Conditions: Idiopathic Pulmonary Fibrosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 347
Healthy volunteers: no

Brief summary:
Identifying biomarkers to predict the clinical course and benefits of therapy early in the course of the disease remains one of the most urgent and relevant challenges to improve overall patient management, to prevent treatment delay or overtreatment. This study is conducted to examine the effect of nintedanib treatment on change in biomarkers indicative of extracellular matrix turnover which have been shown recently to correlate with disease progression. This study further aims to confirm the association of biomarker course during the first three months of treatment and disease progression.

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:
c03495745-05
EudraCT No.:
2015-003148-38
BI Trial No.:
   1199.227
BI Investigational 
Product(s):
   Ofev®, nintedanib
Title:
A 12-week, double blind, randomised, placebo controlled, parallel 
group trial followed by a single active arm phase of 40 weeks 
evaluating the effect of oral nintedanib 150 mg twice daily on change 
in biomarkers of extracellular matrix (ECM) turnover in patients with 
idiopathic pulmonary fibrosis (IPF) and limited forced vital capacity 
(FVC) impairment.
Brief Title:
Effect of nintedanib on biomarkers of ECM turnover in patients with 
IPF and limited FVC impairment
Clinical Phase:
IV
Trial Clinical 
Monitor:
Phone:
 Fax: 
Coordinating 
Investigator:
   
  
  
,
  
  
   Phone:
 Fax: 
Status:
   Final Protocol (Revised Protocol (based on global amendment 4))
Version and Date:
Version: 5.0
Date: 09 Jul 2018
Page 1 of 95
Proprietary confidential information.
2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product: Ofev®
Name of active ingredient: Nintedanib
Protocol date:
11 Feb 2016
Trial number:
1199.227
Revision date:
09 Jul 2018
Title of trial:
A 12-week, double blind, randomised, placebo controlled, parallel group trial 
followed by a single active arm phase of 40 weeks evaluating the effect of oral 
nintedanib 150 mg twice daily on change in biomarkers of extracellular matrix 
(ECM) turnover in patients with idiopathic pulmonary fibrosis (IPF) and limited
forced vital capacity (FVC) impairment.
Coordinating
Investigator:
Trial site(s):
Multi-centre, multi-national trial
Clinical phase:
IV
Objective(s):
To investigate the effect of nintedanib on various extracellular matrix (ECM) 
turnover biomarkers and the predictive value of change in those ECM biomarkers 
on disease progression.
Methodology:
12-week randomised, double blind, parallel group, placebo controlled phase 
followed by a single active arm phase of 40 weeks
No. of patients: 
~490 enrolled (screened) patients
total entered:
~350 entered (randomised) patients 
each treatment:
Nintedanib: 117
Placebo: 233 *
*applicable to 12-week randomised part of the trial 
Diagnosis :
Idiopathic Pulmonary Fibrosis (IPF)
Main criteria
for inclusion:
Male or female patients aged ≥40 years at Visit 1 (screening); IPF diagnosis based 
upon ATS/ERS/JRS/ALAT 2011 guideline within 3 years of Visit 0; HRCT 


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Name of company:
Boehringer Ingelheim 
Name of finished product: Ofev®
Name of active ingredient: Nintedanib
Protocol date:
11 Feb 2016
Trial number:
1199.227
Revision date:
09 Jul 2018
performed within 18 months of Visit 0; confirmation of diagnosis by central 
review of chest HRCT and surgical lung biopsy (later if available) prior to 
randomisation; FVC ≥ 80% predicted of normal at Visit 1 (screening) 
Test product(s):
Nintedanib
dose:
300 mg daily (150 mg bid) with possibility to reduce total daily dose to 200 mg 
(100 mg bid) to manage adverse events (AEs)
mode of 
administration:
oral 
Comparator products:
Placebo matching Nintedanib
dose:
Not applicable
mode of 
administration:
oral 
Duration of treatment:
52 weeks 
Endpoints
Primary Endpoint:

Rate of change (slope) in blood CRPM from baseline to week 12
Key Secondary Endpoint:

Proportion of patients with disease progression as defined by absolute 
FVC (% predicted) decline ≥10% or death until week 52
Secondary Endpoints:

Rate of change (slope) in blood C1M from baseline to week 12

Rate of change (slope) in blood C3M from baseline to week 12
Further Endpoints (selected):
 


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Name of company:
Boehringer Ingelheim 
Name of finished product: Ofev®
Name of active ingredient: Nintedanib
Protocol date:
11 Feb 2016
Trial number:
1199.227
Revision date:
09 Jul 2018
 
 
Safety criteria:
Adverse events (especially SAE and other significant AE), physical examination, 
weight measurements, 12 lead electrocardiogram, vital signs and laboratory 
evaluations.
Statistical methods:
Random coefficient regression models for continuous endpoints, Log rank tests, 
Kaplan-Meier plots and Cox regressions for time to event endpoints, logistic 
regression models or other appropriate methods for binary endpoints


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1.
Informed consent should be obtained before any study procedure including the shipment of the HRCT image and 
biopsy sample (if available) for central review. 
2.
At visit 1, height measurement should be included.
3.
PK samples will be taken at Visits 3, 6 and 10 just prior to drug administration. Patients will be provided with a PK 
card/diary to support the record of the exact clock time of medication intake three days prior to PK sampling.
4.
Blood samples for serum banking and pharmacogenetics may be drawn from all randomised patients who received at 
least one dose of trial medication and who gave a separate informed consent. Patients will be asked to participate in 
the biobanking subset, i.e. pharmacogenetic and serum biobanking. Still, the participation is voluntarily and not a pre-
requisite for participation in the trial. The single pharmacogenetic sample will be drawn at Visit 2 or at any other 
subsequent visit after randomisation. Serum banking samples shall be drawn as per Flow Chart.
5.
SGRQ, UCSD-SOBQ: the first procedure at the clinic.
6.
Patient diary will be issued at Visit 2 and will be reviewed at each clinic visit up until Visit 10. Content to be discussed 
and reviewed by the site staff as it pertains to AEs and concomitant therapy and times of drug intake three days prior 
to the PK sampling.
7.
Including acute IPF exacerbations
8.
Patients who prematurely discontinue from the trial and don’t accept to attend all planned visits will be contacted for 
vital status collection at week 52.
9.
No fasting required.
10.
If performance compliance is below 80% or as deemed necessary by the site.


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11.
To be performed after pre-dose PK sample (if applicable) and after current visit exams.
12.
Perform only if abnormal or findings needing follow-up recorded at Visit 10.
13.
Visit 1 should only be conducted after IPF diagnosis has been confirmed by central review. 
14.
In case of dose change of nintedanib (reduction or re-escalation), dose adjustment visit must be conducted to allow 
dispensing of new medication kit.
15.
Early end of treatment visit to be completed for all patients who withdraw or discontinue study treatment prematurely.
Patients who prematurely discontinue treatment will then be invited to attend all visits as planned until week 52 (Visit 
10).
16.
Screening period (period between Visit 1 and 2) should last 14 days (2 weeks). The screening period may be 
prolonged by additional 2 week for any reasons, i.e. total 28 days (4 weeks). Eligible patients can be randomised once 
central lab results have been received and are found to be consistent with eligibility criteria.  
17. 
4 days prior to planned PK sampling site should preferably contact the patient to record times of drug intake within 
patient diary. Patient should record times of drug intake three days prior to the PK sampling.
18.
In women of childbearing potential.
19. 
Applicable only if patient doesn’t accept to attend remaining scheduled visits. 


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................15
MEDICAL BACKGROUND.............................................................................15
1.1
DRUG PROFILE................................................................................................16
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....19
RATIONALE FOR PERFORMING THE TRIAL.........................................19
2.1
TRIAL OBJECTIVES........................................................................................20
2.2
BENEFIT - RISK ASSESSMENT.....................................................................20
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................22
OVERALL TRIAL DESIGN AND PLAN .......................................................22
3.1
3.1.1
Administrative structure of the trial .................................................................23
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................25
SELECTION OF TRIAL POPULATION .......................................................26
3.3
3.3.1
Main diagnosis for trial entry ............................................................................26
3.3.2
Inclusion criteria .................................................................................................26
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Removal of patients from therapy or assessments...........................................29
Removal of individual patients .............................................................................29
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................30
3.3.4.2
4.
TREATMENTS...................................................................................................31
TREATMENTS TO BE ADMINISTERED.....................................................31
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........31
4.1.2
Method of assigning patients to treatment groups...........................................32
4.1.3
Selection of doses in the trial..............................................................................33
4.1.4
Drug assignment and administration of doses for each patient......................33
4.1.5
Blinding and procedures for unblinding...........................................................35
Blinding.................................................................................................................35
4.1.5.1
Unblinding and breaking the code ........................................................................35
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................35
4.1.7
Storage conditions...............................................................................................35
4.1.8
Drug accountability.............................................................................................36


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CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................36
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....36
Recommendations for managing adverse events (exceptions include diarrhea and 
4.2.1.1
liver enzyme elevations) .......................................................................................36
Recommendations for management of diarrhea ...................................................37
4.2.1.2
Recommendations for management of liver enzyme elevation............................39
4.2.1.3
Management of acute IPF exacerbations and acute deteriorations.......................40
4.2.1.4
4.2.2
Restrictions ..........................................................................................................40
Restrictions regarding concomitant treatment ......................................................40
4.2.2.1
Restrictions on diet and life style..........................................................................41
4.2.2.2
Restrictions regarding women of childbearing potential......................................42
4.2.2.3
TREATMENT COMPLIANCE........................................................................42
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................43
TRIAL ENDPOINTS..........................................................................................43
5.1
5.1.1
Primary Endpoint ...............................................................................................43
5.1.2
Secondary Endpoints..........................................................................................43
ASSESSMENT OF EFFICACY........................................................................44
5.2
ASSESSMENT OF SAFETY.............................................................................45
5.3
5.3.1
Physical examination ..........................................................................................45
5.3.2
Vital Signs............................................................................................................46
5.3.3
Safety laboratory parameters ............................................................................46
5.3.4
Electrocardiogram ..............................................................................................46
5.3.5
Other safety parameters.....................................................................................47
5.3.6
Assessment of adverse events.............................................................................47
Definitions of AEs ................................................................................................47
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................50
 
ASSESSMENT OF EXPLORATORY BIOMARKER(S)..............................53
5.5
5.5.1
Analytical determinations ..................................................................................54
5.5.2
Biobanking...........................................................................................................54
OTHER ASSESSMENTS...................................................................................55
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................55
5.7
6.
INVESTIGATIONAL PLAN.............................................................................56
VISIT SCHEDULE.............................................................................................56
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................57
6.2
6.2.1
Screening and run-in period(s)..........................................................................57
6.2.2
Treatment period(s)............................................................................................58
6.2.3
Follow Up Period and Trial Completion...........................................................62


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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................64
STATISTICAL DESIGN - MODEL.................................................................64
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................64
7.2
PLANNED ANALYSES.....................................................................................64
7.3
7.3.1
Primary endpoint analyses.................................................................................65
7.3.2
Secondary endpoint analyses .............................................................................65
7.3.4
Safety analyses.....................................................................................................66
INTERIM ANALYSES ......................................................................................67
7.4
HANDLING OF MISSING DATA ...................................................................67
7.5
7.5.1
Efficacy endpoints...............................................................................................67
7.5.2
Safety endpoints ..................................................................................................68
RANDOMISATION ...........................................................................................68
7.6
DETERMINATION OF SAMPLE SIZE .........................................................68
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........71
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................71
DATA QUALITY ASSURANCE ......................................................................72
8.2
RECORDS...........................................................................................................72
8.3
8.3.1
Source documents ...............................................................................................73
8.3.2
Direct access to source data and documents.....................................................73
8.3.3
Storage period of records ...................................................................................73
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS73
8.4
8.4.1
Listedness.............................................................................................................73
8.4.2
Expedited reporting............................................................................................74
STATEMENT OF CONFIDENTIALITY........................................................74
8.5
END OF TRIAL..................................................................................................74
8.6
PROTOCOL VIOLATIONS .............................................................................74
8.7
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY..............................................................................74
9.
REFERENCES....................................................................................................75
PUBLISHED REFERENCES............................................................................75
9.1
UNPUBLISHED REFERENCES......................................................................79
9.2
10.
APPENDICES.....................................................................................................80
CRITERIA FOR HRCT/BIOPSY CENTRAL................................................80
10.1
CREATININE CLEARANCE...........................................................................80
10.2
DLCO...................................................................................................................91
10.5


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................92


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ABBREVIATIONS
AE
Adverse Event
AESI
ALAT
ALP
ALT
AST
ATP
ATS
Adverse Event of Special Interest
Latin American Thoracic Association
Alkaline phosphatase
Alanine transaminase
Aspartate aminotransferase
Adenosine triphosphate
American Thoracic Society
AUC
b.i.d.
Area under the Curve
bis in die (twice daily dosing)
BI
Boehringer Ingelheim
BIRDS
BS
C1M
C3M
CA
Boehringer Ingelheim Regulatory Documents for Submission
Biomarker Set
Collagen 1 degraded by MMP-2/9/13
Collagen 3 degraded by MMP-9
Competent Authority
CI
Confidence Interval
CML
CNS
Local Clinical Monitor 
Central Nervous System
CRA
Clinical Research Associate
CRF
CRO
CRPM
Case Report Form
Clinical Research Organisation
C-reactive protein degraded by MMP-1/8
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
DDI
DEDP
DILI
DLCO
Clinical Trial Report
Drug-drug interaction
Drug exposure during pregnancy
Drug induced liver injury
Carbon monoxide diffusing capacity
DMC
DNA
Data Monitoring Committee
Deoxyribonucleic Acid
eCRF
ePRO
ECG
ECM
Electronic Case Report Form
Electronic Patient Reported Outcome
Electrocardiogram
Extracellular matrix
EDC
EDTA
EOT
Electronic Data Capture
Ethylendiamintetraacetate
End of treatment


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ERS
European Respiratory Society
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
FDA
FGFR
FVC
Flow Chart
Food and Drug Administration
Fibroblast growth factor/receptor
Forced vital capacity
GCP
GGT
GI
ß-HCG
Good Clinical Practice
Gamma-glutamyl transferase
Gastrointestinal
β-human Chorionic Gonadotropin  
HPC
HRCT
Human Pharmacology Center
High Resolution Computer Tomography
IB
ICH GCP
Investigator’s Brochure
International Conference on Harmonisation Good Clinical Practice
IEC
INR
IPF
Independent Ethics Committee
International normalised ratio
Idiopathic pulmonary fibrosis
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
IVRS
Interactive Voice Response System
IWRS
JRS
LC-MS/MS
LDH
Interactive Web-based Response System
Japanese Respiratory Society
Liquid chromatography-tandem mass spectrometry
Lactate dehydrogenase
LoEE
List of Essential Element 
MedDRA
MMPs
Medical Dictionary for Drug Regulatory Activities
Metalloproteinases
MMRM
Mixed Effects Model for Repeated Measures
MST
N/A
NAC
nRTKs
Medical Sub team
Not Applicable
n-acetylcysteine
Non-receptor tyrosine kinases
OPU
Operative Unit
p.o.
per os (oral)
PCC
PD
PDGFR
Protocol Challenge Committee
Pharmacodynamic/ Pharmacodynamics
Platelet derived growth factor/receptor


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PFT
PG
PK
PKS
PT
PTT
Pulmonary Function Test
Pharmacogenetics
Pharmacokinetic Set
Pharmacokinetic/ Pharmacokinetics
Prothrombin time 
Partial thromboplastin time
q.d.
RDC
quaque die (once a day)
Remote Data Capture
REP
RS
RTKs
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present  
Randomised Set
Receptor tyrosine kinases
SAE
Serious Adverse Event
s.c.
SGRQ
SOP
Subcutaneous
St. George’s Respiratory Questionnaire
Standard Operating Procedure
SPC
SP-D
SpO2
Summary of Product Characteristics
Surfactant Associated Protein-D
Oxygen Saturation
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TMW
TS
Trial Medical Writer
Treated Set
TSAP
TSH
UIP
ULN
UCSD-SOBQ
VEGFR
Trial Statistical Analysis Plan
Thyroid stimulating hormone
Usual Interstitial Pneumonia
Upper Limit Normal 
UCSD Shortness of Breath Questionnaire
Vascular endothelial growth factor/receptor


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Idiopathic pulmonary fibrosis (IPF) is a rare disease of unknown aetiology that is 
characterized by progressive fibrosis of the interstitium of the lung, leading to decreasing 
lung volume and progressive pulmonary insufficiency [P11-07084].
The course of the disease in individual patients is variable: some patients progress rapidly,
others have periods of relative stability punctuated by acute exacerbations and others progress 
relatively slowly. Acute exacerbations of IPF are events of respiratory deterioration of 
unidentified cause that occur in 5–10% of patients annually and are associated with a very 
poor outcome [R12-2786]. 
IPF is most prevalent in middle aged and elderly patients, and usually presents between the 
ages of 40 and 70 years. The median life expectancy in IPF patients after diagnosis is 2 to 3 
years [P11-07084].
The latest update on clinical practice guideline for the treatment of IPF, jointly issued in 2015
by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese 
Respiratory Society (JRS) and Latin American Thoracic Association (ALAT) has provided a 
conditional recommendation for treatment with nintedanib or pirfenidone for the majority of 
IPF patients, taking into account individual patient values and preferences [P15-07362]. 
Conventional IPF treatments such as n-acetylcysteine (NAC), corticosteroids, 
cyclophosphamide, cyclosporine and azathioprine are not approved treatments for IPF, and 
their efficacy is questionable or even harmful [P15-07362; P12-06085; P14-07665]. Non-
pharmacological therapies such as pulmonary rehabilitation and long-term oxygen therapy 
are recommended for some patients, but their efficacy in patients with IPF has not been 
established. Lung transplant has been shown to positively impact survival in patients with 
IPF. [R11-5086; R12-2785]. Although the number of patients transplanted due to IPF has 
increased steadily over the last years, the scarce availability of donor organs, as well as the 
comorbidities and advanced age preclude many patients from referral to lung transplant [R12-
3676; R12-3474].
Pirfenidone, a compound which demonstrated anti-fibrotic activity in non-clinical models, 
was first licensed in Japan in 2008 based on two local trials which showed a reduced decline 
of vital capacity under treatment with the compound [R06-2070; R10-4316]. In the
international Phase III CAPACITY program, pirfenidone demonstrated efficacy on the 
primary FVC lung function endpoint in only one of two confirmatory trials [R11-4827]. The
additional confirmatory ASCEND Phase III trial requested by FDA met the primary endpoint 
of change from baseline FVC % predicted [R14-2103]. Pirfenidone is also licensed since 
February 2011 for the treatment of mild to moderate IPF in the European Union and since 
October 2014 for the treatment of IPF in the United States of America. It is also licensed in
several other countries.
Nintedanib is a small molecule intracellular tyrosine kinase inhibitor which has demonstrated 
anti-fibrotic and anti-inflammatory activity in preclinical models [P08-08684; P14-02860]. 
The two replicate Phase III INPULSIS trials and the Phase II TOMORROW trial consistently 
showed positive results for the efficacy of nintedanib 150 mg twice daily versus placebo in 


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patients with IPF. Both INPULSIS trials showed that nintedanib reduced the annual rate of 
decline in FVC (mL/year) by approximately 50%, consistent with slowing disease 
progression [P14-07514; P11-11216]. Based on these three clinical trials, nintedanib was 
approved for the treatment of IPF in the USA in October 2014, in the European Union in 
January 2015 and in Japan in July 2015. As of 20 October 2015, nintedanib has also been 
approved in Canada, Switzerland, Russia, Australia, Chile, Ecuador and Taiwan and it has 
been submitted for marketing authorization in other countries across the world.
Although nintedanib and pirfenidone can be considered a standard of care for patients 
diagnosed with IPF, it remains unclear when to start and when to stop treatment with either of 
the drugs, given the unpredictability of clinical course in the individual patient as well as the 
lack of biomarkers to inform patient management and therapeutic response.
With the introduction of nintedanib in the treatment algorithm of IPF, there is an additional 
need to further characterize its profile in patients at an early disease stage, i.e. in patients with  
limited lung volume impairment, and to address the question when to start treatment in these 
patients. Currently, many physicians apply a wait and watch strategy for these patients as 
there are no markers to predict the individual course in a given patient or response to 
treatment which may result in a delay of treatment initiation. Identifying biomarkers to 
predict the clinical course and benefits of therapy for a given patient early in the course of the 
disease remains one of the most urgent and relevant challenges in patient management
DRUG PROFILE
1.2
Nintedanib is a small molecule that inhibits a distinct spectrum of receptor tyrosine kinases 
(RTKs) and non-receptor tyrosine kinases (nRTKs) at pharmacologically relevant 
concentrations. Among them, FGFR (fibroblast growth factor/receptor), PDGFR (platelet 
derived growth factor/receptor) and VEGFR (vascular endothelial growth factor/receptor) 
have been implicated in IPF pathogenesis. Nintedanib binds competitively to the adenosine 
triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signalling 
which is crucial for the proliferation, migration, and transformation of fibroblasts 
representing essential mechanisms of the IPF pathology [P08-08684; P14-02860]. 
A soft gelatin capsule formulation of nintedanib is used in humans. Maximum plasma 
concentrations occur between 2 - 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 15 to 20%) and a delayed absorption was observed compared to 
administration under fasted conditions. Nintedanib is recommended to be taken with food. 
Nintedanib is preferentially distributed in plasma, with a blood to plasma ratio of 0.87; the 
terminal half-life is in the range of 7 to 19 h. The absolute bioavailability of nintedanib was 
slightly below 5%. Nintedanib 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 a maximum measured concentration of the analyte in plasma (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. 


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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 compared to 
administration of nintedanib alone. Since potent P-gp inducers may decrease exposure to 
nintedanib, selection of alternative treatment with no or minimal P-gp induction should be 
considered. 
The clinical efficacy of nintedanib has been studied in over 1400 patients with IPF in one 
phase II dose finding study (TOMORROW) including four different doses of nintedanib, and 
two replicate phase III (INPULSIS 1 and 2) trials. These were randomised, double-blind, 
placebo-controlled studies comparing treatment with nintedanib twice daily to placebo for 52 
weeks. A statistically significant reduction in the annual rate of decline of FVC (in mL) was 
demonstrated in patients receiving nintedanib 150 mg bid compared to patients receiving 
placebo. The treatment effect on FVC was consistent in all 3 studies, i.e. a relative reduction 
of approximately 50% between nintedanib and placebo. Furthermore, nintedanib 150 mg bid 
significantly reduced the risk of first acute exacerbation compared with placebo in 
INPULSIS-2 and in the TOMORROW trial, and reduced the risk of adjudicated 
confirmed/suspected acute exacerbations by 68% in a pre-specified sensitivity analysis of  
pooled data from the INPULSIS® trials, supporting the effect of nintedanib on slowing 
disease progression [P14-07514; P11-11216].
The safety profile of nintedanib has been investigated comprehensively. The proportion of 
patients with serious adverse events was similar in the nintedanib and placebo groups. 
The risks of treatment with nintedanib in adult patients are primarily related to the 
gastrointestinal tract (nausea, vomiting, diarrhea, abdominal pain) and to increases in liver 
enzymes aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline 
phosphatase (ALP), gamma-glutamyl transferase (GGT) and bilirubin. The most frequently 
reported adverse event was diarrhea which was mild to moderate in intensity for the vast 
majority of patients and lead to treatment discontinuation in less than five percent of patients 
treated with nintedanib. Weight decrease and decreased appetite have also frequently been 
reported in studies with nintedanib. 
Potential risks of nintedanib treatment also include arterial hypertension, GI perforations, 
thromboembolism and bleeding. Patients treated with full-dose anticoagulation or at known 
risk for bleeding were excluded from the INPULSIS trials. This has led to recommendations 
stating that patients at known risk for bleeding should be treated with nintedanib only if the 
anticipated benefit outweighs the potential risk. Although cardiac disorder AEs were 
balanced between the nintedanib and placebo groups, a higher proportion of patients in the 
nintedanib groups had myocardial infarctions. Conversely, a lower proportion of patients in 
the nintedanib groups had other ischemic heart disease. ‘Other ischemic heart disease’ was a 
pre-defined category including terms such as coronary artery disease, angina pectoris, 
coronary angioplasty, coronary artery stenosis, myocardial ischemia, coronary artery stent 
insertion, electrocardiogram (ECG) ST segment depression. The clinical significance of this 
finding is unknown, and further observation is needed.
For patients finalizing the 52 week study treatment in the TOMORROW and INPULSIS 
trials, participation in open label extension trials (1199.35 and 1199.33) was offered. Long 
term treatment in these still ongoing open label extension trials confirm the safety profile 
observed in the phase II and III trials [P15-09876].


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Nintedanib has also demonstrated efficacy and tolerable safety in patients with non-small cell 
lung cancer who failed first line treatment [P11-00203], as well as in patients with advanced 
renal cell cancer [P13-06268], ovarian cancer [P11-10116] and hepatocellular carcinoma 
[P13-12693]. Furthermore, nintedanib is also being investigated in other oncological 
indications, such as mesothelioma [P14-08020].
For a more detailed description of the drug profile, refer to the current Investigator’s 
Brochure (IB) which is included in the Investigator Site File (ISF).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Until recently, IPF was essentially an untreatable disease. With the availability of specific 
antifibrotic drugs like nintedanib and pirfenidone, a major advance in the management of IPF 
has been achieved. However, based on the heterogeneity of disease progression and the lack 
of validated prognostic biomarkers, the clinical course in an individual patient remains
unpredictable which is also true for the individual response to treatments.
Retrospective studies have identified several factors at a single point in time (baseline 
factors) or over time (longitudinal factors) that are associated with increased mortality in IPF. 
Change in physiologic measures over time, such as absolute decline in FVC % predicted 
normal by 10% or more, are associated with reduced survival; This association is only seen 
after a minimum of 6-12 months [R06-4127; R10-6539; P05-02699; R06-4126]. However, 
change in pulmonary function in the prior year does not predict the subsequent change in 
pulmonary function in the following year [R14-1149]. In addition, none of these markers has 
been validated prospectively. Several serum proteins at baseline (e.g. KL-6, MMP-7, 
surfactant protein D) have also been shown to weakly correlate with the clinical course of the 
disease [R15-4126 ; R10-6378 ; R15-4125], but none of these markers have been assessed 
longitudinally.
A key hallmark in the pathology of IPF is dysregulation in connective tissue turnover within 
the lungs, resulting in excessive accumulation of distorted extracellular matrix and scarring 
which is considered a final common pathway in lung fibrosis. This deranged equilibrium is 
determined by several components including fibroblast proliferation, migration and 
differentiation, ECM synthesis by active myofibroblasts, collagen cross-linking and matrix 
degradation by various enzymes like metalloproteinases (MMPs). 
The prospective observational PROFILE study [R15-1220] has recently shown that disease 
progression and prognosis can be determined through temporal changes in extracellular 
biomarkers indicating the defective and excessive matrix turnover potentially directly 
reflecting disease activity. In addition, the magnitude of change in ECM biomarkers related 
to the subsequent risk of disease progression and these changes provided the ability to predict 
outcome at an earlier stage (after 3 months) compared to physiologic measures of lung 
function. It remains to be determined whether baseline or change in ECM biomarkers will 
predict response to treatment.
Identifying biomarkers to predict the clinical course and benefits of nintedanib therapy, e.g. 
effect of nintedanib on surrogate biomarkers early in the course of the disease remains one of 
the most urgent and relevant challenges to improve overall patient management, prevent 
treatment delay or overtreatment.
This study is conducted to examine for the first time the treatment effect of nintedanib on 
change of biomarkers indicative of extracellular matrix turnover which have been shown 
recently to predict disease progression in the PROFILE study [R15-1220]. 


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This study further aims to confirm the association of biomarker course during the first three 
months of treatment and disease progression as observed in PROFILE and to assess whether 
nintedanib treatment during the first 12 weeks alters this association or not.
TRIAL OBJECTIVES
2.2
The primary objective of the trial will be to assess the effect of nintedanib on rate of change 
in extracellular matrix (ECM) turnover biomarker CRPM over 12 weeks which has shown to
strongly associate with disease progression in patients with IPF in the PROFILE cohort
[R15-1220].
A secondary objective is to confirm the observed results from the PROFILE cohort, i.e. to 
assess the predictive value of change in extracellular matrix (ECM) biomarkers CRPM, C1M 
and C3M over 12 weeks for disease progression as defined by FVC decline ≥10% or death 
over 52 weeks [R15-1220].This will be done primarily within patients randomised to 12 
weeks placebo treatment, since placebo treatment is expected not to impact change in 
extracellular matrix (ECM) biomarkers CRPM, C1M and C3M over 12 weeks nor disease 
progression which will facilitate interpretation of obtained results. 
Additionally, a further secondary objective will be to assess how nintedanib treatment during 
the first 12 weeks of the trial affects the association between change in extracellular matrix 
(ECM) biomarkers CRPM, C1M and C3M over 12 weeks and disease progression. The 
corresponding analyses will comprise all patients treated with nintedanib including patients
who are initially on placebo.
Analyses related to both primary and secondary objectives need to be considered as a whole 
in order to understand the complex network of associations between biomarkers, their change 
over time, the potential impact of treatment and the ultimate outcome of disease progression.
Further objectives are to assess the effect of nintedanib on rate of change in additional ECM 
turnover biomarkers and (based on the main and secondary objective) the predictive value of 
the corresponding rate of change for disease progression. Furthermore, the trial will evaluate 
changes in pulmonary function over time using home and standard in clinic spirometry and 
their correlation. 
BENEFIT - RISK ASSESSMENT
2.3
The favourable benefit-risk ratio based on the so far acquired knowledge about nintedanib is 
the rationale to conduct further studies with nintedanib in idiopathic pulmonary fibrosis.
As described in Section 1, patients with IPF, including patients with only limited FVC 
impairment, may benefit from lesser decline in lung function and hence slower disease 
progression as a result of treatment with nintedanib [P15-09946]. In addition, nintedanib 
significantly reduced the risk of first acute exacerbation in 2 out of 3 clinical trials [P11-
11216, P14-07514].


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Two thirds of the patients in this trial will be treated with placebo for the first 12 weeks of the 
trial. A 1:2 randomization (nintedanib:placebo) increases the number of patients treated with 
placebo during the first 12 weeks and consequently increases the power of assessing the
association between change in the extracellular matrix (ECM) biomarker CRPM over 12 
weeks and disease progression in placebo treated patients.  Change in the extracellular matrix 
(ECM) biomarker CRPM over 12 weeks will be classified as stable or falling [≤ 0 
ng/ml/month] or rising [> 0 ng/ml/month] in line with the PROFILE cohort [R15-1220]. A 12 
week placebo period is considered acceptable given that the in- and exclusion criteria assure 
inclusion of patients with mostly preserved lung function at baseline. In addition, it is unclear 
if patients would even receive antifibrotic treatment as in clinical practice. IPF patients with 
limited lung function impairment might not be reimbursed in some countries depending on a 
FVC % predicted threshold (e.g. >80%predicted).
Following the 12 week placebo controlled period all patients in this trial will continue further 
treatment with nintedanib. This will allow active treatment also to patients previously on 
placebo. In the subgroup of patients by baseline FVC (>80% versus ≤ 80% predicted) in the 
pooled INPULSIS data set, the risk of disease progression (time to FVC decline >10% or 
death) up to 12 weeks was low and similar in patients treated with placebo and nintedanib 
(approximately 10% of patients, respectively), although there was a risk reduction in favour 
of nintedanib by approx. 40% in the end of the 52 week treatment period for both subgroups 
and a consistent effect on reducing the annual rate of decline by 50%, similar to the primary 
outcome in the overall population [P15-09946].
The risks of treatment with nintedanib are described in Section 1.2. The most common side 
effects of nintedanib are of gastrointestinal nature (diarrhea, nausea, vomiting, abdominal 
pain), as well as liver enzyme elevations.
Safety monitoring in this trial will consist of regular visits to the investigational site, timely 
blood analyses and specific monitoring procedures to follow-up potential hepatic enzyme 
elevation (potential for drug-induced liver injury), see also Section 5.3.6.1.
In case of lack of tolerability, symptomatic treatment, dose adjustments and/or interruptions 
of trial drugs (at the discretion of the investigator) should be considered to allow for 
resolution of the symptoms (Section 4.2.1).
Based on the mode of action of nintedanib, especially on the inhibition of VEGF or VEGF 
receptors, arterial hypertension, gastrointestinal perforations, thromboembolism and bleeding 
have been identified as potential risks of nintedanib treatment. Therefore, patients requiring 
full dose concomitant anticoagulation, fibrinolysis or high-dose antiplatelet therapy will be 
excluded from this trial.
The mode of action of nintedanib indicates a high potential for teratogenicity and/or 
embryotoxicity, including fetotoxicity/lethality. In women of childbearing potential receiving 
nintedanib, contraceptive measures must be employed 28 days before treatment initiation, 
during the treatment and for a period of 3 months after last drug intake.
Overall, the clinical safety profile of nintedanib as established during the development 
programs including patients with less advanced disease is interpreted as favourable for the 
intended indication of IPF.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a multi-centre, multinational, prospective trial. The trial comprises two periods. The 
first period is a 12 week, randomised, double blind, placebo controlled, parallel group period 
to assess the effect of nintedanib 150 mg bid on change of ECM biomarker turnover 
indicative of disease progression compared to placebo. The second period is a single arm, 
open label, active treatment period (nintedanib 150 mg bid) of 40 weeks duration. The total 
treatment period duration is 52 weeks. (Table 3.1:1).
Table 3.1:1 Summary of treatments
Number of patients 
per treatment arm
Treatment period
Period 1
12 week, randomised, 
double blind, placebo 
controlled, parallel group
Period 2
40 week, single arm, 
open label, active 
treatment period
Treatment
~117
nintedanib 150 mg bid*
nintedanib 150 mg bid*
Treatment
~233
placebo matching 
nintedanib 150 mg bid*
nintedanib 150 mg bid*
Total number 
of patients
~350
*Permanent or intermittent dose reduction to a total daily dose of nintedanib 200 mg as well 
as subsequent re-escalation are allowed, further details are described in Section 4.2.1.
The overall trial scheme is presented in Figure 3.1:1.
Figure 3.1:1 Trial scheme
nintedanib 150 mg
bid / ~350 patients
Screening
(V1 - V2)
2 weeks
(V10 - V11)
4 weeks
Treatment Period/ 
Period 2 (V5-V10)
40 weeks,
single arm, open label, 
active treatment
Follow-up 
nintedanib 150 mg bid / 
~117 patients
placebo 150 mg bid/
~233 patients
Treatment Period / Period 1
(V2-V5) 12 weeks, 
randomised, double blind, placebo 
controlled, parallel group


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After signing the informed consent (prior to any trial related procedures including any 
medication washout), the HRCT scan and surgical lung biopsy sample (later if available) will 
be sent for central review. Screening visit (Visit 1) should only be performed after the 
diagnosis of IPF has been confirmed by the central review. The screening period, i.e. period 
between Visit 1 and 2 should last from 14 days (2 weeks) to a maximum of 28 days (4 
weeks).
Patients whose central lab results are available and who meet all inclusion and none of the 
exclusion criteria may be randomised into the 12-week, double-blind treatment period in 
which they will be receiving either of two possible treatments:  nintedanib of total daily dose 
300 mg administered twice daily, 150 mg in the morning and 150 mg in the evening or 
equivalent placebo bid in double-blind fashion. The chance of receiving either of the above 
mentioned treatments will be 1 (active treatment): 2 (placebo). Randomisation will be 
performed using an Interactive Response Technology System (IRT). Following the 
randomised, double blind, placebo controlled treatment period, all patients will enter the 
single arm, open label, active treatment period of 40 weeks. All patients previously receiving 
placebo will start taking nintedanib. During the trial patients will be returning to the clinic for 
the visits as per Flow Chart for the assessment of efficacy and safety parameters as well as
assessment of compliance with the study drug. 
Dose adjustment visits may occur at any time to manage adverse events. Permanent or 
intermittent dose reduction to a total daily dose of nintedanib 200 mg, i.e. 100 mg bid and 
drug interruptions are allowed to manage AEs as described in Section 4.2.1. Re-escalation to 
nintedanib 150 mg bid is allowed as described in Section 4.2.1. Each time a dose reduction or 
re-escalation is made, the patient must return for an unscheduled visit.
Upon completion of the 52 week treatment period (12 weeks Part 1 and 40 weeks Part 2), 
patients will enter a 28 day (4 week) Follow-Up period. Each patient will attend a total of 12
scheduled visits (Visit 0 and Visits 1 to 11 scheduled as per Flow Chart). Patients, who 
prematurely and permanently discontinue study treatment prior to 52 weeks, will be asked to 
return to the clinic and attend all visits as originally planned per protocol Flow Chart.
Each patient’s participation in the trial is estimated to last a total of approximately 58 weeks.
Depending on patient's informed consent, a blood sample for pharmacogenetics should be 
drawn at Visit 2 or at any subsequent visit from any randomised patients who received at 
least one dose of trial medication.
For an overview plan of procedures please refer to the Flow Chart at the beginning of this 
protocol.
Adverse events will be collected, documented and reported from the time the patient signs an 
Informed Consent up until 28 days after the last dose of study medication. 
3.1.1
Administrative structure of the trial
The sponsor of this trial is Boehringer Ingelheim (BI). Clinical trial drug supplies, i.e. trial 
medication will be provided by the sponsor.


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Boehringer Ingelheim has appointed the 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,
-
ensure appropriate training and information to Local Clinical Monitors (CML), 
Clinical Research Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons and relevant local information 
can be found in the ISF.
A Coordinating Investigator has been nominated and will be responsible to coordinate 
investigators at different centres participating in this multicentre trial. The Coordinating 
investigator was selected by the sponsor. 
 will review the trial protocol, any subsequent 
amendments to the protocol and the (draft) Clinical Trial Report (CTR). 
will provide 
 
signature on the final protocol signature page and amendments and will provide 
 signature 
on the CTR indicating that, to the best of the co-ordinator’s knowledge, the final CTR
accurately describes the conduct and results of the trial.
Sites selected for participation will consist of centres experienced in the treatment and 
management of IPF.
The following local facilities/equipment along with the medically needed equipment to 
routinely treat patients are required at the trial site: 

equipment for measuring body height

scales for measuring patient weight

sphygmomanometer (blood pressure instrument)

12-lead ECG device

refrigerator

freezer (-20°C) 

laboratory tabletop centrifuge (ambient)

equipment for DLCO measurements (or availability to perform measurements if not 
available directly at the site)

device for pulse oximetry measurement

premises for performing PFTs, blood and/or urine sampling and handling of samples 
(PK/PD/PG/ biomarker and or safety)

weather station (to measure atmospheric temperature, barometric pressure and 
humidity), all parameters will be needed for spirometer calibration 


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
internet access

analogue fax line
CROs: 

CRO for provision of in clinic spirometers and home spirometry devices.

CRO/s for HRCT and surgical lung biopsy reviews 

CRO for central laboratory for safety laboratory, biomarkers, PK and 
pharmacogenetic sampling logistics. 

CROs for provision of CRAs. 
IRT: An IRT (IVRS/IWRS, ie Interactive Voice/Web Response System) will be used for 
randomisation in this trial and for appropriate re-supply and assignments of trial medication 
to patients during treatment period. The ability to unblind will be available via the IRT.
Relevant documentation on the participating (Principal) Investigators and other important 
participants will be filed in the trial master file (TMF) in accordance with BI SOPs
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
Patients with idiopathic pulmonary fibrosis having a FVC of at least 80% of the predicted
normal value at baseline will be eligible for participation in this trial. It is considered 
acceptable in this patient population to include a 12 week placebo-controlled treatment phase 
(refer to Section 2.3) in order to compare the effect of nintedanib versus placebo on change in 
ECM biomarker turnover.
In the PROFILE study [R15-1220], these biomarkers have shown their predictive potential 
for disease progression as early as after the period of 3 months.
A 1:2 randomisation (nintedanib:placebo) increases the number of patients treated with 
placebo during the first 12 weeks and consequently increases the power of assessing the
association between change in the extracellular matrix (ECM) biomarker CRPM over 12 
weeks and disease progression in placebo treated patients.  Change in the extracellular matrix 
(ECM) biomarker CRPM over 12 weeks will be classified as stable or falling [≤ 0 
ng/ml/month] or rising [> 0 ng/ml/month] in line with the PROFILE cohort [R15-1220].
Fibrotic remodelling of the lung interstitial tissue with subsequent restrictive ventilatory 
defect represents the core element of the histopathology of IPF. Therefore, FVC decline is 
considered a marker of disease progression and will be assessed via supervised spirometry at 
regular clinic visits as well as via home spirometry. Home spirometry may allow a more 
sensitive estimate of lung function decline based on more points of measurement resulting in 
higher accuracy and/or less variability in calculating the slope. Consequently, this study will 
also provide the opportunity to compare changes in FVC over the course of the study using 
standard clinic spirometry compared to home measurements, i.e. generate data on the general 
feasibility and validity of home spirometry in IPF.


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After 12 weeks of double-blind treatment, all patients will enter the 40 week single active 
arm phase of the trial to potentially benefit from nintedanib treatment. Total treatment 
duration of 52 weeks is considered adequate to assess disease progression and the predictive 
value of ECM biomarker turnover in this patient population.
The most frequent symptoms in patients with IPF are dyspnoea and cough. These symptoms 
substantially reduce the quality of life and cause major restriction in everyday life, as well as 
incapacity in many patients with IPF. Therefore, a number of patient-reported outcome 
instruments (questionnaires) will be used to document the effect of nintedanib on symptoms
(shortness of breath) and patient’s health related quality of life.
The frequency of visits will allow close monitoring of adverse events, as well as control of 
liver enzyme values, consistent with the recommendations of the prescribing information for
nintedanib.
SELECTION OF TRIAL POPULATION
3.3
Participation in this trial will be available to patients with IPF who meet the eligibility 
requirements specified in this protocol. 
Recruitment will be competitive. The patients will be recruited from approximately 100 trial
sites. Additional sites may be initiated to ensure trial recruitment as well as sponsor timelines.
Every effort should be made to keep patients in the study until completion of all study related 
procedures described in the clinical trial protocol. 
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
Any patients with confirmed diagnosis of IPF and who comply with eligibility requirements 
may qualify for participation in the trial.
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 
participation in the trial including any study related procedures being performed 
[including any required washout as well as sending HRCT and lung biopsies (the 
latter if available)];  


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2. Male or female patients aged ≥ 40 years at Visit 1;
3. A clinical diagnosis of IPF within the last 3 years from Visit 0, based upon the 
ATS/ERS/JRS/ALAT 2011 guideline (P11-07084);
4. Chest high resolution computed tomography (HRCT) scan performed within 18
months of Visit 0;
5. Combination of HRCT pattern and surgical lung biopsy pattern (the latter if 
available) as assessed by central review are consistent with the diagnosis of IPF
(Appendix 10.1);
6. FVC ≥ 80% of predicted normal at visit 1. NOTE: If this is not achieved at the 
screening visit, the visit may be repeated once within two weeks.
3.3.3
Exclusion criteria
1.
ALT, AST > 1.5 fold upper limit of normal (ULN) at Visit 11;
2.
Total bilirubin > 1.5 fold ULN at Visit 11;
3.
Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic 
impairment;
4.
Relevant airways obstruction [i.e. pre-bronchodilator FEV1/FVC < 0.70      
(i.e. 70%) at Visit 1];
5.
History of myocardial infarction within 6 months of visit 1 or unstable angina 
within 1 month of Visit 1;
6.
Bleeding Risk:
•
Known genetic predisposition to bleeding;
•
Patients who require fibrinolysis, full-dose therapeutic anticoagulation 
(e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin etc.) or 
high dose antiplatelet therapy2;
•
History of haemorrhagic central nervous system (CNS) event within 12 
months prior to Visit 1;
•
History of haemoptysis or haematuria, active gastro-intestinal bleeding 
or ulcers and/or major injury or surgery within 3 months prior to Visit 1;
•
International normalised ratio (INR) > 2 at Visit 11;
•
Prothrombin time (PT) and partial thromboplastin time (PTT) > 150% 
of ULN at Visit 11;
7.
Planned major3 surgery during the trial participation, including lung
transplantation, major abdominal or major intestinal surgery;
8.
History of thrombotic event (including stroke and transient ischemic attack)
within 12 months of Visit 1;


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9.
Creatinine clearance < 30 mL/min calculated by Cockcroft–Gault formula at
Visit 1 (Appendix 10.2);
10.
Treatment with nintedanib, pirfenidone, azathioprine, cyclophosphamide,
cyclosporine, any other investigational drug, n-acetylcysteine, 
prednisone/prednisolone >15 mg daily or >30 mg every 2 days OR use of 
other systemic corticosteroids as well as any investigational drugs within 4 
weeks of Visit 2;
11.
Known hypersensitivity to nintedanib, peanut, soya or to any other 
components of the study medication;
12.
Prior discontinuation of nintedanib treatment due to intolerability/ adverse
events considered drug related;
13.
A disease or condition which in the opinion of the investigator may interfere
with testing procedures or put the patient at risk when participating in this trial;
14.
Alcohol or drug abuse which in the opinion of the treating physician would
interfere with the treatment and would affect patient’s ability to participate in 
this trial;
15.
Patients not able to understand and follow any study procedures such as but
not limited to home spirometry6, including completion of self-administered 
questionnaires without help;
16.
Women who are pregnant, nursing, who plan to become pregnant while in the 
trial or female patients with positive pregnancy (ß-HCG) test at Visit 1 and/or 
Visit 2;
17.
Women of childbearing potential4 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 correctly5.
NOTE: In women of childbearing potential receiving nintedanib, 
contraceptive measures must be employed 28 days before treatment 
initiation, during the treatment and for a period of 3 months after last drug 
intake;
18.
Patients with acute IPF exacerbation or any respiratory tract infection in the
four weeks prior to Visit 1 or during the screening period.
Visit 1 and/or Visit 2 should be postponed in case of an IPF exacerbation or 
respiratory tract infection. Refer to Section 6.1 for information on re-
scheduling of visits;
19.
Patients who are or have been participating in another trial with investigational


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drug/s within one month prior to Visit 1 and patients who have previously 
been enrolled in this trial.
1Laboratory parameters found abnormal at visit 1 may be re-tested once prior to      
Visit 2.
2Exceptions: prophylactic low dose heparin or heparin flush as needed for 
maintenance of an indwelling intravenous device (e.g., enoxaparin 4000 IU s.c. per 
day) and prophylactic use of antiplatelet therapy (e.g., acetyl salicylic acid up to 325 
mg/d, and/or clopidogrel at 75 mg/d, and/or equivalent doses of other antiplatelet 
therapy).
3Definition of major is per investigator judgement.
4Women of childbearing potential are defined as: Any female who has experienced 
menarche and does not meet the criteria for "women not of childbearing potential” 
defined as: Women who are postmenopausal (12 months with no menses without an 
alternative medical cause) or who are permanently sterilised (e.g., tubal occlusion, 
hysterectomy, bilateral oophorectomy or bilateral salpingectomy). 
5A list of contraception methods meeting these criteria is provided in the patient 
information.
6Patient will need to perform at least one home spirometry manoeuvre between Visit 1 
and Visit 2 (in order to obtain baseline PFT values) to be eligible for the trial.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial treatment if:
•
The patient withdraws consent for study treatment or study participation, without the 
need to justify the decision;
•
The patient needs to take concomitant drugs that interfere with the investigational 
product (Section 4.2.2);
•
The patient can no longer be treated with trial medication for other medical reasons 
(such as surgery, adverse events, other diseases, or pregnancy);
If a patient becomes pregnant or pregnancy is suspected during the trial, the patient 
will be permanently discontinued from the study treatment and will be followed up 
until birth or otherwise termination of pregnancy, please see Section 5.3.7.
•
The patient experiences signs and symptoms of acute myocardial ischemia or stroke;
•
The patient experiences hepatic injury defined as follows:
-
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


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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 and tenderness, fever and/or rash.
•
For potential drug induced liver injury (DILI) follow up requirements please see 
Sections 4.2.1.3 and 5.3.6.1.
•
The patient experiences unacceptable toxicity despite dose adjustments and 
supportive care
•
Gastrointestinal perforation;
•
Major surgery including abdominal or intestinal surgery;
•
Signs or symptoms of acute myocardial ischemia, stroke, deep vein thrombosis and 
pulmonary embolism
In addition, permanent discontinuation of nintedanib should be considered in the following 
situations:
•
Patients who require full dose therapeutic anticoagulation or high dose antiplatelet 
therapy;
•
Increased risk of bleeding (e.g. gross/ frank haemoptysis or haematuria, active 
gastro-intestinal bleeding or ulcers).
In such cases, continuation of nintedanib should be discussed with the patient and the 
decision based on an individual benefit-risk assessment documented in the source data. 
If a patient permanently discontinues a study drug, he/she will undergo procedures for early 
treatment discontinuation and will be invited to attend all planned study visits until week 56 
as outlined in the flow chart.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the 
(e)CRF. These data will be included in the trial database and reported.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim 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).


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
Patients will be randomised 1:2 to 300 mg nintedanib daily (i.e. one capsule of nintedanib 
150 mg in the morning and one capsule of nintedanib 150 mg in the evening) or matching 
placebo (i.e. one capsule of matching placebo in the morning and one in the evening) during 
the first 12 weeks of the treatment period. For the subsequent 40 weeks all randomised 
patients will enter the single active arm treatment. All patients previously receiving placebo 
will start taking nintedanib.
During the trial, permanent or intermittent dose reduction to a total daily dose of nintedanib 
200 mg, i.e. 100 mg bid and intermittent drug interruptions are allowed to manage AEs as 
described in Section 4.2.1. Re-escalation to nintedanib 150 mg bid is also allowed as 
described in Section 4.2.1.
Trial medication will be provided as a medication kit. One medication kit will contain seven 
blister cards each containing 10 soft gelatin capsules of either blinded nintedanib 150 mg, or 
blinded nintedanib 100 mg, or matching placebo (for blinded part of the trial) and open label 
nintedanib 150 mg, or open label nintedanib 100 mg (for the open label part) thus allowing 
sufficient amount of medication for approximately one month.  Sufficient amount of kits, 
each identified with a unique medication number, will be dispensed to each patient 
throughout the trial via IRT. No active comparator is used in this trial.
Trial medication is manufactured by Boehringer Ingelheim.
4.1.1
Identity of BI investigational product(s) and comparator product(s)
Table 4.1.1: 1
Nintedanib:
Substance:
Nintedanib (Ofev®)
Pharmaceutical formulation:
Soft gelatin capsule
Source:
BI Pharma GmbH & Co. KG
Unit strength:
150 mg, 100mg
Posology
1 capsule, bid
Route of administration:
Oral (swallowed)


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Table 4.1.1: 2
Placebo matching Nintedanib
Substance:
N/A
Pharmaceutical formulation:
Soft gelatin capsule
Source:
BI Pharma GmbH & Co. KG
Unit strength:
N/A
Posology
1 capsule, bid 
Route of administration:
Oral (swallowed)
4.1.2
Method of assigning patients to treatment groups
To guarantee the double-blind design of the study, all treatments will be indistinguishable for 
the patient as well as for the investigator.
After final assessment of all inclusion and exclusion criteria, each eligible patient will be 
randomly assigned in 1:2 ratio (treatment: placebo) to one of the two treatment options at 
Visit 2 (double blind phase applicable to the first 12 weeks only). An interactive voice 
response system (IRT) will be used for randomisation to a specific treatment group in this 
trial and for the appropriate supply and re-supply of study medication to patients throughout 
the trial. Patients will be randomised to receive either an active drug at a dosage of 150 mg 
bid or matching placebo. 
Documents such as but not limited to user guides, instructions, worksheets on the IRT will be 
stored in the ISF.
Note that the medication number is different from the patient number (the latter one is 
assigned after the informed consent process has been completed). 


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4.1.3
Selection of doses in the trial
A dose of nintedanib 150 mg bid (total daily dose of 300 mg) was selected for this trial as this 
is the recommended dose based on prescribing information in participating countries as well 
as the dose that has shown to be efficacious in two replicate phase III trials. 
Dose adjustments are permitted as per Section 4.2.
4.1.4
Drug assignment and administration of doses for each patient
Drug assignment
Dosage for an individual patient will be assigned by means of an IRT at Visit 2. Patients
will be randomised to receive either an active drug at a dosage of 150 mg bid or matching 
placebo.
At Visit 5, all patients will start receiving open label nintedanib for the remainder of the trial.  
Patients previously receiving placebo will now start receiving nintedanib. All patients will 
remain on the same dose they were previously receiving unless prescribed otherwise by the 
investigator. Patients, site staff and trial team will remain blinded to patient’s previously 
randomised treatment group.
Study treatment will comprise of 1 capsule twice daily throughout the trial (refer to Section 
4.1). Treatment kits containing 4 weeks + 1 week reserve treatment (one treatment kit 
containing 7 blister cards each having 10 capsules) will be dispensed to the patients.  
To ensure patients receive adequate supply of study medication, kits will be dispensed at 
clinic visits in quantities outlined in Table 4.1.4: 1. Unscheduled re-supplies with additional 
medication kits will be possible via the IRT.
Table 4.1.4: 1 Quantity of medication kits dispensed
Visit
Week
Number of medication 
kits
2
0
1*
3
4
1*
4
8
1*
5
12
3**
8
24
3**
9
36
4**
* Double-blind study drug
**Open label active treatment study drug


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The investigational product should only be dispensed to participating patients according to 
the protocol by authorised personnel as documented on the Investigator’s Trial Staff List. All 
unused medication must be returned to the Sponsor. Receipt, usage and return must be 
documented on the respective forms. Any discrepancies must be accounted for.
Drug administration
•
Study drug will be administered orally on a twice daily basis (bid). At all clinic visits 
the study drug will be administered at the study site (after any sampling 
procedures and PFTs). The patients should swallow the study medication unchewed 
together with a glass of water (~250 mL), and should observe a dose interval of 
approximately 12 hours. Study drug needs to be taken at approximately the same time 
every day (preferably 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 
administered drug after the meal. 
•
If a dose of nintedanib is missed, i.e. not taken between 06:00 and 11:00 in the 
morning, and between 18:00 and 23:00 in the evening, administration should resume 
at the next scheduled time at the recommended dose. No catch up of missed doses is 
permitted.
Patients experiencing adverse effects requiring temporary drug discontinuation (refer to 
Section 4.2.1 and 4.2.2) may start to receive study drug at 100 mg bid. The dose can also be 
reduced without prior discontinuation, i.e. immediately stepping down from 150 mg bid to 
100 mg bid if necessary. In the case of severe toxicity or when the reduced dose is again not 
tolerated, drug treatment must be stopped and cannot be restarted. All dose reductions must 
be approved by the Investigator or delegated site staff at the site (during the scheduled or 
unscheduled visit) and the reason for reduction must be documented.  
In case of adverse events requiring dose reduction (refer to Sections 4.2.1 and 4.2.2), 100 mg 
bid (or matching placebo) will be assigned by IRT upon call of the Investigator. The colour 
of the 150 mg capsules and the 100 mg capsules will be slightly different; the packaging will 
remain the same (same number of capsules per blister, same number of blisters per box).  
If the reduced dose is well tolerated, re-escalation to 150 mg bid is possible, according to 
procedures described in Section 4.2.1.1. 
The amount of study drug dispensed at the time of dose reduction and dose re-escalation is 
dependent upon the amount of time between the unscheduled visit and the next planned study 
visit.  Therefore at unscheduled visits for dose reductions and dose re-escalations, IRT will 
assign only the number of boxes of study medication needed until the next predicted planned 
patient visit as noted within the IRT system.


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4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Patients, Investigators and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial will remain blinded with regard to the randomised treatment 
assignments until after database lock.
The randomisation code will be kept secret by Clinical Trial Support up to database lock.
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.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions
(SUSARs), it may be necessary for a representative from Boehringer Ingelheim’s
Pharmacovigilance group to access the randomisation code for individual patients during trial
conduct. The access to the code will only be given to authorised Pharmacovigilance
representatives and not be shared further.
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.
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 used and unused trial medication must be returned to the sponsor. Receipt, usage and 
return must be documented on the respective forms. Account must be given for any 
discrepancies.


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4.1.8
Drug accountability
The Investigator and/or Pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the Sponsor when the following requirements are 
fulfilled:

Approval of the trial protocol by the 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

Availability of the proof of a medical license for the principal Investigator

Availability of Form 1572 (as applicable)
The Investigator and/or Pharmacist and/or investigational drug storage manager 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 / Pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. At the time of return to the 
Sponsor and/or appointed CRO, the Investigator / Pharmacist / investigational drug storage 
manager 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.
Recommendations for managing adverse events (exceptions include diarrhea 
4.2.1.1
and liver enzyme elevations)
•
If a patient experiences adverse events considered related to the trial medication,
symptomatic treatment should be initiated (e.g. anti-emetic treatment such as 
dimenhydrinat if appropriate). 
•
Patients experiencing adverse events considered related to nintedanib may require 
drug interruption or reduction of dose (at the discretion of the investigator) to allow 
for resolution of symptoms. 
•
After resolution of AE, nintedanib may be reintroduced and re-escalated to the higher 
dose (at the discretion of the investigator):


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If dose has been reduced, consider re-escalation to 150 mg bid  
-
If treatment was temporarily interrupted, resume treatment at the full dose 
(150 mg bid), or at the reduced dose (100 mg bid), which subsequently may be 
re-escalated to the full dose (150 mg bid).
•
For adverse events not related to the trial medications, treatment interruptions are 
allowed. Nintedanib should then be resumed at the same dose taken prior to 
interruption.  
•
In the occurrence of acute IPF exacerbations all treatment options considered 
adequate by the investigator are allowed, except concomitant treatment with 
pirfenidone.  
Recommendations for management of diarrhea
4.2.1.2
The Common Terminology Criteria for Adverse Events (CTCAE Version 4.0) grading will 
be used to grade the severity of all AEs and SAEs of diarrhea. Management 
recommendations for diarrhea are based on the CTCAE grades.
In general, diarrhea should be managed as early as possible after onset of first symptoms with 
standard antidiarrheal symptomatic treatment, e.g. loperamide.
The medical judgement should be used in decision of the use preventive treatment with 
loperamide after the first episode of diarrhea.  
If diarrhea persists despite optimal symptomatic treatment, treatment interruption (for a 
maximum of 4 weeks) and dose reduction of nintedanib should be considered based on the 
recommendations described in Table 4.2.1.2: 1


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Table 4.2.1.2: 1 Recommendations for management of diarrhea
CTCAE 
Grade
Description
Symptomatic Treatment
Action with study medication
1
Increase of <4 
stools per day over 
baseline
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/day1) until bowel movements 
cease for 12 hours
Continue same dose of study 
medication
2
Increase of 4-6 
stools per day over 
baseline
Initiate/continue anti-diarrheal 
medicines;
If diarrhea grade 2 persists for 
≥48-72 hours assess for 
dehydration and electrolyte 
imbalance; 
In addition, consider IV fluids and 
electrolyte replacement as 
clinically indicated.
If diarrhea grade 2 persists for ≥48-
72 hours despite optimal 
symptomatic care: 
1.
Interrupt study medication 
until recovery
2.
Reduce dose to 100 mg bid 
after recovery 
3.
Re-escalate to 150 mg bid if 
deemed clinically 
appropriate
3
Or
4
Increase of ≥ 7 
stools per day over 
baseline; 
incontinence; 
Or
Life threatening 
consequences
Follow recommendations above.
In addition, consider stool work-
up to exclude infectious colitis; 
aggressive IV fluid replacement 
≥24 hours, hospitalisation as 
clinically indicated; consider 
referral to a GI specialist to rule 
out potential differential 
diagnoses.
1.
Interrupt study medication
until recovery
2.
Reduce dose to 100 mg bid 
after recovery
3.
Consider re-escalation to 
150 mg bid if deemed 
clinically appropriate
In case of recurrence of diarrhea
grades 3 or 4 despite optimal 
symptomatic treatment and dose 
reduction, study medication should 
be permanently discontinued.
1Refer to national prescribing information


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Recommendations for management of liver enzyme elevation
4.2.1.3
For a detailed guidance on how to manage liver enzyme elevations, please refer to table 
4.2.1.3: 1
Table 4.2.1.3: 1
Recommendations for managing liver enzyme elevations
AST /ALT ≥3 but <5 x ULN
AST /ALT ≥5 but <8 x ULN
Signs of hepatic 
injury 2
Reduce study medication to 100 mg bid or 
interrupt (at the discretion of the 
investigator) 
Repeat Lab tests1 in 48/72 hours, at week 1 
and week 2 
Interrupt study medication
Repeat Lab tests1 in 48/72 hours, at week 1
and week 2 
Permanently 
discontinue study 
medication
If AST /ALT < 3 x 
ULN within 2 weeks
If AST /ALT 
≥3 ULN
at 2 weeks
If AST /ALT < 3 x 
ULN within 2 weeks
If AST /ALT ≥3 
ULN
at 2 weeks
Re-escalate study 
medication to 150 mg 
bid if reduced; restart at 
100 mg bid if 
interrupted
Repeat Lab tests1 in 2 
and 4 weeks
Interrupt study 
medication
Repeat Lab 
tests1 in 1 and 2 
weeks
Reintroduce study 
medication at 100 mg 
bid
Lab tests1 in 1, 2 and
4 weeks
Permanently 
discontinue study 
medication
If AST / ALT ≥ 3 x 
ULN within 2 weeks
If at 2 weeks
If AST / ALT ≥ 3 x 
ULN within 2 weeks
Permanently 
discontinue study 
medication 
AST / ALT     
< 3 x ULN
reintroduce 
study 
medication; lab 
tests1 every 
week as needed
If AST / ALT ≥ 
3 x ULN
permanently 
discontinue 
study 
medication 
Permanently 
discontinue study 
medication
1Laboratory tests include ALT, AST, total bilirubin, eosinophils, INR


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2 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.
For potential drug induced liver injury (DILI) follow up requirements please see Section 
5.3.6.1.
Immediately refer to Section 5.3.6.1 in case AST and/or ALT ≥3 fold ULN is combined with 
total bilirubin ≥2 fold ULN.
Management of acute IPF exacerbations and acute deteriorations
4.2.1.4
In case of acute IPF exacerbation, all treatment options considered adequate by the 
Investigator / caregiver are allowed, except concomitant treatment with pirfenidone.   
Although it is not generally recommended, the patient may interrupt study treatment if this is 
considered necessary (e.g., if short-term full anticoagulation is performed). In case of 
significant deterioration (absolute FVC decline >10%, DLCO >15%) all approved 
medications can be freely initiated or increased at the investigator‘s discretion.
Definition of Acute IPF Exacerbations
Otherwise unexplained clinical features within one month, including all of the following:
• Unexplained worsening or development of dyspnoea within 30 days;
• New diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal 
abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) 
since last visit;
• Exclusion of infection as per routine clinical practice and microbiological studies;
• Exclusion of alternative causes as per routine clinical practice, including:
o
Left heart failure
o
Pulmonary embolism
o
Identifiable cause of acute lung injury
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Concomitant medications (or therapy) to provide adequate care may be given as clinically 
necessary. If restricted concomitant therapy is necessary treatment with study medication 
should be permanently discontinued (except in case of acute IPF exacerbations – refer to 
Section 4.2.1.1).


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Table 4.2.2.1: 1
Permitted and Restricted Concomitant therapy 
Prior to 
randomisation
During 
treatment 
period
After EOT 
(Follow-up 
Period)
After early
EOT5
Nintedanib
Not permitted in 
the 4 weeks prior 
to visit 2 1
Study 
medication
Permitted
Permited6
Pirfenidone, N-
acetylcysteine, 
Azathioprine, 
Cyclophosphamide,  
Cyclosporine
Not permitted in 
the 4 weeks prior 
to visit 2 1
Not permitted
Not permitted
Permitted
Prednisone/ 
Prednisolone and/or 
other systemic
corticosteroid2
Not permitted in 
the 4 weeks prior 
to visit 2 1
Not permitted
Not permitted
Permitted
Investigational 
Medication
Not permitted in 
the 4 weeks prior 
to visit 2 1
Not permitted
Not permitted
Not permitted
Anticoagulation at full 
dose3, antiplatelet 
therapy at high dose 4,
fibrinolysis
Permitted
Not permitted
Not permitted
Permitted
1. Washout should not occur before the patient has signed informed consent
2. Prednisone/ Prednisolone >15 mg daily or >30 mg every 2 days OR use of other systemic 
corticosteroids within 4 weeks of visit 2.
3. Anticoagulation at full dose (vitamin K antagonists, direct thrombin inhibitors, heparin, 
hirudin, etc). Exceptions: 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)
4. Antiplatelet therapy at high dose. Exceptions: prophylactic use of antiplatelet therapy 
(e.g. acetylsalicylic acid up to 325 mg/day and/or clopidrogrel at 75 mg/day and/or 
equivalent doses of other antiplatelet therapy) is allowed 
5. For patients who withdrew study medication before the planned EOT date and decide to 
attend all remaining study planned visits.
6. At the discretion of the treating physician.
Restrictions on diet and life style
4.2.2.2
There are no restrictions on diet and life style.


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Restrictions regarding women of childbearing potential 
4.2.2.3
The anti-angiogenic properties of nintedanib indicate a high potential for teratogenicity 
and/or embryotoxicity, including fetotoxicity/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
The Investigator will maintain accurate records of receipt of all study medication, including 
dates of receipt. In addition, accurate records will be kept regarding when and how much of 
each study medication is dispensed to, and used by each individual patient in the study. 
Reasons for deviating from the expected dispensing regimen must be recorded. A Drug 
Accountability Form, provided for this purpose, will be signed by the Investigator or delegate 
at the conclusion of the study. At the completion of the study, in order to satisfy regulatory 
requirements regarding drug accountability and destruction, all used and unused packages 
must be returned to the Sponsor or its designee. 
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. A compliance worksheet will be provided in the ISF. 
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% without identified cause like AE or 
consent withdrawal, site staff will explain to the patient the importance of treatment 
compliance. 
Compliance will be verified by the on-site monitor authorised by the Sponsor.


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
Note that all endpoints based on spirometry are measured by clinic spirometry unless 
explicitly stated otherwise.
5.1.1
Primary Endpoint
The primary endpoint is the rate of change (slope) in blood CRPM from baseline to week 12.
5.1.2
Secondary Endpoints
The key secondary endpoint is the proportion of patients with disease progression as defined 
by absolute FVC (% predicted) decline ≥10% or death until week 52 based on in clinic 
supervised spirometry.
Secondary endpoints are the rate of change (slope) in blood C1M from baseline to week 12 
and the rate of change (slope) in blood C3M from baseline to week 12.


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ASSESSMENT OF EFFICACY
5.2
Measurements of biomarkers
Blood samples collected from patients at visits will allow measurement of following 
concentrations: 
 collagen 1 degraded by MMP-
2/9/13 (C1M), collagen 3 degraded by MMP-9 (C3M),
 C-reactive protein degraded by MMP-1/8 (CRPM), and citrullinated vimentin
Sample collection is described in Section 5.5. More details of sample collection and 
processing will be given in a lab manual.
Measurements of in clinic FVC
Spirometry devices for in clinic measurements as well as devices for home spirometry will be 
supplied by a central vendor to all participating sites.
In clinic spirometry performance will be centrally reviewed. On-going feedback and training 
will be provided. Predicted normal values shall be calculated according to ECSC [R94-1408].
The spirometers and their use, including daily calibration, must meet ATS/ ERS criteria (P05-
12782). Spirometry will be conducted while the patient is in a seated position. The test will 
be done in triplicate and selection of the best result done according to the guidelines. 
Spirometric results will be electronically transmitted and confirmed by central reading.
Further details on in clinic spirometry shall be provided in the ISF.
For each patient, pulmonary function testing will always start at approximately the same time 
of the day within ±90 minutes maximum difference from measurement time at Visit 1. 
On days of clinic visits (including the screening visit), patients must refrain from strenuous 
activity at least 12 hours prior to pulmonary function testing.


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Smoking should be discouraged throughout the study day (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).
Washout of bronchodilators (betamimetics and anticholinergics) need to be observed prior to 
in clinic spirometry (8 hours for short acting and 24 hours for long acting bronchodilators). 
 
 
 
 
 
 
 
 
 
Carbon Monoxide Diffusion Capacity and Oxygen Saturation.
The site will use its own carbon monoxide diffusion capacity (DLCO) equipment and 
conduct all measurements with the same equipment (e.g. if several devices would be 
available at the site). Single-breath DLCO will be carried out according to the ATS / ERS 
guideline on DLCO measurements [R06-2002]. Before beginning the test, the manoeuvers 
should be demonstrated and the subject carefully instructed. Please refer to Appendix 10.5 for 
additional information. The DLCO assessment should be performed after the FVC 
assessment.
Oxygen saturation (SpO2) will be measured at rest by standard pulse oximetry (unaffected 
skin of earlobe or fingertip or forehead) and the recorded value will be entered in eCRF.
 
ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
Physical examination includes assessment of heart, lung, abdomen and measurement of 
weight. Height will also be measured at Visit 1. Abnormal finding at the time of screening 
will be recorded as baseline conditions on the appropriate eCRF page. New abnormal 


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findings or worsening of baseline conditions detected at the subsequent physical 
examinations will be recorded as adverse events on the appropriate eCRF page.
5.3.2
Vital Signs
Vital signs including measurements of systolic and diastolic blood pressure and pulse rate, 
will be measured with the patient seated after having rested for at least 5 minutes at each on 
site visit.
5.3.3
Safety laboratory parameters
The laboratory tests will include:
•Haematology: complete blood count with platelet count and automated differential.
•Chemistry: sodium, potassium, creatinine, creatinine clearance calculated by 
Cockcroft–Gault formula, aspartate aminotransferase (AST), alanine transaminase 
(ALT), gamma-glutamyl transferase  (GGT), total protein, alkaline phosphatase 
(ALP), total bilirubin, lactate dehydrogenase (LDH), creatinine kinase and thyroid 
stimulating hormone (TSH).
•Coagulation: International normalized ratio (INR) and partial thromboplastin time 
(PTT).
•Urine: pregnancy testing 
If laboratory values indicate toxicity, adequate and more frequent blood sampling will be 
performed at the discretion of the investigator.
Laboratory analysis during main visits 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. No fasting is required. 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.
In case of liver enzymes elevation, close monitoring must be ensured by the investigator 
(Section 4.2.1.3).
5.3.4
Electrocardiogram
12-lead ECGs are to be conducted with site equipment as specified in the Flow Chart. 
Changes should be examined, compared to previous test, and assessed for clinical relevance. 
Clinically relevant findings at Visit 1 will be recorded as baseline conditions, new abnormal 
findings thereafter will be recorded as adverse events.


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5.3.5
Other safety parameters
Medical history
All active and relevant historical disorders will be recorded on the Medical History/Baseline 
Conditions eCRF page at the screening visit (Visit 1).
A patient diary will be used by all patients in this trial. The diary will be used to prompt 
patient recollection during adverse event, concomitant therapies and times of drug intake 
three days prior to the PK sampling. Instructions for use of the diary will be provided in the 
ISF.
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 authorisation 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 hospitalisation or prolongation of existing hospitalisation,

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 


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require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse. Any suspected transmission via a medicinal product of an infectious agent is 
considered a serious adverse reaction.
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
For Japan only: 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”
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. These events 
should always be reported as SAEs as described in Section 5.3.7.
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.
The following are considered as AESIs: adverse events relating to gastrointestinal perforation 
and hepatic injury.
Hepatic Injury
In this study protocol, hepatic injury is defined as follows:

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.


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These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, 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
The intensity of diarrhea adverse events should in addition be classified and recorded in the 
(e)CRF according to the Common Terminology Criteria for Adverse Events (CTCAE)
version 4 [R10-4848].
Table 5.3.6.1:1
CTCAE Categorization for diarrhea
CTCAE Grade
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 characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship


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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. 
preexisting or concomitant diseases, or co-medications).
• The event is typically drug-related and infrequent in the general population not
exposed to drugs (e.g. Stevens-Johnson syndrome).
• An indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship
could be:
• No plausible time to onset of the event relative to the time of drug exposure is 
evident (e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / 
weeks of drug administration; 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.
For Japan only: The reason for the decision on causal relationship for unlisted AEs needs to 
be provided in the eCRF.
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) / eCRF by the 
Investigator:
•
From signing the informed consent onwards through the Residual Effect Period 
(REP), until individual patient’s end of trial:
-all AEs (serious and non-serious) and all AESIs.
However, if an individual patient discontinues trial medication prematurely but
stays in the trial (i.e. if further visits incl. telephone visits, or vital status assessments are 
planned) from then on and until the individual patient’s end of the trial the Investigator 
must report related SAEs and related AESIs.


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•
After the individual patient’s end of 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.
The Residual Effect Period (REP) is defined as 28 days after the last trial medication 
application. 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 only: All SAEs 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 
(e)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 (e)CRF and SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions


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Changes in vital signs, 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 rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s
unique entry point (country-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). 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and 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. 
 
 
 
 
 


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ASSESSMENT OF EXPLORATORY BIOMARKER(S)
5.5
Blood samples will be taken according to the Flow Chart for the analysis of exploratory 
biomarkers. 
These samples will be stored for up to 3 years after the end of the clinical trial.
Samples will be shipped from the sites to a central laboratory for short-term storage. These
samples will be shipped in batches from the central laboratory to Boehringer Ingelheim or to
another location for biomarker analyses or long-term storage.
In order to better understand the effects of nintedanib on the disease, mechanistic and disease 
related biomarkers will be assessed in peripheral blood of randomised patients.
The assessment of exploratory biomarkers is a key feature of this clinical trial with the aim to 
better characterise and understand the disease, as well as their potential predictive value for 
treatment response. All biomarkers related to IPF pathology will be explored pre during and
post treatment with nintedanib or placebo in serum and plasma and will be correlated with the 
clinical endpoints.
 
 


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Methods and timing of sample collection
Whole blood will be collected for the preparation of serum, plasma and 
 
Collection time points are outlined in the Flowchart and respective footnotes. 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.
The samples will be shipped to the central laboratory and later analysed at the sponsor or a 
contractor of the sponsor. 
5.5.1
Analytical determinations
The analytical methods for the analysis of biomarkers from blood will be given in detail in a 
analytical biomarker report.
5.5.2
Biobanking
To allow for future scientific analyses, all patients will be asked for additional samples. Only 
if a separate specific informed consent is given in accordance with local ethical and 
regulatory requirements, DNA and/or serum banking samples will be taken, processed and 
stored. Participation in the DNA and/or serum banking part is voluntary and not a 
prerequisite for participation in the study.


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Serum banking
To enable future not yet specified biomarker analyses additional blood will be collected into 
serum collection tubes. This sample will be collected according to the Flow Chart. Details on 
sample collection and processing will be given in the ISF. This sample will be stored up to 15 
years after the end of the trial and may be used for further characterization of IPF patients.
Approximately 100 mL of blood will be collected for serum banking.  Detailed instructions 
for serum banking sampling, handling and shipment of samples are provided in the ISF.
DNA banking
The DNA sample derived from the original blood sample will be stored by Boehringer
Ingelheim for up to 15 years after the end of the clinical trial or until there is no more 
material available for tests. The stored DNA may be used at a later time for 
pharmacogenomic analyses.  
Methods and timing of DNA banking sample collection
An amount of approximately 8.5 mL blood will be collected per PaxGene DNA blood 
sampling tube for those patients who signed a separate informed consent concerning the
Sample DNA banking part with any other blood sampling after randomisation. The Paxgene 
Blood DNA tubes can be stored and shipped at room temperature within 14 days. If a longer 
storage and shipment period for Paxgene Blood DNA tubes is necessary, the blood samples 
have to be stored at a temperature of approximately -20°C or below.
Once frozen, thawing of the samples should be avoided except for analysis.
Detailed instructions for pharmacogenomics sampling, handling and shipment of samples are
provided in the ISF.
OTHER ASSESSMENTS
5.6
Not applicable.
APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements conducted in the trial are using standard methods.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
This trial starts with Visit 0 during which informed consent process shall be undergone 
HRCT scans and biopsies (later if available) shall be sent for central review to confirm the 
diagnosis of IPF. Further the trial consists of screening visit (Visit 1) and screening period
lasting 14 days (2 weeks), treatment period lasting 52 weeks and follow-up period lasting 28 
days (4 weeks). The treatment period will consist of two parts. At Visit 2 patients will be 
randomised into double-blind portion of the study. Additional clinic visits of the double blind 
period will be scheduled at week 4, 8 and 12 (Visits 3, 4 and 5). At Visit 5, i.e. after 
completing the randomised, double blind treatment all patients will enter the single arm, open 
label, active treatment period. During this period patients will visit the clinic for scheduled 
visits at week 16, 20, 24, 36 and 52 (Visits 6, 7, 8, 9 and 10). The follow-up visit (Visit 11) 
will be scheduled 28 days post-treatment. Unscheduled visits may be conducted anytime if 
deemed necessary.
Time windows to be adhered to for scheduling of visits are shown in the Flow Chart. Sites 
should make every attempt to adhere to the protocol time windows as close as possible. The 
screening period (between Visit 1 and Visit 2) may be extended by additional 2 weeks (i.e. 28 
day total) for any reasons (e.g. exacerbation, lab results receipt, etc.). All onsite visits from 
Visits 1 to Visit 11 will be scheduled in the morning, in order to guarantee start of pulmonary 
function testing at approximately the same time of the day (recommended time for PFTs from 
8:00 till 11.00 a.m.; any subsequent PFTs should preferably be done within ± 90 minutes 
from the measurement at Visit 1). Patients should make every attempt to complete the study 
as specified. Investigators should encourage patient treatment compliance and adherence to 
other protocol specific activities.
All deviations from the planned visit schedule will be documented. 
Rescheduling prior to randomisation.
• if a patient experiences acute IPF exacerbation or respiratory tract infection between Visit 0 
and Visit 1, the Visit 1 will be postponed until complete recovery from the infection or 
exacerbation, preferably 4 weeks following the recovery from the infection or exacerbation.
• laboratory parameters found abnormal at visit 1 may be re-tested once prior to Visit 2.
• if the screening period (2 weeks and 2 additional weeks for administrative reasons) needs to 
be extended further (counted from Visit 1), the clinical monitor should be contacted.
Reasoned prolongation of the screening period may be allowed by the clinical monitor.
• if a patient experiences an IPF exacerbation or respiratory tract infection during the 
screening period (2 weeks) between Visit1 and Visit 2, the Visit 2 will be postponed until 
complete recovery from the infection or exacerbation, preferably 4 weeks following the 
recovery from the infection or exacerbation.
Patients should make every attempt to adhere to the protocol. Investigators should encourage 
patient treatment compliance and adherence to other protocol related activities.
Subsequent visits should always be planned to take place at scheduled dates in line with the 
protocol Flow Chart.


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DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening and run-in period(s)
Visit 0
Informed consent will be obtained prior to patient participation in the trial, which includes 
any study related procedures, medication washout procedures or restrictions. Furthermore, 
the patient will be asked to give informed consent to the pharmacogenomic (optional DNA 
and serum banking sample) analyses. HRCT and biopsy tissue samples (later if available) 
shall be sent for central review. Call the IRT to register a new patient into the study.
Visit 1
Visit 1 may only be performed once the central HRCT and biopsy tissue sample reading 
confirm the IPF diagnosis
At Visit 1:
- Verify medication washout compliance
- Record demographic data 
- Conduct relevant medical history and physical examination including height and weight
measurements, vital signs (blood pressure and pulse rate), pulse oximetry (Sp02) and 12-lead 
ECG. The vital signs (seated), pulse oximetry and ECG should be conducted following five 
minutes rest and prior to screening pulmonary function testing and DLCO measurement
- Perform blood collections for haematology, serum chemistry, coagulation panel and urine 
pregnancy test (if applicable). Blood samples shall be sent to central laboratory; for further 
information refer to Laboratory Manual in the ISF
- Perform pulmonary function testing in the morning preferably between 08:00 – 11:00. 
Patients must demonstrate FVC ≥ 80% to be eligible.
- Perform DLCO measurement
- Review and record all adverse events experienced since signed informed consent
- Record concomitant therapy for the previous 3 months in the eCRF as described in Section 
4.2. 
- Review inclusion and exclusion criteria
- Instruct and train patients on how to perform and record PFTs at home
- Give instructions on medication restrictions and washout requirements for the screening 
period and subsequent visits
- Instruct patients to bring all study-related equipment to the clinic at each visit
- Schedule the next clinic visit in 14 days (2 weeks), additional 2 weeks are allowed for 
administrative reasons
Screening period


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6.2.2
Treatment period(s)
The order of procedures should be as follows: patient self-administered questionnaires (if 
applicable), blood collections (as per Flow Chart), vital signs and ECG (if applicable), PFTs, 
medication administration (if applicable).  
Observations / Procedures
Visit 2 (randomisation visit)
Optional - Call the patient the day before the clinic visit to remind the clinic visit next day. 
Remind the patient medication washout requirements (if applicable) and to bring all study 
related supplies (home spirometer) to the clinic visit. 
 
 
- Review and record all adverse events experienced and changes in concomitant therapy.
- Review all inclusion and exclusion criteria
- Perform blood collections for haematology, serum chemistry, coagulation panel and urine 
pregnancy test (if applicable) including biomarker serum and plasma samples, biomarker 
RNA sample, optional serum banking sample and optional DNA banking sample if 
applicable (later sample may be collected at any time as of Visit 2). For further details on 
safety lab collections refer to Section 5.3.3. For further details on biomarker related 
collections refer to Section 5.5. Blood samples shall be sent to central laboratory; for further 
information follow Laboratory Manual in the ISF
- Record vital signs (blood pressure and pulse rate) before PFTs and with the patient seated 
and rested for at least five minutes
- Record patient weight
- Perform supervised PFTs
- Perform randomisation in case patient is eligible 
- Call IRT to randomise the patient and dispense the first blinded medication kit (period 
between Visit 2 and Visit 3) 


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- Instruct patient to take the first capsule at the clinic under trial staff supervision. Refer to 
Section 4.1.4. Instruct patient on further medication intake, please refer to Section 4.2
regarding possible dose reductions, interruptions and management of drug relates AEs
- Dispense the Patient Diary and instruct the patient on its use 
- Schedule next planned clinic visit. Instruct patients to bring all study related treatments to 
the next clinic visit
Visits 3 and 4  
Optional - Call the patient the day before the clinic visit to remind the clinic visit next day. 
Remind the patient medication washout requirements (if applicable) and to bring all study 
related supplies (home spirometer, patient diary, treatments, etc.) to the clinic visit. 
 
- Review and discuss new Patient Diary entries with the patient 
- Review and record all adverse events experienced and changes in concomitant therapy
- Perform blood collections and urine pregnancy test (if applicable). Refer to Section 5.3.3  
- Collect biomarker serum and plasma samples, optional serum banking sample and optional 
DNA banking sample if applicable (later sample may be collected at any time as of Visit 2). 
Refer to Section 5.5
 
- Record vital signs (blood pressure and pulse rate) before PFTs and with the patient seated 
and rested for at least five minutes (at Visit 3 only)
- Record patient weight
- Perform supervised PFTs
- Perform Study Drug Compliance Check
- Call IRT to dispense the blinded medication kits (for further details refer to Section 4.1.4)
- Administer morning dose of the trial drug from newly dispensed kit at the site 
- Schedule next planned clinic visit. Instruct patients to bring all study related treatments to 
the next clinic visit


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Visit 5  
Optional - Call the patient the day before the clinic visit to remind the clinic visit next day. 
Remind the patient medication washout requirements (if applicable) and to bring all study 
related supplies (
 patient diary, treatments, etc.) to the clinic visit.
 
 
- Review and discuss new Patient Diary entries with the patient 
- Review and record all adverse events experienced and changes in concomitant therapy
- Record vital signs (blood pressure and pulse rate) before PFTs and with the patient seated 
and rested for at least five minutes
- Record patient weight
- Perform safety laboratory collections and urine pregnancy test (if applicable). For further 
details refer to Section 5.3.3
- Collect biomarker serum and plasma samples, optional serum banking sample and optional 
DNA banking sample if applicable (later sample may be collected at any time as of Visit 2). 
Refer to Section 5.5
 Section 5.5
- Perform supervised PFTs
- Perform Study Drug Compliance Check
- Call IRT to dispense the open label medication kits (for further details refer to Section 4.1.4) 
- Instruct patient to take the first capsule of open label medication at the clinic under trial 
staff supervision. Refer to Section 4.1.4 Instruct patient on further medication intake, please 
refer to Section 4.2 regarding possible dose reductions, interruptions and management of drug 
relates AEs.
- Schedule next planned clinic visit. Instruct patients to bring all study related treatments to 
the next clinic visit.
Visits 6, 7, 8 and 9  
Optional - Call the patient the day before the clinic visit to remind the clinic visit next day. 
Remind the patient medication washout requirements (if applicable) and to bring all study 
related supplies (
, patient diary, treatments, etc.) to the clinic visit.
 
- Review and discuss new Patient Diary entries with the patient
- Review and record all adverse events experienced and changes in concomitant therapy


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- Record vital signs (blood pressure and pulse rate) before PFTs and with the patient seated 
and rested for at least five minutes (Visit 6, 8 and 9)
- Record patient weight
- Perform safety laboratory collections and urine pregnancy test. For further details refer to 
Section 5.3.3.
- Collect biomarker serum and plasma samples, optional serum banking sample and optional 
DNA banking sample if applicable (later sample may be collected at any time as of Visit 2). 
Refer to Section 5.5
 
 
- Perform supervised PFTs.
- Perform Study Drug Compliance Check
- Call IRT to dispense the open label medication kits (for further details refer to Section 4.1.4) 
(not applicable at Visit 6 and 7)
- Administer morning dose of the trial drug from the newly dispensed kits at the site (not 
applicable at Visit 6 and 7, as kits dispensed at Visit 5 will be used at these visits)
- Schedule next planned clinic visit. Instruct patients to bring all study related treatments to 
the next clinic visit
Visit 10 (End of treatment visit)
Optional - Call the patient the day before the clinic visit to remind the clinic visit next day. 
Remind the patient medication washout requirements (if applicable) and to bring all study 
related supplies (home spirometer, patient diary, treatments, etc.) to the clinic visit.
 
- Review and discuss new Patient Diary entries with the patient 
- Review and record all adverse events experienced and changes in concomitant therapy
- Perform blood collections for haematology, serum chemistry, coagulation panel and urine 
pregnancy test (if applicable), including biomarker serum and plasma samples, biomarker 
RNA sample, optional serum banking sample and optional DNA banking sample if 
applicable (later sample may be collected at any time as of Visit 2). For further details on 
safety lab collections refer to Section 5.3.3. For further details on biomarker related 
collections refer to Section 5.5. Blood samples shall be sent to central laboratory; for further 
information follow Laboratory Manual in the ISF.
 


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- Perform physical examination including vital signs (blood pressure and pulse rate) and 
perform 12-lead ECG before PFTs with the patient seated and rested for at least five minutes. 
- Record patient weight
- Perform supervised PFTs
- Perform Study Drug Compliance Check
- Administer the last morning dose of the trial drug at the site. Collect remaining study drug. 
After the last dose of trial medication the Investigator / the treating physician may initiate 
further IPF treatment in line with the protocol Section 4.2.2. 
- Call IRT to record End of Treatment
 
- Schedule next planned clinic visit (the Follow-up visit). Instruct patients to bring all 
remaining study supplies to the next clinic visit
6.2.3
Follow Up Period and Trial Completion
Visit 11 (Follow-up Visit) 
Patients will be contacted once at the end of the follow up period. Adverse events and 
concomitant therapies will be reviewed and recorded. Urine pregnancy test will be performed 
in applicable patients. A 12-lead ECG and physical examination including vital signs should 
be performed if these were abnormal at Visit 10. Remaining trial supplies should be collected.
Premature withdrawal
Patients who prematurely discontinue study drugs (refer to Section 3.3.4) before the planned 
end of treatment at Visit 10, should come to the clinic as soon as possible after last drug 
intake for an early EOT visit. Reason for discontinuation must be documented in the eCRF. 
For detailed description of the trial procedures at this visit, please refer to the Flow Chart. 
In addition patients will be invited to attend all remaining planned visits and perform all 
study procedures 
 If a patient doesn’t accept to attend 
remaining study visits, collect the home spirometer and any trial related supplies and contact 
patient for vital status collection at week 52.The need to come to remaining scheduled visits 
in case of prematurely discontinuation of trial medication will be explained to patients prior 
to their participation in the trial. 


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Vital status information
In case of an early discontinuation of trial medication, if the patient does not agree to come to 
future visits as planned, any attempt will be made to get information on vital status at Week 
52 (refer to Flow Chart).
Patients will be asked to agree to be contacted by the site personnel, which could be by 
telephone calls, to allow collection of this information.
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.
Collection of vital status will be performed in accordance with national ethical and regulatory 
guidelines. The need for vital status information will be explained to patients prior to their 
participation in the trial.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is a randomised, placebo controlled, multi-centre, multinational, prospective, double 
blind trial to investigate the effect of oral nintedanib 150 mg twice daily on change in 
biomarkers of extracellular matrix (ECM) turnover in patients with idiopathic pulmonary 
fibrosis (IPF) and preserved forced vital capacity (FVC).
The primary endpoint is the rate of change (slope) in blood CRPM from baseline to week 12. 
Therefore, the rate of change (slope) in blood CRPM will be analyzed using random 
coefficient regression (random slopes and intercepts) model including gender, age and height
as covariates.
The secondary endpoint, proportion of patients with disease progression defined by FVC 
decline ≥10% or death, will be analysed using logistic regression models or other appropriate 
methods.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The objective of this study, demonstrating a treatment effect of nintedanib at a dose of 150 
mg bid compared to placebo for the rate of change (slope) in blood CRPM, will be tested 
using the following null hypothesis.
H0: No difference in the rate of change (slope) in blood CRPM evaluated from 
baseline until 12 weeks of treatment between nintedanib mg bid and placebo.
The alternative hypothesis is
Ha: The rate of change (slope) in blood CRPM is different for patients taking 
nintedanib 150 mg bid than those taking placebo.
The hypothesis will be tested using 5% level of significance (two-sided test).
PLANNED ANALYSES
7.3
The statistical analysis will be based on the following populations.
Treated Set (TS):
The treated set (TS) consists of patients who are randomised to a treatment group and
receive at least one dose of study medication
Randomised Set (RS):


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The Randomised set (RS), consists of those patients who were randomised to a
treatment group.
 
 
The efficacy and safety analysis will be conducted on the TS. Efficacy parameters will be 
analysed from an as randomised perspective and safety parameters from an as treated 
perspective, respectively. For efficacy analysis, all measurement performed within the first 12 
weeks will be used. Efficacy evaluations done after lung transplant will not be used for the 
efficacy analyses; sensitivity analyses will be performed including these data.
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 
potential important protocol violations (those that relate to patient safety or efficacy) will be 
identified at Blinded Review Planning Meetings and listed in the clinical trial report.
7.3.1
Primary endpoint analyses
The primary endpoint is the rate of change (slope) in blood CRPM evaluated from baseline 
over 12 weeks (expressed in ng/mL/month) estimated from measurements taken over 12 
weeks of treatment. The rate of change (slope) in blood CRPM is assumed to be linear within 
each subject over the 12 weeks period. The intercepts and slopes will be assumed to be 
normally distributed with arbitrary covariance matrix. Gender, age and height which are usual 
predictors of FVC will also be included in the model. Baseline blood CRPM will be 
measured at visit 2. No imputation is planned if this assessment is not available for a patient. 
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. Significance tests will be based on least-squares 
means using a two-sided α=0.05 (two-sided 95% confidence intervals). Analyses will be 
implemented using SAS® Version 9.4.
The linearity assumption for the rate of change (slope) in blood CRPM will be tested and 
sensitivity analysis will be done with alternative models described in the Trial Statistical 
Analysis Plan (TSAP). The effect of missing data will be investigated using pattern-mixture 
models. Depending on the pattern of the missingness in the data, multiple imputation 
methods may also be considered.
 
7.3.2
Secondary endpoint analyses
For the key secondary endpoint, proportion of patients with disease progression as defined by 
FVC decline ≥10% or death over week 52, two main analyses are planned. 
Firstly, in order to assess the predictive value of change in extracellular matrix (ECM) 
biomarker CRPM over 12 weeks for disease progression as defined by FVC decline ≥10% or 


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death over 52 weeks, a logistic regression (or a similar appropriate) analysis including 
baseline blood CRPM and the rate of change (slope) in blood CRPM over the first 12 weeks 
as covariates will be applied for the placebo treated patients only.
Secondly, in order to assess how nintedanib treatment during the first 12 weeks affects the 
association between change in extracellular matrix (ECM) biomarker CRPM over 12 weeks 
and disease progression, a logistic regression (or a similar appropriate) analysis including 
baseline blood CRPM, rate of change (slope) in blood CRPM over the first 12 weeks, 
treatment and treatment CRPM slope interaction as covariates will be applied. The interaction 
term will be of primary interest within this analysis. More details will be given in the TSAP.
Both analyses will be repeated for rate of change (slope) in the biomarkers C1M and C3M 
defined as secondary endpoints. Reasonably, baseline CRPM as covariate will be replaced by 
baseline C1M/C3M in these analyses.
7.3.4
Safety analyses
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 
adverse events with an onset between start of treatment and end of the residual effect period 
(REP), a period of 28 days 
after the last dose of trial medication, will be assigned to the treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
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 28 days. Adverse events that start before first drug intake and deteriorate 
under treatment will also be considered as ‘treatment-emergent’.


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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 the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
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.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
 
 
 
 
INTERIM ANALYSES
7.4
No interim analysis is planned.
HANDLING OF MISSING DATA
7.5
7.5.1
Efficacy endpoints
In efficacy analyses of continuous endpoints, missing data will not be imputed. In the 
analyses of the time-to-event endpoints, missing or incomplete data are managed by standard 
survival analysis techniques. These will be described in detail in the TSAP.
In the analyses of the categorical endpoints, missing data will be imputed using the worst 
case.


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7.5.2
Safety endpoints
Missing or incomplete AE dates will be imputed according to BI standards. With respect to 
other safety evaluations, it is not planned to impute missing values.
 
RANDOMISATION
7.6
Patients will be randomised in blocks to double-blind treatment with an unequal probability 1
to 2 of assignment to nintedanib and placebo. BI will arrange for the randomisation and the 
packaging and labelling of trial medication. The randomisation 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. All members of the 
Medical Project Team will remain blinded to the randomisation schedule until after the final 
database is locked.
DETERMINATION OF SAMPLE SIZE
7.7
The sample size calculations are based on change relative to baseline in biomarker levels of 
serum CRPM, serum C1M and serum C3M (unpublished data, no reference available). The 
sample size calculations are based on two-sided tests (α =0.05) to detect a difference in 
means of two independent samples with a 1:2 randomisation ratio nintedanib:placebo in the 
samples with a power of 90%. No multiplicity adjustments are made as part of the power 
calculation, and no adjustment is made for a potential subject withdrawal. Sample size 
calculations are performed for assumed differences between treatment group and placebo of 
20% and 30% difference. Due to the lack of data from respective IPF patients and since there 
is no evidence biomarker courses are principally different across both indications, data from 
two studies of RA patients are used to estimate the standard deviation over time in biomarker 
values relative to baseline: Study A) RA patients including a placebo group and a treatment 
group with measurements of serum CRPM, serum C1M and serum C3M at baseline, weeks 4, 
16, and 24; and Study B) RA patients including a placebo group and a treatment group with 
measurements of serum CRPM, serum C1M and serum C3M at baseline, weeks 4, and 12.
The hypothesis to be tested can be formulated as:
H0:
µTreatment = µPlacebo
tested confirmatively against the alternative
Ha:
µTreatment    µPlacebo
where µTreatment is the change in biomarker relative to baseline in the treatment group, and 
µPlacebo is the change relative to baseline in the placebo group.


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Table 7.7:1 
Data of standard deviation over time in changes relative to baseline
Data of standard deviation over time in changes relative to baseline 
CRPM
C1M
C3M
Placebo
Treatment
Placebo
Treatment
Placebo
Treatment
Study A
Week 4
42%
(n=100)
34%
(n=143)
44% 
(n=116)
41% 
(n=176)
38% 
(n=116)
31% 
(n=176)
Week 16
33% 
(n=88)
36% 
(n=128)
42% 
(n=102)
58% 
(n=156)
32% 
(n=102)
27% 
(n=156)
Week 24
31% 
(n=83)
32% 
(n=131)
53% 
(n=97)
53% 
(n=162)
33% 
(n=97)
31% 
(n=162)
Study B
Week 4
40% 
(n=71)
25% 
(n=66)
48%
(n=76)
68%
(n=75)
43% 
(n=71)
66% 
(n=67)
Week 12
43% 
(n=52)
47% 
(n=68)
45% 
(n=54)
55% 
(n=73)
44% 
(n=50)
44% 
(n=68)
Based on Table 7.7:1, sample sizes will be calculated for a range of common standard 
deviations of 30%; 40% and 50%.
Table 2 gives the calculated sample size numbers for assumed relative treatment differences 
of 20 and 30 percent.
Table 7.7:2 
Sample sizes for common standard deviations of 30%, 40%, and 50%; 
significance level 5%; power 90% with a 1:2 randomisation ratio 
nintedanib:placebo
Sample sizes for common standard deviations of 30%, 40%, and 50%; significance level 
5%; power 90% with a 1:2 randomisation ratio nintedanib:placebo
Common STD 30%
Common STD 40%
Common STD 50%
n
n
n
nintedanib
placebo
total
nintedanib
placebo
total
nintedanib
placebo
total
20%
37
73
110
64
128
192
100
199
299
30%
17
33
50
29
58
87
45
89
134
If the true standard deviation of change in CRPM relative to baseline lies between 30 and 50 
percent, a total number of patients between 110 and 300 would be needed to detect a 


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treatment group difference of 20% with a power of 90% with a treatment allocation ratio of 
1:2 (Nintedanib:Placebo).
However, the key secondary endpoint requires more patients for two reasons: firstly, only 
patients initially treated with Placebo are analysed in the first step (reducing the actual sample 
size for this analysis to 2/3 of the total sample size) and secondly, some loss of information is 
associated with the planned analysis due to the binary state of the endpoint. To be more 
precise, with n=350 randomised patients, n=233 patients will be initially treated with Placebo
and based on the INPULSIS results [P14-07514], we expect to observe a total of about 40% 
of disease progression as defined by FVC decline ≥10% or death over week 52 for that 
treatment group. Using available data from the observational PROFILE study [R15-1220], 
we further expect roughly half of the patients to have rising biomarker values (slope greater 
than zero) and the remaining patients having stable biomarker values (slope less or equal to 
zero) resulting in about equally sized groups if the rate of change (slope) in blood CRPM 
from baseline to week 12 is dichotomized. With the stated sample size, an absolute difference 
in rates of at least 20% (i.e. 30% vs 50% of patients with disease progression) can be detected 
with a power of 88%. 
For these reasons, a sample size of n=350 patients (117 on nintedanib and 233 on placebo) is 
planned for this study.
Calculations were performed using nQuery Advisor® 6.1.1 statistical package by Statistical 
Solutions Ltd.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
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 current version).
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), the
EU regulation 536/2014 the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) and other relevant regulations.
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.
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 only: 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 finalisation 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 according to ICH GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional patient-information form retained by the Investigator as 
part of the 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.


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For Japan only: The Investigator must give a full explanation to trial patients including the 
items listed below in association with the use of the patient information form, which is 
prepared avoiding the use of technical terms and expressions. The patient is 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.
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.
To ensure good quality data, investigators and study site personnel will be familiarized with 
the study protocol, procedures and principles of GCP during the investigator meeting and/or 
trial initiation visit. An ISF with all necessary trial related documentation and handling 
procedures will be provided. 
A central laboratory will be used for analysis of all blood samples. 
To ensure standardization in FVC measurement, a central spirometry review will be in place. 
Spirometry devices will be supplied to all participating sites/patients. 
Data will be captured using an RDC system. Training will be provided to all investigators, 
coordinators and CRAs to ensure consistency and accuracy of the data. The data will be 
source verified by the CRA during regular onsite monitoring. 
Data management procedures to ensure the quality of the data are described in detail in the 
trial data management and analysis plan which is available in the TMF.
Coding of concomitant medications is according to the World Health Organisation drug 
dictionary and coding of AEs is according to the MedDRA dictionary.
RECORDS
8.3
Electronic Case Report Forms (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.


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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 CRF 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.
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 CRA / on site monitor 
and auditor may review all CRF / 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
For Japan only:
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
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 AE 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 IB (c01805141-17). 
The current versions of these reference documents are provided in the ISF. No AE are 
classified as listed for trial design, or invasive procedures.


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8.4.2
Expedited reporting
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the
requirements defined in this CTP.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
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 the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”). 
The IEC / competent authority in each participating EU member state will be notified about 
the end or early termination of the trial.
For Japan only: 
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
For Japan only: 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
For Japan only: 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.


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9.
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Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, 
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nintedanib versus sunitinib in previously untreated renal cell carcinoma (RCC) 
patients. 49th Ann Mtg of the American Society of Clinical Oncology.
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Yen CJ, Kim TY, Feng YS, Chao Y, Lin DY, Studeny M, Hocke J, Huang 
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P14-02860
Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B Anti-fibrotic and anti-
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Richeldi L, et al, INPULSIS Trial Investigators. Efficacy and safety of 
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Scagliotti GV, Leighl NB, Nowak AK, Pavlakis N, Popat S, Sorensen JB, 
Barrueco J, Kaiser R, Loembe AB, Mueller M, Wangenheim U von, Reck M
Nintedanib plus pemetrexed/cisplatin followed by maintenance nintedanib for 
unresectable malignant pleural mesothelioma (MPM): an international, 
multicenter, randomized, double-blind, placebo-controlled phase II study.
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Chicago, 30 May - 3 Jun 2014
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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)
P14-16496
Wuyts WA, Antoniou KM, Borensztajn K, Costabel U, Cottin V, Crestani B, 
Grutters JC, Maher TM, Poletti V, Richeldi L, Vancheri C, Wells AU
Combination therapy: the future of management for idiopathic pulmonary 
fibrosis? Lancet Respir Med 2, 933 - 942 (2014)
P14-17347
Ogura T, Taniguchi H, Azuma A, Inoue Y, Kondoh Y, Hasegawa Y, Bando 
M, Abe S, Mochizuki Y, Chida K, Klueglich M, Fujimoto T, Okazaki K, 
Tadayasu Y, Sakamoto W, Sugiyama Y. Safety and pharmacokinetics of 
nintedanib and irfenidone in idiopathic pulmonary fibrosis. Eur Respir J, 
(2014)
P15-01243 
Spagnolo P, Wells AU, Collard HR. Pharmacological treatment of idiopathic 
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P15-07362
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clinical practice guideline: treatment of idiopathic pulmonary fibrosis: 
executive summary: an update of the 2011 clinical practice guideline. Am J 
Respir Crit Care Med 192 (2), 238 - 248 (2015)
P15-08362
Raghu G, et al, ATS, ERS, JRS, and ALAT
An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of 
idiopathic pulmonary fibrosis: executive summary: an update of the 2011 
clinical practice guideline.
Am J Respir Crit Care Med 192 (2), 238 - 248 (2015)
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Crestani B, Ogura T, Pelling K, Coeck C, Quaresma M, Kreuter M, Kaye M.
Interim analysis of nintedanib in an open-label extension of the INPULSIS 
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Maher TM, Flaherty KR, Noble PW, Vancheri C, Wuyts WA, Kimura T, 
Hallmann C, Stowasser S, Richeldi L. Effect of baseline FVC on lung function 
decline with nintedanib in patients with IPF. Eur Respir J 46 (Suppl 59), 
(2015)
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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 26 (4), 720 - 735 (2005)
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S, Itoh H, Ohi M, Sato A, Kudoh S, Research Group for Diffuse Lung 
Diseases in Japan, Raghu G Double-blind, placebo-controlled trial of 
pirfenidone in patients with idiopathic pulmonary fibrosis.Am J Respir Crit 
Care Med 171, 1040 – 1047 (2005)
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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)
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Changes in clinical and physiologic variables predict survival in idiopathic 
pulmonary fibrosis.Am J Respir Crit Care Med 168, 538 - 542 (2003)
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Takahashi H, Nakata K, Sato A, Takeuchi M, Raghu G, Kudoh S, Nukiwa T,
Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic 
pulmonary fibrosis. Eur Respir J 35 (4), 821 - 829 (2010)
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M, Bando M, Sugiyama Y, Totani Y, Ishizaki T, Ichiyasu H, Suga M, Hamada 
H, Kohno N. Prognostic value of circulating KL-6 in idiopathic pulmonary 
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Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, 
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CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary 
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R15-1220
Jenkins RG, Simpson JK, Saini G, Bentley JH, Russell AM, Braybrooke R, 
Molyneaux PL, McKeever TM, Wells AU, Flynn A, Hubbard RB, Leeming 
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collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis 
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(2002)
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UNPUBLISHED REFERENCES
9.2
c01805141-17 Investigator’s brochure: BIBF 1120, Indication: Idiopathic pulmonary 
Fibrosis. 1199.P3. Version 10. 23 Sep 2015.


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10.
APPENDICES
CRITERIA FOR HRCT/BIOPSY CENTRAL 
10.1
All chest HRCTs, and histopathology slides of surgical lung biopsies (the latter if available) 
will be centrally reviewed.
In the absence of a surgical lung biopsy, chest HRCT must qualify as “consistent with UIP”.
This will be defined as meeting either criteria A, B and C, or criteria A and C, or criteria B 
and C 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.
Appearances of a fibrosing lung disease with no definite HRCT features of a specific etiology 
will be considered “possible IPF”. Convincing HRCT appearances of a diffuse lung disease 
other than IPF will be considered “definitely not IPF”. “Possible IPF” and “definitely not 
IPF” will not be allowed for inclusion in the trial.
In the presence of a surgical lung biopsy, the histology will be reviewed based on the 
ATS/ERS/JRS/ALAT guidelines [P11-07084]. In such case, there will be a multi-disciplinary 
team approach (radiologist and pathologist) to confirm or exclude the diagnosis of IPF. An 
HRCT "possible IPF" coupled with a surgical biopsy of “definite UIP” or "probable UIP", 
upon multidisciplinary team discussion, could qualify for inclusion as “consistent with IPF”.
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)


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DLCO
10.5
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. Raw data (gas mixture, equation used for prediction of normal, 
further adjustments made if so) must be traced.
Predicted DLCO corrected for haemoglobin (Hb) expressed in g x dL-1 (R06-2002) can be 
calculated as:

Predicted DLCO corrected for Hb = Predicted DLCO x (1.7Hb/(10.22+Hb)) for males 
aged 15 years or above

Predicted DLCO corrected for Hb = Predicted DLCO x (1.7Hb/(9.38+Hb)) for 
females and children aged less than 15 years
DLCO results from Visit 1 will be corrected for haemoglobin (value obtained at Visit 1) by 
the site. 


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
23 February 2016
EudraCT number
2015-003148-38
BI Trial number
1199.227
BI Investigational Product(s)
nintedanib
Title of protocol
A 12-week, double blind, randomised, placebo 
controlled, parallel group trial followed by a single 
active arm phase of 40 weeks evaluating the effect 
of oral nintedanib 150 mg twice daily on change in 
biomarkers of extracellular matrix (ECM) turnover 
in patients with idiopathic pulmonary fibrosis (IPF) 
and limited forced vital capacity (FVC) 
impairment.
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
No content changes
Description of change
The document number on title page and headers 
was wrong.
Rationale for change
Not Applicable
Number of global amendment
2
Date of CTP revision
25 February 2016
EudraCT number
2015-003148-38
BI Trial number
1199.227
BI Investigational Product(s)
nintedanib
Title of protocol
A 12-week, double blind, randomised, placebo 
controlled, parallel group trial followed by a single 
active arm phase of 40 weeks evaluating the effect 
of oral nintedanib 150 mg twice daily on change in 


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biomarkers of extracellular matrix (ECM) turnover 
in patients with idiopathic pulmonary fibrosis (IPF) 
and limited forced vital capacity (FVC) 
impairment.
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
No content changes
Description of change
Not Applicable
Rationale for change
Technical error during signature workflow
Number of global amendment
3
Date of CTP revision
04 May 2017
EudraCT number
2015-003148-38
BI Trial number
1199.227
BI Investigational Product(s)
nintedanib
Title of protocol
A 12-week, double blind, randomised, placebo 
controlled, parallel group trial followed by a single 
active arm phase of 40 weeks evaluating the effect 
of oral nintedanib 150 mg twice daily on change in 
biomarkers of extracellular matrix (ECM) turnover 
in patients with idiopathic pulmonary fibrosis (IPF) 
and limited forced vital capacity (FVC) 
impairment.
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 


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IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Flow Chart: Biomarker serum and plasma, 
RNA, PK and optional serum banking 
samples collections added
2. Explanatory Note 2 on page 29, Old text 
“or”, new text “and/or”
3. Page 45, fingertip added as a possibility to
perform measurement of oxygen saturation
4. Further explanation added regarding visit 
planning and conduct on pages 56, 58 and 
62 
Description of change
Change 1: correction of typo, allow consistency in 
procedures between visit 10 (EOT) and Early EOT
Change 2 and 3: correction of typos, maintain 
consistency within the clinical project
Change 4: further clarification of visit planning and 
visit conduct
Rationale for change
Correction of Typos, additional clarification and 
explanation of trial related procedures, align 
procedures within the clinical project
Number of global amendment
4
Date of CTP revision
09 July 2018
EudraCT number
2015-003148-38
BI Trial number
1199.227
BI Investigational Product(s)
nintedanib
Title of protocol
A 12-week, double blind, randomised, placebo 
controlled, parallel group trial followed by a single 
active arm phase of 40 weeks evaluating the effect 
of oral nintedanib 150 mg twice daily on change in 
biomarkers of extracellular matrix (ECM) turnover 
in patients with idiopathic pulmonary fibrosis (IPF) 
and limited forced vital capacity (FVC) 
impairment.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 


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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
5.1.3
Description of change
 
 
 
 
Rationale for change
Section to be changed
Description of change
Rationale for change
 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03495745
5.0
clinical-trial-protocol-version-5
A 12-week, double blind, randomised, placebo controlled, parallel group trial
followed by a single active arm phase of 40 weeks evaluating the effect of oral
nintedanib 150 mg twice daily on change in biomarkers of extracellular matrix
(ECM) turnover in patients with idiopathic pulmonary fibrosis (IPF) and limited
forced vital capacity (FVC) impairment.
Author-Trial Clinical
Pharmacokineticist
10 Jul 2018 10:32 CEST
Author-Trial Clinical Monitor
10 Jul 2018 10:37 CEST
Approval-Team Member Medical
Affairs
10 Jul 2018 10:50 CEST
Author-Trial Statistician
10 Jul 2018 16:25 CEST
Approval-Therapeutic Area 
16 Jul 2018 10:42 CEST
Verification-Paper Signature
Completion
16 Jul 2018 10:46 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03495745
5.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c10844794-02
BI Trial No.:
1199.227
Title:
A 12-week, double blind, randomised, placebo controlled, parallel
group trial followed by a single active arm phase of 40 weeks
evaluating the effect of oral Nintedanib 150 mg twice daily on 
change in biomarkers of extracellular matrix (ECM) turnover in 
patients with idiopathic pulmonary fibrosis (IPF) and limited forced 
vital capacity (FVC) impairment.
Including Protocol Amendments 1, 2, 3 and 4 [c03495745-05]
Investigational
Product(s):
Ofev®, Nintedanib
Responsible trial 
statistician(s):
Phone:
Fax:    
Phone:
Fax:    
Date of statistical 
analysis plan:
19 JUL 2018 SIGNED
Version:
Final
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINT(S).....................................................................................................10
5.1
PRIMARY ENDPOINT .....................................................................................10
5.2
SECONDARY ENDPOINT(S) ..........................................................................10
5.2.1
Key secondary endpoint(s).................................................................................10
5.2.2
Secondary endpoint(s) ........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................18
6.1
TREATMENT(S)................................................................................................18
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................26
6.3
PATIENT SETS ANALYSED...........................................................................29
6.5
POOLING OF CENTRES .................................................................................30
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................30
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................31
7.
PLANNED ANALYSIS......................................................................................34
7.3
TREATMENT COMPLIANCE........................................................................35
7.4
PRIMARY ENDPOINT .....................................................................................35
7.4.1
Primary analysis..................................................................................................35
 
7.5
SECONDARY ENDPOINT(S) ..........................................................................39
7.5.1
Key secondary endpoint(s).................................................................................39


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7.5.2
Other Secondary endpoints................................................................................41
7.8
SAFETY ANALYSIS..........................................................................................47
7.8.1
Adverse events.....................................................................................................47
7.8.2
Laboratory data ..................................................................................................52
7.8.3
Vital signs.............................................................................................................52
7.8.4
ECG......................................................................................................................52
7.8.5
Others...................................................................................................................52
8.
REFERENCES....................................................................................................53
10.
HISTORY TABLE..............................................................................................68


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LIST OF TABLES
Table 6.1: 1 
Summary of analysed periods according to the type of endpoint.....................20
Table 6.2: 1
Important protocol violations (IPVs)................................................................26
Table 6.3: 1
Patient sets analysed .........................................................................................29
 
Table 7.8.1: 1 Adverse events by system using aggregated terms ..........................................49
Table 10: 1
History table .....................................................................................................68


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP
Term
Definition / description
AE
Adverse event
ALQ
Above limit of quantification
ALT
Alanine aminotransferase
AR
Autoregressive 
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical (Classification System)
ATS/ERS/
JRS/ALAT 
2011 
guideline
American Thoracic Society/European Respiratory Society/Japanese 
Respiratory Society/Latin American Thoracic Association guideline on 
idiopathic pulmonary fibrosis treatment / 2011
BFVC
Baseline FVC
BIcMQ
Boehringer Ingelheim customized MedDRA query
BIRDS
Boehringer Ingelheim regulatory document system
BLQ
Below limit of quantification
BM
Biomarker
BRPM
Blinded report planning meeting
CNS
Central nervous system
cpm
count per million
CRF
Case Report Form
CT
Concomitant therapies
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database lock
DBLM
Database lock meeting
DILI
Drug induced liver injury
DLCO
Carbon monoxide diffusion capacity
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DVT
Deep vein thrombosis
ECG
Electrocardiogram
ECM
Extracellular matrix


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Term
Definition / description
EMA
European Agency for the Evaluation of Medicinal Products
EOT 
End of treatment
FDR
False discovery rate
FUP
Follow-up period
FVC
Forced vital capacity
GGT
Gamma-Glutamyltransferase
GI
Gastrointestinal
Hb
Hemoglobin
HGNC
Human Gene Nomenclature Committee
HLT
Higher level term
HRCT
High-resolution computed tomography
ICH
International Conference on Harmonisation
IPF
Idiopathic pulmonary fibrosis
IPV
Important protocol violation
IXRS
Interactive voice/web response system
LLOQ
Lower limit of quantification
MACE
Major adverse cardiac events
MAR
Missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed model repeated measurements
MQRM
Medical Quality Review Meeting
N
Number of patients
NOA
not analysed
NOR
no valid result
NOS 
no sample available
PD
Pharmacodynamics
PK
Pharmacokinetics
PKS
Pharmacokinetics set
PN
Preferred name
PT
Preferred term
PV
Pharmacovigilance


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Term
Definition / description
RS
Randomized set
SD
Standard deviation
SE
Standard error
SEM
Standard error of the mean
SMQ
Standardised MedDRA Query
SOC
System organ class
SpO2
Oxygen saturation on pulse oximetry
TS
Treated Set
TSAP
Trial statistical analysis plan
ULOQ
Upper limit of quantification
ULN
Upper limit normal


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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 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, randomization.
Standard analyses on biomarkers and those on biomarker study endpoints will be described within 
this Statistical Analysis Plan.
SAS® Version 9.4 (or later version) will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Not applicable


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5.
ENDPOINT(S)
Refer to Section 6.6 for missing baseline assessment.
Refer to Section 6.7 for baseline value definition.
5.1
PRIMARY ENDPOINT
The primary endpoint is the rate of change (slope) in blood CRPM from baseline to week 12.
5.2
SECONDARY ENDPOINT(S)
Secondary efficacy endpoints are described in Section 5.1.2 of CTP. Additional information is 
provided only on selected endpoints in the TSAP.
5.2.1
Key secondary endpoint(s)
The key secondary endpoint is the proportion of patients with disease progression as defined 
by absolute FVC (% predicted) decline ≥10% or death until week 52 based on in clinic 
supervised spirometry.
5.2.2
Secondary endpoint(s)
Secondary endpoints are the rate of change (slope) in blood C1M from baseline to week 12 
and the rate of change (slope) in blood C3M from baseline to week 12.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For treatment specifications, see Section 4 of CTP.
The following trial periods will be defined: screening, post-randomisation, blinded treatment 
period (with sub-periods off-treatment, post-treatment and follow-up), open-label treatment 
period (with sub-periods off-treatment, post-treatment and follow-up) and post-study as 
follows:
Note: Post-treatment reflects the residual effect period.
Note: the last day of each of the following periods is excluded.

Screening: from informed consent to randomisation

Post-randomisation (optional): from randomisation to first randomised trial drug intake in 
blinded treatment period

Blinded treatment period: from first randomised trial drug intake (or re-start of treatment 
if interruption) to last randomised trial drug intake (or the day before start date of 
interruption, if interruption) plus one day
o
Blinded off-treatment (optional): from start date of interruption to re-start of 
blinded treatment
o
Blinded post-treatment (optional)[a]: from the last blinded trial drug intake plus 
one day to last blinded trial drug intake plus 28 days plus one day or day of 
first open-label treatment administration (whichever occurs earlier)
o
Blinded follow-up (optional): from last blinded trial drug intake plus 29 days 
up to the beginning of post-study period. This period is only created if last 
blinded trial drug intake took place more than 28 days before trial completion, 
or for patients having prematurely discontinued the blinded treatment and still 
continuing the trial
•
Open-label treatment period: from first open label nintedanib intake (or re-start of 
treatment if interruption) to last open label nintedanib intake (or the day before start 
date of interruption, if interruption) plus one day
o
Open-label off-treatment (optional): from start date of interruption to re-start of 
open-label treatment
o
Open-label post-treatment (optional)[a]: from the last open-label trial drug 
intake plus one day to last open-label trial drug intake plus 28 days plus one 
day
o
Open-label follow-up (optional): from last open-label trial drug intake plus 29 
days up to the beginning of post-study period. This period is only created if 


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last open-label trial drug intake took place more than 28 days before trial 
completion, or for patients having prematurely discontinued the open-label 
treatment and still continuing the trial

Post-study: from the latest of 
o
last trial drug intake plus 29 days 
o
date of trial completion 
o
follow-up visit
o
early end of treatment visit plus 1 day to database lock
[a] In addition, a post-treatment period of 7 days will be used for adverse event 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.
In addition to the above periods, the following additional period is defined:

Overall: Combines all available data from Blinded treatment period and Open-label 
treatment period.
For safety analyses, data up to the end of the blinded / open-label post-treatment period will 
be considered on-treatment. For on-treatment efficacy analyses, data up to the day after last 
trial drug intake (included) will be considered.
For efficacy analyses patients will be assigned to the treatment group they were randomised 
to, for safety analyses patients will be assigned to the treatment group they were treated in.
Details are provided in Table 6.1: 1.


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Table 6.1: 1
Summary of analysed periods according to the type of endpoint
Studied period
Analysed endpoint
Start date
End date [1]
For primary analysis (rate of change 
(slope) in blood CRPM from baseline to 
week 12)
Baseline (see Section 6.7)
Visit 5 (after time windowing, refer to Section 6.7)
Data up to the day after last blinded trial drug intake (included).
For the key secondary endpoint 
(Proportion of patients with disease 
progression as defined by absolute FVC 
(% predicted) decline ≥10% or death until 
week 52)
Main analysis:
Baseline (see Section 6.7)
Sensitivity analysis: Visit 5 
(start of open label treatment)
Visit 10 (after time windowing, refer to Section 6.7)
Data up to the day after last open-label trial drug intake (included).
For secondary endpoints (rate of change 
(slope) in blood C1M and C3M from 
baseline to week 12)
Baseline (see Section 6.7)
Visit 5 (after time windowing, refer to Section 6.7)
Data up to the day after last blinded trial drug intake (included).
For  efficacy endpoints from week 12 to 
week 52 (open-label period)
Visit 5 (start of open label 
treatment)
Note: Covariates can be 
measured before Visit 5.
Visit 10 (after time windowing, refer to Section 6.7)
Data up to the day after last trial open-label drug intake (included).
For efficacy endpoints from baseline to 
week 12 (blinded period)
Baseline (see Section 6.7)
Visit 5 (after time windowing, refer to Section 6.7)
Data up to the day after last blinded trial drug intake (included).


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Table 6.1: 1 (continued)
Summary of analysed periods according to the type of endpoint
Studied period
Analysed endpoint
Start date
End date [1]
 
 
 
 
 
 
Rates of decline during blinded period
Baseline (see section 6.7)
Visit 5 (after time windowing, refer to Section 6.7)
Data up to the day after last blinded trial drug intake (included).


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Table 6.1: 1 (continued)
Summary of analysed periods according to the type of endpoint
Studied period
Analysed endpoint
Start date
End date [1]
Rates of decline during open-label period
Visit 5 (start of open label 
treatment)
Note: Covariates can be 
measured before Visit 5.
Visit 10 (after time windowing, refer to Section 6.7)
Data up to the day after last trial open-label drug intake (included).
 


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Table 6.1: 1 (continued)
Summary of analysed periods according to the type of endpoint
Studied period
Analysed endpoint
Start date
End date [1]
AEs and laboratory data
On-treatment period safety (AEs, 
laboratory data, including enzymes 
elevation) during blinded treatment period
Date of first trial drug 
intake
First day of documented intake of open-label treatment or last blinded trial drug intake 
plus 28 days or end of treatment, whichever occurs first
Off-treatment periods not excluded. However, for safety listings, anything happening during a treatment 
interruption will be flagged as occurring during the off-treatment period (even if between [last trial drug intake; last 
trial blinded drug intake + 28 days])
On-treatment period safety (AEs, 
laboratory data, including enzymes 
elevation) during open label treatment 
period
First day of 
documented intake of 
open-label treatment
Last open label drug intake plus 28 days or end of treatment, whichever occurs first
Off-treatment periods not excluded. However, for safety listings, anything happening during a treatment 
interruption will be flagged as occurring during the off-treatment period (even if between [last trial drug intake; last 
trial open label drug intake + 28 days])
On-treatment period safety (AEs, 
laboratory data, including enzymes 
elevation) during overall treatment period
Date of first trial drug 
intake
Last drug intake plus 28 days or end of treatment, whichever occurs first
Off-treatment periods not excluded. However, for safety listings, anything happening during a treatment 
interruption will be flagged as occurring during the off-treatment period (even if between [last trial drug intake; last 
trial drug intake + 28 days])


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Table 6.1: 1 (continued)
Summary of analysed periods according to the type of endpoint
Studied period
Analysed endpoint
Start date
End date [1]
On-treatment period safety: Liver enzyme 
and bilirubin elevation between periods 
(i.e.: the elevation of bilirubin appears 
within 30 days of the elevation of AST 
and/or ALT, but in different period)
Date of first trial drug 
intake
Last open label drug intake plus 28 days or end of treatment, whichever occurs first
Off-treatment periods not excluded. However, for safety listings, anything happening during a treatment 
interruption will be flagged as occurring during the off-treatment period (even if between [last trial drug intake; last 
trial open label drug intake + 28 days])


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Table 6.1: 1 (continued)
Summary of analysed periods according to the type of endpoint
Studied period
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2
IMPORTANT PROTOCOL VIOLATIONS
The following table defines the different categories of important protocol violations. The final 
column describes which protocol violations will be used to exclude patients from which 
analysis set(s).
Table 6.2: 1
Important protocol violations (IPVs)
Category /
Code
Description
Requirements / Classification
Excluded 
from
A
Entrance criteria not met
A1.1
Age < 40 years at Visit 1
Inclusion criterion 2 not met as specified in 
the protocol.
Automatic IPV
None
A1.2
No clinical diagnosis of IPF within 
the last 3 years from Visit 0, based 
upon the ATS/ERS/JRS/ALAT 
2011 guideline
Inclusion criterion 3 not met as specified in 
the protocol.
Automatic IPV
None
A1.3
No chest high resolution computed 
tomography (HRCT) scan 
performed within 18 months of 
Visit 0
Inclusion criterion 4 not met as specified in 
the protocol.
Automatic IPV
None
A1.4
Combination of HRCT pattern and 
surgical lung biopsy pattern (the 
latter if available) as assessed by 
central review is not consistent 
with the diagnosis of IPF
Inclusion criterion 5 not met as specified in 
the protocol.
Automatic IPV
None
A1.5
FVC < 80% of predicted normal at 
visit 1
Inclusion criterion 6 not met as specified in 
the protocol but it was agreed during MQRM 
to only flag patients with FVC ≤0.79
Automatic IPV
None
A2.1
ALT, AST, Total bilirubin > 1.5 
fold upper limit of normal (ULN) 
at Visit 1
Exclusion criteria 1 or 2 met as specified in 
the protocol
Automatic IPV
None
A2.2
Underlying chronic liver disease 
(Child Pugh A, B or C hepatic
impairment
Exclusion criterion 3 met as specified in the 
protocol
Automatic IPV
None
A2.3
Relevant airways obstruction [i.e. 
pre-bronchodilator FEV1/FVC < 
0.70 (i.e. 70%) at Visit 1]
Exclusion criterion 4 met as specified in the 
protocol but it was agreed during MQRM to 
only flag patients with FEV1/FVC ≤0.65
Automatic IPV
None
A2.4
History of myocardial infarction 
within 6 months of visit 1 or 
unstable angina within 1 month of 
Visit 1
Exclusion criterion 5 met as specified in the 
protocol (for more details refer to the 
protocol)
Automatic IPV
None
A2.5
Bleeding Risk
Exclusion criterion 6 met as specified in the 
protocol
Automatic IPV
None
A2.6
Planned major surgery during the 
trial participation, including lung
transplantation, major abdominal 
or major intestinal surgery
Exclusion criterion 7 met as specified in the 
protocol
Automatic IPV
None
A2.7
History of thrombotic event 
(including stroke and transient 
ischemic attack) within 12 months 
of Visit 1
Exclusion criterion 8 met as specified in the 
protocol
Automatic IPV
None


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Table 6.2: 1 (continued)
Important protocol violations (IPVs)
Category /
Code
Description
Requirements / Classification
Excluded 
from
A2.8
Creatinine clearance < 30 mL/min 
calculated by Cockcroft–Gault 
formula at Visit 1
Exclusion criterion 9 met as specified in the 
protocol
Automatic IPV
None
A2.9
Treatment with Nintedanib, 
pirfenidone, azathioprine, 
cyclophosphamide, cyclosporine, 
any other investigational drug, n-
acetylcysteine,
prednisone/prednisolone >15 mg 
daily or >30 mg every 2 days OR 
use of other systemic 
corticosteroids as well as any 
investigational drugs within 4
weeks of Visit 2
Exclusion criterion 10 met as specified in the
protocol
Automatic IPV
None
A2.10
Known hypersensitivity to 
nintedanib, peanut, soya or to any 
other components of the study 
medication
Exclusion criterion 11 met as specified in the 
protocol
Automatic IPV
None
A2.11
Prior discontinuation of nintedanib 
treatment due to intolerability/ 
adverse events considered drug 
related
Exclusion criterion 12 met as specified in the 
protocol
Automatic IPV
None
A2.12
A disease or condition which in the 
opinion of the investigator may 
interfere with testing procedures or 
put the patient at risk when 
participating in this trial
Exclusion criterion 13 met as specified in the 
protocol
Automatic IPV
None
A2.13
Alcohol or drug abuse which in the 
opinion of the treating physician 
would interfere with the treatment 
and would affect patient’s ability to 
participate in this trial
Exclusion criterion 14 met as specified in the 
protocol
Automatic IPV
None
A2.14
Inability to understand and follow 
any study procedures such as but
not limited to home spirometry, 
including completion of self-
administered questionnaires 
without help
Exclusion criterion 15 met as specified in the 
protocol
Automatic IPV
None
A2.15
Women who are pregnant, nursing, 
or who plan to become pregnant 
while in the trial, or not willing or 
able to use highly effective 
methods of birth control
Exclusion criteria 16 and/or 17 met as 
specified in the protocol
Automatic IPV
None
A2.16
Acute IPF exacerbation or any 
respiratory tract infection in the
four weeks prior to Visit 1 or 
during the screening period.
Exclusion criterion 18 met as specified in the 
protocol
Automatic IPV
None
A2.17
Participation in another trial with 
investigational drug/s within one 
month prior to Visit 1 or previous
enrollment in this trial
Exclusion criterion 19 met as specified in the 
protocol
Automatic IPV
None


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Table 6.2: 1 (continued)
Important protocol violations (IPVs)
Category /
Code
Description
Requirements / Classification
Excluded 
from
B
Informed consent
B1
Informed consent not available/not 
done
Inclusion criterion 1 not met as specified in 
the protocol.
Automatic IPV
All
B2
Informed consent too late
Inclusion criterion 1 not met as specified in 
the protocol.
Medical review during MQRM, BRPM or 
DBLM
None
B3
Informed consent not given for
pharmacogenetics samples 
(unspecified part) but blood sample 
drawn for testing
According to pharmacogenetics database and 
CRF
Automatic IPV
None
B4
Informed consent for
pharmacogenetics samples 
(unspecified part) too late but 
blood sample drawn for testing
Medical review during MQRM, BRPM or 
DBLM
None
B5
Informed consent not given for
serum banking samples 
(unspecified part) but blood sample 
drawn for testing
According to serum banking database and 
CRF
Automatic IPV
None
B6
Informed consent for
serum banking samples 
(unspecified part) too late but 
blood sample drawn for testing
Medical review during MQRM, BRPM or 
DBLM
None
C
Trial medication and 
randomisation
C1
Incorrect trial medication taken
Wrong medication number use at any time 
(after Visit 2) during the trial. IPV only if 
medication error leads to an actual treatment 
switch (will be determined after unblinding). 
Medical review of MQRM listings
None
C2
Randomisation not followed
Wrong medication number given leading to 
the patient taking treatment different from the 
one randomized by IXRS at time of
randomisation (Visit 2). IPV only if 
medication error leads to an actual treatment 
switch. (will be determined after unblinding).
Medical review of MQRM listings
None
C3
Overall Compliance not between 
80% and 120% inclusive
Medical review during MQRM
None
C4
Medication code broken 
inappropriately
Except for emergency situation.
Medical review of MQRM listings
None
C5
Drug not permanently discontinued 
despite criteria of Section 3.3.4.1 
of CTP met
Medical review of MQRM listings
None
D
Concomitant medication
D1
Patient received prohibited 
concomitant therapies during 
treatment phase
Medical review of MQRM
listings
None


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Table 6.2: 1 (continued)
Important protocol violations (IPVs)
Category /
Code
Description
Requirements / Classification
Excluded 
from
E
Missing data
E1
No post-baseline blood CRPM
assessments up to Week 12
Automatic IPV
None
 
 
 
 
F
Incorrect timing
 
 
1Time deviations will only be flagged as important PV, when leading to exclusion of the entire subject from an analysis set
Source: BI reference document ‘Protocol Violation Handling Definitions’ (001-MCS-50-413_RD-01) (2)
For analyses defined in this section, the blinded and open-label period will be analyzed 
separately and additionally, a pooled analysis across both periods will be performed but 
including displays by randomized treatment.
6.3
PATIENT SETS ANALYSED
Patient sets will be used as defined in the CTP, Section 7.3.
The following table shows which patient set will be used for which class of endpoints.
Table 6.3: 1
Patient sets analysed
Patient set
Class of endpoint
RS
TS
Primary and key secondary 
endpoints 
X
Secondary endpoints 
X
Further endpoints
X
Safety endpoints 
X
Demographic/baseline 
characteristics
X
Disposition
X
Note that the number of patients with available data for an endpoint may differ. For details, 
see Section 6.6.


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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, the efficacy analyses as well as safety analyses will be evaluated by observed case
analysis, i.e. using only available data without imputation.
In efficacy analyses of continuous endpoints, missing data will not be imputed. Depending on 
the respective endpoint, random coefficient regression or Mixed Model Repeated 
Measurements (MMRM) will be applied, which both analyse all available information from 
the observed data, using the within-patient correlation structure to provide information about 
the unobserved data. This method does not employ explicit imputation to handle missing data.
 
 
 
 
 
 


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In the analyses of the binary endpoints, missing data will be imputed using the worst case.
 
 
 
According to (001-MCS-36-472_RD-01) (6), missing biomarker data (NOS - no sample 
available, NOR - no valid result, NOA - not analysed) will not be imputed. 
Handling of data below or above the limit of quantification:
- BLQ data will be replaced by ½ LLOQ
- ALQ data will be replaced by ULOQ, if ULOQs are available. Otherwise, ALQ data will be 
excluded from the analysis.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For an overview on planned visits refer to Flow Chart in the CTP.
As a general rule, last assessment before first trial drug intake (included) will be used as 
baseline. If the baseline value is missing and the screening value is available, then the baseline 
value will be defined as the screening value taken closest to baseline date. 
A windowing will be performed as described in Tables 6.7: 1 and 6.7: 2, in order to assign 
data to the relevant study visit based on the actual day of the assessment. Data will be 
analyzed 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.


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If after windowing of visits at baseline, two values fall within the same baseline interval, then 
the last value will be taken into account. If after windowing of post-baseline visits, two visits 
fall in the same interval, then the measurement 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. The same rules will be applied for laboratory measurements.
If after windowing of post-baseline visits, two values fall within the same interval “Follow-
up”, then only the first value will be taken into account.


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7.
PLANNED ANALYSIS
For End of Text tables, the set of summary statistics is: N / Mean / SD / Min / Median / Max
(7). 
Tabulations of frequencies for categorical data will include all possible categories 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.
 
 
 
 
 
 
 
 
 
 
 


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7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis
Please refer to Section 7.3.1 of the CTP.
The primary analysis will be done on the TS.
All visits from baseline to week 12 will be included in the primary analysis, after time-
windowing. Measurements after week 12 (after time windowing) are not taken into 
consideration for this endpoint.
Refer to Section 9.1 for SAS code specifications.
Efficacy evaluations done after lung transplant will not be used for the efficacy analyses.


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
The key secondary endpoint is defined as the proportion of patients with disease progression 
as defined by absolute FVC (% predicted) decline ≥10% or death until week 52.
The following analyses are planned:

Firstly, in order to assess the association of change in extracellular matrix (ECM) 
biomarker CRPM over 12 weeks with disease progression as defined by FVC decline 
≥10% or death over 52 weeks, a logistic regression analysis including baseline blood 


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CRPM and the rate of change (slope) in blood CRPM over the first 12 weeks as 
covariates will be applied for the placebo treated patients only.
By doing this, the potential of CRPM as a prognostic biomarker is evaluated.

Secondly, in order to assess how Nintedanib treatment during the first 12 weeks 
affects the association between change in extracellular matrix (ECM) biomarker 
CRPM over 12 weeks and disease progression, a logistic regression analysis including 
baseline blood CRPM, rate of change (slope) in blood CRPM over the first 12 weeks, 
treatment and treatment CRPM slope interaction as covariates will be applied. The 
interaction term will be of primary interest within this analysis.

Thirdly, in order to assess whether the overall treatment regimen affects disease 
progression as defined by FVC decline ≥10% or death over 52 weeks, a logistic 
regression analysis including baseline blood CRPM and randomized treatment as 
covariates will be applied. The treatment effect will be of primary interest within 
this analysis.

Fourthly, in order to assess whether rate of change (slope) in blood CRPM over the 
first 12 weeks to some extent explains the effect of treatment regimen on disease 
progression as defined by FVC decline ≥10% or death over 52 weeks, a logistic 
regression analysis including baseline blood CRPM, rate of change (slope) in blood 
CRPM over the first 12 weeks and randomized treatment as covariates will be applied.
The treatment effect will be of primary interest within this analysis.
Patients who died or progressed in the blinded phase are not at risk in the open label period, 
but will be considered in the main analysis (including their progression and/or death).
 
 
 
 
 
 
 


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The four main analyses of the key secondary endpoint outlined at the beginning of this section 
will be repeated by replacing CRPM by C1M and C3M, respectively.
7.5.2
Other Secondary endpoints
The following secondary endpoints are defined:

Rate of change (slope) in blood C1M from baseline to week 12

Rate of change (slope) in blood C3M from baseline to week 12
Please refer to Section 7.3.2 of the CTP for further details of the analysis.
This endpoint will be analyzed in a similar manner as the primary endpoint. Reasonably, 
baseline CRPM as covariate will be replaced by baseline C1M and C3M in these analyses.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse events
Unless otherwise specified, analyses of adverse events will be descriptive in nature and will 
be based on BI standards (10). No hypothesis testing is planned. All analyses of AEs will be 
based on the number of patients with AEs and NOT on the number of AEs.
Furthermore, for analysis of AE attributes such as duration, severity, etc. multiple AE 
occurrence data on the CRF, will be collapsed into AE episodes provided that all of the 
following applies:
•
The same MedDRA lowest level term was reported for the occurrences
•
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)
•
Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence


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For further details on summarization of AE data, please refer to the guideline “Analysis and 
Presentation of Adverse Event Data from Clinical Trials” (10).
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 till 28 days 
after last drug intake (end of the residual effect period) will be assigned to the randomised 
treatment. Note that analysis of adverse events will be repeated considering only data until 7 
days after last drug intake as treatment emergent (see also Section 6.1). Adverse events that 
start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’.
All adverse events occurring before first drug intake and do not deteriorate under treatment 
will be assigned to ‘screening’ or ‘post-randomisation’ and all adverse events occurring after 
last drug intake will be assigned to ‘residual effect period', ‘post-study’ or ‘follow-up’ (for 
listings only). Also, all AEs occurring between the start of an interruption and the end of 
interruption will be assigned to ‘off-treatment’ period in the listings. For details on the 
treatment definition, see Section 6.1.
According to ICH E3 (11), AEs classified as ‘other significant’ 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 Blinded Report Planning 
Meeting. 
An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarized 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 (11), 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 dose reduction, for patients with adverse events leading to treatment 
discontinuation, for patients with serious adverse events , for patients with related adverse 
events and for patient with significant (protocol-specified) AEs (as ticked in the AE page of 
the CRF).
The system organ classes will be sorted according to the standard sort order specified by 
EMA, preferred terms will be sorted by frequency (within system organ class). 
Specific tables will be created in order to describe diarrhoea events: 
- Display of the diarrhoea specific page of the CRF 
- Summary of diarrhoea events including time to onset, number and duration of episodes


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- Summary of diarrhoea adverse events including seriousness, clinical consequences (dose 
reduction, drug discontinuation or drug interruption) and outcome 
Also, a Kaplan-Meier plot of time to first diarrhoea event will be drawn by treatment. 
Similar summary tables including seriousness, clinical consequences and outcome will also be 
presented to describe the bleeding adverse events. Depending on the number of patients 
having such adverse events, summary tables including time to onset, number of episodes and 
duration together with Kaplan-Meier plot of time to first event may also be produced.
The following adverse event groupings have been defined outside the trial protocol:
Table 7.8.1: 1 Adverse events by system using aggregated terms
System
Safety Topic
Definition (selection criteria)
Gastrointestinal 
Diarrhoea
PT Diarrhoea
Nausea
PT Nausea
Abdominal pain
HLT ‘Gastrointestinal and abdominal pains (excl 
oral and throat)
Vomiting
PT Vomiting
Pancreatitis
SMQ Acute pancreatitis (narrow)
Gastrointestinal 
perforation
SMQ Gastrointestinal perforation (narrow)
Hepatobiliary 
Drug-induced liver 
injury (DILI)
PT Drug-induced liver injury
Hepatic disorders 
(broad)
Drug related hepatic 
disorders
Liver related 
investigations
Cholestasis and 
jaundice of hepatic 
origin
Hepatitis non-
infectious
Table to show cumulative row for all 4 SMQs below, 
followed by a cumulative row for each subSMQ, 
followed by all PTs driving that subSMQ
SMQ Drug related hepatic disorders –
comprehensive search (narrow) OR
SMQ Liver related investigations, signs and 
symptoms (broad) OR
SMQ Cholestasis and jaundice of hepatic origin 
(narrow) OR
SMQ Hepatitis, non-infectious (narrow)
Hepatic failure
SMQ Hepatic failure, fibrosis and cirrhosis and other 
liver damage-related conditions (narrow) 
Cardiovascular
Arterial 
thromboembolism
SMQ Embolic and thrombotic events, arterial 
(narrow) 
Myocardial infarction
SMQ Myocardial infarction (narrow)
Stroke
PV Endpoint, see Section 9.2 for included Preferred 
Terms


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Table 7.8.1: 1 (continued)
Adverse events by system using aggregated terms
System
Safety Topic
Definition (selection criteria)
MACE
Fatal events in SOC Cardiac
Fatal events in SOC Vascular
Any fatal or nonfatal events in SMQ Myocardial 
infarction (narrow)
PTs Cardiac death, Sudden death, Sudden Cardiac death
Any fatal or nonfatal Stroke events as defined in 
respective PV Endpoint
Cardiac failure
SMQ Cardiac failure (narrow)
QT prolongation
SMQ Torsade de pointes/QT prolongation (narrow)
Venous 
thromboembolism
SMQ Embolic and thrombotic events, venous (narrow)
Pulmonary embolism
PT Pulmonary embolism
DVT
PT Deep vein thrombosis 
Hypertension
SMQ Hypertension (narrow)
Metabolic
Decreased appetite
PT Decreased appetite
Weight decreased
PTs: Weight decreased, Abnormal loss of weight
Blood
Thrombocytopenia
PTs: Thrombocytopenia, Platelet count decreased, 
Immune thrombocytopenic purpura
Haematopoietic 
thrombocytopenia
SMQ Haematopoietic thrombocytopenia (broad)
Neutropenia
SMQ Agranulocytosis (narrow) OR
SMQ Haematopoietic leukopenia (narrow)
Bleeding
GI bleeding – oral
GI bleeding – upper
GI bleeding – lower
GI bleeding –
nonspecific
Skin bleeding
Respiratory bleeding
CNS bleeding
Urogenital bleeding
Other bleeding
SMQ Haemorrhage terms (excl laboratory terms) (narrow) 
displayed in total and then according to categories:

Gastrointestinal – oral

Gastrointestinal – upper

Gastrointestinal – lower

Gastrointestinal – nonspecific

Skin

Respiratory

CNS

Urogenital

Other
See Section 9.3 for PT lists of the bleeding subcategories.
Psychiatric 
Depression
SMQ Depression (excl suicide and self-injury) (narrow)
Suicide
SMQ Suicide/self-injury (narrow)
Renal
Renal failure
SMQ Acute renal failure (narrow)
Proteinuria
SMQ Proteinuria (narrow)
Glomerulonephritis
SMQ Chronic kidney disease (broad)
Cutaneous
Severe skin reactions
SMQ Severe cutaneous adverse reactions (narrow)
Pruritus
PT Pruritus
Rash
BIcMQ subsearch “Skin rash” (narrow)


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Table 7.8.1: 1 (continued)
Adverse events by system using aggregated terms
System
Safety Topic
Definition (selection criteria)
Liver laboratories
Hepatic enzyme 
increased
Following PTs:
Alanine aminotransferase abnormal
Alanine aminotransferase increased
Aspartate aminotransferase abnormal
Aspartate aminotransferase increased
Hepatic enzyme abnormal
Hepatic enzyme increased
Hepatic function abnormal
Hypertransaminasaemia
Liver function test abnormal
Transaminases abnormal
Transaminases increased
Blood alkaline phosphatase abnormal
Blood alkaline phosphatase increased
Gamma-glutamyltransferase abnormal
Gamma-glutamyltransferase increased
Hyperbilirubinaemia
Following PTs:
Blood bilirubin abnormal
Blood bilirubin increased
Blood bilirubin unconjugated increased
Hyperbilirubinaemia
Icterus index increased
Jaundice
Jaundice hepatocellular
Bilirubin conjugated abnormal
Bilirubin conjugated increased
Alanine 
aminotransferase 
increased
Following PTs:
Alanine aminotransferase increased
Alanine aminotransferase abnormal
Aspartate 
aminotransferase 
increased
Following PTs:
Aspartate aminotransferase increased
Aspartate aminotransferase abnormal
Gamma-glutamyl-
transferase increased 
Following PTs:
Gamma-glutamyltransferase increased
Gamma-glutamyltransferase abnormal
Blood alkaline 
phosphatase increased
Following PTs:
Blood alkaline phosphatase increased
Blood alkaline phosphatase abnormal
These definitions are based on MedDRA version 21.0. 
For analyses defined above, the blinded and open-label period will be analyzed separately. 
Additionally, a pooled analysis across both periods will be performed but including displays 
by randomized treatment.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(see DM&SM: Display and Analysis of Laboratory Data) (12).
Please refer to Section 7.3.4 of the CTP. Please refer to Section 5.4.4 for a definition of liver 
enzyme elevations.
Specific tables will be presented to describe liver enzyme elevations as defined in Section
5.4.4 by treatment group:

Summary table of liver enzyme elevation including time to first onset and number of
patients with liver enzyme elevation.

Kaplan-Meier plot of time to first liver enzyme elevation (if sufficient number of
events). No statistical test will be performed.

Summary table of individual maximum liver enzyme and bilirubin elevations

Plot of time course profile of liver enzyme for patients having liver enzyme and
bilirubin elevation
7.8.3
Vital signs
Only descriptive statistics (by visit and change from baseline) are planned for this section of 
the report.
7.8.4
ECG
Not applicable.
7.8.5
Others
Not applicable.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
001-MCS-50-413: "Handling of Protocol Violations in Clinical Trials and Projects",
current version; group: Study Conduct; IDEA for CON.
3
001-MCG-741: "Clinical subgroup analyses for local and regional Populations in Asia -
Clinical Bridging Study Waiver (BSW) and Descriptive Subgroup Analysis (SGA) 
Reports” , current version; IDEA for CON.
4
Jones PW, Forde Y. St George’s Respiratory Questionnaire Manual.                         
Version 2.3, 20.06.2009 [R12-2870].
5
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
6
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
7
001-MCG-159_RD-03: “Standard table shells for inferential and descriptive End-of-
Text tables (EoT-Catalogue)”, current version; IDEA for CON.
8
Rubin, DB. Multiple Imputation for Nonresponse in Surveys. New York: Wiley, 1987
[R12-2378].
9
Fairclough DL (2002). “Models for Longitudinal Studies II” (chapter 4), in Design and 
analysis of quality of life studies in clinical trial. CRC Press, p. 83-105 [R15-6302].
10
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
11
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports,
current version.
12
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
23-SEP-16
None
This is the initial TSAP with necessary 
information for trial conduct
Final
19-JUL-18
(ext) / 
All
This is the final TSAP