of 
lung 
fibrosis 
> 10% on HRCT performed 
within 12 months of Visit 1
Inclusion criterion 4 not met; or extent of 
fibrosis ≤ 10% according to database 
(evaluated by central review)
$XWRPDWLF,3'

$GGLWLRQDOQRWH
,IWKH+5&7VFDQLVROGHUWKDQPRQWKV
EXW LW LV UHDG E\ WKH FHQWUDO UHYLHZ WKH
FDVHLVQRWDQ,3'6LPLODUO\LIWKHLPDJH
DFTXLVLWLRQ FULWHULD DUH QRW PHW EXW WKH
LPDJHZDVUHDGWKHFDVHLVQRWDQ,3'
None
A1.4
For patients with underlying 
connective tissue disease 
(CTD):  stable CTD as 
defined by no initiation of 
new therapy or withdrawal 
of therapy for CTD within 6 
weeks prior to Visit 1.
Inclusion criterion 5 not met.
$XWRPDWLF,3'

$GGLWLRQDOQRWH
$Q\ FKDQJH LQ &7' WKHUDS\ ZLWKLQ  
ZHHNVSULRUWR9LVLWLVWREHFRQVLGHUHG
DV,3'
None


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 48 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.2: 1 
Important protocol deviations (continued) 
Category/Code
Description
Requirements
Excluded from
A2
Exclusion criteria met
A2.1
Patient has laboratory values 
that indicate additional risk 
at Visit 1:
a) >1.5xULN for AST or 
ALT
b) >1.5xULN for Bilirubin
c) Creatinine clearance < 30 
ml /min (Cockcroft-Gault 
formula)
Laboratory values out of tolerated ranges 
at visit 1 according to the database:
a) 1.5xULN for AST or ALT (exclusion 
criterion 1 not met)
b) 1.5xULN for Bilirubin (exclusion 
criterion 2 not met)
c) Creatinine clearance < 30 ml /min 
(Cockcroft-Gault 
formula) 
(exclusion 
criterion 3 not met)
$XWRPDWLF,3'

$GGLWLRQDOQRWH
,Q WKH &75 7DEOH LW VKRXOG VKRZ ZKLFK
FULWHULD DUH YLRODWHG KRZHYHU GHYLDWLRQV
RI PXOWLSOH VXEFDWHJRULHV ZLOO RQO\
FRXQWHGRQFHWRZDUGVWKHRYHUDOOFDWHJRU\
None
A2.2
Patient with other under-
lying diseases, conditions or 
risks which are excluded as 
per clinical trial protocol
a) chronic liver disease 
(Child Pugh A, B or C 
hepatic impairment)
b) IPF
c) Significant pulmonary 
Arterial Hypertension
d) Major extrapulmonary 
physiological restriction
e) Cardiovascular disease 
within 6 months of Visit 1
f) Bleeding risk
g) History of thrombotic 
events within 12 months of 
Visit 1
h) Known hypersensitivity 
to the trial medication or its 
components
i) Peanut allergy
Pathients who:
a) suffer from chronic liver disease (Child 
Pugh A, B or C) (exclusion criterion 4 
met)
b) are diagnosed with IPF (exclusion 
criterion 8 met)
c) show significant pulmonary arterial 
hypertension (exclusion criterion 9 met)
d) 
show 
major 
extrapulmonary 
physiological restriction (exclusion crite-
rion 12 met) or according to central review 
(“are there any co-existing HRCT features 
that would exclude this patient” is ticked 
with “yes”)
e) have a history of cardiovascular disease 
within 6 months of Visit 1 (exclusion crite-
rion 13 met)
f) have extended bleeding risk (exclusion 
criterion 14 met)
g) have a history of thrombotic events 
within 12 months of Visit 1 (exclusion 
criterion 15 met)
h) have a known and documented 
hypersensitivity to the trial medication or 
its components (exclusion criterion 16 
met)
i) have a known and documented peanut 
allergy (exclusion criterion 17 met)
at visit 1.
$XWRPDWLF,3'

$GGLWLRQDOQRWH
,Q WKH &75 7DEOH LW VKRXOG VKRZ ZKLFK
FULWHULD DUH YLRODWHG KRZHYHU GHYLDWLRQV
RI PXOWLSOH VXEFDWHJRULHV ZLOO RQO\
FRXQWHGRQFHWRZDUGVWKHRYHUDOOFDWHJRU\
None


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 49 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.2: 1 
Important protocol deviations (continued) 
Category/Code
Description
Requirements
Excluded from
A2.3
Forbidden previous therapy 
as per clinical trial protocol
a) Previous treatment with 
nintedanib or pirfenidone
b) 
Other 
investigational 
therapy received witin 1 
month 
or 
6 
half-lives 
(whichever greater) prior to 
Visit 1
c) Any of the following 
medications for the treat-
ment of ILD: azathioprine 
(AZA), 
cyclosporine, 
mycophenolate 
mofetil 
(MMF), 
tacrolimus, 
oral 
cortico-steroids 
(OCS) 
>20mg/day 
and 
the 
combination of OCS + AZA
+ n-acetylcysteine (NAC) 
within 4 weeks of Visit 2, 
cyclophosphamide within
8 
weeks 
of 
Visit 
2, 
rituximab within 6 months 
of Visit 2
Patients who have:
a) ever been treated with nintedanib or 
pirfenidone (exclusion criterion 5 met)
b) received other investigational therapy 
witin 1 month or 6 half-lives (whichever 
greater) prior to Visit 1 (exclusion criterion 
6 met)
c) used azathioprine, cyclosporine, MMF, 
tacrolimus, OCS >20mg/day and the 
combination of OCS+AZA+NAC within 4 
weeks of Visit 2, cyclophosphamide within 
8 weeks of Visit 2, rituximab within 6 
months of Visit 2 (exclusion criterion 7 
met)
0DQXDO ,3' EDVHG RQ H[FOXVLRQ FULWHULD
DQGRUWREHLGHQWLILHGDWWKHVLWHOHYHORQ
WKHPDQXDO3'ORJ

$GGLWLRQDOQRWH
,Q WKH &75 7DEOH LW VKRXOG VKRZ ZKLFK
FULWHULD DUH YLRODWHG KRZHYHU GHYLDWLRQV
RI PXOWLSOH VXEFDWHJRULHV ZLOO RQO\
FRXQWHGRQFHWRZDUGVWKHRYHUDOOFDWHJRU\
None
A2.4
Potential risk related to 
fetotoxicity
Women who fulfil the following criteria at 
Visit 1 and:
a) are pregnant, nursing, or who plan to 
become pregnant while in the trial 
(exclusion criterion 21 met)
b) are of childbearing potential not willing 
or able to use highly effective methods of 
birth control per ICH M3 (exclusion 
criterion 22 met)

$XWRPDWLF,3'

$GGLWLRQDOQRWH
,Q WKH &75 7DEOH LW VKRXOG VKRZ ZKLFK
FULWHULD DUH YLRODWHG KRZHYHU GHYLDWLRQV
RI PXOWLSOH VXEFDWHJRULHV ZLOO RQO\
FRXQWHGRQFHWRZDUGVWKHRYHUDOOFDWHJRU\
None
B
Informed Consent
B1
Informed consent not given
Inclusion criterion 1 not met
$XWRPDWLF,3'
All


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 50 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.2: 1 
Important protocol deviations (continued) 
Category/Code
Description
Requirements
Excluded from
B2
Informed consent given too 
late
eCRF date of informed consent is after 
date of Visit 1
$XWRPDWLF,3'

$GGLWLRQDOQRWH
6LJQDWXUH RI WKH ZURQJ ,& YHUVLRQ DQG
ODWHUVLJQDWXUHRIWKHFRUUHFWRQHZLOODOVR
EH SDUW RI WKLV ,3' FDWHJRU\ 7KLV FDQ
KRZHYHURQO\EHGHWHUPLQHGYLDDPDQXDO
SURFHVV
None
B3
Informed consent not given 
or withdrawn for optional
HRCT but optional HRCT 
done
According to HRCT database and eCRF 
page informed consent for optional HRCT
0DQXDO,3'
None
C
Trial 
medication 
and 
randomisation
C1
Incorrect trial medication 
taken between baseline and 
Week 52
Medication taken (between randomisation 
and Week 52) that is not matching the 
treatment a patient was randomised to.
7KLV
FDQ
RQO\
EH
GHWHUPLQH
DIWHU
XQEOLQGLQJ 3URJUDPPLQJ VXSSRUW IRU
OLVWLQJ JHQHUDWLRQ QHHGHG EXW D PDQXDO
DOORFDWLRQSURFHVV

$GGLWLRQDOQRWH
,QWKH&757DEOHRQO\WKHGHYLDWLRQLWVHOI
ZLOOEHVKRZQDGGLWLRQDOLQIRUPDWLRQHJ
GRVH OHYHO WLPH SRLQW GXUDWLRQ RI WKH
ZURQJPHGLFDWLRQLQWDNHHWFZLOOEHSDUW
RIDOLVWLQJ
None
C2
Randomisation not followed
The wrong medication kit is given, leading 
to the patient taking treatment different 
from the one randomised by IRT at time of 
randomisation (Visit 2).
7KLV
FDQ
RQO\
EH
GHWHUPLQH
DIWHU
XQEOLQGLQJ 3URJUDPPLQJ VXSSRUW IRU
OLVWLQJ JHQHUDWLRQ QHHGHG EXW D PDQXDO
DOORFDWLRQSURFHVV
$GGLWLRQDOQRWHV
7KLVLVRQO\DQ,3'LIWKHPHGLFDWLRQHUURU
OHDGVWRDQDFWXDOWUHDWPHQWVZLWFK
None


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 51 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.2: 1 
Important protocol deviations (continued) 
Category/Code
Description
Requirements
Excluded from
C3
Overall compliance between 
randomisation and Week 52 
not between 80% and 120% 
inclusive (or noncompliance 
based 
on 
investigator 
assessment)
In case calculated overall compliance is 
missing: If the answer to the question “Did 
the patient take trial medication as 
instructed?” of the eCRF is “No” at at least 
one of the visits where the compliance 
cannot be calculated, then an IPD will be 
flagged. Otherwise no IPD
although 
calculated overall compliance is missing.
$XWRPDWLF ,3' ZLWK UHYLHZ RI 0450
OLVWLQJV
None
C4
Trial 
medication 
not 
interrupted when ALT or 
AST ≥ 5 fold ULN
Based on eCRF dose interruption and 
adverse event pages between first drug 
intake and and Week 52
0DQXDO,3'
None
C5
Trial 
medication 
not 
permanently 
discontinued 
after signs of liver enzyme 
elevations were observed 
that 
a) are indicative of hepatic 
injury as defined in Section 
5.3.6.1 of the CTP
b) correspond to ALT or 
AST ≥ 3 fold ULN despite 
dose reduction or treatment 
interruption for 2 weeks or 
more
All patients where signs of liver enzyme 
elevations are not dealt with according to
the requirements of the CTP.

3URJUDPPDWLFVXSSRUWZLOOEHUHTXLUHGWR
IODJ SDWLHQWV ZKR PD\ IXOILO WKH FULWHULD
KRZHYHU D PDQXDO UHYLHZ RI RXWSXWV LV
UHTXLUHG

$GGLWLRQDOQRWH
,Q WKH &75 7DEOH LW VKRXOG VKRZ ZKLFK
FULWHULD DUH YLRODWHG KRZHYHU GHYLDWLRQV
RI PXOWLSOH VXEFDWHJRULHV ZLOO RQO\
FRXQWHG
RQFH
WRZDUGV
WKH
RYHUDOO
FDWHJRU\
None


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 52 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.2: 1 
Important protocol deviations (continued) 
Category/Code
Description
Requirements
Excluded from
D
Concomitant Medication
D1
Patients who received either 
azathioprine, cyclosporine, 
tacrolimus, 
Rituximab, 
Cyclophosphamide, 
mycophenolate 
mofetil, 
OCS >20mg/day for the 
treatment of ILD or CTD:
a) within the first 6 months 
of study treatment
b) after 6 months of study 
treatment without significant 
deterioration of ILD or CTD
Patients should be flagged program-
matically 
who 
take 
any 
of 
the 
aforementioned medications. It would 
have to be manually checked if:
a) Any of these medications is used during 
the first 6 months of study AND NO 
documentation of exacerbation of ILD is 
provided; or if the medication is used for 
the treatment of the CTD.
b) Any of these medications is used after 6 
months of study medication AND NO 
documentation of worsening of the ILD or 
exacerbation of ILD is provided; or no 
documentation of worsening of the CTD is 
provided

3URJUDPPDWLFVXSSRUWZLOOEHUHTXLUHGWR
IODJ SDWLHQWV ZKR PD\ IXOILO WKH FULWHULD
KRZHYHU D PDQXDO UHYLHZ RI RXWSXWV LV
UHTXLUHG

$GGLWLRQDOQRWH
,Q WKH &75 7DEOH LW VKRXOG VKRZ ZKLFK
FULWHULD DUH YLRODWHG KRZHYHU GHYLDWLRQV
RI PXOWLSOH VXEFDWHJRULHV ZLOO RQO\
FRXQWHGRQFHWRZDUGVWKHRYHUDOOFDWHJRU\
None
D2
Patients who received either 
pirfenidone, nintedanib (in 
another occurrence than as 
study medication) or any 
other 
investigation 
drug 
during the entire duration of 
their study participation.
Any
occurrence of such concomitant 
therapy is to be flagged as IPD. 

$XWRPDWLF,3'

$GGLWLRQDOQRWH
,Q WKH &75 7DEOH LW VKRXOG VKRZ ZKLFK
PHGLFDWLRQZDVWDNHQKRZHYHUGHYLDWLRQV
UHJDUGLQJ PXOWLSOH PHGLFDWLRQV ZLOO RQO\
FRXQWHGRQFHWRZDUGVWKHRYHUDOOFDWHJRU\
Automatic PDs are those detected via an automated programming process using SAS®. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 53 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.3
PATIENT SETS ANALYSED
x
Screened set (SCS):
o
This patient set includes all patients having signed informed consent. 
x
Randomised set: (RS) 
o
This patient set includes all randomised patients, whether treated or not. 
x
Treated set (TS):
o
This patient set includes all randomised patients who received at least one dose 
of trial medication. The TS also reflects the “the overall population” for the 
analyses and is considered as one of the two co-primary populations. 

The subpopulation of patients with “HRCT with UIP-like fibrotic 
pattern only” (actual HRCT pattern as documented in the eCRF) is 
considered as the second co-primary population. 

The subpopulation of patients with “other HRCT fibrotic patterns” 
(actual HRCT pattern as documented in the eCRF) is referred to as 
complementary population 
Both subpopulations are mutually exclusive, and together they form the overall 
population. Evaluations will be done on both co-primary populations and the 
complementary population. 
x
PK set (PKS)
o
This patient set includes those patients in the TS with at least one valid plasma 
concentration available
Please note: Details on which set or population is used for which analysis and output can be 
found in this statistical analysis plan. 
6.4
SUBGROUPS
The subgroups listed in Table 6.4: 1 will be investigated, provided that the: 
x
actual size of the individual subgroup expression level is large enough (>10% of the 
treated patients)
x
distribution of patients within subgroup expression level across the two treatment arms
allow for meaningful analyses. Groups that are too small will be pooled in a meaningful 
manner. Selected variables as defined in Section 5.4 will be used to characterize the study 
population in all subgroups. In addition, evaluations will be performed to determine efficacy 
as well as safety in these pre-selected subgroups. For more details on the planned analysis, 
please refer to Section 7.4.3.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 54 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.4: 1 
Subgroup analyses – List of subgroups 
Description
of study 
population
[1][2]
Efficacy analyses on 
the primary endpoint 
in the overall 
population [1][3]
Safety 
analyses in 
the overall 
population
[1][3]
Gender (Male / Female)
X
X
X
Age (<65 / ≥65)
X
X
X
Race[4] (White / Asian / Black or African 
American)
X 
X 
X 
Baseline FVC % predicted (≤70% / >70%)
X
X
X
Underlying clinical ILD diagnosis 
(Hypersensitivity pneumonitis / Idiopathic 
nonspecific interstitial pneumonia / Unclassifiable 
idiopathic interstitial pneumonia / Autoimmune 
ILD[5] / Other ILDs[6])
X 
X 
X 
Baseline bodyweight (≤65kg / >65kg)
X
X
Patients receiving / not receiving DMARDs with 
known hepatotoxic effects at baseline
X 
X 
Patients receiving / not receiving DMARDs with 
known gastrointestinal effects at baseline
X 
X 
Methotrexate use at baseline (Yes / No)
X
X
[1] For more details regarding analyses, please refer to Table 7.4.3: 1. 
[2] The description of study population for all described subgroups will be provided for the two co-primary 
populations as well as for the complementary population
[3] Please note that the primary endpoint analyses and safety analyses by subgroup will also be performed in the 
co-primary population of patients with “HRCT with UIP-like fibrotic pattern only” for gender, age and race
[4] Please note that only single race respondents are taken into account. “American Indian or Alaska Native” 
patients, or patients that classify themselves as “Native Hawaiian or other Pacific Islander”, are pooled with 
“Asian” patients in the subgroup evaluations, due to the very low number of patients in those expression 
levels.
[5] For the purpose of the subgroup analysis based on grouped clinical ILD diagnoses, a new category of 
“Autoimmune ILDs” was created. This category includes all cases from the individual eCRF categories of 
“Rheumatoid Arthritis associated ILD”, “Systemic sclerosis associated ILD”, “Mixed connective tissue 
disease” as well as cases identified as “autoimmune ILD” from the eCRF category of “Other fibrosing ILD”
(see Table 9.13: 1 for details). The classification of these cases in the eCRF category“Other fibrosing ILD 
was reviewed and confirmed by the Steering Committee.
[6] For the purpose of the subgroup analysis based on grouped clinical ILD diagnoses a new category of “Other 
ILDs” was created. This category includes all cases from the individual eCRF categories of “Exposure-
related ILD”, “Sarcoidosis” as well as cases itentified as other ILD (“other ILD” and “exposure-related ILD”
– see Table 9.13: 1 for details) from the eCRF category of “Other fibrosing ILD”. The classification of these
cases in the eCRF category“Other fibrosing ILD” was reviewed and confirmed by the Steering Committee
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
In general, missing data will not be imputed. Exceptions are detailed in the subsequent 
subsections. 
Two patients with non-determined HRCT pattern by central readers were randomised by 
mistake, and those patients will generally be evaluated according to the information used 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 55 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
during their randomisation in the IRT system (“other HRCT fibrotic patterns” for both 
patients) in all analyses considering the actual HRCT pattern, including the primary analysis. 
They will be evaluated as “Patients with HRCT with UIP-like fibrotic pattern only” in the 
sensitivity analysis investigating the potential effect of mis-stratification. 
6.6.1
Primary endpoint
The statistical model used for primary analysis (see Section 7.3.1 of CTP) allows for missing 
data, assuming they are missing at random (MAR). Even patients with only one post-baseline 
assessment can be included in the model and can therefore participate in variance estimation. 
The statistical model assumes that patients who prematurely discontinue study participation
would have behaved similarly to those who remained in the study.
Sensitivity analyses using alternative assumptions will be conducted to investigate the 
potential effect of missing data on the results of the primary analysis (see Section 7.4.2 and 
Section 9.12.1).  
6.6.2
Secondary and further endpoints
6.6.2.1 Change from baseline endpoints 
The statistical Mixed effect Model for Repeated Measures (MMRM) used for the analysis of 
continuous secondary endpoints allows for form-level missing data, assuming they are 
missing at random. Item-level data for the PRO measures will be handled according to the 
instructions provided by the instrument developer.
6.6.2.1.1 
K-BILD
Missing item scores are imputed based on the average of the non-missing item scores within 
the domain, rounded to the nearest integer. If the missing items are >50% per domain, then 
the domain score is set to missing. If item 15 is missing, it will be replaced by the average of 
all available items 1-14. If any of the domain scores are missing, the total score is set to 
missing.
6.6.2.1.2 
L-PF
The L-PF scores represent means. Missing items are generally not counted in the 
denominator. Please note the following exception for the Dyspnea score items 1, 2.4-10 and 
12
x
If “No” is ticked and “B” is ticked, then the item is not scored and does not contribute 
to the denominator. 
x
if “No” is ticked and neither “A” nor “B” is ticked, the item is counted as missing 
BUT the item DOES contribute to the denominator
If the missing items are ≥50% within a score, then the corresponding score is set to missing.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 56 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.6.2.1.3
PF-IQOLS
Missing item scores are imputed by using the average of all available individual dimension 
ratings (items 1-16) for the missing item. If the missing items are >50%, then the PF-IQOLS 
score is set to missing.
6.6.2.2
Time-to-event endpoints 
In the analyses of the time-to-event endpoints, missing or incomplete data will be managed by 
standard survival analysis techniques (i.e. censoring). 
For the time to first acute ILD exacerbation, or first non-elective hospitalization in case of 
partially missing dates, the following imputation will be done:  
x
If day is missing, then imputed day will be the 15th of the month 
x
If day and month are missing, then imputed date will be the 1st of July of the (non-
missing) year
x
If year is missing, date will not be imputed
A missing or incomplete date of death will be imputed/completed so that the derived date is 
the earliest possible date which is on or after date of onset of the fatal AE, and on or after 
treatment start (in case this AE is treatment emergent), and on or after date of last contact.
6.6.2.3
Categorical endpoints
In the analyses of the binary endpoints, patients with missing data will be considered as 
non-responders (worst case analysis). 
6.6.3
Other variables 
6.6.3.1 Concomitant therapies 
In case of (partially) missing start and end dates of concomitant therapies, the dates will be 
imputed so that the extent of exposure to the concomitant therapy is maximal, i.e. the first day 
(month) of the month (year) for incomplete start dates and the last day (month) of the month 
(year) for incomplete end dates.
6.6.3.2
Safety endpoints
Missing or incomplete AE dates will be imputed according to BI standards (7).
6.6.3.3
Trial diagnosis date 
In case of partially missing date of trial diagnosis, the following imputation will be done: 
x
If day is missing, then imputed day will be the 1st of the month 
x
If day and month are missing, then imputed date will be the 1st of January of the 
(non-missing) year
x
If year is missing, date will not be imputed


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 57 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.6.3.4 Pharmacokinetic endpoints 
Missing data and outliers of PK data are handled according to (4).
Handling of missing PK data will be performed according to the BI standard procedure (5).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
As a general rule, the last assessment / measurement observed prior to start of trial medication 
will be assigned to baseline. Note that for some trial procedures (e.g. body weight, vital signs, 
laboratory tests) this may be the value measured on the same day trial medication was started. 
In these cases it will be assumed that the measurements were taken prior to the intake of any 
study medication (if the measurement time was not captured). If no further data available, this 
can also be the last screening assessment.
Visit windowing will be performed as described in Table 6.7: 1, Table 6.7: 2, Table 6.7: 3 and 
Table 6.7: 4, in order to assign data to the relevant study visit based on the actual day of the 
assessment. Data will be analysed using the re-calculated visits in the statistical tables.
However, in the listings, all visits performed will be displayed (even if outside time-window), 
along with the re-calculated visit.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 58 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.7: 1 
Time windowing rules for spirometry (FVC), physical exam, vital signs
Time window of actual day [1]
Allocated to
Start (Sn) day
End (included) 
(En) day
Length 
of 
the 
time-
window 
[days]
Visit 
number 
(n)
Visit name
Planned day 
of the visit 
(Vn)
-84
1
85
2
Baseline
1
2
22
21
3
2 weeks
15
23
36
14
4
4 weeks
29
37
64
28
5
6 weeks
43
65
127
63
6
12 weeks
85
128
211
84
7
24 weeks
169
212
309
98
8
36 weeks
253
310
373
64
9
52 weeks
365
374 (Sp)
Ep
= (Vp
+
Vp+1)/2 = 533
Ep-Sp +1 = 
160
10
68 weeks
477 (Vp)
Ep + 1
(Vp+1 + Vp+2)/2
Ep+1-Sp+1 +1
11
84 weeks
589 (Vp+1)
…
…
…
…
Every 
16 
weeks 
thereafter
…
[1] First trial drug intake date is taken into account as a reference to calculate time windows
Table 6.7: 2 
Time windowing rules for K-BILD, L-PF, PF-IQOLs, SpO2 
Time window of actual day [1]
Allocated to
Start day
End 
day 
(included)
Length 
of 
the 
time-
window 
[days]
Visit 
number
Visit name
Planned day of 
the visit
-84
1
85
2
Baseline
1
2
127
126
6
12 weeks
85
128
211
84
7
24 weeks
169
212
309
98
8
36 weeks
253
310
373
64
9
52 weeks
365
[1] First trial drug intake date is taken into account as a reference to calculate time windows
Note: SpO2 not measured at visits 6 and 8


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 59 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.7: 3 
Time windowing rules for DLCO 
Time window of actual day [1]
Allocated to
Start (Sn) day
End (included) 
(En) day
Length 
of 
the 
time-
window 
[days]
Visit 
number 
(n)
Visit name
Planned day 
of the visit 
(Vn)
-84
1
85
2
Baseline
1
128
211
84
7
24 weeks
169
310
373
64
9
52 weeks
365
374 (Sp)
Ep
= (Vp
+
Vp+1)/2 = 533
Ep-Sp +1 = 
160
10
68 weeks
477 (Vp)
Ep + 1
(Vp+1 + Vp+2)/2
Ep+1-Sp+1 +1
11
84 weeks
589 (Vp+1)
…
…
…
…
Every 16 weeks 
thereafter
…
[1] First trial drug intake date is taken into account as a reference to calculate time windows
Table 6.7: 4 
Time windowing rules for laboratory measurements (and pregnancy test)
Time window of actual day [1]
Allocated to
Start day
End 
day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned 
day 
of the visit
-42
1
43
2
Baseline
1
2
22
21
3
2 weeks
15
23
36
14
4
4 weeks
29
37
64
28
5
6 weeks
43
65
106
42
6
12 weeks
85
107
148
42
6a
18 weeks
127
149
190
42
7
24 weeks
169
191
232
42
7a
30 weeks
211
233
281
49
8
36 weeks
253
282
337
56
8a
44 weeks
309
338
373
36
9
52 weeks
365
374
449
76
9a
60 weeks
421
450
505
56
10
68 weeks
477
506 (Sp)
Ep
= (Vp
+
Vp+1)/2 = 561
Ep-Sp +1 = 56
10a
76 weeks
533 (Vp)
Ep + 1
(Vp+1
+
Vp+2)/2
Ep+1-Sp+1 +1
11
84 weeks
589 (Vp+1)
…
…
…
…
Every 8 weeks 
thereafter
…
[1] First trial drug intake date is taken into account as a reference to calculate time windows
If after windowing of visits at baseline, two or more values fall within the same baseline 
interval, then the last value prior to first drug intake will be taken into account. If after 
windowing of post-baseline visits, two visits fall in the same interval, then the measurement 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 60 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
closest to the planned visit will be taken into account. In case two measurements are 
equidistant from the planned visit, then the last one will be picked. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 61 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.
PLANNED ANALYSIS
Planned analyses can be categorized based on: 
x
The study period for which they are performed: 
o
Over 52 weeks (Part A) and over the whole trial (Part A and Part B together) 
x
The study population for which they are performed: 
o
The co-primary populations (“overall” population or sub-population of patients 
with “HRCT with UIP-like fibrotic pattern only”), or the complementary 
patient population of patients with “other HRCT fibrotic patterns”. 
Unless specified otherwise, analyses over 52 weeks (Part A) and over the whole trial (Part A 
and Part B) will be produced on both co-primary populations. In addition, selected analyses
over 52 weeks and over the whole trial will be produced on the complementary population of 
patients with “other HRCT fibrotic patterns”. Details can be found in subsequent sections.
Please note that analyses based on the complementary population will, by default with only 
few exceptions, be part of the CTR appendix. 
The labelling and display format of statistical parameters will follow BI standards (9). For 
End-Of-Text tables, the set of summary statistics is: N / Mean / SD / Min / Median / Max. In 
descriptive statistics tables, mean, sd and median will be rounded to one additional digit than 
the raw individual value. In case extreme data outside of the expected range are observed,
quartiles and percentiles will be presented additionally. 
Tabulations of frequencies for categorical data will include all categories depicted in the 
eCRF and will display the number of observations in a category as well as the percentage (%) 
relative to the respective treatment group (unless otherwise specified, all patients in the 
respective patient set whether they have non-missing values or not). Percentages will be 
rounded to one decimal place. The category missing will be displayed only if there are 
actually missing values.
If not otherwise specified, two-sided p-values and confidence intervals will be displayed. 
Please note that the depiction of p-values in outputs will be limited to the following 
evaluations: 
x
Primary analysis performed in both co-primary populations 
x
Sensitivity analyses of the primary endpoint analysis in both co-primary populations 
x
Nominal p-values for the evaluation of the main secondary endpoints, evaluated in 
both co-primary populations 
x
Interaction p-values for the efficacy evaluations in the subgroup analyses  
The primary analyses will include all treated patients.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 62 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
A table in the CTR will present the number of patients screened, randomised and treated. The 
number of patients prematurely discontinuing their study treatment will be shown with the 
reasons for discontinuation. The number and percent of patients completing the end of 
treatment visit and the number of patients with treatment ongoing will also be presented.
Please note there will be ongoing patients at the time of the data cut-off for the primary 
analysis; at the time point when the final analysis will take place there will not be any more 
ongoing patients in this trial. Where percentages are shown, the denominator will be the 
number of patients treated in each treatment group.
Descriptive statistics as well as frequency counts will be provided for all demographic and 
baseline characteristics depicted in Section 5.4.1. The CTR tables will show the relevant 
descriptive statistics (number and percent within categories; other descriptive statistics for 
continuous variables) by treatment arm. 
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. 
7.2.1
Baseline conditions and cardiovascular medical history
The baseline conditions will be included as coded items using the current Medical Dictionary 
for Regulatory Activities (MedDRA) version in use at BI at the time of database lock. They 
will be summarised by MedDRA system organ class (SOC) and Preferred Term. The CTR
table will show the counts of patients with a Baseline condition in each SOC present (SOC 
sorted by standard European Medicines Agency (EMA) order) and then the conditions 
(preferred terms) under that SOC in descending order of overall prevalence. This summary 
will be produced on all patients and by the patient’s underlying HRCT patterns.
The relevant cardiovascular medical history will be summarised, with particular focus on 
myocardial infarction, transient ischemic attacks, stroke, cardiac arrhythmia and heart failure.
7.2.2
Concomitant therapies
The following categories of concomitant therapies have been created:
x
Previous therapies 
o
Defined as treatments with an end date before first trial drug intake.  
x
Baseline therapies
o
Defined as treatments with a start date before first trial drug intake and taken 
after or on the day of the first trial drug intake.
x
On-treatment concomitant therapies
o
Defined as treatments with a start date after or on the day of first trial drug 
intake and before or on the day of last trial drug intake. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 63 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
x
Post-study drug discontinuation therapies 
o
Defined as treatments with a start date after last trial drug intake and before 
trial completion (as defined in Section 6.2.3 of the CTP). 
The analysis of concomitant therapies will be based on the following groupings of the 
aforementioned categories of concomitant therapies:
x
Baseline therapies
x
Baseline and on-treatment concomitant therapies 
x
On-treatment concomitant therapies
Concomitant therapies will be described over the first 52 weeks, as well as over the entire 
duration of the study. 
Table 7.2.2: 1 and Table 7.2.2: 2 summarise the concomitant therapy outputs which will be 
provided over 52 weeks and over the whole trial respectively. Summaries by ATC and 
preferred name (PN) will use the ATC3 code, and will be sorted by alphabetical ATC class 
and decreasing frequency of PN in all patients within ATC class. Summaries by Customized 
drug groupings of interest (CDG) will be sorted by alphabetical CDG and decreasing 
frequency of PN in all patients within CDG. CDGs can be found in Section 9.7. Restricted or 
forbidden concomitant therapies including categorisations as well as World Health 
Organization Drug Dictionary (WHO-DD) code are listed in Section 9.8. Please note that the 
most recent WHO-DD version in use at BI at the time of database lock is used.
Table 7.2.2: 1 Concomitant therapy outputs over 52 weeks. 
By ATC and PN
By CDG and PN
Co-primary
populations
Complementary
population 
Co-primary
populations
Complementary
population
Baseline therapies
15.1
16.1.13.1
15.1
16.1.13.1
All baseline and on-
treatment 
concomitant therapies 
with a frequency >2% 
in at least one 
treatment arm
15.1
16.1.13.1
- 
- 
All baseline and on-
treatment 
concomitant therapies
16.1.13.1
16.1.13.1
- 
- 
All on-treatment 
restricted
concomitant therapies
- 
- 
15.1
16.1.13.1
All on-treatment 
prohibited 
concomitant therapies
- 
- 
16.1.13.1
16.1.13.1


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 64 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 7.2.2: 2 Concomitant therapy outputs over the whole trial. 
By ATC and PN
By CDG and PN
Co-primary
populations
Complementary
population
Co-primary
populations
Complementary
population 
All baseline and on-
treatment 
concomitant therapies 
with a frequency >2% 
in at least one 
treatment arm
16.1.13.1
16.1.13.1
- 
- 
All baseline and on-
treatment 
concomitant therapies
16.1.13.1
16.1.13.1
- 
- 
All on-treatment 
restricted
concomitant therapies
- 
- 
16.1.13.1
16.1.13.1
All on-treatment 
prohibited 
concomitant therapies
- 
- 
16.1.13.1
16.1.13.1
Definitions of restricted and prohibited medications are depicted in Section 4.2.2 of the CTP.
Please note that disease-modifying anti-rheumatic drugs (DMARDS) with known hepatotoxic 
or gastrointestinal effects – which are part of the CDGs – taken at baseline or prescribed 
on-treatment will be shown additionally in a separate output for convenience. Section 9.7
shows which medications were considered to belong to the two categories of DMARDs.
7.3
TREATMENT COMPLIANCE
Treatment compliance will be computed for both treatment arms. Missed medication intakes, 
excluding those in accordance with the requirements of the CTP (e.g. due to the occurrence of 
an adverse event) will be assessed. The outputs will show the number of patients who have 
missed at least one dose, as well as a percentage value of medication taken compared to what 
the patients should have received. The percentage rate shown will be the average percentage 
rate over all patients.
Additional outputs will be created to investigate whether patients were treated as specified 
according to the definitions given in Section 4 of the CTP. These outputs show: 
x
The dose levels used
x
The appropriate use of the dose reduction scheme
The evaluations will be done on the co-primary populations as well as on the complementary 
population, for the first 52 week period and over the whole trial, and only descriptive statistics 
for the raw values as well as the categorisations for compliance shown in Section 5.4.2 will be 
created for this part of the report.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 65 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.4
PRIMARY ENDPOINT
The primary efficacy endpoint is the annual rate of decline in Forced Vital Capacity (FVC; 
expressed in ml over 52 weeks). Please see Sections 7.2, 7.3 and 7.3.1 of the CTP for 
additional information on the underlying hypotheses, multiplicity adjustments and assessment 
strategy. 
7.4.1 
Primary analysis 
The primary analysis will be based on the TS (according to randomised treatment), using all 
available data from baseline (excluded) up to Week 52, including visits done after premature 
treatment discontinuation, EOT visits and follow-up visits done before Week 52 (i.e. 
including all measurements after first drug intake and before or on day 373). Patients will be 
analysed based on the fibrotic pattern data entered in the eCRF, which may not necessarily 
coincide with data used for randomisation. Details on sensitivity analyses can be found in 
Section 7.4.2.
The primary analysis uses a restricted maximum likelihood (REML) based approach with a 
random slope and intercept modelThe analysis will include the fixed, categorical effects of 
treatment, HRCT pattern, fixed continuous effects of time and baseline FVC (ml) as well as 
the treatment-by-time and baseline-by-time interactions. Random effects will be included for 
patient response for both time and intercept. 
The statistical model can be written as follows: 
ݕ௜௝௞௠= (Ƚ + a௜+ Ԃ௠+ ߚ଴ܵ௜+ ߬௞) + (ɀ + g௜+ ߚ௦ܵ௜+ ߮௞)t௜௝+ ݁௜௝
(a௜, g௜) ~ ܰଶ (૙, ࢳ)
݁௜௝ 
݅݅݀
~
 
 ܰ (0, ߪଶ)
The components of the model are as follows: 
yijkm 
= 
response variable for patient i with HRCT pattern m at visit j receiving 
treatment k
Į 
= 
mean patient intercept
ai 
= 
random intercept effect  for patient i, i=1,2,… 
Ԃ௠ 
= 
intercept coefficient of HRCT pattern (“other HRCT fibrotic patterns” as 
the class reference)
ߚ0
= 
intercept coefficient of baseline FVC (ml) 
ܵ݅
= 
baseline FVC (ml) measurement for patient i
߬݇
= 
intercept coefficient of the effect of treatment k, k=1,2
γ 
= 
mean patient slope 
gi 
= 
random slope effect for patient i
ߚݏ
= 
slope coefficient of baseline FVC (ml) 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 66 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
߮݇
= 
slope coefficient of the effect of treatment k
tij 
= 
time of measurement j for patient i, j= 1,2,… J 
eij 
= 
the random error associated with the jth visit of patient i. Measurement 
errors are independent and normally distributed with mean 0 and 
variance ߪ2, and uncorrelated with ai and gi.
ࢳ 
= 
a 2x2 unstructured covariance matrix 
For the co-primary evaluation of FVC (in ml over 52 weeks) in patients with “HRCT with 
UIP-like fibrotic pattern only”, the following model will be utilised:
ݕ௜௝௞= (Ƚ + a௜+ ߚ଴ܵ௜+ ߬௞) + (ɀ + g௜+ ߚ௦ܵ௜+ ߮௞)t௜௝+ ݁௜௝
(a௜, g௜) ~ ܰଶ (૙, ࢳ)
݁௜௝ 
݅݅݀
~
 
 ܰ (0, ߪଶ)
The components of the model are as follows: 
yijk 
= 
response variable for patient i at visit j receiving treatment k
Į 
= 
mean patient intercept
ai 
= 
random intercept effect  for patient i, i=1,2,… 
ߚ0
= 
intercept coefficient of baseline FVC (ml) 
ܵ݅
= 
baseline FVC (ml) measurement for patient i
߬݇
= 
intercept coefficient of the effect of treatment k, k=1,2
γ 
= 
mean patient slope 
gi 
= 
random slope effect for patient i
ߚݏ
= 
slope coefficient of baseline FVC (ml) 
߮݇
= 
slope coefficient of the effect of treatment k
tij 
= 
time of measurement j for patient i, j= 1,2,… J
eij 
= 
the random error associated with the jth visit of patient i. Measurement 
errors are independent and normally distributed with mean 0 and 
variance ߪ2, and uncorrelated with ai and gi.
ࢳ 
= 
a 2x2 unstructured covariance matrix 
For both models, the Kenward-Roger approximation will be used to estimate denominator 
degrees of freedom and adjust standard errors. Significance tests will be based on least-
squares means using a two-sided α = 0.05 (two-sided 95% confidence intervals).The primary 
treatment comparison of slopes will be assessed through the treatment-by-time interaction 
coefficient.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 67 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
In the event of non-convergence, the following methods will be attempted (in order) to 
overcome it:
1. Add the ‘singular=1e-10’ option in the model statement – This raises the threshold at 
which columns are declared linearly dependent (from typically 1e-12).  
2. Set ‘maxiter=100’ in the Proc Mixed statement – This increases the number of 
convergence iterations used from a default of 50. 
3. Set ‘scoring=4’ to specify use of the Fisher scoring algorithm in the first 4 iterations.
4. Include the statement ‘performance nothread’ – this removes multi-threading from 
the calculations.
5. Provide starting values for covariance parameters using a ‘parms’ statement. 
Estimates will be obtained from using a simpler covariance matrix.
The first model to converge will be used as the primary analysis on the analysis of the FVC 
rate of decline at week 52.
Patients will be analysed according to the stratum to which they belong to, regardless of any 
miss-assignment to treatment based on identification of the wrong stratum. 
Please refer to Section 9.5 for more details concerning the statistical model and SAS code 
specifications.
For the primary endpoint a Hochberg procedure will be used in order to maintain an overall 
type 1 error rate of 5%. Statistical significance will be declared if the primary endpoint 
analyses in both co-primary populations are significant at the two-sided 5% level, or if the 
analyses in either co-primary population are statistically significant at the two-sided 2.5% 
level. No other endpoints i.e. secondary or further endpoints will be evaluated in a 
confirmatory manner.
Please note that for completeness the same evaluation of FVC (in mL over 52 weeks) that is 
done for the co-primary patient population of patients with “HRCT with UIP-like fibrotic 
pattern only” will be run as well in patients with “other HRCT fibrotic patterns” utilising the 
same model, but no p-value will be shown. 
7.4.2 
Sensitivity analyses 
Sensitivity analyses for FVC (in ml over 52 weeks) using different assumptions will be 
conducted to investigate the potential effect of data handling, missing data and the analysis 
model (e.g. assumption of linearity) on the results of the main analysis. In addition, it will be 
evaluated, whether potential discrepancies between IRT and eCRF of HRCT pattern have an 
impact if more than 3% of the randomised patients show such discordance. 
For all sensitivity analyses to data handling assumptions the estimate, two-sided 95% 
Confidence Interval and p-value of the treatment effect will be represented on the same Forest 
plot. Tables presenting the results of the sensitivity analyses will be created in addition to 
graphical representations, and included in the CTR Appendix. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 68 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Interpretation of sensitivity analyses: 
Separate forest-plots will be produced for each of the co-primary evaluations in Section 15 of 
the CTR. In case the results of some of the sensitivity analyses are inconsistent with those of 
the primary analysis (i.e. the treatment effect estimate of a sensitivity analysis lies outside the 
confidence interval of the treatment effect of the primary analysis), clinical input will be 
needed to assess the clinical relevance of the difference.
Sensitivity analyses described in the CTP will be discussed in this section, additional 
sensitivity analyses in Section 9.12.
7.4.2.1 Sensitivity to data handling assumptions 
7.4.2.1.1
Statistical model using on-treatment measurements only
A sensitivity analysis including only on-treatment measurements of FVC (ml) will be 
presented. The same model as for the primary analysis will be used (see Section 7.4.1). This 
model implies that data are assumed to be missing at random (MAR) and it is implicitly 
supposed that patients who dropout would have behaved similarly to those who remained in 
the study. 
This analysis is considered of principal importance amongst the planned sensitivity analyses 
since it most closely reflects the expected biologic effect of nintedanib in the treatment of 
patients with PF-ILD.  
7.4.2.1.2
Sensitivity to missing data handling
To investigate the potential impact of missing data on the treatment effect, patients will be 
classified into different patterns depending on the availability of data:
x
Patients with a 52 week FVC value (see Table 6.1.1: 1 for further information 
regarding the analysis period):
1. Those who received trial drug until 52 weeks (defined as patients who did not 
prematurely discontinue the trial medication before 52 weeks according to the 
“end of trial medication” page of the eCRF) (pattern 1)
2. Those who prematurely discontinued trial drug before 52 weeks (as per 
information given on the “end of trial medication” page of the eCRF) but who 
were followed up until week 52 (pattern 2) 
x
Patients without a 52 week FVC value: 
3. those who were alive at 52 weeks (based on “vital status” page of the eCRF, and 
no fatal AE recorded on the “adverse event” page of the eCRF) (pattern 3) 
4. those who died before 52 weeks (based on “vital status” page of the eCRF, or fatal 
AEs recorded on the “adverse event” page of the eCRF) (pattern 4) 
These four patterns will be used in sensitivity analyses to estimate the treatment effect under 
differing assumptions regarding the persistence of efficacy post withdrawal of randomised 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 69 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
treatment. As described hereafter, three resulting alternative analyses will be defined. See an 
overview in Table 7.4.2.1.2: 1.
Multiple imputation will be used to handle missing data at week 52. Non-monotone missing 
data and/or missing data at visits before week 52 will not be imputed. The imputation model 
will be similar to the statistical model of the primary analysis (see Section 7.4.1).
The number of imputations will be set to 1000 in order to ensure adequate efficiency for the 
estimation of missing data. For each imputed dataset, the same statistical model as defined for 
the primary analysis will be used for the analysis as depicted in Section 7.4.1. The results will 
be pooled following the standard multiple imputation procedure (16). See also Section 9.5.3
for further technical information on the implementation of the multiple imputation approach. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 70 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 7.4.2.1.2: 1 
Primary and sensitivity analyses for handling of missing data  
Analysis
Pattern 3: Missing week 52 data in 
patients still alive at 52 weeks
Pattern 4: Missing week 52 data in 
patients who died before 52 weeks
Handling of 
missing week 52 
data
Underlying 
assumption 
regarding 
persistence of 
efficacy post-
withdrawal
Handling of 
missing week 52 
data 
Underlying 
assumption 
regarding 
persistence of 
efficacy after death
Primary
no imputation
assumes MAR
no imputation
assumes MAR
Sensitivity 1[1]
based upon the
slope (SE) 
estimates in Drug 
and Placebo in
patients of pattern 
2, multiple 
imputation of 
missing week 52 
data in the 
respective 
treatment group
rate of decline in 
patients with missing 
week 52 data is 
similar to rate of 
decline in patients of  
pattern 2 in the 
respective treatment 
group (e.g. treatment 
effect persists in 
same manner as for 
pattern 2 patients 
after trial drug 
discontinuation)
multiple imputation 
of missing 52 week 
data due to death 
based on the same 
slope (SE) 
estimates in 
Placebo patients of 
pattern 2, but 
truncated[3] to force 
the slope in patients 
who died to be 
more severe than in 
those who survived
Assuming that deaths 
observed in the trial 
will likely be related 
to worsening of the 
underlying disease, it 
seems reasonable to 
assume that the 
unobserved FVC 
values should on 
average be lower than 
those in patients who 
did not die prior to 
week 52
Rate of decline in 
patients who died 
before week 52 is 
similar to rate of 
decline in the Placebo 
patients of pattern 2 
with most severe 
slopes
Sensitivity 2[1]
based upon the 
slope (SE) 
estimates in 
Placebo patients of 
pattern 2: multiple 
imputation of 
missing week 52 
data in all patients 
regardless of 
treatment group
rate of decline in all 
patients with missing 
week 52 data is 
similar to rate of 
decline in Placebo 
patients of pattern 2 
(e.g. treatment effect 
does not persist after 
trial drug 
discontinuation)
Sensitivity 3[2]
based upon the 
slope (SE) 
estimates in 
Placebo patients 
from the primary 
analysis model 
(MMRM),  i.e. in 
patients from 
pattern 1 or 2: 
multiple 
imputation of 
missing week 52 
data in all patients 
regardless of 
treatment group
rate of decline in all 
patients with missing 
week 52 data is 
similar to rate of 
decline estimated in 
all Placebo patients 
(e.g. treatment effect 
does not persist after 
trial drug 
discontinuation)
multiple imputation 
of missing 52 week 
data due to death 
based on the same 
slope (SE) 
estimates in all 
Placebo patients 
(i.e. in patients 
from pattern 1 or 
2), but truncated[3]
to force the slope in 
patients who died to 
be more severe than 
in those who 
survived 
Assuming that deaths 
observed in the trial 
will likely be related 
to worsening of the 
underlying disease, it 
seems reasonable to 
assume that the 
unobserved FVC 
values should on 
average be lower than 
those in patients who 
did not die prior to
week 52
Rate of decline in 
patients who died 
before week 52 is 
similar to rate of 
decline in the Placebo 
patients (i.e. in 
patients from pattern 
1 or 2) with most 
severe slopes


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 71 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
[1] Sensitivity analyses 1 and 2 will only be performed if the number of patients in pattern 2 is greater than 10 
(from both Nintedanib and Placebo group for sensitivity analysis 1 and from placebo group for sensitivity 
analysis 2)
[2] Patients falling into pattern 2 are used as the basis for multiple imputations but since the number of patients 
in that pattern may be small, a third sensitivity analysis will be performed to confirm the robustness of the 
primary analysis results.
[3] If β represents the true slope with f(β) ~ N(Ⱦ෠, ɐෝଶ) where Ⱦ෠and ɐෝare the placebo slope and SE estimates from 
either patients in pattern 2 or all placebo patients, then sampling for patients who died prior to 52 weeks is 
restricted to the interval (െλ, Ⱦ෠] of the truncated distribution f(β)/2. In this way, it is guaranteed that, on 
average, the imputed FVC slope for patients who died is steeper than the average slope in patients who 
survived to week 52.
In addition to the patterns defined in the scope of the multiple imputation, the number (and 
percentage) of patients in each possible pattern of FVC data will be explored. Graphs showing 
FVC data over time in each pattern of monotonic missing data will also be provided. These 
outputs will be shown in the CTR Appendix. 
7.4.2.2
Sensitivity to the analysis model 
7.4.2.2.1
Sensitivity to linearity assumption
The linearity assumption for the decline in FVC [ml/yr] will be explored graphically. The 
following graphical displays will be provided: 
x
The mean (± Standard Error of the Mean (SEM)) observed FVC [ml] for each 
treatment group over time 
x
The mean (± SEM) observed FVC change from baseline [ml] for each treatment group 
over time
x
The mean (± SEM) estimated FVC [ml] for each treatment group over time (as 
estimated in the primary analysis)
The following alternative models will also be performed and a graphical display only will be 
provided: 
x
A polynomial time model (quadratic form in t) will be explored
x
An exponential model (of the form: a + b exp(-c*t)) will be explored as well
For each model, a plot will be provided representing both the mean (± SEM) estimated FVC 
[ml] over time and the mean (± SEM) estimated FVC [ml] over time using the linear form (by 
treatment group). 
In these models, data are assumed to be missing at random, which implies that patients who 
dropout would have behaved similarly to those who remained in the study.  
7.4.2.2.2
Sensitivity to mis-stratification
If potential discrepancies between IRT and eCRF with regard to HRCT pattern exceed 3% of 
the randomised patients a statistical model similar to the one depicted in Section 7.4.1
analysis will be used, with baseline FVC (ml) and HRCT pattern (“HRCT with UIP-like 
fibrotic pattern only” / “other HRCT fibrotic patterns”) as covariates. The values used for 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 72 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
HRCT pattern will however not come from the eCRF, but reflect the values used during the 
randomisation process and stored with the IRT provider. 
7.4.3 
Subgroup analyses 
For each subgroup analysis (refer to Section 6.4 for an overview of subgroups) of the primary 
endpoint, the heterogeneity of the subgroup treatment effect on the slope will be estimated: A 
random slope and intercept mixed model will be fitted based upon the statistical model for the 
primary analysis but parametrised using the treatment-by-subgroup and the treatment-by-
subgroup-by-time interaction terms. A contrast statement, with appropriate contrasts, will be 
used to conduct an F-test of heterogeneity across all expression levels of the subgrouping. The 
results will be discussed and may be explored further. 
It can be shown that the following simplified, saturated model is equivalent to the fully 
specified model and will therefore be used for the analysis of subgroups: 
ݕ௜௝௞௠௨= (Ƚ + a௜+ Ԃ௠+ ߚ଴ܵ௜+ ߜ௞௨) + (ɀ + g௜+ ߚ௦ܵ௜+ ߠ௞௨)t௜௝+ ݁௜௝
(a௜, g௜) ~ ܰଶ (૙, ࢳ)
݁௜௝ 
݅݅݀
~
 
 ܰ (0, ߪଶ)
The components of the model are identical to the primary model (see Section 7.4.1 for 
explanation of notions) only adding the subgroup covariate: 
Ɂ௞௨ 
= 
intercept coefficient for the effect of treatment k in subgroup category u 
for patient i 
Ʌ௞௨ 
= 
slope coefficient for the effect of treatment k in subgroup category u for 
patient i
Please note: For the subgroups where the co-primary population is also evaluated, the term for 
HRCT pattern will be excluded from the model. In addition, evaluations are also only 
reasonable if enough subjects are present within the subgroup – for this evaluation there need 
to be at least 5 observations per treatment per subgroup expression level per visit. If this is not 
given, it is possible to pool similar subgroup expression levels together. Whether subgroup
expression levels can and should be pooled will be decided at the final Blinded Report 
Planning Meeting (BRPM) and documented in the minutes. Section 9.8 of the CTR will then 
also discuss the pooling of subgroup expression levels and provide a medical rationale. 
In addition to the subgroup evaluations described above, one output will be computed treating 
the HRCT pattern and its expression levels (“HRCT with UIP-like fibrotic pattern only” / 
“other HRCT fibrotic patterns”) as subgroups. The model would exclude the term for the 
HRCT pattern, and the obtained interaction p-value would serve as objective measurement 
whether the results of the primary endpoint are consistent between the subpopulation of 
patients with “HRCT with UIP-like fibrotic pattern only” and the subpopulation of patients 
with “other HRCT fibrotic patterns”.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 73 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 7.4.3: 1 Subgroup analyses – List of analyses
Description of 
study population
x
Disposition of patients
x
Demographic data
x
Trial indication characteristics
x
Baseline pulmonary efficacy variables
x
Baseline conditions
x
Exposure to study drug over 52 weeks 
x
Exposure to actual treatment dose received over 52 weeks
Efficacy analyses 
on the primary 
endpoint in the 
overall population 
[1]
x
Forest-plot for rate of decline in FVC (ml/yr) over 52 weeks in 
all subgroups: representation on the same graph of the 
estimate, 95% Confidence Interval and p-value of F-test for 
heterogeneity across all levels of the subgrouping.
x
Rate of decline in FVC (ml/yr) over 52 weeks by subgroup 
x
Graphical representation of the mean (SEM) observed FVC 
change from baseline (ml) over time by subgroup over 52 
weeks
x
Graphical representation of the mean (SEM) estimated FVC 
change from baseline (ml) over time by subgroup over 52 
weeks
Safety analyses in 
the overall 
population [1][2]
x
Adverse event overall summary over 52 weeks
x
Frequency of patients with adverse events by SOC and PT 
over 52 weeks 
x
Frequency of patients with adverse events occurring with 
incidence in preferred term > 5% in at least one treatment arm 
by SOC and PT over 52 weeks 
x
Frequency of patients with serious adverse events by SOC and 
PT over 52 weeks 
x
Frequency of patients with investigator defined related adverse 
events by SOC and PT over 52 weeks 
x
Frequency of patients with adverse events leading to treatment 
discontinuation events by SOC and PT over 52 weeks 
x
Frequency of patients with adverse events leading to death by 
SOC and PT over 52 weeks 
x
Frequency of patients with adverse events by safety topic over 
52 weeks 
x
Frequency of patients with serious adverse events by safety 
topic over 52 weeks
[1]
Please note that the primary endpoint analyses and safety analyses by subgroup will also be performed in
the co-primary population of patients with “HRCT with UIP-like fibrotic pattern only” for gender, age and 
race
[2]
The depicted evaluations over 52 wees will also be repeated over the whole trial. The outputs over the
whole trial will also contain incidence rates per 100 patient years.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 74 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.5
SECONDARY ENDPOINTS 
Please note that any p-values presented for secondary endpoints will be considered nominal in 
nature and no adjustment for multiplicity will be made.
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the protocol. 
7.5.2
Secondary endpoints
All secondary endpoints are defined over the 52 weeks period only. 
7.5.2.1 Main secondary efficacy endpoints  
7.5.2.1.1
King’s Brief Interstitial Lung Disease Questionnaire (K-BILD) Total Score
The absolute change from baseline in K-BILD total score between week 52 and baseline will 
be presented graphically as well as numerically to illustrate the impact of the underlying 
condition on the patient’s health status. The descriptive analyses of the absolute change from 
baseline in K-BILD total score will also be shown for the complementary population. 
All sub-domain scores (breathlessness and activities, psychological, chest symptoms) will 
also be presented for all time points separately, as well as change from baseline. 
In addition to the descriptive evaluation, absolute change from baseline in K-BILD total score 
between week 52 and baseline will also be analysed in the TS using a restricted maximum 
likelihood (REML) based repeated measures approach. An unstructured variance-covariance 
structure will be used to model the within patient measurements. In the event of 
non-convergence, the same methods used in the primary analyses (Section 7.4.1) will be 
implemented to overcome the issue. The HRCT pattern will be included as a covariate (with 
exception when the analysis is run in the co-primary population of patients with “HRCT with 
UIP-like fibrotic pattern only”) as well as the baseline K-BILD total score.
A graph of the mean K-BILD total score absolute change from baseline (± SEM) over time 
for each treatment group will be displayed. The same graph will be performed on adjusted 
mean changes from baseline.
7.5.2.1.2
Time to death
A stratified log-rank test will be used to evaluate the effect of Nintedanib on time to death 
compared to Placebo. The test will be stratified by the randomisation stratification variable 
HRCT pattern (“HRCT with UIP-like fibrotic pattern only” vs. “Other HRCT fibrotic 
patterns”, as documented in the CRF). A Cox proportional-hazards model stratified by the 
same factors as the log-rank test will be used to derive the hazard ratio and 95 % confidence 
interval (CI) between the two randomised treatment regimens (Hazard ratios <1 will favour 
nintedanib). In the co-primary population of patients with “HRCT with UIP-like fibrotic 
pattern only”, the respective analyses will be performed without stratification.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 75 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Breslow’s method for handling ties will be used. Kaplan-Meier plots by treatment group will 
also be presented. The assumption of proportional hazards and the homogeneity of the hazard 
ratio will be checked descriptively.
If the proportion of patients experiencing an event is less than 5%, only frequencies of events 
by treatment group will be provided for this endpoint. In this case no other analyses will be 
performed.
7.5.2.1.3
Time to first acute ILD exacerbation or death
The same type of evaluation as described for time to death (see Section 7.5.2.1.2) will be 
implemented. If, however, the proportion of patients experiencing at least 1 acute ILD 
exacerbation over 52 weeks is less than 5%, then only frequencies of events by treatment 
group will be provided for this endpoint. In this case no other analyses will be performed.
7.5.2.2 Other secondary efficacy endpoints 
7.5.2.2.1
Time to death due to respiratory cause
In general, the same type of evaluation for time to death due to respiratory cause will be 
implemented as described for time to death (see Section 7.5.2.1.2). However; only patients 
whose cause of death was attributed to respiratory causes (as determined by an independent 
adjudication committee) will be included. If the proportion of such patients within the first 52
weeks is less than 5%, then only frequencies of events by treatment group will be provided for 
this endpoint. In this case no other analyses will be performed. 
7.5.2.2.2 
Time to progression or death 
The same type of evaluation as described for time to death (see Section 7.5.2.1.2) will be 
implemented for this endpoint. If, however, the proportion of patients experiencing a 
progression (see Section 5.2.2.2.2 for details about the definition of progression) within the 52 
week period is less than 5%, then only frequencies of events by treatment group will be 
provided. In this case no other analyses will be performed. 
7.5.2.2.3
Relative decline from baseline in FVC % pred
Patients will be categorised based on the relative decline since baseline in FVC % pred greater 
than 5% or 10%. Comparisons between treatment groups will be performed using a logistic 
regression model adjusting for the continuous covariate baseline FVC % pred and the binary 
covariate HRCT pattern. The likelihood-ratio test will be used to test for differences between 
treatments. Adjusted odds ratios together with 95% confidence intervals will be used to 
quantify the effect of treatment, comparing nintedanib 150 mg bid to placebo as the reference.
Additionally, descriptive analyses of the relative change from baseline in FVC % pred will be 
shown, for the co-primary populations as well as for the complementary population. 
7.5.2.2.4 
Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (L-PF)  
The absolute change from baseline in L-PF symptoms dyspnoea domain score between week 
52 and baseline will be presented graphically as well as numerically to illustrate the impact of 
the underlying condition on the patient’s health status. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 76 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
The absolute change from baseline in L-PF symptoms cough domain score between week 52 
and baseline will be presented graphically as well as numerically to illustrate the impact of the 
underlying condition on the patient’s health status. 
The descriptive analyses of the absolute change from baseline in L-PF symptoms dyspnoea 
domain score as well as L-PF symptoms cough domain score will also be shown for the 
complementary population. 
In addition to the descriptive evaluation, absolute change from baseline in L-PF symptoms 
dyspnoea domain score between week 52 and baseline, as well as in L-PF symptoms cough 
domain score between week 52 and baseline will also be analysed using a restricted maximum 
likelihood (REML) based repeated measures approach. An unstructured variance-covariance
structure will be used to model the within patient measurements. In the event of 
non-convergence, the same methods used in the primary analyses (Section 7.4.1) will be 
implemented to overcome the issue. The HRCT pattern will be included as a covariate (with 
exception when the analysis is run in the co primary population of patients with “HRCT with 
UIP-like fibrotic pattern only”) as well as the respective baseline L-PF symptoms score. 
7.6
FURTHER ENDPOINTS
All further endpoints will be considered exploratory in nature, and no p-values will be 
presented.
7.6.1
Over 52 weeks
7.6.1.1
Time to first non-elective hospitalisation or death
The same type of evaluation as described in Section 7.5.2.1.2 will be implemented. If, 
however, the proportion of patients experiencing a non-elective hospitalisation over 52 weeks 
is less than 5%, then only frequencies of events by treatment group will be provided for this 
endpoint. In this case no other analyses will be performed. 
7.6.1.2 Absolute change from baseline in FVC 
The absolute change from baseline in FVC – in ml, but also % pred – at week 52 will be 
analysed using a restricted maximum likelihood (REML) based repeated measures approach. 
Analyses will include the fixed, categorical effects of HRCT pattern, treatment, visit, and 
treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline and 
baseline-by-visit interaction. An unstructured (co)variance structure will be used to model the 
within-patient measurements. In the event of non-convergence, the same methods that are 
used for the primary endpoint analysis as described in Section 7.4.1 will be used to overcome 
the issue. The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. The HRCT pattern will be included as a covariate (with exception when the analysis 
is run in the co primary population of patients with “HRCT with UIP-like fibrotic pattern 
only”) as well as the baseline FVC value. Additionally, descriptive analyses of the absolute 
change from baseline will be shown, for the co-primary populations as well as for the 
complementary population. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 77 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.6.1.3 Absolute decline from baseline in FVC % pred 
The same type of evaluation as described in Section 7.5.2.2.3 will be implemented for this 
endpoint. 
7.6.1.4 Carbon Monoxide Diffusion Capacity (DLCO) % pred 
A similar analysis based on a restricted maximum likelihood (REML) based repeated 
measures approach as depicted in Section 7.6.1.2 will be performed for the absolute change in 
DLCO % pred. The HRCT pattern will be included as a covariate (with exception when the 
analysis is run in the co primary population of patients with “HRCT with UIP-like fibrotic 
pattern only”) as well as the baseline DLCO value
7.6.1.5 Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (L-PF)
The absolute change from baseline in L-PF total score between week 52 and baseline will be 
presented graphically as well as numerically to illustrate the impact of the underlying 
condition on the patient’s health status. 
The absolute change from baseline in L-PF impact score between week 52 and baseline will 
be presented graphically as well as numerically to illustrate the impact of the underlying 
condition on the patient’s health status. 
The absolute change from baseline in L-PF symptoms total score between week 52 and 
baseline will be presented graphically as well as numerically to illustrate the impact of the 
underlying condition on the patient’s health status. 
The absolute change from baseline in L-PF symptoms fatigue domain score between week 52 
and baseline will be presented graphically as well as numerically to illustrate the impact of the 
underlying condition on the patient’s health status. 
The descriptive analyses of the absolute change from baseline in L-PF total score, L-PF 
impact score, L-PF symptoms total score and L-PF symptoms fatigue domain score will also 
be shown for the complementary population. 
In addition to the descriptive evaluation, absolute change from baseline in L-PF total score 
between week 52 and baseline, in L-PF impact score between week 52 and baseline, in L-PF 
symptoms total score between week 52 and baseline and in L-PF symptoms fatigue domain 
score between week 52 and baseline will also be analysed using a restricted maximum 
likelihood (REML) based repeated measures approach. An unstructured variance-covariance 
structure will be used to model the within patient measurements. In the event of 
non-convergence, the same methods used in the primary analyses (Section 7.4.1) will be 
implemented to overcome the issue. The HRCT pattern will be included as a covariate (with 
exception when the analysis is run in the co primary population of patients with “HRCT with 
UIP-like fibrotic pattern only”) as well as the respective baseline L-PF score.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 78 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.6.1.6 Pulmonary Fibrosis Impact on Quality of Life Scale (PF-IQOLS)
The absolute change from baseline in PF-IQOLS summary score (which is the average of the 
individual dimension ratings) between week 52 and baseline will be presented graphically as 
well as numerically to illustrate the impact of the underlying condition on the patient’s health 
status. The descriptive analyses of the absolute change from baseline will also be shown for 
the complementary population. 
In addition to the descriptive evaluation, absolute change from baseline in PF-IQOLS 
summary score between week 52 and baseline will also be analysed using a restricted 
maximum likelihood (REML) based repeated measures approach. An unstructured variance-
covariance structure will be used to model the within patient measurements. In the event of 
non-convergence, the same methods used in the primary analyses (Section 7.4.1) will be 
implemented to overcome the issue. The HRCT pattern will be included as a covariate (with 
exception when the analysis is run in the co primary population of patients with “HRCT with 
UIP-like fibrotic pattern only”) as well as the respective baseline PF-IQOLS summary score.
7.6.2
Over the whole trial
7.6.2.1
Time to first acute ILD exacerbation or death
The same type of evaluation as described in Section 7.5.2.1.3 will be implemented, but data 
over the whole trial duration will be taken into consideration. Similarly, if the proportion of 
patients experiencing at least 1 acute ILD exacerbation is less than 5%, then only frequencies 
of events by treatment group will be provided for this endpoint. In this case no other analyses 
will be performed. 
7.6.2.2
Time to death
The same type of evaluation as described in Section 7.5.2.1.2 will be implemented, but data 
over the whole trial duration will be taken into consideration. If the proportion of patients 
experiencing an event is less than 5%, only frequencies of events by treatment group will be 
provided for this endpoint. In this case no other analyses will be performed. 
7.6.2.3
Time to death due to respiratory cause
The same type of evaluation as described in Section 7.5.2.2.1 will be implemented, but data 
over the whole trial duration will be taken into consideration. Similarly, if the proportion of 
such patients is less than 5%, then only frequencies of events by treatment group will be 
provided for this endpoint. In this case no other analyses will be performed. 
7.6.2.4 Time to progression or death 
The same type of evaluation as described in Section 7.5.2.2.2 will be implemented, but data 
over the whole trial duration will be taken into consideration. Similarly, if the proportion of 
patients experiencing a progression is less than 5%, then only frequencies of events by 
treatment group will be provided. In this case no other analyses will be performed.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 79 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.6.2.5
Time to first non-elective hospitalisation or death
The same type of evaluation as described in Section 7.6.1.1 will be implemented, but data 
over the whole trial duration will be taken into consideration. Similarly, if the proportion of 
patients experiencing a non-elective hospitalisation is less than 5%, then only frequencies of 
events by treatment group will be provided for this endpoint. In this case no other analyses 
will be performed. 
7.6.2.6 Descriptive evaluations of lung function parameters 
Descriptive analyses of the absolute change from baseline of FVC in ml, FVC (% of 
predicted) and DLCO (% of predicted), as well as the relative change from baseline in FVC 
(% of predicted) will be shown, for the co-primary populations as well as for the 
complementary population. 
7.6.3
Pharmacokinetics
Descriptive analysis
Trough concentrations (i.e. pre-dose concentrations) of nintedanib at Visits 4 and 7 will be 
used. If both concentrations are available, the geometric mean will be used. If one trough 
concentration value is missing or invalid, the other one will be used without adjustment. To 
account for potential dose reductions, all trough concentrations will be dose normalised by the 
actual dose taken by the patient at the time of PK sampling. The dose normalised trough 
concentrations for nintedanib (Cpre,ss_D) will be summarised descriptively. These analyses 
will be performed using the PKS. 
7.6.4
Biomarkers
All biomarker evaluations will be specified and reported separately.
7.6.5 
Longitudinal HRCT assessments 
All evaluations of the optional longitudinal HRCT assessments will be specified and reported 
separately.
7.7
EXTENT OF EXPOSURE
Exposure will be presented based on dose received and time to first dose reduction or 
interruption. Reasons for dose reduction or interruption will be presented. Exposure will be 
summarised and presented separately over the first 52 weeks and over the whole trial. In 
addition, exposure will be presented for patients taking DMARDs with known hepatotoxic or 
gastrointestinal effects at baseline and on-treatment. Please see Section 5.4.3 for details. 
7.7.1
Over 52 weeks
In addition to both co-primary populations, exposure data over 52 weeks will also be
summarised on the complementary patient population i.e. patients with “other HRCT fibrotic 
patterns”. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 80 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
The duration on treatment and dose intensity will be computed overall, as well as on the 
individual dose strengths. A summary of treatment interruptions will be created including 
number of patients with at least one interruption, number and reason of interruptions, as well 
as time to first interruption. A similar summary will be performed for dose changes. 
For the co-primary populations only, a Kaplan-Meier plot of time to premature treatment 
discontinuation will be produced. Similarly, Kaplan-Meier plots will be performed for time to 
first dose reduction and for time to first treatment interruption. No statistical tests will be 
performed.
7.7.2
Over the whole trial
Similar to the 52 week period, exposure data over the whole trial will be summarised on both
co-primary populations, as well as the complementary patient population.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. Particular focus will be given to 
evaluations over the 52 week period (Part A of the study). 
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of patients with AEs and NOT on the number of 
AEs.
For analysis multiple AE occurrence data on the eCRF will be collapsed into an AE provided 
that all of the following applies:
x
All AE attributes are identical (LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI; CTCAE if 
applicable) 
x
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence). 
For further details on summarization of AE data, please refer to (7, 8). 
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake until last drug 
intake + 28 days (and + 7 days as sensitivity analysis) will be assigned to the randomised 
treatment.
All adverse events occurring before first drug intake will be assigned either to ‘screening’ or 
‘post-randomisation’ (for listings only).  
All adverse events occurring after last drug intake + 28 days (and + 7 days as sensitivity 
analysis) will be assigned to ‘post-treatment’ or ‘follow-up’ or ‘post-study’ (for listings only). 
All adverse events occurring between the start of an interruption of trial medication and the 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 81 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
end of interruption of trial medication will be assigned to ‘off-treatment’ period in the listings.
For details on the treatment definition, see Section 6.1.
According to ICH E3 (10), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant adverse events with (i) ‘action taken = 
discontinuation’ or ‘action taken = reduced’, or (ii) marked haematological and other lab 
abnormalities or lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting.
Adverse events related to gastrointestinal perforation and hepatic injury will be considered as 
protocol-specified AEs of special interest (AESIs), and ticked as such in the eCRF.
Table 7.8.1: 1 Protocol-specified AESI 
Protocol-specified AESI
AE type
Gastrointestinal perforation
AEs established for other tyrosine 
kinase inhibitors as possible adverse 
reactions
Hepatic injury
Other AEs of interest
Further adverse event groupings by safety topic have been defined outside the trial protocol, 
which will be continuously updated at project level (18). These safety topics are deemed of 
particular importance, and these definitions can be based on selection of coded terms based on
MedDRA. The latest approved version of the project level overview archived prior to either 
DBL will be used in the corresponding CTR. 
7.8.1.1 Over 52 weeks 
An overall summary of adverse events having occurred over the first 52 weeks will be 
presented on the co-primary populations, as well as on the complementary population,,
including all AEs occurring between first drug intake until: 
x
last drug intake + 28 days (and + 7 days as sensitivity analysis) for patients who
prematurely discontinued the study medication before 52 weeks (i.e. 372 days after 
first trial drug intake)
x
week 52 for patients who did not prematurely discontinue the study medication before 
52 weeks 
The frequency of patients with adverse events in the co-primary populations, as well as in the 
complementary population, will be summarised by treatment, primary system organ class and 
preferred term. Separate tables will be provided for patients with other significant adverse 
events according to ICH E3 (10) and for patients with protocol-specified adverse events of 
special interest (as ticked in the AE page of the eCRF [gastrointestinal perforation and hepatic 
injury]). Displays will also be provided for patients with any adverse events, severe adverse 
events and also serious adverse events, for patients with adverse events occurring with an 
incidence in preferred term greater than 5% (in at least one treatment arm), for patients with 
adverse events leading to permanent dose reduction, for patients with adverse events leading 
to treatment discontinuation, for patients with investigator defined drug-related adverse 
events, for patients with drug-related serious adverse events (in co-primary populations only),


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 82 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
and for patients with adverse events leading to death. Further, the frequency of patients with 
adverse event by system will be provided. 
The frequency of patients with adverse events will also be provided by system, safety topic, 
subcategory (if applicable) and preferred term, with groupings as defined in (18). These 
displays will focus on patients with any adverse events, patients with serious adverse events 
and patients with related adverse events.
Additional outputs will be created for the subgroups depicted in Section 6.4 focusing on the 
overall summary of adverse events, patients with adverse events occurring with an incidence 
in preferred term greater than 5% (in at least one treatment arm), patients with serious adverse 
events and patients with related adverse events. An exact overview can be found in 
Table 7.4.3: 1.
The system organ classes (SOC) will be sorted according to the standard sort order specified 
by EMA, preferred terms will be sorted by frequency in Nintedanib treatment arm (within 
SOC).
7.8.1.2
Over the whole trial 
Time at risk analyses of AEs will be presented and incidence rates per 100 patient years will 
be calculated based on the first onset of an AE (see Section 7.8.1.5 for details). An overall 
summary of adverse events over the whole trial will be presented on the co-primary 
populations. 
The frequency of patients with adverse events in the co-primary populations, as well as in the 
complementary population, will be summarised by treatment, primary system organ class and 
preferred term. Separate tables will be provided for patients with other significant adverse 
events according to ICH E3 (10) and for patients with protocol-specified adverse events of 
special interest (as ticked in the AE page of the eCRF [gastrointestinal perforation and hepatic 
injury]). Displays will also be provided for patients with any adverse events, severe adverse 
events and also serious adverse events, for patients with adverse events occurring with an 
incidence in preferred term greater than 5% (in at least one treatment arm), for patients with 
adverse events leading to permanent dose reduction, for patients with adverse events leading 
to treatment discontinuation, for patients with investigator defined drug-related adverse 
events, for patients with drug-related serious adverse events (in co-primary populations only),
and for patients with adverse events leading to death. Further, the frequency of patients with 
adverse event by system will be provided. 
The overall summary of adverse events and the frequency of patients with adverse events (by 
treatment, primary system organ class and preferred term) will also be presented on patients 
with “other HRCT fibrotic patterns”. Separate tables will be provided for patients with 
protocol-specified adverse events of special interest, for patients with serious adverse events, 
for patients with adverse events leading to permanent dose reduction, for patients with 
adverse events leading to treatment discontinuation, and for patients with adverse events 
leading to death.  
Displays by safety topic will also be created over the whole trial, as well as outputs for the 
subgroups. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 83 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.8.1.3
Adjudicated adverse events
An independent adjudication committee will review all fatal cases and adjudicate cause of
death to respiratory, cardiovascular or other. The adjudication committee will also review all 
AEs categorised as MACE according to the definition in the adjudication charter. 
In addition to standard safety analyses, the frequency of patients with AEs leading to death
will be summarised by treatment, adjudicated cause of death (Cardiovascular, Respiratory or 
Other), and PT.
The frequency of patients with AEs categorised as MACE (that is all AEs categorised as
MACE and therefore sent for adjudication) will be summarised by treatment and outcome of
adjudication (adjudicated as MACE or adjudicated as not MACE). The frequency of patients
with AEs adjudicated as MACE will also be summarised by treatment and PT.
7.8.1.4 Adverse events with additional information collection 
Diarrhoea, bleeding and ILD are AEs with additional AE-specific information collected on 
the eCRF. These are investigator reported on the eCRF and will be identified using this 
information for this analysis. That is if the diarrhoea information has been completed for an 
adverse event then the adverse event will be considered as diarrhoea for this analysis 
regardless of subsequent MedDRA coding of the verbatim term. Likewise, if the bleeding 
information has been completed for an adverse event then the adverse event will be 
considered as bleeding for this analysis regardless of subsequent MedDRA coding of the 
verbatim term. The same applies to ILD.
The frequency of patients with AEs with additional information collection will be summarised 
by treatment, primary SOC and PT separately for diarrhoea, bleeding and ILD. The additional 
information collected will also be summarised at the AE level rather than at the patient level 
separately for diarrhoea, bleeding and ILD. For the time to first onset of diarrhoea, bleeding 
or ILD, respectively, Kaplan-Meier plots by treatment will be created. The same censoring 
rules as for time to first liver enzyme elevation will be used. See Table 5.4.4: 1 and 
Table 5.4.4: 2 for details. Please note that these evaluations are prepared for the co-primary 
populations, as well as in the complementary population, and covering both analysis periods 
“over 52 weeks” and “over the whole trial”.
7.8.1.5 Exposure adjusted analysis of adverse events 
For a specific AE, the total AE time at risk [years] is defined as the sum of time at risk [days] 
across all contributing patients / 365.25, with for each patient the time at risk [days] defined 
as follows: 
x
Date of first start of AE – date of first study medication administration +1 day for 
patients with the specific AE
x
End of time at risk – date of first study medication administration + 1 day for patients 
without the specific AE
For the AE analyses over 52 weeks, the end of time at risk is the end of the REP for patients 
who discontinue prior to week 52 or day 373 for patients who do not discontinue prior to 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 84 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
week 52. For the AE analyses over the whole trial, the end of time at risk is the minimum of 
either “+28 days after termination of trial mediation” or the date of the corresponding 
database lock. 
The AE incidence rate [1/100 Patient years (pt-yrs)] = 100 * number of patients with specific 
AE / total specific AE time at risk [years]. The 95% confidence intervals for incidence rates 
are derived using the method described by Rothman and Greenland (2008) (19).
The incidence rate ratio for a given AE is defined as the incidence rate of that event in 
patients in the Nintedanib 150mg bid treatment group divided by the incidence rate of that 
event in the Placebo group. The estimates and 95% confidence intervals for incidence rate 
ratios are based on a Cochran-Mantel-Haenszel test.
The incidence rate difference for a given AE is defined as the incidence rate of that event in 
patients in the Nintedanib 150mg bid treatment group minus the incidence rate of that event in 
the Placebo group. The estimates and 95% confidence intervals for incidence rate differences 
are derived based on the method described in Greenland and Robins (1985) (20).
For this trial, separate frequency tables based on SOC and PT, but also on safety topic level, 
will be created for the week 52 analyses as well as for the analyses over the whole trial, for 
the overall population, showing the incidence rate, incidence rate ratio and incidence rate 
difference (each with 95% confidence interval) per the aforementioned specifications, and 
added to Section 16.1.13.1. 
7.8.2 
Laboratory data 
The analyses of laboratory data will be descriptive in nature and based on SI units according 
to BI standards (11). Please refer to Section 7.3.4 of the CTP for further details. All analyses 
will be performed on the co-primary populations as well as on the complementary patient 
population. The main focus of the analysis of laboratory parameters will be on the first 52 
weeks; however, all analyses of laboratory data will be repeated with data collected over the 
whole trial for all analyses populations. 
Descriptive statistics for laboratory tests based on US conventional units will be provided in 
addition for the co-primary populations as well as on the complementary patient population, 
covering both analysis periods “over 52 weeks” and “over the whole trial”. All of these 
outputs will be part of the CTR appendix. 
7.8.2.1 Over 52 weeks 
A thorough description of liver enzymes and bilirubin elevations over 52 weeks will be given, 
as defined in Section 5.4.4, including a display of maximum individual elevation. A summary 
table of liver enzymes and bilirubin elevations over 52 weeks will also be provided (please 
refer to Table 6.7: 4 for time windowing definition). The time to onset of first liver enzyme 
and bilirubin elevation [days] will be summarized by categories (≥1-≤30; ≥31-≤60; ≥61-≤90;
≥91). For each patient having experienced a liver enzyme and bilirubin elevation, a graphical 
representation of AST, ALT and bilirubin over time will be provided. In addition, a Kaplan-
Meier plot of time to first liver enzyme elevation (if at least 5% of patients show liver enzyme 
elevations) will be created and evaluated


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 85 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.8.2.2
Over the whole trial
The analysis of liver enzyme elevations over the whole trial will be performed as depicted in 
Section 7.8.2.1 above. 
7.8.3
Vital signs
7.8.3.1 Over 52 weeks 
Summary statistics will be presented for observed values and change from baseline by 
treatment and visit. The frequency of patients with marked changes in vital signs over 52 
weeks will also be summarised by treatment according to the endpoints defined in 
Section 5.4.5 of this document. Please note that these evaluations are prepared for the co-
primary populations, as well as in the complementary population. 
7.8.3.2
Over the whole trial
The analysis of vital signs over the whole trial will be performed as depicted in 
Section 7.8.3.1 above.
7.8.4
ECG
Not applicable. 
7.8.5
Others
Not applicable.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 86 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.
REFERENCES
1
&303,&+: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
0&6: “Statistical Analysis Plans (SAPs)”, current version; IDEA for CON.
3
0&*B5': “Standard table shells for inferential and descriptive Company 
Standard Displays (CSD-Catalogue)”, current version; IDEA for CON.
4
0&6: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON. 
5
0&6B5': "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON. 
6
0&6: "Identify and Manage Important Protocol Deviations (iPD)", current 
version; IDEA for CON.
7
0&*B5': "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
8
0&*: "Analysis and Presentation of Adverse Event Data from Clinical Trials", 
current version; IDEA for CON.
9
0&*: "Reporting of Clinical Trials and Project Summaries", current version; 
IDEA for CON.
10
&303,&+: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version
11
0&*: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.
12
Patel AS, Siegert RJ, Brignall K, Gordon P, Steer S, Desai SR, Maher TM, Renzoni EA, 
Wells AU, Higginson IJ, Birring SS. The development and validation of the King’s 
Brief Interstitial Lung Disease (K-BILD) health status questionnaire. Thorax 2012; 67
(9), 804-810 [R12-4171] 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 87 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
13
Macintyre N, Crapo RO, Viegi G, Johnson DC, Grinten CPM van der, Brusasco V, 
Burgos F, Casaburi R, Coates A, Enright P, Gustafsson P, Hankinson J, Jensen R, 
McKay R, Miller MR, Navajas D, Pedersen OF, Pellegrino R, Wanger J. Standardisation 
of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 
2005; 26 (4), 720 – 735 [R06-2002] 
14
Wilson SR, Knowles SB, Mulligan M, Chausow A, Ayala E, Wise RA, et al. Relative 
and absolute reliability and other properties of the Asthma Impact on Quality of Life 
Scale (A-IQOLS) and Flanagan QOLS: results of the AQOLIS test-retest study. ATS 
2016, 112th Int Conf of the American Thoracic Society (ATS), San Francisco, 13 - 18
May 2016. Am J Respir Crit Care Med 2016; 193, A2679, Abstr [R16-2387] 
15
Wilson S, Wise RA, Knowles SB, Huang Q, Wei CY, Castro M. Psychometric 
properties of the Asthma Impact on Quality of Life Scale (A-IQOLS) and the Flanagan 
QOLS in adults with well-controlled asthma:baseline results in the LASST trial. ATS 
2015, 111th Int Conf of the American Thoracic Society (ATS), Denver, 15 - 20 May 
2015. Am J Respir Crit Care Med 2015; 191, A5189, Abstr [R16-2388] 
16
Rubin, DB. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & 
Sons. 1987. [R12-2378] 
17
Japanese Ministry of Health, Labour and Welfare, Format for Preparing the Common 
Technical Document for Submission of New Drug Applications to Reduce Total Review 
Time, 2011 [R18-1356] 
18
Specifications for adverse event groupings by safety topic for Nintedanib: 
Nintedanib / Clinical / interstitial lung disease / Project Data Management and Statistics 
/ Section 8 PSAP and Programming / 8-07-other-safety-topic-definition, current version; 
BIRDS. 
19
Rothman KJ, Greenland S, Lash TL. Modern epidemiology. 3rd ed. Philadelphia: 
Lippincott Williams & Wilkins, 2008. [R10-1239] 
20
Greenland S and Robins JM. Estimation of a common effect parameter from sparse 
follow-up data, Biometrics 1985, 41: 55-68 [R09-1299] 
21
%,.0('&236%83: Clinical Bridging Study Waiver (BSW) and Subgroup 
Analysis (SGA) Reports for Asian countries, current version; IDEA for CON. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 88 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.
ADDITIONAL SECTIONS
9.1 
K-BILD SCORING INSTRUCTIONS
9.1.1
Overview
The K-BILD is comprised of 15 items in three distinct health status domains, including 
breathlessness and activities (items 1, 4, 11, and 13), chest symptoms (items 2, 7, and 9), and 
psychological (items 3, 5, 6, 8, 10, 12, and 14) domains. A final item is used to assess the 
impact of the respondent’s lung condition on their financial state. Rasch analysis confirmed 
the 15 items could be combined into a total score (12). The domain and total scores each 
range from 0–100, and higher scores indicate a better health status. 
Response options for all 15 items are on a 7-point Likert scale, ranging from 1 to 7. For each 
of the items, the response options vary, including: item 1 (1 = “Every time,” 7 = “Never”); 
items 2–4, and 6–14 (1 = “All of the time,” 7 = “None of the time”); item 5 (1 = “None of the 
time,” 7 = “All of the time”); and item 15 (“A significant amount,” 7 = “Not at all”).
9.1.2 
Scoring Algorithm 
To score the K-BILD, the Likert response scale weightings for individual items are combined, 
to ensure they detect progressive change in health status. Table 9.1.2: 1 shows the recoded 
scale weightings associated with each raw, item-level score value. Raw domain and total 
scores are then calculated by summing the recoded scale values provided in that table.
Table 9.1.2: 1 K-BILD Response Option Weightings
Item
Response
1 
2 
3 
4 
5 
6 
7 
1 
0 
1 
2 
3 
4 
5 
6 
2 
0 
0 
1 
1 
2 
2 
3 
3 
0 
1 
2 
3 
4 
5 
6 
4 
0 
0 
1 
1 
2 
2 
3 
5 
0 
0 
1 
1 
1 
2 
2 
6 
0 
1 
2 
3 
4 
5 
6 
7 
0 
0 
1 
1 
2 
2 
3 
8 
0 
0 
1 
1 
2 
2 
3 
9 
0 
0 
1 
1 
1 
2 
2 
10
0 
1 
2 
3 
4 
5 
6 
11
0 
1 
2 
3 
4 
5 
6 
12
0 
1 
2 
3 
4 
5 
6 
13
0 
1 
2 
3 
4 
5 
6 
14
0 
1 
2 
3 
4 
4 
5 
15
0 
0 
1 
1 
1 
2 
2 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 89 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Finally, the raw domain and total scores are transformed to a range of 0–100 by using logit 
values and a simple look-up table to yield interval-level scores, where higher scores indicate 
better health status. Thus, for each raw summed domain and total score, look up the 
corresponding transformed domain and total score from Table 9.1.2: 2 below.
Table 9.1.2: 2 K-BILD Score Transformations 
Breathlessness and Activities
Chest Symptoms
Psychological
Total
Raw
Score
Transformed
Score
Raw
Score
Transformed
Score
Raw
Score
Transformed
Score
Raw
Score
Transformed
Score
0 
0 
0 
0 
0 
0 
0 
0 
1 
10.4
1 
17.3
1 
10.6
1 
9.2
2 
17.7
2 
32.1
2 
17.5
2 
15.3
3 
22.9
3 
44
3 
21.9
3 
19.4
4 
27
4 
54.3
4 
25.3
4 
22.6
5 
30.3
5 
63.7
5 
28
5 
25.1
6 
33.1
6 
73.4
6 
30.2
6 
27.2
7 
35.6
7 
85.2
7 
32.2
7 
29
8 
37.8
8 
100
8 
33.9
8 
30.5
9 
39.9
9 
35.5
9 
32
10
41.9
10
37
10
33.3
11
43.9
11
38.5
11
34.4
12
45.9
12
39.8
12
35.5
13
48
13
41.2
13
36.5
14
50.2
14
42.5
14
37.5
15
52.5
15
43.8
15
38.4
16
55.2
16
45.1
16
39.3
17
58.5
17
46.4
17
40.1
18
62.7
18
47.7
18
40.9
19
68.8
19
49.1
19
41.7
20
79.9
20
50.5
20
42.4
21
100
21
52
21
43.2
22
53.5
22
43.9
23
55.2
23
44.6
24
56.9
24
45.2
25
58.8
25
45.9
26
60.8
26
46.5
27
63
27
47.2
28
65.5
28
47.8
29
68.3
29
48.5


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 90 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 9.1.2: 2 K-BILD Score Transformations (continued) 
Breathlessness and Activities
Chest Symptoms
Psychological
Total
30
71.6
30
49.1
31
75.6
31
49.7
32
80.9
32
50.4
33
88.6
33
51
34
100
34
51.6
35
52.2
36
52.9
37
53.5
38
54.1
39
54.8
40
55.4
41
56.1
42
56.7
43
57.4
44
58.1
45
58.8
46
59.5
47
60.2
48
61
49
61.8
50
62.6
51
63.5
52
64.4
53
65.3
54
66.4
55
67.5
56
68.7
57
70
58
71.5
59
73.2
60
75.2
61
77.6
62
80.6
63
84.6
64
90.8
65
100


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 91 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.2 
L-PF SCORING INSTRUCTIONS
9.2.1
Symptoms
9.2.1.1
Dyspnea (items 1-12) 
For items 1, 2, 4-10, and 12: 
x
if “No” is ticked and “A” is ticked, the score is 5
x
if “No” is ticked and “B” is ticked, the item is not scored and does not  contribute to the 
denominator 
if “No” is ticked and neither “A” nor “B” is ticked, the item is counted as missing and 
handled per “Instructions for Missing Items”.  Items for which this occurs DO contribute 
to the denominator 
For items 3 and 11: 
x
scores equal whichever box is ticked (0-4) 
Dyspnea Symptom Score =
sum of responses from items 1 െ12
total score possible for items without “No”/”B” response × 100
9.2.1.2 Cough (items 13-18) 
Cough Symptom Score = sum of responses from items 13 െ18
24 
× 100
9.2.1.3
Energy (items 19-23) 
For items 19-22: 
x
scores equal whichever box is ticked (0-4) 
For item 23: 
x
if “Yes” is ticked, score equals whichever box is ticked (0-4)
x
if “No” is ticked, the item is not scored and does NOT contribute to denominator 
Energy Symptom Score =
sum of responses from items 19 െ23
total score possible (20 or 16 if response for 23 is “No”) × 100


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 92 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.2.1.4
Symptoms Total Score
Symptoms Total Score = (Dyspnea Symptom +  Cough Symptom +  Energy Symptom)
3 
9.2.2
Impacts
9.2.2.1
Dyspnea (items 1-6)
Dyspnea Impact Score = sum of responses from items 1 െ6
24 
× 100
9.2.2.2 Cough (items 7-11) 
Cough Impact Score = sum of responses from items 7 െ11
20 
× 100
9.2.2.3
Energy (items 13-14) 
Energy Impact Score = sum of responses from items 13 െ14
8 
× 100
9.2.2.4 Global (items 12, 15-21) 
Global Impact Score = sum of responses from items 12, 15 െ21
32 
× 100
9.2.2.5
Impacts Total Score
Impacts Total Score = (Dyspnea Impact +  Cough Impact +  Energy Impact +  Global Impact)
4 
9.3
PF-IQOLS SCORING INSTRUCTIONS
9.3.1
Summary score
The scoring of the PF-IQOLS follows Flanagan’s practice in that a very straightforward 5-
point Likert-type rating scale is used, and the scoring is analogous to that of the QOLS – i.e., 
the summary score is the average of the individual dimension ratings 1-16. The response 
option for all items ranges from 1 (no negative effect at all) to 5 (extremely negative effect). 
Therefore the score range for the summary score is 1.0-5.0. The individual item scores can be 
directly taken from the answered questions in the questionnaire. Please see more details in the 
questionnaire (Figure 9.3.1: 1 and Figure 9.3.1: 2) 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 93 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Figure 9.3.1: 1 Part I of the PF-IQOLS Questionnaire.


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 94 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Figure 9.3.1: 2 Part II of the PF-IQOLS Questionnaire


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 95 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.4
ADDITIONAL ANALYSES FOR REGIONAL SUBMISSIONS
For the Japanese submission, the analyses will be conducted according to “Format for 
Preparing the Common Technical Document for Submission of New Drug Applications to 
Reduce Total Review Time” (17). 
For the analysis due to local regulatory submission (21), the following patient subsets are 
defined. 
Table 9.4: 1 
Patient subset definitions for local regulatory submission in Asia
Category
Patient Subset
Local
Japanese patients 
Chinese patients
The patients in each local site and Asian race will be included (e.g. 
Japanese patients: Site in Japan and single race is Asian). If Asian race 
will be “Multiple” and multiple race responder will be “Asian & xxx”, 
the patient will be handled as “Asian”. (e.g. Japan: Site in Japan and 
multiple race is Asian & White.)
East Asia
East Asian patients
The patients from East Asian countries or region (i.e. Japan, Korea and 
China) with Asian race. Asian race definition is same definition as for 
local category.
Some outputs from CTR Section 15 or section 16 will be selected for the patient subsets 
defined in Table 9.4: 1. Due to small sample size of some of the patient subsets, some tables 
might be skipped. The same analysis models as defined in Section 7 will be used. A detailed
plan will be described in the CSAP. In the event of non-convergence, the same methods as 
described in Section 7.4.1 will be used to overcome the issue. But in case of very limited 
number of patients, the more simplified model or descriptive statistics may be used if 
convergence is not achieved via the described methods in Section 7. These patient subset 
analyses will not be produced as part of the CTR appendix and will not be described in the 
text of the CTR.
Other subset analysis than described in Table 9.4: 1 may be conducted in response to 
regulatory requests and the detailed plan for that case will be described in the CSAP. 
9.5
PROGRAMMING CODE FOR INFERENTIAL ANALYSIS
9.5.1
Primary endpoint model 
The key code is given below. Time is defined as duration since first trial drug intake divided 
by 365.25. Visit is the visit number. For the co-primary population, please remove HRCT as 
variable from the model. 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 96 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
ODS OUTPUT estimates=estimateout;
PROC MIXED data=FVC cl method=reml  order= formatted covtest; 
CLASS  
patient treatment hrct; 
MODEL
endpoint= treatment treatment*time hrct fvcbaseline fvcbaseline*time /solution CL 
ddfm=KR;
RANDOM
intercept time/ type=un subject=patient;
ESTIMATE
'Nintedanib' fvcbaseline*time meanbase treatment*time 0 1 / e CL;
ESTIMATE
'Placebo' fvcbaseline*time meanbase treatment*time 1 0 / e CL;
ESTIMATE
'Nintedanib 150mg bid – Placebo’ treatment*time -1 1 / e CL;
RUN;
ODS OUTPUT CLOSE;
9.5.2
Primary endpoint subgroup analysis model:
Example subgroup used: Gender (Male / Female).
ODS OUTPUT   estimates=estimatesout Contrasts=contrastsout ;
PROC MIXED data=FVC cl method=reml  order= formatted covtest; 
CLASS patient treatment hrct subgroup; 
MODELendpoint= treatment*subgroup treatment*subgroup*time
 
 
hrct fvcbaseline fvcbaseline*time
/solution CL ddfm=KR;
RANDOM
intercept time/ type=un subject=patient;
ESTIMATE
'Nintedanib - Female' fvcbaseline*time meanbase treatment * subgroup *time 0 0 1 0
/ cl e;
ESTIMATE
'Placebo - Female' fvcbaseline*time meanbase treatment * subgroup *time 1 0 0 0 
/ cl e;
ESTIMATE
'Nintedanib - Male' fvcbaseline*time meanbase treatment * subgroup *time 0 0 0 1 /
cl e;
ESTIMATE
'Placebo - Male' fvcbaseline*time meanbase treatment * subgroup *time 0 1 0 0 
/ cl e;
ESTIMATE
'Nintedanib – Placebo Female'  subgroup * treatment *time
 -1 0 1 0 / e CL;
ESTIMATE
'Nintedanib – Placebo Male'   subgroup * treatment *time
0 -1 0 1 / e CL;
CONTRAST
'F-test of heterogenety at 52 weeks'
subgroup * treatment *time -1 1 1 -1 / e;
RUN;
ODS OUTPUT CLOSE ;
9.5.3
Implementation of multiple imputation:
The following steps provide a guidance of how missing FVC data at week 52 will be
implemented in patients of pattern 3 and 4 using multiple imputation. Refer to 
Table 7.4.2.1.2: 1 for the description of patterns and the different sensitivity analyses 
regarding handling of missing data. 
1. Run the MMRM of the primary analysis (either including patients of pattern 2 only for 
sensitivity analyses 1 and 2 or on all patients for sensitivity analysis 3) to get the slope 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 97 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
estimates (SE) by treatment group. Let ߚመD and ߪොD denote the slope (SE) estimates in 
Nintedanib 150 mg and ߚመPand ߪොP the slope (SE) estimates in placebo.
2. Let βD and βP represent the true slopes in drug and placebo respectively with f(βD) ~ 
N(ߚመ஽, ߪොଶ
஽) and with f(βP) ~ N(ߚመ௉, ߪොଶ
௉), using the slope (SE) estimates obtained in 
step 1.  
3. Imputation of missing week 52 data in patients of pattern 3: 
Multiple impute missing values (1000 imputations per patient). To do so, draw 
random slopes from the distributions defined in step 2. Considering that the 
withdrawal of a patient leading to missing data can occur at any time during the 
study, the timepoint of the last available FVC value has to be taken into account to 
impute the missing FVC value at 52 weeks.
FVC week 52 imputedij = last FVC value availablei + ߚመij(time between date of 
last FVC value availablei and planned 52 week timepoint [days]) 
where i denotes the indicator of the ith patient, j the indicator of the jth imputation 
and  ߚመij denotes a random slope sampled from the distribution mentioned in step 
3a for the ith patient in the jth imputation. Depending on the sensitivity analysis, 
use either random slopes drawn from f(βD) for patients randomised to Nintedanib 
150 mg in sensitivity analysis 1 or f(βP) for all patients in sensitivity analyses 2 
and 3. 
4. Imputation of missing week 52 data in patients of pattern 4: 
Multiple impute missing values (1000 imputations per patient). To do so, draw 
random slopes from the truncated distribution f(βP)/2 restricted to the interval 
(െλ, ߚመ௉] defined in step 2.  
See step 3 for further details on how to use these slopes to impute the missing 
values at week 52. 
5. Run the MMRM of the primary analysis on each imputed dataset, using a "by 
_IMPUTATION_ " statement.
6. Combine the estimates obtained in step 5 using PROC MIANALYZE. 
9.6
SPECIAL ADAM COMPOSITION INSTRUCTIONS
9.6.1
ADEX
The analysis of exposure will be based on the drug administration as planned and documented 
in the eCRF, i.e. the derivation of ADEX will be mainly based on EC. In case an 
administration entry for a visit is missing, it will be checked whether the patient was treated 
using the compliance data in XA; if this is the case, the missing drug administration data will 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 98 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
be replaced using the drug dispensation data in DA for the same visit if available. Treatment 
start will be the first treatment date/time as in ADEX. 
9.7
LIST OF BI CUSTOMISED DRUG GROUPINGS OF INTEREST
Drug groupings of interest for this trial are shown in the following Table. 
Table 9.7: 1 
Concomitant Therapy groupings 
CT grouping name
Type of grouping
Biologic DMARDs
SDG
Non-biologic DMARDs
SDG
Antithrombotic drugs 
SDG
The table below shows the overview of medications that are considered to fall into the 
respective category of Disease-Modifying Anti-Rheumatic Drugs (DMARDS) with known 
hepatotoxic or gastrointestinal effects. Please note that an individual substance can occur in 
both categories. 
Table 9.7: 2 
DMARDS with known hepatotoxic or gastrointestinal effects 
DMARDS with known
hepatotoxic effects
DMARDS with known
gastrointestinal effects
WHO-DD decode
WHO-DD code
WHO-DD decode
WHO-DD code
LEFLUNOMIDE
01414801001
ABATACEPT
05514401001
METHOTREXATE
00113801001
LEFLUNOMIDE
01414801001
METHOTREXATE 
SODIUM
00113802001
METHOTREXATE
00113801001
TOCILIZUMAB
01759101001
METHOTREXATE 
SODIUM
00113802001
TOFACITINIB
07918601001
SULFASALAZINE
00001601001
TOFACITINIB 
CITRATE
07918602001
TOFACITINIB
07918601001
TOFACITINIB 
CITRATE
07918602001


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 99 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.8
SPECIFICATION OF RESTRICTED AND FORBIDDEN CONCOMITANT 
THERAPIES
Categorisations and detailed information on WHO-DD code can be found in the following 
Table.
Table 9.8: 1 
Prohibited or restricted concomitant therapies 
Type of medication
Category of drugs 
WHO-DD code
Prohibited 
Full dose therapeutic 
anticoagulation or high 
dose antiplatelet therapy
0000000126
Prohibited 
Pirfenidone 
06225101001
Prohibited 
Nintedanib 
08403301001, 08403302001 
Restricted
Oral corticosteroids 
(OCS)
0000000010
Restricted
Immunomodulatory 
medications for ILD 
00001501001, 00001502001, 
00021101001, 00021102001, 
00549701001, 01275102001, 
01275104001, 01402501001 
01219901001, 01219902001 
9.9
LIST OF POTENTIAL TERMS FOR HEPATIC INJURY DERIVATION
The table below shows the list of potentially relevant MedDRA preferred terms to support the 
derivation of a potential hepatic injury. 
Table 9.9: 1 
List of potentially relevant MedDRA preferred terms
Symptom
MedDRA
Vomiting 
PT Vomiting
Fatigue
PT Fatigue
Nausea
PT Nausea
Right upper abdominal quadrant pain or 
tenderness
HLT “Gastrointestinal and abdominal pains 
(excl oral and throat)”
Fever
PT Pyrexia
Rash
BIcMQ skin rash (narrow)


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 100 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
9.10
LIST 
OF 
PREFERRED 
TERMS 
INCLUDED 
IN 
STROKE 
PHARMACOVIGILANCE ENDPOINT
Amaurosis fugax
Amyloid related imaging abnormalities
Basal ganglia haemorrhage
Basilar artery occlusion
Basilar artery thrombosis
Brachiocephalic artery occlusion
Brain stem haematoma
Brain stem haemorrhage
Brain stem infarction
Brain stem ischaemia
Brain stem stroke
Brain stem thrombosis 
Carotid aneurysm rupture 
Carotid arterial embolus
Carotid artery occlusion
Carotid artery thrombosis 
Central nervous system haemorrhage
Cerebellar artery occlusion
Cerebellar artery thrombosis
Cerebellar embolism
Cerebellar haematoma
Cerebellar haemorrhage
Cerebellar infarction
Cerebellar ischaemia
Cerebral arteriovenous malformation haemorrhagic 
Cerebral artery embolism
Cerebral artery occlusion
Cerebral artery thrombosis
Cerebral haematoma
Cerebral haemorrhage
Cerebral haemorrhage foetal
Cerebral haemorrhage neonatal
Cerebral infarction
Cerebral infarction foetal
Cerebral ischaemia
Cerebral thrombosis 
Cerebrovascular accident
Embolic cerebral infarction
Embolic stroke 
Haemorrhage intracranial
Haemorrhagic cerebral infarction
Haemorrhagic stroke 
Haemorrhagic transformation stroke 
Intracranial haematoma
Intracranial tumour haemorrhage 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 101 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Intraoperative cerebral artery occlusion
Intraventricular haemorrhage 
Intraventricular haemorrhage neonatal
Ischaemic cerebral infarction
Ischaemic stroke
Lacunar infarction 
Lateral medullary syndrome
Pituitary haemorrhage
Pituitary infarction
Post procedural stroke 
Precerebral artery occlusion
Putamen haemorrhage
Reversible ischaemic neurological deficit
Ruptured cerebral aneurysm
Stroke in evolution 
Subarachnoid haemorrhage 
Subarachnoid haemorrhage neonatal 
Subdural haemorrhage neonatal 
Thalamic infarction
Thalamus haemorrhage 
Thrombotic cerebral infarction 
Thrombotic stroke 
Transient ischaemic attack
Vertebral artery occlusion
Vertebral artery thrombosis
9.11
LIST OF TERMS FOR THE CATEGORISATION OF BLEEDING EVENTS
SMQ Haemorrhage terms (excl laboratory terms) (narrow)
9.12
ADDITIONAL SENSITIVITY ANALYSES
9.12.1
Tipping point analysis
An additional approach compared to the already discussed methods in Section 7.4.2 is to 
evaluate the robustness of the primary analysis to the missing at random (MAR) assumption 
by performing a tipping point sensitivity analysis. The aim of the tipping point approach is to 
assess how severe departures from MAR could be in order to reverse conclusions from the 
primary analysis under different assumptions regarding a declining persistence of efficacy
post withdrawal of the randomised treatment. The robustness of the results will be discussed 
based on the magnitude of deviations from MAR required to change the results. 
As a first step non-monotone missing data will be imputed m = 100 times using MCMC 
(Markov Chain Monte Carlo) to generate m data sets of longitudinal spirometry data (FVC 
[mL]) with monotone missingness pattern. Such a missingness pattern is the pre-requisite for 
subsequently applying sequential imputation and means that once a patient has a missing FVC 
value at a particular time point, FVC values at all subsequent time points also have missing 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 102 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
values. The seemingly large number of imputations (m=100) is chosen to minimize the 
standard error of those FVC estimates that are produced to fill the missing values. The seed 
number will be set to 1199247. 
Once the monotone missing pattern has been created, the tipping point analysis for the 
longitudinal FVC data can commence and will be based on the Multiple Delta Adjustment 
Method. Data in each of the 100 generated datasets, now exhibiting a monotone missingness 
pattern, will be imputed once by using sequential regression. A delta adjustment will be added 
to each imputed value. The value of each delta adjustment will be given by: 
ߜ௜௝= ܵ௜כ ߮௝
Ɂ୧୨ 
= 
adjustment for a patient in treatment i at visit j
S୧ 
= 
shift parameter for treatment i (i=1,2) 
ɔ୨ 
= 
number of weeks between visit j-1 and visit j
For patients in both treatment arms, the delta adjustment (ᆄ) will be proportional to the time 
between the visits. For patients with more than one monotone missing visit, multiple 
adjustments must be applied and since the imputation method is sequential, the effect of the 
adjustments is cumulative. S1 and S2 therefore represent the slope of a linear adjustment over 
time. This step will be repeated for a variety of combinations of S1 and S2. The reason for 
selection of ranges of S1 and S2 is described below.  
For each combination of shift values S1 and S2 the m complete data sets will be analysed 
using the primary analysis model. The estimate of treatment difference at week 52 will be 
derived. Rubin’s rules (16) will be used to combine the results from the analyses for each pair 
of S1 and S2 to provide the required inferences for all combinations of shift parameters S1 and 
S2. Point estimates for treatment differences and respective p-values will be reported for all 
combinations of S1 and S2 in a cross-table.
The selection of shift values S1 and S2 is based on considerations of plausible and implausible 
cumulative changes of FVC (ml) values at week 52 (the end of Part A) of the patient 
population included into the trial, as well as observations made based on INPULSIS-1 and 
INPULSIS-2, given the possible range of missing data patterns.
In a first step the following combinations of S1 and S2 will be tested to cover a clinically
reasonable space:
x
S1, S2, = -20, -16, -13, -10, -6, -3, 0, +3, +6, +10 (resulting in 10x10 = 100 
combinations matrix). 
These shift parameters (-20 to +10) translate into 
x
Covering a median adjustment in imputed FVC (mL) at week 52 on patient level
of -453 mL at the value -20 
o
(-320 ml with only 1 missing value at week 52 to -749 ml with 7 missing 
values up to week 52) 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 103 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
x
To a median adjustment in imputed FVC (mL) at week 52 on patient level of +227 mL 
at the value +10
o
(+160 ml with 1 missing value at week 52 to +374 ml with 7 missing values
up to week 52) 
See Table 9.12.1: 1 for additional details.
Table 9.12.1: 1 
Overview of the median adjustment in imputed FVC (mL) at week 52 
Shift
parameter
Median adjustment in imputed FVC (mL) at week 52 on patient level
Overall
1
missing
value
2
missing
values
3
missing
values
4
missing
values
5
missing
values
6
missing
values
7
missing
values
-20
-453
-320
-467
-626
-677
-695
-718
-749
-18
-408
-288
-420
-563
-609
-625
-646
-674
-16
-363
-256
-374
-500
-541
-556
-575
-599
-14
-317
-224
-327
-438
-474
-486
-503
-524
-12
-272
-192
-280
-375
-406
-417
-431
-449
-10
-227
-160
-234
-313
-338
-347
-359
-374
-8
-181
-128
-187
-250
-271
-278
-287
-299
-6
-136
-96
-140
-188
-203
-208
-215
-225
-4
-91
-64
-93
-125
-135
-139
-144
-150
-2
-45
-32
-47
-63
-68
-69
-72
-75
0
0
0
0
0
0
0
0
0
2
45
32
47
63
68
69
72
75
4
91
64
93
125
135
139
144
150
6
136
96
140
188
203
208
215
225
8
181
128
187
250
271
278
287
299
10
227
160
234
313
338
347
359
374
After investigation of estimates and p-values from these analyses further combinations with 
refined ranges of S1 and S2 may be used for the tipping point analysis. 
9.13
LIST OF UNDERLYING ILD GROUPINGS FOR “OTHER FIBROSING 
ILD” ENTRIES
Patients, who have been entered in the eCRF as “other fibrosing ILD” were re-grouped for the 
analysis based on the following table (Table 9.13: 1).


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 104 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 9.13: 1 Other Fibrosing ILD grouping
Other Fibrosing ILD
Grouping
ILD ASSOCIATED WITH LUPUS
autoimmune ILD
POLYMYOSITIS CTD ILD
autoimmune ILD
DESQUAMATIVE INTERSTITIAL PNEUMONIA
other ILD
PULMONARY FIBROSIS WITH AUTO-IMMUNE FEATURES
autoimmune ILD
CHRONIC EOSINOPHILIC PNEUMONIA
other ILD
FIBROSIS AND EMPHYSEMA
other ILD
PLEURO-PULMONARY FIBROELASTOSIS
other ILD
RESPIRATORY BRONCHIOLITIS-ILD WITH FIBROSIS
other ILD
PPFE (PLEUROPARENCHYMAL FIBROELASTOSIS)
other ILD
FIBROELASTOSIS
other ILD
LIPOIDIC FIBROSIS
other ILD
AFTER CHEMOTHERAPY
exposure related ILD
UCTD-ILD WITH POSITIVE ANTI-PL7 AUTO-AB
autoimmune ILD
OVERLAP NSIP - OP.  NO UNDERLYING CTD
other ILD
OUTCOME OF ACUTE INTERSTITIAL PNEUMONIA
other ILD
SJOGREN DISEASE ILD
autoimmune ILD
IDIOPATHIC PLEUROPARENCHYMAL FIBROELASTOSIS (PPFE)
other ILD
SJOGREN'S SYNDROME
autoimmune ILD
IDIOPATHIC PLEUROPARENCHYMAL FIBROELASTOSIS
other ILD
IGG4 RELATED LUNG DISEASE
other ILD
SJOGREN SYNDROME ASSOCIATED ILD
autoimmune ILD
COMBINED PULMONARY FIBROSIS AND EMPHYSEMA
other ILD
SJOGREN'S SYNDROME ILD
autoimmune ILD
PULMONARY ALVEOLAR PROTEINOSIS
other ILD
MPA ASSOCIATED ILD
autoimmune ILD
ANCA ASSOCIATED ILD
autoimmune ILD
PLUEROPARENCHYMAL FIBROELASTOSIS
other ILD
CRYPTOGENICORGANIZING PNEUMONIA,IDIOPATHICDISEASE
other ILD
CRYPTOGENICORGANIZINGPNEUMONIA,IDIOPATHIC DISEASE
other ILD
UNDIFFERENTIATED CONNECTIVE TISSUE DISEASE-ILD
autoimmune ILD
CTD-OP
autoimmune ILD
UNCLASSIFIED CONNECTIVE TISSUE DISEASE
autoimmune ILD
SJOGREN SYNDROME
autoimmune ILD
CTD-ILD
autoimmune ILD 


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 105 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 9.13: 1 Other Fibrosing ILD grouping (continued) 
Other Fibrosing ILD
Grouping
LUNG FIBROSIS IN ANTISYNTHETASE SYNDROME
autoimmune ILD
INTERSTITIAL PNEUMONIA WITH AUTOIMMUNE FEATURES
autoimmune ILD
IPAF
autoimmune ILD
CRYPTOGENIC ORGANIZING PNEUMONIA
other ILD
SJÃ–GREN SYNDROME
autoimmune ILD
SYSTEMIC LUPUS ERYTHEMATOSUS-ILD
autoimmune ILD
CT-ILD
autoimmune ILD
PLEUROPARENCHYMAL FIBRIOELASTOSIS
other ILD


Boehringer Ingelheim
TSAP for BI Trial No: 1199.247
Page 106 of 106
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
10.
HISTORY TABLE
Table 10: 1 
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
04-JAN-17
None
This is the initial TSAP with necessary 
information for trial conduct
Final
14-DEC-18
1-9 
This is the final TSAP
