Clinical trial NCT01619085
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim
Start date: 2012-06-06; Completion date: 2021-02-01
Enrollment: 752 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The aim of this extension trial is to assess the long-term safety of BIBF 1120 treatment in patients with Idiopathic Pulmonary Fibrosis who have completed one year treatment and the follow up period in the double-blind phase III placebo controlled parent trials (1199.32 and 1199.34), who wish to continue treatment with BIBF 1120.

Detailed description:

Arms: arm 1: patient to receive a capsule containing Nintedanib twice a day
Interventions: intervention 1: Nintedanib
Intervention descriptions: intervention 1: Nintedanib twice a day

Protocol documents:
Prot_002.pdf: 
Clinical Trial Protocol
Doc. No.: c01765254-09
EudraCT No.:
BI Trial No.:
2011-002766-21
1199.33
BI Investigational
Product:
BIBF 1120 (nintedanib)
Title:
An open-label extension trial of the long term safety of oral BIBF 1120 
in patients with Idiopathic Pulmonary Fibrosis (IPF)
Clinical Phase:
III
Trial Clinical 
Monitor:
Phone :
 
Fax : 
Co-ordinating 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on Global Amendment 3))
Version and Date:
Version: 4.0
Date: 28 Mar 2017
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BIBF 1120 (nintedanib)
Protocol date:
Trial number:
Revision date:
28 Mar 2017
27 Jan 2012
1199.33
Title of trial:
An open-label extension trial of the long term safety of oral BIBF 1120 in patients 
with Idiopathic Pulmonary Fibrosis (IPF)
Co-ordinating 
Investigator :
Trial sites:
Multi-centre, multi-national
Clinical phase:
III
Objective:
The primary objective of this study is to assess the long-term safety of BIBF 1120
treatment in patients with Idiopathic Pulmonary Fibrosis who have completed one 
year treatment and the follow-up period in the phase III trials 1199.32 and 1199.34.
Methodology:
Open-label, multi-centre, extension trial
No. of patients: 
total entered:
Approximately 750 patients
each treatment:
Approximately 600 patients treated with BIBF 1120 150 mg bid
Approximately 150 patients treated with BIBF 1120 100 mg bid
Diagnosis :
Idiopathic Pulmonary Fibrosis (IPF)
Main criteria
for inclusion:
Completion of one year treatment and follow-up period in 1199.32 or 1199.34 trial.
Test product:
Nintedanib
doses:
300 mg (150 mg bid)
200 mg (100 mg bid)
mode of admin.:
p.o.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BIBF 1120 (nintedanib)
Protocol date:
Trial number:
Revision date:
28 Mar 2017
27 Jan 2012
1199.33
Comparator products:
Not applicable
dose:
mode of admin.:
Duration of treatment: Treatment duration for each patient will be variable. Treatment will be stopped if a 
reason for withdrawal is met. The trial is estimated to last a total of approximately 6 ½ 
years.
Criteria for efficacy:
Not applicable
Criteria for safety:
Adverse events, physical examination including weight, vital signs, laboratory 
evaluations.
Statistical methods:
Descriptive statistics of adverse events and other safety parameters.


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FLOW CHART
Visit
1 1, 2
2 1, 2
3
4
5
6
6a
7
7a
8
8a
9
Xa9
X9
EOT10
FU11
Week
-6 to 0
0
2
4
6
12
18
24
30
36
42
48
56 + 
every 
16w
64 + 
every 
16w
Day
Time window (days)
-42 to 1
1
15
±3
29
±3
43
±3
85
±3
127
±7
169
±7
211
±7
253
±7
295
±7
337
±7
±14
±14
+7
Informed consent
X3
Demographics
X
Baseline Conditions
X
Physical examination (incl. weight)
X4
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X4
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Laboratory tests
X4
X
X
X
X
X
X8
X
X8
X
X8
X
X8
X
X
Pregnancy test 5
X
X
X
X
X
X
X
X
X
X
X
PFT (FVC)
X
X
X
X
X
X
X
X
X
X
X
Review of in-/exclusion criteria
X
IVRS/IWRS
X
X
X
X
X
X
X
X
Dispense trial drug 6
X
X
X
X
X
X
X
First drug intake
X
Collect trial drug
X
X
X
X
X
X
X
Drug Accountability check
X
X
X
X
X
X
X
Adverse events, Concomitant 
Therapy
X7
X7
X
X
X
X
X
X
X
X
X
X
Exacerbations
X
X
X
X
X
X
X
X
X
X
X
X
Trial medication termination
X
Conclusion of patient participation
X


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FLOW CHART (Cont.)
1.
Visit 1 and Visit 2 may occur on the same date if the period between Visit 9 (End of Treatment) of the previous trial (1199.32 or 1199.34) and the first visit for 
1199.33 is ≤ 6 weeks. This rule does not apply to patients requiring washout of bronchodilators, as they will need to sign informed consent at Visit 1 in order to be 
asked to perform washout for PFT at Visit 2.
2.
Visit 1 should occur at least one day after the Follow-up Visit of the parent trial and Visit 2 within 12 weeks of Visit 9 (End of Treatment) of the parent trial (1199.32 
or 1199.34).
3.
The patient is required to sign informed consent prior to any study related activities.
4.
For patients performing Visit 1 and Visit 2 on the same day, eligibility assessment will be based on laboratory data from Visit 9 of the parent trial. Laboratory tests, 
physical examination and vital signs will be performed only once on that day and will be recorded under Visit 2 in the eCRF.
5.
Urine dipstick pregnancy tests will be provided by central lab and should be performed in all women of childbearing potential. If urine test is not acceptable to local 
authorities, a blood test can be done at a local laboratory.
6.
An additional visit must be performed in case of dose reduction or increase. Please refer to Section 6.2.4 for visit procedures.
7.
Only medical conditions that are occurring concomitantly at the time of screening will be recorded as baseline conditions on the 1199.33 Remote Data Capture (RDC) 
system. This also applies to ongoing AEs from the parent trial at the time of screening. See ISF for further instructions.
8.
Laboratory test only for liver function monitoring: AST, ALT and bilirubin. Blood may be collected at the investigational site, primary physician (GP or 
Pulmonologist) or external laboratory with specific study kits and sent to the central laboratory for analysis. Information, agreement and training of the primary 
physician or local laboratory will be ensured on an individual site basis.
9.
Same scheme should be repeated as often as needed: one complete visit every 16 weeks and one intermediate visit for liver function monitoring.
10. End of Treatment Visit to be performed if a reason for withdrawal is met. Please refer to Section 3.3.4.
11. A Follow-up (FU) Visit should be planned for 28 days after last drug intake (+7 days window). 


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FLOW CHART FOR PATIENTS WHO CONTINUE TREATMENT 
AFTER THE DATABASE LOCK FOR THE FINAL ANALYSIS1
1.
Patients who require continuation of treatment within this trial after the database lock for the final analyses will 
have reduced number of trial visits and reduced trial related procedures as described in this flow chart. The 
objective of these visits will be to dispense new study drug and collect information regarding adverse events and 
concomitant medication.
2.
Patients continuing treatment after the final analysis (patients who don’t have access to nintedanib outside the 
clinical trial) are required to sign an informed consent explaining the objective and study related procedures of the 
trial after the final analysis. This should happen prior to any study related activities of this new trial period.
3.
Same scheme should be repeated as often as needed: one visit every 16 weeks.
4.
End of Treatment Visit to be performed if a reason for withdrawal is met. Please refer to Section 3.3.4.
5.
A Follow-up (FU) Visit should be planned for 28 days after last drug intake (+7 days window). 
Visit
X 3
EOT 4
FU 5
Week
every 
16w
EOT +28 
days
Day
Time window (days)
±14
+7
Informed consent
X2
IVRS/IWRS
X
X
Dispense trial drug 
X
Collect used and unused trial drug
X
X
Adverse events
X
X
X
Concomitant therapy
X
X
X
Trial medication termination
X
Conclusion of patient participation
X


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
FLOW CHART FOR PATIENTS WHO CONTINUE 
TREATMENT AFTER THE DATABASE LOCK FOR THE 
FINAL ANALYSIS1............................................................................................6
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................13
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 17
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................17
2.2
TRIAL OBJECTIVES.......................................................................................17
2.3
BENEFIT - RISK ASSESSMENT ...................................................................17
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 19
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................19
3.1.1
Administrative structure of the trial...................................................19
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................20
3.3
SELECTION OF TRIAL POPULATION ......................................................21
3.3.1
Main diagnosis for study entry............................................................21
3.3.2
Inclusion criteria...................................................................................21
3.3.3
Exclusion criteria ..................................................................................21
3.3.4
Removal of patients from therapy or assessments.............................23
3.3.4.1
Removal of individual patients................................................23
3.3.4.2
Discontinuation of the trial by the sponsor..............................24
4.
TREATMENTS........................................................................................ 25
4.1
TREATMENTS TO BE ADMINISTERED....................................................25
4.1.1
Identity of BI investigational product and comparator product......25
4.1.2
Method of assigning patients to treatment groups ............................25
4.1.3
Selection of doses in the trial................................................................26


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4.1.4
Drug assignment and administration of doses for each patient .......26
4.1.5
Blinding and procedures for unblinding ............................................27
4.1.5.1
Blinding....................................................................................27
4.1.5.2
Procedures for emergency unblinding .....................................27
4.1.6
Packaging, labelling and re-supply .....................................................27
4.1.7
Storage conditions.................................................................................27
4.1.8
Drug accountability ..............................................................................28
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................29
4.2.1
Rescue medication, emergency procedures, and additional 
treatment................................................................................................29
4.2.1.1
Management of diarrhoea ........................................................29
4.2.1.2
Management of liver enzyme elevation...................................30
4.2.1.3
Management of acute exacerbations........................................31
4.2.1.4
Management of other adverse events.......................................31
4.2.2
Restrictions............................................................................................32
4.2.2.1
Restrictions regarding concomitant treatment .........................32
4.2.2.2
Restrictions on diet and life style.............................................32
4.3
TREATMENT COMPLIANCE.......................................................................33
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 34
5.1
TRIAL ENDPOINTS.........................................................................................34
5.1.1
Primary Endpoint.................................................................................34
5.1.2
Secondary Endpoints............................................................................34
................................................................................34
5.2
ASSESSMENT OF EFFICACY.......................................................................34
5.3
ASSESSMENT OF SAFETY............................................................................35
5.3.1
Physical examination ............................................................................35
5.3.2
Vital signs...............................................................................................36
5.3.3
Safety laboratory parameters..............................................................36
5.3.4
Electrocardiogram................................................................................37
5.3.5
Other Safety parameters......................................................................37
5.3.6
Assessment of adverse events...............................................................37
5.3.6.1
Definitions of adverse events...................................................37
5.3.7 Adverse event and serious adverse event reporting...........................39
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................40
5.5
ASSESSMENT OF EXPLORATORY BIOMARKER(S).............................40
5.6
OTHER ASSESSMENTS .................................................................................40
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................40


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6.
INVESTIGATIONAL PLAN.................................................................. 41
6.1
VISIT SCHEDULE............................................................................................41
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................41
6.2.1
Screening................................................................................................41
6.2.2
Treatment period ..................................................................................42
6.2.3
End of trial and follow-up period........................................................42
6.2.4
Dose modification visit..........................................................................42
6.2.5. Period after the database lock for the final analysis..........................43
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 44
7.1
STATISTICAL DESIGN - MODEL................................................................44
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................44
7.3
PLANNED ANALYSES....................................................................................44
7.3.1
Primary endpoint analyses...................................................................44
7.3.2
Secondary endpoint analyses ...............................................................45
...................................................................45
7.3.4
Safety analyses.......................................................................................45
7.3.5
Pharmacokinetic analyses ....................................................................46
7.4.
INTERIM ANALYSES .....................................................................................46
7.5
HANDLING OF MISSING DATA ..................................................................46
7.6
RANDOMISATION ..........................................................................................47
7.7
DETERMINATION OF SAMPLE SIZE ........................................................47
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 48
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................48
8.2
DATA QUALITY ASSURANCE .....................................................................49
8.3
RECORDS..........................................................................................................50
8.3.1
Source documents .................................................................................51
8.3.2
Direct access to source data and documents.......................................51
8.3.3
Storage of records .................................................................................51
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................52
8.4.1
Listedness...............................................................................................52
8.4.2
Expedited reporting to health authorities and IECs/IRBs................52
8.5
STATEMENT OF CONFIDENTIALITY.......................................................52
8.6
COMPLETION OF TRIAL..............................................................................52


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8.7
PROTOCOL VIOLATIONS ............................................................................52
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT 
OF TRIAL RELATED INJURY......................................................................53
9.
REFERENCES......................................................................................... 54
9.1
PUBLISHED REFERENCES...........................................................................54
9.2
UNPUBLISHED REFERENCES.....................................................................54
10. APPENDICES .......................................................................................... 55
10.1
GUIDANCE FOR HEPATIC ENZYME INCREASES.................................55
10.1.1 Clinical Evaluation of Liver Injury.....................................................56
10.1.1.1 Introduction..............................................................................56
10.1.1.2 Procedures................................................................................56
11. DESCRIPTION OF GLOBAL AMENDMENTS................................. 58


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ABBREVIATIONS
AE
ALT
AST
ATS
Adverse Event
Alanine aminotransferase
Aspartate aminotransferase
American Thoracic Society
AUC
BI
bid
CA
CK
CK-MB
Area under the curve
Boehringer Ingelheim
bis in die (twice daily)
Competent Authority
Creatinine kinase
Creatine kinase - MB fraction
Cmax
Maximum measured concentration of the analyte in plasma
CML
CNS
Clinical Monitor Local
Central  Nervous System
CRA
CRF
CRO
Clinical Research Associate
Case Report Form
Clinical Research Organisation
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
DILI
DLCO
Clinical Trial Report
Drug Induced Liver Injury
Carbon monoxide Diffusion Capacity
ECG
eCRF
Electrocardiogram
Electronic Case Report Form
e.g.
Exempli gratia (for example)
EOT
End of Treatment
ERS
EudraCT
FDA
FGFR
FU
FVC
European Respiratory Society
European Clinical Trials Database
Food and Drug Administration
Fibroblast growth factor/receptor
Follow-up
Forced Vital Capacity
GCP
gMean
GP
HCV
HEV
HRCT
Good Clinical Practice
Generalized Mean
General Practitioner
Hepatitis C Virus
Hepatitis E Virus
High Resolution Computerized Tomography
ICH
International Conference on Harmonisation
IEC
INR
IPF
IPV
Independent Ethics Committee
International Normalised Ratio
Idiopathic Pulmonary Fibrosis
Important Protocol Violation
IRB
Institutional Review Board
ISF
Investigator Site File


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IU
IUD
IUS
i.v.
IVRS
IWRS
International Unit
Intrauterine device
Intrauterine system
Intravenous
Interactive Voice Response System 
Interactive Web Response System
MedDRA
NAC
OPU
PA
PDGFR
PFT
p.o.
PT
PTT
qd
RDC
RNA
SAE
s.c.
SGRQ
SOP
SUSAR
t1/2
TCM
TDMAP
TS
TSAP
TSH
UGT
ULN
VEGFR
w
WHO
6-MWT
Medical Dictionary for Drug Regulatory Activities
N-acetyl cysteine
Operative Unit
Alkaline phosphatase
Platelet derived growth factor/receptor
Pulmonary Function Test
Per os (oral)
Prothrombin Time
Partial Thromboplastin Time
Quoque die (once a day)
Remote Data Capture
Ribonucleic acid
Serious Adverse Event
Sub cutaneous
Saint George’s Respiratory Questionnaire
Standard Operating Procedure
Suspected Unexpected Serious Adverse Reaction
Terminal half life
Trial Clinical Monitor
Trial Data Management and Analysis Plan
Treated Set
Trial Statistical and Analysis Plan
Thyrotrophin-stimulating hormone
UDP-glucosyltransferase
Upper Limit of Normal
Vascular endothelial growth factor/receptor
Week
World Health Organization
6 Minute Walk Test


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Idiopathic Pulmonary Fibrosis (IPF) is a chronic disease of unknown aetiology that is 
characterized by progressive fibrotic destruction of the lung, resulting in disabling dyspnoea
and poor gas exchange. The average life expectancy in IPF patients is 2-3 years. 
The only drug that has been registered in a number of countries for the treatment of IPF is
pirfenidone. It was launched in Japan in 2008 under the brand name Pirespa® and was 
approved for the treatment of mild-to-moderate IPF in Europe and Canada in 2011 (under the 
brand name Esbriet®). Following the successful completion of a third Phase III trial (PIPF-
016, ASCEND) pirfenidone was recently approved by the US FDA for the treatment of IPF. 
Other pharmacologic options include corticosteroids, azathioprine, cyclophosphamide, and 
N-acetyl cysteine, albeit none of these has been proven efficacious in clinical trials compared 
with placebo, and none is indicated for the treatment of IPF. Thus, despite the availability of 
pirfenidone and the possibility of lung transplantation, the medical need for efficacious and 
safe treatment of IPF remains high.
Nintedanib has been developed for the treatment of IPF and for several cancer types in two 
separate clinical development programmes. 
In IPF the clinical proof of concept for nintedanib was established in the 52-week phase II 
trial 1199.30 (P11-11216). Based on this trial, it was considered that nintedanib may confer 
clinical benefit to patients with IPF with acceptable safety.
Two phase III international, double-blind, placebo-controlled trials of identical study design 
1199.32 and 1199.34 confirmed the efficacy and safety of nintedanib 150 mg bid versus 
placebo in patients with IPF (P14-07514) (refer to Section 1.2). Based on the overall 
evidence, nintedanib was approved by the US FDA for the treatment of IPF in October 2014. 
The current study 1199.33 is a long-term extension study of the Phase III trials and such it is 
conducted to evaluate the long-term safety and tolerability of nintedanib in IPF.  
1.2
DRUG PROFILE
Nintedanib is a small molecule tyrosine kinase inhibitor of the Platelet Derived Growth 
Factor Receptor (PDGFR) α and β, Fibroblast Growth Factor Receptor (FGFR) 1- 3, and 
Vascular Endothelial Growth Factor Receptor (VEGFR). Nintedanib binds competitively to 
the 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. In addition, nintedanib inhibits Flt-3, Lck, Lyn, 
and Src kinases (U07-1248).
Nintedanib is currently in clinical development for several types of cancer. In line with the 
pre-clinical findings, the clinical development programme has provided data suggesting that 


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nintedanib is active against a number of advanced malignancies including lung, ovarian, 
kidney, liver, and colorectal cancer. 
Inhibition of FGFR-1 and PDGFR has been proposed as effective principle for the treatment 
of IPF (P07-00109). Furthermore, VEGFR inhibition may also have favourable effects, 
although the precise role of down-regulation of VEGF-mediated actions in IPF has not yet 
been fully elucidated (R07-0002). Oral administration of nintedanib to rats with bleomycin-
induced lung fibrosis resulted in nearly complete attenuation of fibrosis histologically not 
only when started at day 1 after bleomycin administration, but also when administered only 
from day 10 to 21. In this model, nintedanib thus may be acting directly against the fibrotic 
processes, rather than solely through inhibition of inflammation.
A soft gelatin capsule formulation of nintedanib is used in humans. After oral administration, 
nintedanib was absorbed moderately fast. Maximum plasma concentrations (Cmax) occurred 1 
to 4 hours after administration. Steady state was reached within 9 days of treatment at the 
latest. The gMean terminal half-life (t1/2) was 18 hours after intravenous administration. The 
major route of elimination of total [14C] radioactivity was via the faeces / biliary excretion, 
while the contribution of renal excretion was low (0.7% of an orally administered radioactive 
dose). An absolute bioavailability of slightly below 5% was observed by an intra-individual 
comparison of dose normalized AUC of 100 mg nintedanib administered orally and 6 mg 
nintedanib administered intravenously. The total percentage absorbed was estimated to be at 
least 23% compared to an absolute bioavailability of the parent alone of about 5%, thereby 
confirming the large amount of metabolite formed during intestinal and/or hepatic first pass 
metabolism. 
The by far most frequent metabolites were BIBF 1202 formed by ester cleavage and the 
subsequently glucuronidation formed BIBF 1202-glucuronide. The glucuronidation of 
BIBF 1202 was mainly through UGT1A1 (liver and intestine) and UGT1A7, UGT1A8 and 
UGT1A10 (intestine). Drug-drug interactions based on cytochrome P450 dependent 
pathways are not expected for nintedanib.
In vitro transporter profiling of BIBF 1120 and BIBF 1202 showed that BIBF 1120 - but not 
BIBF 1202 - is a P-gp substrate. The effect of xenobiotics interacting with P-gp is currently 
not known.
In the IPF phase II proof-of-concept trial 1199.30, 432 patients with consistent IPF were 
randomized, with baseline characteristics comparable across groups. The results of the 
primary endpoint analyses, annual rate of FVC decline, were: 0.19 L (placebo); 0.17 L (50 
mg qd); 0.21 L (50 mg bid); 0.16 L (100 mg bid); and 0.06 L (150 mg bid: -68% reduction in 
rate of decline vs. placebo, p=0.0136; closed-testing multiplicity corrected: p=0.0639). At 
end of study, FVC% pred was better preserved in the 100 mg bid (p=0.0314) and 150 mg bid 
(p=0.0002) groups when compared to placebo. FVC signal robustness was supported by 
results of body plethysmography and oxygen saturation. Compared to placebo, fewer patients 
had acute exacerbations in the 150 mg bid group (p=0.0150), and there were a greater number 
of SGRQ 4-point scale responders in the 100 mg bid (p=0.0069) and 150 mg bid (p=0.0341) 
groups.  No effect was observed on DLCO and 6-MWT. The number of deaths was not 


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significantly different between groups. Discontinuations (26.2%; 22.4% due to AE) were 
more frequent with 150 mg bid (37.6%; 31.8%), but less with 100 mg bid (16.3%; 15.1%), 
compared to placebo (28.2%; 24.7%).
The adverse events most frequently leading to discontinuation were diarrhoea, nausea, and 
vomiting (in the group receiving 150 mg twice a day as compared with those receiving 
placebo, the respective rates were 11.8% vs. 0%, 4.7% vs. 0%, and 2.4% vs. 1.2%). Among 
the 85 patients in the group receiving 150 mg of the study drug twice a day, 4 (4.7%) had 
serious gastrointestinal events and 5 (5.9%) had severe gastrointestinal events, especially 
diarrhoea, as compared with no patients in the placebo group.
Clinically significant elevations in liver enzymes levels (at least three times the upper limit of 
the normal range for ALT or AST at any time after baseline) were observed in 6 patients in 
the group receiving 150 mg of nintedanib twice a day (7.1%), 1 in the group receiving 100 
mg twice a day and none in the placebo group. All aminotransferase levels normalized or 
decreased from elevated levels with continued treatment (in 3 patients receiving 150 mg 
twice a day and 1 patient receiving 100 mg twice a day), with a dose reduction (from 150 mg 
twice a day to 100 mg twice a day in 1 patient), or with withdrawal of the drug (in 2 patients 
receiving 150 mg twice a day). 
For patients of the Phase II study participation in the open label rollover trial 1199.35 was 
offered. This study is currently ongoing. 
Overall, it was considered that nintedanib may confer clinical benefit to patients with IPF 
with an acceptable safety profile. The benefit/risk assessment of the Phase II trial results 
justified initiation of 2 large Phase III trials. Trials 1199.32 (U13-2381-01) and 1199.34 
(U13-2382-01), which are the parent trials of the current 1199.33 trial, evaluated the safety 
and efficacy of the 150 mg bid dose versus placebo when given over 52 weeks. 
In total 515 patients were randomised in study 1199.32 and 551 patients in study 1199.34. 
The primary endpoint of the annual rate of decline in FVC was met in both studies. In study 
1199.32 the adjusted annual rate of decline in FVC was -239.91 mL/year in the placebo 
group and -114.65 mL/year in the nintedanib group. The difference between treatment groups 
was 125.26 mL/year (95% CI: 77.68, 172.84) and was statistically significant (p<0.0001). In 
study 1199.34 the adjusted annual rate of decline in FVC was -207.32 mL/year in the placebo 
group and -113.59 mL/year in the nintedanib group. The difference between the treatment 
groups was 93.73 mL/year (95% CI: 44.78, 142.68) and was statistically significant 
(p=0.0002). 
Change from baseline in SGRQ total score at 52 weeks was a key secondary endpoint in the 
studies. In study 1199.32 there was a small difference between the treatment groups in favour 
of nintedanib: -0.05 (95% CI: -2.40, 2.50), which was not statistically significant (p=0.966). 
In study 1199.34 the difference between the treatment groups was -2.69 (95% CI:-4.95, -
0.43) in favour of nintedanib and was statistically significant (p=0.0197).


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Time to first acute IPF exacerbation over 52 weeks was a key secondary endpoint in the 
studies. In study 1199.32 there was no difference between the treatment groups and the 
hazard ratio (HR) was 1.15 (95% CI: 0.54, 2.42; p=0.673). In study 1199.34 the risk of  
having a first acute IPF exacerbation was significantly lower in the nintedanib group than in 
the placebo group, with a HR of 0.38 (95% CI: 0.19, 0.77; p=0.005).
In both studies, survival endpoints showed a consistent numerical difference in favour of 
nintedanib. The HR for time to death over 52 weeks in a pre-specified pooled analysis of both 
studies was 0.70 (95% CI 0.43, 1.12; p = 0.1399).
As expected, the most frequent AEs were gastrointestinal disorders. Diarrhoea was reported 
in 61.5% of the patients in the nintedanib group in study 1199.32 and in 63.2% of the patients 
in study 1199.34 compared to 18.6% and 18.3% in the placebo group, respectively. Liver 
enzyme elevations were more frequent in the nintedanib group than in the placebo group in 
both studies: aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] 
≥3xULN was observed in 4.9% of the patients in the nintedanib group versus 0.5% of the 
patients in the placebo group in study 1199.32 and in 5.2% of the patients in the nintedanib 
group versus 0.9% of the patients in the placebo group in study 1199.34. There was no Hy’s 
law case in the nintedanib group.
Please refer to the current version of the Investigator’s Brochure (U07-1248) for complete 
and updated information on nintedanib in IPF. 


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
The aim of this extension trial is to provide nintedanib treatment for all patients who have 
completed one year treatment and the follow up period in the double-blind phase III placebo 
controlled parent trials (1199.32 and 1199.34), who may have experienced benefit from the 
study medication and wish to receive treatment.
Moreover it is designed to determine the tolerability and safety of nintedanib and to follow up 
on survival in IPF patients treated for a long period.
Throughout this protocol, each time “parent trial” is quoted it refers to the 1199.32 and 
1199.34 trials (EudraCT no. 2010-024251-87 and no. 2010-024252-29).
2.2
TRIAL OBJECTIVES
The primary objective is to assess long term safety of treatment with oral nintedanib in 
patients with Idiopathic Pulmonary Fibrosis (IPF).
Please refer to Section 5 for a detailed description of the trial endpoints.
2.3
BENEFIT - RISK ASSESSMENT
Nintedanib has shown robust, reproducible, statistically significant, and clinically meaningful 
effects on the decline in lung function as measured by FVC. In two large, international, 
placebo-controlled phase III trials of identical design, nintedanib 150 mg bid statistically and 
clinically significantly reduced the annual rate of decline in FVC over 52 weeks compared 
with placebo indicating a relative difference of approximately 50% between nintedanib and 
placebo. This effect of nintedanib is considered consistent with slowing disease progression 
as measured by FVC.
The risks of treatment with nintedanib are primarily related to the gastrointestinal tract 
(nausea, vomiting, diarrhoea, abdominal pain) and to increases in liver enzymes (AST, ALT, 
ALKP, gamma-GT) and bilirubin. Also weight decrease and decreased appetite have 
frequently been reported in studies with nintedanib. Moreover, based on experience with 
other tyrosine kinase inhibitors, impairment of immune and of kidney function, intestinal 
perforations, increases in blood pressure as well as potential bleeding and thrombotic events
should be carefully monitored and evaluated in clinical trials. In patients who develop severe
symptoms of gastrointestinal toxicity not amenable to symptomatic treatment with standard
measures, severe liver enzyme elevations, severe drug-related infections, or uncontrolled
hypertension, treatment with nintedanib must be discontinued and appropriate therapeutic
measures taken (refer to Section 4.2.1.1). Liver enzymes must be followed closely during 
treatment with nintedanib.


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The dose of nintedanib must be reduced to 100mg bid, or nintedanib must be discontinued in 
the event of hepatic toxicity and further treatment withheld until recovery of the abnormal 
laboratory parameters (refer to Section 4.2.1.2).
Patients with IPF may benefit from lesser decline in lung function and hence slower disease
progression as a result of treatment with nintedanib. In addition, nintedanib may reduce the 
risk of acute IPF exacerbations and worsening of patient’s quality of life. Finally, nintedanib
may ultimately be found to reduce mortality. Overall, the benefit/risk profile of nintedanib, as 
established during the phase II and III trials is interpreted as favourable for the treatment of 
IPF.
Although rare, a potential for drug-induced liver injury is under constant surveillance by 
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and 
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients’ 
safety.
Patients who are offered to enter this open label extension trial must have participated in a 
phase III parent trial (1199.32 or 1199.34) for one year. All patients will be treated with 
active drug. Patients who have not tolerated the blinded study drug or discontinued for any 
reason are not eligible for the extension trial. Patients who were randomized to placebo in the 
parent trial will be receiving the active drug for the first time. Similar safety monitoring
procedures as in the phase III trials will be applied.
The routine safety monitoring established in the parent study is considered appropriate for the 
long term follow-up of the patients. It consists of regular visits to the investigational site, 
blood analyses and specific monitoring procedures to follow-up potential hepatic enzyme 
elevation. In case it is considered adequate by the investigator, the dose of nintedanib may be 
reduced to 100 mg bid or dosing may be interrupted.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multi-centre, multi-national, prospective, open label extension clinical trial. It is 
planned to include approximately 750 patients with IPF who have completed 52 weeks of 
treatment and the follow up period of the phase III parent trials. Only patients enrolled in the 
parent trials (1199.32 and 1199.34) will be eligible.
After signing Informed Consent and if all eligibility criteria are met, patients will initiate 
treatment with nintedanib (Visit 2). Please refer to Section 4.1.2 for the method of assigning 
patients to treatment groups.
Overall, the trial is estimated to last a total of approximately 6 ½ years. Treatment will be 
stopped if a reason for withdrawal is met (refer to Section 3.3.4). 
Patients’ participation starts once they have signed the Informed Consent form and it is 
concluded when they have undergone the Follow-up Visit (unless the patient is lost to follow 
up or informed consent is withdrawn). Adverse events are collected during all the trial period 
and are considered under treatment until 28 days after drug discontinuation.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
BI has appointed a Trial Clinical Monitor (TCM), responsible for coordinating the activities 
required in order to manage the trial in accordance with applicable regulations and internal 
standard operating procedures (SOPs), directing the clinical trial team in the preparation, 
conduct, and reporting of the trial, ordering the materials as needed for the trial, ensuring 
appropriate training and information of Clinical Monitors Local (CML), Clinical Research 
Associates (CRAs), and investigators of participating countries.
Data Management and Statistical evaluation will be performed by BI according to BI SOPs. 
For these activities, a Trial Data Manager and a Trial Statistician have been appointed.
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 will be given in the Clinical Trial 
Master File (CTMF) document.
The organisation of the trial in the participating countries will be done by the respective local 
BI organisation (Operating Unit (OPU)) or by a Contract Research Organisation (CRO) with 
which the responsibilities and tasks will have been agreed and a written contract filed before 
initiation of the clinical trial. In each OPU participating in this study, a CML was appointed 
responsible for coordinating the activities required in order to manage the trial in accordance 
with applicable regulations and internal SOPs in the countries covered by the respective BI 
OPU.


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A Co-ordinating Investigator was nominated to coordinate investigators at different sites 
participating in this multicentre trial. 
 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 (draft) Clinical Trial Report (CTR) indicating that, to the best of Co-ordinator’s 
knowledge, the final CTR accurately describes the conduct and results of the Trial.
Trial sites consist of specialised referral centres experienced in the management of IPF. 
Documents on participating (Principal) investigators and other important participants, 
especially their curricula vitae, will be filed in the CTMF.
Details of the trial supplies including responsible institutions are given in Section 4 of this 
protocol.
Central laboratory facilities will handle all laboratory analyses of the trial. In addition liver 
enzymes intermediate measurements may be performed in a local laboratory or at a local 
doctor’s office using specific laboratory kits supplied for the study that will be analysed 
centrally.
To assure the standardisation of PFTs, the lung function equipment for spirometry will be 
provided by the sponsor (refer to Section 5.2). 
The ISF will be maintained at the sites as required by local regulation and BI SOP. A copy of 
the ISF documents will be kept as an electronic CTMF document according to BI SOPs.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
The trial will be conducted as a prospective, open-label design with the objective to collect 
long term safety data on nintedanib in patients with IPF. The observation period will extend 
until either every patient is discontinued or a reason for stopping the trial is met (refer to 
Section 3.3.4). Patients who have completed one year treatment plus follow-up period in a 
parent trial are eligible for participation.
The purpose of this trial is to offer the option to all patients who completed the randomized 
phase III trial 1199.32 or 1199.34 to receive nintedanib treatment if they perceive an 
individual benefit. The decision to continue treatment will be made by the patient following a 
discussion with the investigator. The aim of the study is to allow treatment continuation to 
individual patients; therefore, randomization, blinding and use of placebo would not be 
appropriate. 
To obtain information on the long term safety and tolerability of nintedanib, adverse events
and acute IPF exacerbations will be reported, and clinical laboratory tests, electrocardiograms
and lung function tests will be performed. FVC derived endpoints will be assessed and data
on discontinuations and death will be recorded.


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The chosen endpoints are a subset of the endpoints used in the parent trial; no new endpoint 
is introduced in this trial.
3.3
SELECTION OF TRIAL POPULATION
It is anticipated that approximately 750 patients will complete 52 weeks of treatment with 
nintedanib or placebo and the follow up period in the phase III trials 1199.32 and 1199.34
(assuming a similar drop-out rate as in the phase II). These patients will be allowed to 
participate in this extension trial. Patients previously on active treatment will continue; 
patients who received placebo in the parent trial will initiate treatment with nintedanib for the 
first time at Visit 2.
A log of all patients included in the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug (i.e. open label nintedanib) or not.
3.3.1
Main diagnosis for study entry 
Patients with IPF are eligible for inclusion if they fulfil all the inclusion criteria (Section 
3.3.2) and do not present any of the exclusion criteria (Section 3.3.3).
In general patients who have completed the parent trial are eligible. However treatment 
interruption between the parent trial and the extension open label study should not be > 12 
weeks. Patients who had experienced adverse events in the parent trial but were allowed to 
continue receiving blinded study medication either at 150 mg bid dose or at the reduced dose 
level 100 mg bid, will be offered participation in the extension trial. 
3.3.2
Inclusion criteria
1. Signed Informed Consent consistent with ICH-GCP and local laws prior to trial 
participation.
2. Patients from trials 1199.32 or 1199.34 who completed the 52 weeks treatment period 
and performed the follow-up visit.
3.3.3
Exclusion criteria
1. AST, ALT > 1.5 fold ULN
Patients who completed the parent trial with transaminase values > 1.5 fold ULN but < 3 
fold ULN are considered eligible.
2. Bilirubin > 1.5 fold ULN
3. Bleeding risk:


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a. Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. 
vitamin K antagonists, dabigatran, heparin, hirudin), or high dose antiplatelet 
therapy. Exceptions: 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, or clopidogrel at 75 mg/d, or equivalent doses of other 
antiplatelet therapy);
b. Hemorrhagic CNS event, gross / frank haemoptysis or haematuria, active 
gastro-intestinal bleeding or ulcers after completion of the parent trial;
c. Coagulation parameters: International normalised ratio (INR) > 2, prothrombin 
time (PT) and partial thromboplastin time (PTT) > 150% of institutional ULN.
4. Planned major surgery within the next 3 months, including lung transplantation, major 
abdominal or major intestinal surgery.
5. New major thrombo-embolic events developed after completion of the parent trial: 
a. Stroke;
b. Deep vein thrombosis;
c. Pulmonary embolism;
d. Myocardial infarction.
6. Time period > 12 weeks between Visit 9 of the parent trial and Visit 2 of this study.
7. Usage of any investigational drug after completion of the parent trial or planned usage 
of a specific investigational drug during the course of this trial.
8. A disease or condition which in the opinion of investigator may put the patient at risk 
because of participation in this trial or limit the patient’s ability to participate in this
trial.
9. Alcohol or drug abuse which in the opinion of the investigator would interfere with 
trial participation.
10. Pregnant women or women who are breast feeding or of child bearing potential not 
using two effective methods of birth control (one barrier and one highly effective non-
barrier) for at least 1 month prior to Visit 2 and/or not committing to using it until 3 
months after end of treatment. 
Women will be considered to be of childbearing potential unless surgically sterilised 
by hysterectomy or bilateral tubal ligation, or postmenopausal for at least two years.
Highly effective methods of birth control include established use of oral, injected or 
implanted hormonal methods of contraception, placement of an intrauterine device 


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(IUD) or intrauterine system (IUS). A barrier method of contraception includes 
condom or occlusive cap with spermicidal (foam, gel, film, cream, suppository) or 
male sterilization (with appropriate postvasectomy documentation of the absence of 
sperm in the ejaculate).
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
The treatment with nintedanib has to be permanently discontinued in the following 
circumstances:

Liver function impairment (refer to Section 10.1):

ALT or AST ≥8 fold ULN.

ALT or AST ≥3 fold ULN for more than 2 weeks despite dose 
reduction.

ALT or AST ≥3 fold ULN and total bilirubin > 1.5 fold ULN.

ALT or AST ≥ 3 fold ULN and INR > 1.5.

ALT or AST ≥3 fold ULN with the appearance of fatigue, nausea, 
vomiting, right upper abdominal quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (> 5%).

Diarrhoea: reoccurrence of diarrhoea (> 4 stools/day) for 8 or more consecutive 
days despite dose reduction and supportive care as described in Section 4.2.1.1.

Pregnancy (refer to Section 5.3.7).

Planned usage of a specific investigational drug (refer to Section 4.2.2.1).

Treatment interruption. Treatment interruption is acceptable in certain cases and 
for a defined period which are described in Section 4.2.1. 
Similar to the parent study, in the following cases withdrawal of study drug is highly 
recommended. Only in special circumstances, the investigator, upon thorough assessment of 
all available clinical data, and taking into consideration the potential risks associated with 
administration of nintedanib, may decide not to withdraw the patient, even though one or 
more of the below mentioned criteria are fulfilled. However, in such a case, continuation of 
study treatment should be discussed with the patient, and the decision documented in the 
source data.


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
Planned major surgery, including any major abdominal or intestinal surgery.

Patients who require full-dose therapeutic anticoagulation (e.g. vitamin K 
antagonists, dabigatran, heparin, hirudin), or high-dose antiplatelet therapy. 

Major thrombo-embolic events e.g. stroke, deep vein thrombosis, pulmonary 
embolism, myocardial infarction.

Increased risk of bleeding e.g. haemorrhagic CNS event, gross / frank 
haemoptysis or haematuria, active gastro-intestinal bleeding or ulcers.

Deterioration of the disease. A ≥ 10 % decrease in the absolute value of FVC% 
predicted within 12 months is considered deterioration (progression of disease). 
Patients have the right to withdraw from the study at any time without the need to justify the 
decision. The investigator has the right to remove patients from the study for non-
compliance, administrative or other reasons.
Data of patients who discontinue or withdraw prior to medication assignment will be 
recorded in the eCRF. Data of patients who discontinue or withdraw after medication 
assignment must be documented and the reason for withdrawal must be recorded in the 
eCRF. The data must be included in the trial database and must be reported. 
Refer to Section 6.2.2 and Section 6.2.3 for procedures to be followed for patients 
terminating the trial.
Patients who are discontinued from this trial are not allowed to be re-enrolled.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial,
2. Marketing authorization, availability for compassionate use or early access program 
offered by the sponsor (depending on local laws),
3. Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the 
appropriate conduct of the trial.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Nintedanib will be supplied by Boehringer Ingelheim Pharma GmbH & Co. KG.
4.1.1
Identity of BI investigational product and comparator product
All patients will be treated with nintedanib in this trial; there is no active comparator or 
placebo.
Substance:
nintedanib
Pharmaceutical form:
Soft gelatin capsule
Source:
BI Pharma GmbH Co. KG
Unit strengths:
150 mg , 100 mg
Posology:
Twice daily (bid)
Route of administration:
Oral (swallowed)
4.1.2
Method of assigning patients to treatment groups
In the parent blind phase III trials (1199.32 and 1199.34) patients are assigned either active 
drug (nintedanib 150 mg bid) or placebo. In case patients experience adverse events related to 
drug tolerability, a dose reduction to 100 mg bid is allowed (both in active or placebo group).
At the end of treatment (Visit 9) in the parent trials, patients will be taking either 150 mg bid 
blinded study medication (active drug or placebo) or 100 mg bid blinded study medication 
(active drug or placebo) if their dose was permanently reduced during the trial.
Patients taking 150 mg bid blinded study medication (active drug or placebo) in the parent 
trial will be treated with nintedanib 150 mg bid in the current extension trial.
Patients who had the dose reduced to 100 mg bid (active drug or placebo) in the parent trial 
will be allowed to be treated with nintedanib 100 mg bid or 150 mg bid. This will ensure that 
patients who were on reduced dose placebo in the parent trial will have a chance to get the 
full dose in the extension trial. 
The daily dose of nintedanib will be decided at Visit 2 based on discussion between the 
patient and the investigator.


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An Interactive Voice Response System (IVRS) / !"#$%&'#()$ 
*$+ ,$-./"-$ 
01-#$2 3!*,04
will be used to assign medication numbers to eligible patients. Distribution of nintedanib to 
sites will be triggered by IVRS/IWRS.
Details on the IVRS/IWRS system are provided in the ISF.
After conclusion and unblinding of the parent trials, patients who received 100 mg bid (active 
drug or placebo) will also be allowed to increase their nintedanib dose to 150 mg bid, if this 
was not already performed at the beginning of the extension trial and if it is medically 
justified. In this situation, dose increase will need to be assigned through IVRS/IWRS during 
an additional visit (refer to Section 6.2.4).
4.1.3
Selection of doses in the trial
Based on the phase II safety and dose-finding trial 1199.30, a dose of 150 mg bid was 
selected for confirmatory phase III trials (1199.32/.34) (U07-1248). With 150 mg bid, the 
limit of tolerability in IPF patients is considered to be reached. Lower doses may not ensure 
full efficacy benefit. However, in case of lack of tolerability, the dose may be reduced
temporarily or permanently to 100 mg bid. 
4.1.4
Drug assignment and administration of doses for each patient
At Visit 2 patients who meet all eligibility criteria will be assigned trial drug: nintedanib
either 150 mg or 100 mg bid (refer to Section 4.1.2). 
Boxes covering 4 weeks + 1 week reserve treatment will be dispensed to the patient:
-
1 box at day 1 (Visit 2);
-
2 boxes at Visit 4;
-
3 boxes at Visits 6, 7 and 8;
-
4 boxes at Visit 9 and following visits.
Please refer to the Flow Chart for dispensing schedule. The investigational product should 
only be dispensed to participating patients according to the protocol by authorised personnel 
as documented in the form “Trial Staff List”. 
Study drug will be administered orally on a twice daily basis (bid). The patients should 
swallow the study medication unchewed together with a glass of water (~250 mL), and 
should observe a dose interval of 12 hours. Study drug should be taken at the same time every 
day (between 06:00 and 11:00 in the morning, and between 18:00 and 23:00 in the evening).
Because nintedanib may cause stomach discomfort, it is recommended to take the drug after
food consumption.


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If a patient forgets to take one or several doses of nintedanib he/she should take the following
dose according to the protocol: no catch up of missed doses is permitted.
Patients on the 150 mg bid dose may have their dose permanently or temporarily reduced to 
100 mg bid during the course of the extension trial for tolerability reasons, i.e. to manage 
adverse events (refer to Section 4.2.1). Dose reduction/re-escalation will need to be assigned 
through IVRS/IWRS during an additional visit (refer to Section 6.2.4).
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is an open-label trial.
The previous treatment (active drug or placebo) in the blinded parent trials will remain 
unknown until the database lock of the parent studies.
4.1.5.2
Procedures for emergency unblinding
Not applicable.
4.1.6
Packaging, labelling and re-supply
Primary study material will consist of capsules containing nintedanib 150 mg or 100 mg. The 
colour of capsules between the two doses is slightly different.
All study medication will be packaged in one-week blister cards. Blister cards will be 
labelled with a unique identifier for drug accountability and will be labelled according to the 
regulatory requirements of the participating countries. Blisters will be packaged in one month 
boxes. 
For details of packaging and the description of the label, refer to the ISF.
Re-supplies of study medication are planned due to the long duration of the study. The 
medication for re-supply will be packaged in an identical manner as the medication for initial 
supply.
4.1.7
Storage conditions
Nintedanib soft gelatin capsules will be stored in their original packaging under the 
recommended storage conditions, i.e. at room temperature at the study site. Detailed storage 
conditions are described on the study medication labels. The investigational product must be 
stored securely, e.g. in a locked cupboard or at a pharmacy.


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A temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature.
If the storage conditions are found to be outside the specified range, immediately contact the 
sponsor as provided in the instructions for dispensing and storage in the ISF.
4.1.8
Drug accountability
Drug supplies, which will be provided by a CRO appointed by the sponsor, must be kept in a 
secure, limited access storage area under the storage conditions defined by the sponsor. 
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 study protocol by the IRB / ethics committee,

availability of a signed and dated clinical trial contract between the sponsor and the
Principal Investigator / Head of Trial Centre,

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 or immediately imminent 
signing of the clinical trial protocol, 

for countries where it is required, availability of the proof of a medical licence for the 
principal investigator, 

for US, availability of the Form 1572.
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 disposition of unused product. 
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 product 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.


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment
An antidote against nintedanib is not available. Potential side effects of nintedanib have to be 
treated symptomatically.
Dose reduction (150 mg bid to 100 mg bid) or treatment interruption should be considered to 
manage adverse events. No further dose reduction is possible for patients on the 100 mg bid 
regimen. In case of adverse events observed at this dose, treatment interruption should be 
considered.
4.2.1.1
Management of diarrhoea
The guidelines for managing diarrhoea are the same as in the parent protocols.
4-6 extra stools or i.v. fluid intake < 24 hours with no effect on daily living activities 
Patients should be treated according to local standard (e.g. loperamide or equivalent).
If the severity of diarrhoea persists for 8 or more consecutive days despite optimal care, 
nintedanib treatment should be discontinued or reduced until return to less than 4 extra stools 
per day. Drug interruption is limited however to a maximum of 4 weeks and patients may 
restart treatment with nintedanib at a reduced dose (during a dose modification visit, refer to 
Section 6.2.4). 
Dose re-escalation is allowed at any time after the beginning of the reduced dose if medically 
justified.
In case of re-occurrence of diarrhoea for 8 or more consecutive days despite dose reduction 
and after optimal or prophylactic therapy, patients have to permanently stop nintedanib and 
perform an End of Treatment Visit as soon as possible and a Follow-up Visit 28 days after 
last drug intake (refer to the Flow Chart for visit procedures).
> 6 extra stools or incontinence or i.v. fluid intake ≥ 24 hours or hospitalisation or decrease in 
daily living activities
Nintedanib has to be interrupted until return to less than 4 extra stools per day and patients 
should be treated with optimal supportive care (e.g. loperamide or equivalent). Thereafter, 
patients may restart treatment with nintedanib at a reduced dose. 
In case of re-occurrence of diarrhoea for 8 or more consecutive days despite dose reduction 
and after optimal or prophylactic therapy, patients have to permanently stop nintedanib and 
perform an End of Treatment Visit as soon as possible and a Follow-up Visit 28 days after 
last drug intake (refer to the Flow Chart for visit procedures).


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4.2.1.2
Management of liver enzyme elevation
The guidelines for managing liver enzyme elevations are the same as is in the parent 
protocols. The following procedures are based on the FDA Guidance for Industry. Drug-
Induced Liver Injury: Premarketing Clinical Evaluation (P09-12413).
ALT or AST > 1.5 fold ULN and < 3 fold ULN

Continue as planned
ALT or AST ≥3 fold ULN and < 5 fold ULN with no signs of severe liver damage

Reduce to 100 mg bid or interrupt treatment (to be decided by investigator, based 
on individual risk assessment)

Re-test ALT and AST, as well as alkaline phosphatase, total bilirubin and 
eosinophils within 48 to 72 hours, then at approximately 7 days, then at
approximately 2 weeks, and assess signs of severe liver damage:

If ALT and AST < 3 fold ULN after 2 weeks, return to initial dose if 
reduced, restart at reduced dose if interrupted. Monitor lab (see above) 
every 2 weeks for at least 8 weeks.

If ALT and/or AST ≥3 fold ULN after 2 weeks or any time thereafter, 
permanently discontinue study medication.
ALT or AST ≥5 fold ULN and < 8 fold ULN with no signs of severe liver damage

Interrupt treatment.

Re-test ALT and AST, as well as alkaline phosphatase, total bilirubin and 
eosinophils within 48 to 72 hours, then at approximately 7 days, then at 
approximately 2 weeks, and assess signs of severe liver damage:

If AST and ALT < 3 fold ULN after 2 weeks, restart at reduced dose. 
Monitor lab (see above) every week for 4 weeks, then every 2 weeks 
for at least 8 weeks.

If AST and/or ALT ≥3 fold ULN after 2 weeks or any time thereafter, 
permanently discontinue study medication.
ALT or AST ≥ 8 fold ULN or signs of severe liver damage

Permanently discontinue study medication.


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
Patients showing these lab abnormalities need to be followed up according to
Section 10.1.1 of this clinical trial protocol and the “DILI checklist” provided in 
ISF.
Signs of severe liver damage are defined as:
Increase of liver transaminases (ALT or AST ≥ 3 fold ULN) and:

appearance of fatigue, nausea, vomiting, right upper abdominal quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (> 5%); or

Total bilirubin > 1.5 fold ULN; or

INR > 1.5;
Please refer to Section 10.1 for more detailed instructions.
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.
Initial assessment of liver enzyme elevation should be performed at the investigational site. 
Blood samples for additional monitoring may be collected at the investigational site, primary 
physician (GP or Pulmonologist) or external laboratory with specific study kits and sent to 
the central laboratory for analysis.
For patients continuing treatment with nintedanib within this trial after the database lock for 
the final analysis, the liver function monitoring is to be done locally in case of liver enzyme 
elevations. 
4.2.1.3
Management of acute exacerbations
In case of acute exacerbation (refer to Section 5.2), all treatment options considered adequate 
by the investigator / caregiver are allowed. The patient may interrupt study treatment for up 
to 8 weeks if this is considered necessary (e.g., if short-term full anticoagulation is 
performed).
4.2.1.4
Management of other adverse events
Patients who develop an uncontrolled hypertension despite appropriate antihypertensive 
therapy should permanently discontinue study medication.
For AEs that are assessed drug related, a dose reduction or an interruption (of maximum 4 
weeks) can be considered. Re-escalation is allowed at any time after start of dose reduction if 
medically justified.


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For non related AEs, drug interruption may occur for no longer than 12 weeks. Nintedanib
should be re-started at the same dose as it was being taken before interruption.
Summary of allowed interruption periods: 

Acute IPF exacerbations: 8 weeks maximum interruption;

Related AEs: 4 weeks maximum interruption, then dose reduction is recommended, 
then re-escalation to full dose (150 mg bid) is allowed at any time;

Unrelated AEs: 12 weeks maximum interruption.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment

Investigational therapy is not allowed during the entire study period and must not 
have been introduced in the interval between parent trial and enrolment into this 
extension trial. 

Nintedanib is an anti-fibrotic kinase inhibitor which has been shown to have anti-
angiogenic properties. Inhibition of angiogenesis may increase susceptibility to 
bleeding. Therefore, concomitant anticoagulation, fibrinolysis or high-dose 
antiplatelet therapy is contra-indicated (refer to Section 3.3.3 [4 weeks washout]). 
Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K 
antagonists, dabigatran, heparin, hirudin), or high dose antiplatelet therapy are to be 
withdrawn. 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), as well as 
prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 325 mg/d, or 
clopidogrel at 75 mg/d, or equivalent doses of other antiplatelet therapy) should be 
allowed.

The concomitant administration of nintedanib with any drugs which are likely to 
increase gastrointestinal events such as diarrhoea, nausea, vomiting, is discouraged.

Washout of bronchodilators must be observed before spirometry: 24 hours for long 
acting and 8 hours for short acting bronchodilators, if applicable.
4.2.2.2
Restrictions on diet and life style
No restrictions on diet or life style.


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4.3
TREATMENT COMPLIANCE
Study medication will be dispensed to the patient at the study site by responsible site 
personnel. Details regarding dispensing of the study medication to each participating patient, 
including patient identification, the amount of study drug dispensed, the date the drug was 
dispensed, and the number of capsules returned to the site will be recorded in the drug 
accountability form. 
Patients will be instructed to bring all study medication to the clinic at each visit (except 
Visits 3 and 5). The investigator will be responsible for the assessment of patient compliance
and will be encouraged to counsel patients on the importance of taking study medication as 
directed at each visit.
Study medication will be counted by the investigator (or designated site personnel) and 
compliance will be calculated in a worksheet, which must be kept as a source document.
Compliance will be calculated according to the formula: Compliance (%) = Number of 
capsules actually taken since last count × 100 / Number of capsules which should have been 
taken in the same period. Compliance to nintedanib should be between 80% and 120%. 
Patients should not be discontinued for lack of compliance without prior discussion with the 
clinical monitor.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL ENDPOINTS 
5.1.1
Primary Endpoint 
The primary endpoint is the incidence (number and % of patients) of overall adverse events 
over the course of the study, including incidence (number and % of patients) of serious 
adverse events; adverse events leading to discontinuation and fatal adverse events.
5.1.2
Secondary Endpoints
Not applicable.
5.2
ASSESSMENT OF EFFICACY 
Measurements of FVC
Unique spirometry devices (identical to the ones used in the parent studies) will be supplied 
to all participating sites at trial initiation and spirometry performance will be centrally 
reviewed. During the course of the trial and specifically at each interim analysis, the sponsor 
will re-evaluate the use of central spirometry. If applicable, i.e. central spirometry will be no 
longer used, measurements of FVC will be performed using calibrated electronic spirometers 
at the investigational site or at a referral site.
Spirometers and usage of spirometers must meet ATS/ERS criteria (P05-12782), including 
daily calibration of the spirometer, and regular calibration of the calibration pump. 
Spirometry will be conducted while the patient is in a seated position. The test will be done in 


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triplicate and selection of the best result done according to the guidelines. Spirometric results 
captured by spirometers provided by the sponsor will be electronically transmitted and 
confirmed by central reading. 
For each patient, pulmonary function testing will always start at approximately the same time 
of the day (with 60 minutes maximum difference, time will be recorded). On days of clinic 
visits, patients must refrain from strenuous activity at least 12 hours prior to pulmonary 
function testing. 
Smoking should be discouraged throughout the 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).
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:

left heart failure, 

pulmonary embolism,

identifiable cause of acute lung injury.
Acute IPF exacerbations will be collected as adverse events.
5.3
ASSESSMENT OF SAFETY
5.3.1
Physical examination
Physical examination includes assessment of heart, lung, abdomen and measurement of 
weight. Abnormal findings in the parent trial which were recorded as an adverse event and 
are still ongoing at the time of screening, as well as any new abnormal finding at the time of 
screening, will be recorded as baseline conditions on the appropriate eCRF page. New 
abnormal findings or worsening of baseline conditions detected at the subsequent physical 
examinations will be recorded as adverse events on the appropriate eCRF page.


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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: red blood cell count, haemoglobin, haematocrit, mean corpuscular 
volume, white blood cell count including differential, platelet count.

Chemistry: creatinine, AST, ALT, total protein, alkaline phosphatase, total 
bilirubin.

Coagulation: International normalized ratio (INR) and partial thromboplastin time 
(PTT).
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. 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. 
Additionally, all patients will have intermediate liver function monitoring visits (AST, ALT 
and bilirubin) when the interval between 2 regular visits exceeds 8 weeks. At these visits 
blood may be collected at the investigational site, primary physician (GP or Pulmonologist) 
or external laboratory. However analysis will still be performed by the central laboratory.
In case of liver enzymes elevation, close monitoring must be ensured by the investigator 
(please refer to Section 4.2.1.2). 
For patients continuing treatment with nintedanib within this trial after the database lock for 
the final analysis, laboratory tests will no longer be part of the trial related procedures. 
However investigators are encouraged to monitor liver function locally according to the 
recommendations provided in the Investigators Brochure and to manage liver enzyme 
elevations according to the recommendations provided in section 4.2.1.2 Management of 
liver enzyme elevations.


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5.3.4
Electrocardiogram
Regular ECGs are to be conducted during the first year of the trial. Rate, rhythm and 
repolarisation changes have to be looked at, compared to previous one, and assessed for 
clinical relevance. Clinically relevant findings at baseline of this trial will be recorded as 
baseline conditions, new abnormal findings thereafter will be recorded as adverse events.
5.3.5
Other Safety parameters
Not applicable.
5.3.6
Assessment of adverse events
5.3.6.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, 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 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.
Every new occurrence of cancer will be reported as a SAE regardless of the duration between 
discontinuation of the drug and the occurrence of the cancer.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which 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
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 


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confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms.
Additional information for Japan: The reason for the decision on causal relationship needs to 
be provided in the eCRF.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product
administered and the AE. 
Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the eCRF.
Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the eCRF, if they are judged clinically relevant by the investigator.
Protocol-specified significant events
Similar to the parent trials, the following are considered as Protocol-specified significant 
events:

Hepatic injury defined by an elevation of AST and/or ALT ≥ 3 fold ULN combined 
with an elevation of bilirubin ≥ 2 fold ULN measured in the same blood draw sample.
Patients showing these lab abnormalities need to be followed up according to Section 
10.1.1 of this clinical trial protocol and the “DILI checklist” provided in ISF.

Adverse events relating to gastrointestinal perforation.
Protocol-specified significant events are to be reported in an expedited manner similar to 
Serious Adverse Events, even if they do not meet any of the seriousness criteria – for details 
please see Section 5.3.7.
Expected Adverse Events
Expected (listed) AEs are described in Section 7.9 of the Investigator’s Brochure (U07-1248).


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5.3.7 
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the observational period of 28 days) 
will be collected, documented and reported to the sponsor by the investigator on the 
appropriate eCRFs / SAE reporting forms. Reporting will be done according to the specific 
definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the
Investigator Site File.
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
Section 5.3.6.1. 
The investigator also has the responsibility to report AEs occurring in a certain period (28 
days) after a patient completes the study drug administration. After this defined period all 
SAEs related to the study drug and/or study design have to be reported by the investigator.
The investigator must report the following events via telephone/fax using the SAE form 
immediately (within 24 hours or the next business day whichever is shorter) to the sponsor: 
SAEs and non-serious AEs occurring at the same time as an SAE and/or which are medically 
related to the SAE(s), and protocol-specified significant events. 
Boehringer Ingelheim has set up a list of AEs which are defined to be always serious. In 
order to support the investigator with the identification of these “always serious adverse 
events”, if a non serious AE is identified to be serious per BI definition, a query will be 
raised. The investigator must verify the description and seriousness of the event. If the event 
description is correct, the item “serious” needs to be ticked and an SAE has to be reported in 
expedited fashion following the same procedure as above.
The list of these adverse events can be found in the ISF.
Additional information for Japan: This information must be also reported immediately to the 
head of the trial site. 
With receipt of any further information to these events, a follow-up SAE report has to be 
provided. SAEs and non-serious AEs must include a causal relationship assessment made by 
the investigator.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File). This 
immediate report is required irrespective of whether the investigational product has been 
administered or not and irrespective of causal relationship. It also applies if new information 
to existing SAEs or protocol-specified significant events becomes available. 
Pregnancy
As mentioned above, due to the reprotoxic potential of nintedanib, a patient must not become 
pregnant while treated with nintedanib and until 3 months after end of treatment.


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However, generally, in rare cases, pregnancy might occur in clinical trials. Once a female 
subject has been enrolled into the clinical trial, after having taken study medication, the 
investigator must report immediately any drug exposure during pregnancy to the sponsor.
Drug exposure during pregnancy has to be reported immediately (within 24 hours or next 
business day whichever is shorter) to the defined unique entry point for SAE forms of the 
respective BI OPU (country-specific contact details will be provided in the Investigator Site 
File). The outcome of the pregnancy associated with the drug exposure during pregnancy 
must be followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for 
Clinical Trials and not the SAE form is to be completed. The ISF will contain the Pregnancy 
Monitoring Form for Clinical Trials (Part A and Part B).
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS 
Not applicable.
5.5
ASSESSMENT OF EXPLORATORY BIOMARKER(S) 
Not applicable.
5.6
OTHER ASSESSMENTS 
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
The scheduled measurements are appropriate to see drug induced changes in vital signs, 
standard laboratory values and ECG. These endpoints are standard and accepted for 
evaluation of safety and tolerability of an oral drug, and they are widely used in this kind of 
study. The timing of all measurements is presented in the Flow Chart.
Spirometry is a validated and well-established measurement tool for lung function testing 
(P05-12782). 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Chart. Some flexibility 
is allowed in scheduling the visits according to visit time windows as specified in the Flow 
Chart. If any visit has to be rescheduled, subsequent visits should follow the original visit 
date schedule (calculated from Visit 2). The trial medication kits contain sufficient 
medication to allow for these time windows. All deviations from the planned visit schedule 
will be documented.
The trial will run until all patients have discontinued treatment or a stopping criterion is met 
according to Section 3.3.4.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening
The study will be explained to all patients who complete the parent trials and are willing to 
continue treatment with nintedanib. No study related procedure should be performed until the 
patient has signed the Informed Consent.
Patients will complete a 52 weeks treatment period with nintedanib (or placebo) at Visit 9 in 
the parent trial (1199.32 or 1199.34) and a follow-up period of at least 28 days without drug
(Follow-up Visit).
After concluding all visits from the parent trial and in order to assess eligibility for the 
extension trial (1199.33), patients are required to perform a screening visit (Visit 1) which 
includes laboratory tests. 
If the period between Visit 9 (End of Treatment) of the parent trial and the first visit of 
1199.33 is ≤ 6 weeks, Visit 1 and Visit 2 may occur on the same date. In this case, eligibility 
assessment will be based on laboratory data from Visit 9 of the parent trial.
Please refer to the Flow Chart for complete procedures at Visit 1.
Patients who have a laboratory test value that is outside the range specified by the exclusion 
criteria may have the test repeated once to determine eligibility; however, the result must be 
available prior to Visit 2.
Details of any patient who has given informed consent for the trial but is found to be 
ineligible must be entered in the Enrolment log and documented in the eCRF.


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6.2.2
Treatment period
If the patient has been determined eligible by the investigator to enter the trial (refer to 
Section 3.3), the investigator will assign a medication number to the patient through 
IVRS/IWRS at Visit 2 (refer to Section 4.1.2). First dose of nintedanib will be administered 
at Visit 2 in the clinic (day 1).
Additional clinic visits will be scheduled after 2, 4, 6, 12, 24, 36 and 48 weeks of treatment 
(Visits 3-9).  Liver function monitoring visits will be performed at 18, 30 and 42 weeks of 
treatment (Visits 6a, 7a and 8a). After the first year of treatment, complete clinic visits will be 
scheduled every 16 weeks with intermediate liver function monitoring visits.
For detailed description of the trial procedures at each visit and dispensing schedule, please 
refer to the Flow Chart.
End of Treatment (EOT)
If a reason for drug discontinuation is met (refer to Section 3.3.4) an EOT Visit should be 
scheduled as soon as possible after last drug intake. Reason for discontinuation must be 
documented in the eCRF.
For detailed description of the trial procedures at the EOT visit, please refer to the Flow 
Chart.
6.2.3
End of trial and follow-up period
A Follow-up (FU) Visit should be planned for 28 days after last drug intake.
For detailed description of the trial procedures at the FU Visit, please refer to the Flow Chart. 
If the reason for removal of a patient from the treatment is an adverse event or an abnormal 
laboratory test result, the patient must be followed until complete resolution or stabilization 
of the event for at least 28 days after onset of the event or until follow-up is considered
adequate by the investigator and the clinical monitor.
A patient will be considered lost to follow-up if the investigator is not able to contact him/her 
despite multiple attempts. Every effort must be made; at least 2 telephone contacts plus 1 
mailing should be documented. The site must notify the clinical monitor prior to designating 
a patient as lost to follow-up. 
6.2.4
Dose modification visit
Every time a dose should be reduced or increased (refer to Section 4.1.4 and Section 4.2.1) 
patients will need to come to the site for a dose modification visit where the following will be 
performed:


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
Physical examination measuring weight;

Vital signs;

Assessment of adverse events, acute exacerbations and concomitant therapy since last 
visit;

PFT (FVC);

Assignment of new dose in IVRS/IWRS;

Dispensing of trial drug;

Drug accountability.
6.2.5.
Period after the database lock for the final analysis
After the database lock for the final analysis (refer to section 7.3) and once consent has 
been provided, the remaining patients in the trial (patients without access to nintedanib 
outside the clinical trial) will be offered continuation of treatment within the trial. This 
period will consist of study visits every 16 weeks (±2 weeks) where the following 
procedures will be conducted:

Assessment of adverse events and concomitant therapy since last visit;

Dispensing of trial drug.
Patients will continue to receive treatment until they meet a reason for discontinuation 
(refer to section 3.3.4) or until access to nintedanib is obtained outside the clinical trial. 
Dose reductions, interruptions and re-escalations are possible at any time during the 
scheduled study visits or between visits to manage adverse events.
End of treatment and follow up visits have to be performed to conclude the treatment 
period and trial participation.
Study procedures per visit are described in the Flow Chart for patients who continue 
treatment after the database lock for the final analysis. Investigators are encouraged to 
monitor liver function locally according to the recommendations provided in the 
Investigators Brochure.
Only Adverse Events, Concomitant medications and reason of trial drug discontinuation 
and trial completion will be collected in the eCRF.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a multicenter, multi-national, open-label clinical trial to investigate the long term 
safety of nintedanib in patients with IPF previously treated in a double-blind phase III
placebo controlled trial (1199.32 or 1199.34).
This statistical paragraph deals with the analyses to be performed on the extension trial only. 
Although data of parent trial will not be described in the scope of these analyses, they will be 
taken into account for adverse events analyses, as described in Section 7.3.4.
As the main objective of this extension trial is to study long-term safety, only descriptive 
statistics will be used. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
All analyses in this trial are descriptive and exploratory in nature. No formal statistical 
inferences are foreseen.
7.3
PLANNED ANALYSES
The treated set (TS) will consist of all patients who received at least one dose of open-label 
study medication.
The definition of important protocol violations (IPV) will be specified in the trial statistical 
analysis plan (TSAP). These IPV definitions will include consideration of important 
violations of entry criteria, treatment non-compliance, prohibited medications and inadequate 
follow-up of hepatic events.
Patients will be analysed according to their randomized treatment group in previous studies 
1199.32/34, and overall.
The last available value between visit 1 and visit 2 (before first trial drug intake) will be 
considered as the baseline, for this extension trial.
The main statistical analyses as described below will be performed based on all data collected 
up to the third interim database lock date (see section 7.4). Afterwards, only adverse events 
and concomitant treatments listings will be provided.
7.3.1
Primary endpoint analyses
The primary objective of the study is to assess the safety of nintedanib, so please refer to 
Section 7.3.4. Number of patients and % will be presented over the extension trial by 


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category for adverse events overall; serious adverse events; adverse events leading to 
treatment discontinuation and fatal adverse events.
7.3.2
Secondary endpoint analyses
Not applicable 
7.3.4
Safety analyses
The planned analysis is described in section 7.3.1 and 7.3.3. 


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All patients in the treated set will be included in the safety analysis. The analyses of adverse 
events 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 (in extension study), based on BI Guideline “Handling of Extension Trials”. 
To this end, all adverse events will be classified according to the following trial periods:
previous trial, between-trials (from follow-up visit in previous trial up to date of informed 
consent in extension study), screening, on-treatment, post-treatment and post-study. 
All adverse events with an onset date from the date of the first dose in the extension trial up 
to 28 days after the end of trial treatment will be assigned to the on-treatment period. Other 
adverse events will be assigned to the previous trial, between-trials, screening, post-
treatment, or post-study period, as appropriate. 
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).
7.3.5
Pharmacokinetic analyses
Not applicable.
7.4.
INTERIM ANALYSES
A first interim analysis will be performed to include safety data from this study in the 
regulatory submission documents of nintedanib in IPF. The appropriate analyses will be 
detailed in the Trial Statistical Analysis Plan; the timing of the interim database lock will be 
defined to allow for presentation of the most complete data.
A second interim analysis will be performed after the last patient entered into the trial has 
reached 48 weeks of treatment. 
A third statistical analysis will be performed allowing the final assessment of all endpoints of 
this trial (refer to section 5.1). This will be the basis of the final Clinical Trial Report.
All the above mentioned analyses in Section 7.3 will be presented at each interim analysis.
Data collected after the third interim DBL date will only be listed once all patients have 
discontinued the trial and then incorporated in a revision of the CTR. Details will be provided 
in the TSAP.
7.5
HANDLING OF MISSING DATA
Missing or incomplete AE dates will be imputed according to BI rules. No imputation is 
planned for other safety criteria. 


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Missing or incomplete data for survival are managed by censored data analyses. No specific 
procedures need to be specified to handle them.
For spirometry endpoints, missing data will not be imputed.
7.6
RANDOMISATION
Not applicable as this is an extension trial. 
7.7
DETERMINATION OF SAMPLE SIZE
Not applicable as this is an extension trial. The number of patients included in this trial will 
correspond to the number of patients having completed 1199.32 and 1199.34 trials and 
willing to participate.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH-GCP and, for Japan, the Japanese GCP regulations (Ministry of Health 
and Welfare Ordinance No. 28, March 27, 1997).
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 general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
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.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.


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Additional information for Japan: 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 supplementary explanation, the trial 
collaborator also signs (or places a seal on) and dates the informed consent.
The following items need to be included:
1. That the clinical trial is aimed at testing.
2. Objectives of the trial.
3. The name, title, and the address of the investigator to contact.
4. Trial procedures.
5. Anticipated benefits of the investigational products and anticipated disadvantages to
the patient.
6. Matters concerning other therapeutic measures.
7. Duration of participation in the clinical trial.
8. That the patient might withdraw from the trial at any time.
9. That patient's refusal of or withdrawal from participation in the trial does not cause
any disadvantages to him or her.
10. That the monitors, the auditors, and the institutional review board are given access to
the relevant source documents on condition that confidentiality of the patient is fully
secured.
11. That privacy of the patient is kept.
12. The office of the medical institution to contact in the event of trial-related injury.
13. That necessary treatment is available to the patient in the event of trial-related injury.
14. Matters concerning compensation in the event of trial-related injury.
15. The type of the IRB which is used for the reviews and deliberations on the matters
such as appropriateness of conducting the clinical trial, the matters to be reviewed
and deliberated by each IRB, and other matters concerning the IRBs involved in the
clinical trial.
16. Other necessary matters concerning the clinical trial.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 


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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 familiarised with 
the study protocol, study procedures and principles of GCP during the Trial Initiation Visit. 
An Investigator Site File (ISF) with all necessary trial related documentation and handling 
procedures will be provided. 
A central laboratory will be used to collect, analyze and report the results of all blood 
samples.
To ensure standardization in FVC measurement, a central spirometry review is put in place: 
unique spirometry devices will be supplied to all participating sites. Two procedures will be 
performed using a CRO to ensure high quality of collected FVC measurements:

Quality Assurance (QA) process designed for providing feedback to the 
investigational site and the CRA on the quality of the data received from the site. 
During this process, a clinical specialist analyses and comments the data according to 
the ATS and study specific guidelines. A site gets an alert fax if all measurements of a 
patient during one visit are not acceptable. 

The Best Test Review (BTR) is designed to choose the best effort that will be used to 
represent the Best value for a particular test set. Only the acceptable efforts should be 
used to determine the best value. This choice is communicated to the Investigator 
whose confirmation is sought.
Data will be collected using a Remote Data Capture (RDC) system. Training will be provided 
to all investigators, coordinators and field monitors to ensure consistency and accuracy of the 
data. The data will be source verified by the field monitors.
Diagnoses and adverse events will be coded using MedDRA, and concomitant medications 
will be coded using WHO Drug Reference List. 
The data management procedures to ensure the quality of the data are described in detail in
the trial data management and analysis plan (TDMAP) available in the CTMF.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the Sponsor via remote 
data capture. 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 entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records. Current medical records must be 
available.
For eCRFs all data must be derived from source documents.
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. 
eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all eCRFs and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.3.3
Storage of records
Additional information for Japan:
Storage period of records
Trial sites:
The trial sites must retain the source documents and essential documents for a period defined 
by the Japanese GCP regulation and the sponsor's SOP.
Sponsor:
The sponsor must retain the essential documents according to the sponsor's SOPs.
When it is no longer necessary for the trial site to retain the source documents and essential 
documents, the sponsor must notify the head of trial site.


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8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not.
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For nintedanib this is the current version of the Investigator’s Brochure (U07-1248). The 
current version of this reference document is provided in the ISF. No AEs are classified as 
listed for study design or invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
8.5
STATEMENT OF CONFIDENTIALITY
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.
8.6
COMPLETION OF TRIAL
Additional information for Japan: When the trial is completed, the investigator should inform 
the head of the trial site of the completion in writing, and the head of the trial site should 
promptly inform the IRB and sponsor of the completion in writing.
Additional information for EU member states: The EC/competent authority in each 
participating EU member state needs to be notified about the end of the trial or early
termination of the trial. 
8.7
PROTOCOL VIOLATIONS
Additional information for Japan: The investigator or sub-investigator should record all CTP 
violations. The investigator should provide and submit the sponsor and the head of the trial 


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site the records of violations infringing the Japanese GCP or violations to eliminate an 
immediate hazard to trial subjects and for other medically inevitable reasons.
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
Additional information for Japan: In the event of health injury associated with this trial, the
sponsor is responsible for compensation based on the contract signed by the trial site.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P05-12782
Miller MR; Hankinson J; Brusasco V; Burgos F; Casaburi R; Coates A; Crapo 
R; Enright P; Grinten CPM van der; Gustafsson P; Jensen R; Johnson DC; 
MacIntyre N; McKay R; Navajas D; Pedersen OF; Pellegrino R; Viegi G; 
Wanger J. Standardisation of spirometry. Eur Respir J 2005; 26 (2), 319-338
P07-00109
Nathan SD. Therapeutic management of idiopathic pulmonary fibrosis: an 
evidence-based approach. Clin Chest Med 2006 Mar; 27 [1 Suppl 1]: S27-35
P09-12413
Guidance for industry: drug-induced liver injury: premarketing clinical 
evaluation (July 2009). Silver Spring: U.S. Department of Health and Human 
Services, Food and Drug Administration, Center for Drug Evaluation and 
Research (CDER), Center for Biologics Evaluation and Research (CBER) 
2009
P11-11216
Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, 
Brown KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, Juhel N, 
Klueglich M, Bois RM du. Efficacy of a tyrosine kinase inhibitor in idiopathic 
pulmonary fibrosis. N Engl J Med 2011; 365(12):1079-1087.
P14-07514
Richeldi L, du Bois RM, Raghu G et al, INPULSIS Trial Investigators. 
Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J 
Med. 2014; 370(22):2071-2082. 
R07-0002
Papaioannou AI, Kostikas K, Kollia P, Gourgoulianis KI. Clinical 
implications for Vascular Endothelial Growth Factor in the lung: friend or 
foe? Respir Res 2006 Oct 17; 7:128
9.2
UNPUBLISHED REFERENCES
U07-1248
 Investigator's brochure: BIBF 1120, Indication: Idiopathic 
Pulmonary Fibrosis. 1199.P3. 
U13-2381-01 
: A 52 weeks, double blind, 
randomized, placebo-controlled trial evaluating the effect of oral BIBF 1120, 
150 mg twice daily, on annual Forced Vital Capacity decline, in patients with 
Idiopathic Pulmonary Fibrosis (IPF). Study 1199.32. 07 April 2014
U13-2382-01
: A 52 weeks, double blind, 
randomized, placebo-controlled trial evaluating the effect of oral BIBF 1120, 
150 mg twice daily, on annual Forced Vital Capacity decline, in patients with 
Idiopathic Pulmonary Fibrosis (IPF). Study 1199.34. 08 April 2014


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10.
APPENDICES
10.1
GUIDANCE FOR HEPATIC ENZYME INCREASES
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.
Table 10.1:1 Handling of transaminase increases
AST or ALT
> 1.5 fold ULN
to
< 3x ULN
≥ 3 fold ULN
to
< 5 fold ULN
≥ 5 fold ULN
to
< 8 fold ULN
≥ 8 fold ULN or signs of 
severe liver damage1
Continue as 
planned 2
Reduce dose
or
interrupt 
treatment3
Interrupt 
treatment
Permanently discontinue 
study medication!
Close 
observation4
Close 
observation4
CLINICAL EVALUATION 
OF LIVER INJURY
(Section 10.1.1)
After 2 weeks or any time later
< 3 fold ULN
≥ 3 fold ULN
< 3 fold ULN
≥ 3 fold ULN
Reduced: return 
to initial dose.
Interrupted:
restart at reduced 
dose.
Monitor bi-
weekly for at 
least 8 weeks
Please refer to 
Section 4.2.1.2
Permanently 
discontinue 
study 
medication!
Close 
observation4
Restart at 
reduced dose
Monitor weekly 
for 4 weeks, 
then bi-weekly 
for at least 8 
weeks
Please refer to 
Section 4.2.1.2
Permanently 
discontinue 
study 
medication!
Close 
observation4
1.
Signs of severe liver damage
Increase of liver transaminases (ALT or AST ≥ 3 fold ULN) and:


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
Appearance of fatigue, nausea, vomiting, right upper abdominal quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (>5%) or;

Total bilirubin > 1.5 fold ULN or;

INR > 1.5.
2.
According to visit schedule. Consider additional control visits as adequate.
3.
To be decided by Investigator, based on individual risk assessment.
4.
Close observation:

Repeat within 48-72 hours all of the following: ALT, AST, alkaline phosphatase, total bilirubin, 
eosinophils.

Re-testing once a week or less if abnormalities stabilize or return to normal.
10.1.1
Clinical Evaluation of Liver Injury
10.1.1.1 Introduction
Alterations of liver laboratory parameters, as described in Section 4.2.1.2 and Section 5.3.6.1
(Protocol-Specified Significant Events), are to be further evaluated using the following 
procedures.
10.1.1.2 Procedures
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) - within 48 
to 72 hours and provide additional blood sample to the central laboratory for automatic reflex 
testing of the below listed laboratory parameters. Only in case whereby the central laboratory 
is not immediately available (e.g. if the logistics are such that the patient’s repeat specimen 
would not reach the central laboratory in a reasonable timeframe), ALT, AST, and bilirubin 
(total and direct) must be evaluated by local laboratory and results must be made available to 
the investigator and to BI as soon as possible.
If ALT and/or AST ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold ULN 
are confirmed, the laboratory parameters described below will be made available to the
investigator and to BI as soon as possible.
Clinical chemistry
Alkaline phosphatase, albumin, PT or INR, CK, CK-MB, ceruloplasmin, α-1 antitrypsin, 
transferrin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C (Anti-
HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti-
HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody 


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(titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, 
Antimitochondrial antibody
Hormones, tumour marker
TSH
Haematology
Thrombocytes, eosinophils
In addition,

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF;

obtain history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets according to the “DILI checklist” provided in the ISF;

obtain a history of exposure to environmental chemical agents (consider home and 
work place exposure) according to the “DILI checklist” provided in the ISF;

provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic 
pathology, e.g. bile duct stones or neoplasm;

initiate close observation of subjects by repeat testing of ALT, AST, and total
bilirubin (with fractionation by total and direct) at least weekly until the laboratory 
ALT and or AST abnormalities stabilize or return to normal, then according to the 
protocol. Depending on further laboratory changes, additional parameters identified 
e.g. by reflex testing will be followed up based on medical judgment and Good 
Clinical Practices (GCP),
and report these via the CRF.


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
15 October 2012
EudraCT number
2011-002766-21
BI Trial number
1199.33
BI Investigational Product(s)
BIBF 1120 (nintedanib)
Title of protocol
An open-label extension trial of the long term 
safety of oral BIBF 1120 in patients with 
Idiopathic Pulmonary Fibrosis (IPF)
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
I)
II)
III)
IV)
V)
VI)
Flow chart (footnote 1)
Abbreviations, Section 2.1, Section 2.3, Section 
3.2, Section 3.3, Section 4.1.2, Section 4.1.7, 
Section 4.2.1.1, Section 5.2.4, Section 5.2.5, 
Section 5.3.2 and Section 7.3.2
Section 3.3.4.1
Section 4.2.1.2 and Appendix 10.1
Section 4.2.1.2
Section 7.3


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Number of global amendment
1
Description of change
I)
II)
III)
IV)
V)
VI)
Addition of guidance for patients requiring 
washout of bronchodilators at study entry.
Administrative changes, corrections and 
clarifications.
Addition of individual withdrawal criterion based 
on FVC% predicted decline over time.
Liver “disease” replaced by liver “damage”; 
“withdraw treatment” replaced by “permanently 
discontinue study medication” and correction of 
formatting mistake in the definition of “signs of 
severe liver damage”.
Clarification on which blood collections may be 
performed outside the investigational site in the 
occurrence of a liver enzyme elevation.
Addition of definition of important protocol 
violations.
Rationale for change
I)
II)
III)
IV)
V)
VI)
Ensure that washout of bronchodilators does not 
occur before obtaining a signed informed consent.
Administrative changes, corrections and 
clarifications.
Provide recommendation to investigators to 
discontinue study medication in case of disease 
progression.
Provide consistency in the same terminology used 
across protocol sections.
Facilitate the logistics related to study procedures, 
especially for patients who need to travel a long 
distance to the investigational site.
Clarify on how and where important protocol 
violations will be defined and specified.


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Number of global amendment
2
Date of CTP revision
09 January 2015
EudraCT number
2011-002766-21
BI Trial number
1199.33
BI Investigational Product(s)
BIBF 1120 (nintedanib)
Title of protocol
An open-label extension trial of the long term 
safety of oral BIBF 1120 in patients with 
Idiopathic Pulmonary Fibrosis (IPF)
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
I)
II)
III)
IV)
V)
VI)
VII)
VIII)
Section 1
Section 2.3
Section 3.3.3
Section 4.1.2
Section 4.2.1.1
Section 4.2.1.4
Section 5 and Section 7.3
Section 7.4
Section 9


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Number of global amendment
2
Description of change
I)
II)
III)
IV)
V)
VI)
VII)
VIII)
Medical Background updated.
Ratio benefit/risk updated according to the new 
version of Investigator Brochure.
Removal of men’s contraception method.
Allow dose reescalation to 150mg bid to patients
entered in the extension trial at a reduced dose 
from the placebo or active arm of the parent trial. 
Allow dose reescalation to 150mg bid at any time 
after a dose reduction for AE.
Clarification of efficacy and safety endpoints.
Frequency of iDBL changed.
Update to include new references.
Rationale for change
I)
II)
III)
IV)
V)
VI)
VII)
VIII)
Approval of Pirfenidone in US and inclusion of 
phase III results.
Updating information on efficacy and safety.
Update in accordance to the last IB version.
Provide patients with the opportunity to receive 
the optimal dose even after V2 and unblinding of 
parent trials.
Provide patients with the opportunity to receive 
the optimal dose even after a period of drug 
reduction > 4 weeks.
Administrative changes.
New iDBL will be set up if requested by Health 
Authorities.
New references available.


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Number of global amendment
3
Date of CTP revision
28 March 2017
EudraCT number
2011-002766-21
BI Trial number
1199.33
BI Investigational Product(s)
BIBF 1120 (nintedanib)
Title of protocol
An open-label extension trial of the long term 
safety of oral BIBF 1120 in patients with 
Idiopathic Pulmonary Fibrosis (IPF)
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
FLOW CHART FOR PATIENTS WHO CONTINUE 
TREATMENT AFTER THE DATABASE LOCK FOR 
THE FINAL ANALYSIS
Description of change
Was added:


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Number of global amendment
3
Visit
X 3
EOT 4
FU 5
Week
every 
16w
EOT 
+28 
days
Day
Time window (days)
±14
+7
Informed consent
X2
IVRS/IWRS
X
X
Dispense trial drug 
X
Collect used and unused 
trial drug
X
X
Adverse events
X
X
X
Concomitant therapy
X
X
X
Trial medication 
termination
X
Conclusion of patient 
participation
X
Rationale for change
As access to nintedanib outside of the clinical 
trial is now available in most of the participating 
countries, the sponsor has decided to terminate 
the trial in these countries and conduct the final 
trial analysis. However in order to ensure 
continuation of treatment with nintedanib, 
patients without access to treatment will continue 
to receive nintedanib in this trial until a reason 
for discontinuation is met.
Section to be changed
4.2.1.2 Management of liver enzyme elevation
Description of change
For patients continuing treatment with nintedanib 
within this trial after the database lock for the 
final analysis, the liver function monitoring is to 
be done locally in case of liver enzyme 
elevations. 
Rationale for change
Instruction for local monitoring of liver function.
Section to be changed
5.3.3 Safety laboratory parameters
Description of change
Was added:
For patients continuing treatment with nintedanib 
within this trial after the database lock for the 
final analysis, laboratory tests will no longer be 
part of the trial related procedures. However 
investigators are encouraged to monitor liver 


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Number of global amendment
3
function locally according to the 
recommendations provided in the Investigators 
Brochure and to manage liver enzyme elevations 
according to the recommendations provided in 
section 4.2.1.2 Management of liver enzyme 
elevations.
Rationale for change
Instruction for local monitoring of liver function.
Section to be changed
6. INVESTIGATIONAL PLAN
Description of change
Was added:
6.2.5. Period after the database lock for the final 
analysis
After the database lock for the final analysis 
(refer to section 7.3) and once consent has been 
provided, the remaining patients in the trial 
(patients without access to nintedanib outside the 
clinical trial) will be offered continuation of 
treatment within the trial. This period will consist 
of study visits every 16 weeks (±2 weeks) where 
the following procedures will be conducted:
- Assessment of adverse events and concomitant 
therapy since last visit;
- Dispensation of trial drug.
Patients will continue to receive treatment until 
they meet a reason for discontinuation (refer to 
section 3.3.4) or until access to nintedanib is 
obtained outside the clinical trial. 
Dose reductions, interruptions and re-escalations 
are possible at any time during the scheduled 
study visits or between visits to manage adverse 
events.
End of treatment and follow up visits have to be 
performed to conclude the treatment period and 
trial participation.
Study procedures per visit are described in the 
Flow chart for patients who continue treatment 
after the database lock for the final analysis.
Investigators are encouraged to monitor liver 
function locally according to the 
recommendations provided in the Investigators 
Brochure.
Only Adverse Events, Concomitant medications 
and reason of trial drug discontinuation and trial 


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Number of global amendment
3
completion will be collected in the eCRF.
Rationale for change
As access to nintedanib outside of the clinical 
trial is now available in most of the participating 
countries, the sponsor has decided to terminate 
the trial in these countries and conduct the final 
trial analysis. However in order to ensure 
continuation of treatment with nintedanib, 
patients without access to treatment will continue 
to receive nintedanib in this trial until a reason 
for discontinuation is met.
Section to be changed
7.3 PLANNED ANALYSES
Description of change
Was added: 
The main statistical analyses as described below 
will be performed based on all data collected up 
to the third interim database lock date (see 
section 7.4). Afterwards, only adverse events and 
concomitant treatments listings will be provided.
Rationale for change
To specify the handling data collected on patients 
continuing treatment with nintedanib in this trial
after the database lock for the final analysis.
Section to be changed
7.4 INTERIM ANALYSES
Description of change
The first Interim analysis will occur when the last 
patient entered will reach 48 weeks of treatment. 
Additional interim analyses could be performed 
upon request from Health Authorities or for 
publication purpose. All the above mentioned 
analyses will be presented at each interim 
analysis.
Was changed to:
A first interim analysis will be performed to 
include safety data from this study in the 
regulatory submission documents of nintedanib 
in IPF. The appropriate analyses will be detailed 
in the Trial Statistical Analysis Plan; the timing 
of the interim database lock will be defined to 
allow for presentation of the most complete data.
A second interim analysis will be performed after 


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Number of global amendment
3
the last patient entered into the trial has reached 
48 weeks of treatment. 
A third statistical analysis will be performed 
allowing the final assessment of all endpoints of 
this trial (refer to section 5.1). This will be the 
basis of the final Clinical Trial Report.
All the above mentioned analyses in Section 7.3 
will be presented at each interim analysis.
Data collected after the third interim DBL date
will only be listed once all patients have 
discontinued the trial and then incorporated in a 
revision of the CTR. Details will be provided in 
the TSAP.
Rationale for change
To specify the handling data collected on patients 
continuing treatment with nintedanib in this trial 
after the database lock for the final analysis.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01765254
9.0
clinical-trial-protocol-revision-03
An open-label extension trial of the long term safety of oral BIBF 1120 in patients
with Idiopathic Pulmonary Fibrosis (IPF)
Approval-Team Member Medical
Affairs
29 Mar 2017 10:17 CEST
Author-Trial Statistician
29 Mar 2017 10:30 CEST
Approval-Trial Clinical Monitor
29 Mar 2017 11:31 CEST
Approval-
 Medical Affairs
29 Mar 2017 16:27 CEST
Verification-Paper Signature
Completion
05 Apr 2017 10:37 CEST


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01765254
9.0

SAP_003.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c02035901-05
BI Trial No.:
1199.33
Title:
An open-label extension trial of the long term safety of oral BIBF 
1120 in patients with Idiopathic Pulmonary Fibrosis (IPF)
(Including Protocol Amendment 3 [c01765254-09] and local 
Protocol Amendments in China [c09814738-01] Czech Republic 
[c09951371-01] Russia [c09951303-01]) and Turkey [c14915336-
01].
Investigational
Product(s):
Nintedanib, BIBF 1120
Responsible trial 
statistician(s):
Phone : 
Fax : 
Date of statistical 
analysis plan:
25 JUL 2017 REVISED 
Version:
REVISED
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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..................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......8
5.
ENDPOINTS ..........................................................................................9
5.1
PRIMARY ENDPOINTS....................................................................................9
5.2
SECONDARY ENDPOINTS..............................................................................9
5.2.1
Key secondary endpoints................................................................................9
5.2.2
Other Secondary endpoints............................................................................9
......................9
......................9
....................10
....................10
....................10
....................10
....................11
....................11
....................11
....................12
....................12
6.
GENERAL ANALYSIS DEFINITIONS...........................................14
6.1
TREATMENT(S)...............................................................................................14
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................15
6.3
PATIENT SETS ANALYSED..........................................................................17
....................................................................................................17
6.5
POOLING OF CENTRES ................................................................................17
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................17
6.6.1 Time to event endpoints......................................................................................18
6.6.2 Concomitant therapies........................................................................................18
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................19
7.
PLANNED ANALYSIS.......................................................................22
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........22
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................22
7.3
TREATMENT COMPLIANCE .......................................................................23
7.4
PRIMARY ENDPOINT(S) ...............................................................................23
7.5
SECONDARY ENDPOINT(S) .........................................................................23
7.5.1
Key secondary endpoint(s) ...........................................................................23
7.5.2
(Other) Secondary endpoint(s).....................................................................23
..............................................................................23
7.7
EXTENT OF EXPOSURE................................................................................24
7.8
SAFETY ANALYSIS.........................................................................................25


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7.8.1
Adverse events ...............................................................................................25
7.8.2
Laboratory data.............................................................................................27
7.8.3
Vital signs.......................................................................................................28
7.8.4
ECG ................................................................................................................28
7.8.5
Others .............................................................................................................28
8.
REFERENCES.....................................................................................29
..30
...30
...30
...30
...30
...31
...31
...31
...31
...31
...32
...32
...33
...33
...33
...34
...34
...34
...34
...34
...34
...34
10.
HISTORY TABLE...............................................................................35


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LIST OF TABLES
Table 6.2: 1
Important protocol violations..........................................................................15
Table 6.6.1: 1
Censoring rules for time to event endpoints...............................................18
Table 6.7: 1
Time windowing rules for spirometry, physical exam, vital signs, pregnancy 
test
19
Table 6.7: 2
Time windowing rules for laboratory measurements......................................20
Table 7.8.1:1
Aggregated adverse events by topic or syndrome......................................26
33
Table 10: 1
History table ....................................................................................................35


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP
Term
Definition / description
AE
Adverse event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BI
Boehringer-Ingelheim
BMI
Body Mass index
BRPM
Blinded report planning meeting
BSA
Body Surface Area
CRF
Case Report Form
CI
Confidence Interval
CT
Concomitant Treatments
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
E
Efficacy
ECG
Electrocardiogram
EMA
European Medicines Agency 
EOT
End of treatment visit
ERS
European Respiratory Society
FVC
Forced Vital Capacity
HR
Heart rate
HRCT
High Resolution Computerized Tomography
ICH
International Conference on Harmonisation
IPF
Idiopathic Pulmonary Fibrosis
IPV
Important Protocol Violation
IXRS
Interactive phone/web Response System
MQRM
Medical Quality Review Meeting
N
Number of patients
NA
Not Applicable


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Term
Definition / description
OC
Observed Case
PN
Preferred Name
PT
Preferred term
PV
Protocol violation
S
Safety
SD
Standard deviation
SDG
Standardised Drug Groupings
SEM
Standard Error of the Mean
SOC
System Organ Class
SSC
Special Search Category
TS
Treated Set
TSAP
Trial statistical analysis plan
ULN
Upper Limit of Normal


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3.
INTRODUCTION
As per ICH E9 (5), 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 Trial Statistical Analysis Plan (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.
In the following, the term ‘parent trial’ refers to 1199.32 or 1199.34 trial. All the following 
analyses mentioned in this TSAP concern 1199.33 data.
Interim outputs will be produced in the scope of the submission of Nintedanib in IPF. These 
are detailed in Section 9.2.
SAS® Version 9.2 (or later) will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Although not planned in the CTP, the time to liver enzyme elevation will be analysed in this 
study.
As per CTP amendment 2, regular interim analyses every 48 weeks have been cancelled, but 
some interim analyses may be done upon request from Health Authorities or for publication 
purposes. 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
The primary focus is on safety endpoints. Please refer to CTP Section 5.1.1. 
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints 
Not applicable.
5.2.2
Other Secondary endpoints
Not applicable.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For treatment specifications, see Section 4 of CTP.
The following periods of interest will be defined: previous trial, between trials, screening, 
off-treatment, treatment period, post-treatment, follow-up and post-study as follows:
Note: the last day of each of the following periods is excluded.

Previous trial: from screening in parent trial to the last trial drug intake in parent trial 
plus 28 days plus one day / or to the date of trial completion in parent trial plus one 
day / or to date of informed consent in 1199.33, whichever occurs later

Between-trials: from end of previous trial period (see above) to date of informed 
consent in 1199.33 

Screening: from date of informed consent in 1199.33 to first trial drug intake in 
1199.33

Treatment period: from first trial drug intake in 1199.33 (or re-start of treatment if 
interruption) to last trial drug intake (or date of interruption if interruption) plus one 
day

Off-treatment: from date of start of interruption to re-start of treatment

Post-treatment: from the last trial drug intake plus one day to last trial drug intake plus 
28 days plus one day

Follow-up: from last trial drug intake plus 28 days + one day (after post-treatment 
period) to date of trial completion plus one day. This period is only created if last trial 
drug intake took place more than 28 days before trial completion.

Post-study: from the last trial drug intake plus 28 days plus one day to database lock 
or from the date of trial completion (after follow-up period) plus one day to database
lock, whichever occurs later
Most treatment periods are optional (e.g. “Between-trials”, “Screening” and “Follow-up” will 
not concern all the patients).
For safety analyses (Section 7.8), data from first trial drug intake in 1199.33 up to 28 days 
after last trial drug intake (included) will be considered as on-treatment period. 


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6.2
IMPORTANT PROTOCOL VIOLATIONS
The following table defines the different categories of important protocol violations (IPV) to 
be considered. Important efficacy IPVs are those that can potentially influence outcome 
measures. Important safety IPVs are those that potentially affect the rights or safety of study 
subjects. All these important protocol violations are listed with appropriate flags indicating 
their potential impact on the analyses. No patients will be excluded from the analyses based 
on those IPVs as no per protocol analysis is planned. Important protocol violations will be 
described only.
Table 6.2: 1
Important protocol violations
Category/
Code
Description
Requirements
Efficacy(
E) or
Safety 
(S)
A
Entrance criteria not met
A1
Inclusion criteria not met
A1.7
Parent study not completed 
Inclusion criteria 2 not met (or parent trial not 
completed or follow-up visit in parent trial not 
performed, as per definition of inclusion 
criteria 2, but according to other CRFs 
information)
Automatic IPV
E
A2
Exclusion criteria not met
A2.1
Laboratory values indicate 
additional risk: > 3 X ULN for AST, 
ALT and >2xULN for Bilirubin
Laboratory values for AST, ALT or Bilirubin 
out of protocol defined ranges with no 
elevation recorded at end of  parent trial, or 
exclusion criteria 1 or 2 not met
Manual IPV
S
A2.3
Patient with other disease(s) which 
are excluded as per exclusion 
criteria
Exclusion criteria 3-4-5-8 not met
Automatic IPV
S
A2.4
Forbidden previous therapy
Exclusion criteria 7 not met
Manual IPV
E
A2.5
Time period between parent trial and 
Visit 2 not observed
Exclusion criteria 6 not met / Time period > 
12 weeks between last trial drug intake of the 
parent trial and Visit 2 of this study
or
Visit 1 did not occur at least one day after the 
Follow-up Visit of the parent trial
Automatic IPV
S


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Table 6.2: 1
Important protocol violations (cont’d)
B
Informed consent
B1
Informed consent not given or given 
too late
Inclusion criteria 1 not met and / or informed 
consent date missing
OR
Informed consent date was after Visit 1 date 
Manual review of MQRMs listings
S
C
Trial medication and 
randomisation
C1
Incorrect trial medication taken
Medication kit assigned at visit 2 not 
matching treatment dose actually received by 
patient 
or
Medication kit received at visit 2 does not 
correspond to the dose to be received 
according to CTP (150mg bid for patients on 
150 bid in parent trial)
Automatic IPV
E
C3
Overall Compliance not between 
80% and 120% inclusive
Compliance <80% or >120%
Automatic IPV
E
C4
Drug interruption longer than 46 
days ; or 93 days in the case of acute 
exacerbations or unrelated AEs
Automatic IPV (reviewed in MQRM listings)
E
C6
Dose Change not in agreement with 
the protocol procedures (see Section 
4.2.1 of CTP)
Manual review of MQRMs listings
S
C7
Drug not permanently discontinued 
despite criteria of Section 3.3.4.1 of 
CTP met
Manual review of MQRMs listings
S
D
Concomitant medication
D1
Prohibited medication use during the 
treatment period
•
Investigational therapy
•
Full dose concomitant 
anticoagulation
•
Fibrinolysis 
•
Antiplatelet therapy 
Manual review of MQRMs listings
S


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Table 6.2: 1
Important protocol violations (cont’d)
E
Missing data
E4
Flow chart not observed for the 
planning of visit 1 and 2
Visit 1 and Visit 2 occurred on the same date 
whereas the period between Visit 9 of the 
parent trial and visit 1 is > 6 weeks.
Automatic IPV
S
F
Incorrect timing 
F1
No adequate follow-up after liver 
enzyme elevation (see Table 10.1.1 
of CTP)
Manual review of MQRMs listings
S
Automatic PVs are those detected via an automated programming process using SAS. 
Manual PVs are those identified during the MQRM meeting through patient listings and/or 
Manuel PV log.
6.3
PATIENT SETS ANALYSED

Treated Set (TS): 
This patient set includes all patients coming from 1199.32/34 who were dispensed 
study medication and were documented to have taken at least one dose of 
investigational treatment.
All analyses will be performed on the Treated Set. Patients will be analysed according to their 
randomized treatment group in parent studies 1199.32/34 (e.g. Nintedanib 150mg or 
placebo), and overall (total column). The column of main interest in the tables will be the 
total column (overall both treatment group in parent studies 1199.32/34) as all patients are 
treated on Nintedanib during the extension study.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in any statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
All analyses will be evaluated by observed case analysis (OC), i.e. using only available data 
without imputation. 


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Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”). (1)
For spirometry endpoints, missing data will not be imputed.
For more details about handling of missing data, see Section 7.5 of CTP.
6.6.1 Time to event endpoints
Missing data for time-to-event endpoints are managed by censored data analyses. No specific
procedures need to be specified to handle them.
If a patient has no event during the studied period then he will be censored on the day 
corresponding to the end date of the studied period. The studied period for each type of 
endpoint is detailed in Table 6.6.1: 1.
Table 6.6.1: 1
Censoring rules for time to event endpoints
Endpoint
Studied period
Censoring rule
Time to death 
Time to first IPF acute
exacerbation
From first trial drug intake 
in 1199.33 to last contact 
date
Patients with no event at 
the cut-off date will be 
censored at their last 
contact date
Time to first dose reduction
Time to first treatment
interruption
Time to permanent 
treatment discontinuation
From first trial drug intake 
in 1199.33 to last trial 
drug intake
Patients with no event at 
the cut-off date will be 
censored at their last trial 
drug intake
Time to first occurrence of 
adverse event of particular 
note
Time to first liver enzyme 
elevation
From first trial drug intake 
in 1199.33 to last trial 
drug intake + 28 days
Patients with no event at 
the cut-off date will be 
censored at their last trial 
drug intake + 28 days
Cut-off date = Date of the interim database lock
6.6.2 Concomitant therapies
In case of (partially) missing start and end dates of concomitant therapies, the dates will be 
imputed so that the extent of exposure to the concomitant therapy is maximal, i.e. the first 
day (month) of the month (year) for incomplete start dates and the last day (month) of the 
month (year) for incomplete end dates.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
As a general rule, last available assessment before first trial drug intake will be used as 
baseline in 1199.33. If no assessment is available at visit 2, visit 1 will be used as baseline in 
1199.33.
A windowing will be performed for all endpoints as described in Table 6.7: 1, 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. No time-windowing will be performed for the follow-up visit.
Table 6.7: 1
Time windowing rules for spirometry, physical exam, vital signs, 
pregnancy test
Time window of actual day [1]
Allocated to
Start (Sn) day
End (included) 
(En) day
Length of 
the time-
window
[days]
Visit number
(n)
Visit name
Planned day 
of the visit
(Vn)
1
1
1
1 or 2 [2]
Baseline
1
2
22
21
3
2 weeks
15
23
36
14
4
4 weeks
29
37
64
28
5
6 weeks
43
65
127
63
6
12 weeks
85
128
211
84
7
24 weeks
169
212
295
84
8
36 weeks
253
296
393
98
9
48 weeks
337 
394
Vp + (Vp+1-Vp)/2 
= 505
Ep-Sp +1
10
64 weeks
449 (Vp)
Vp + 1+ 
(Vp+1-Vp)/2
Vp+1 + (Vp+2-
Vp+1)/2
Ep+1-Sp+1
+1
11
80 weeks
561 (Vp+1)


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Table 6.7: 1
Time windowing rules for spirometry, physical exam, vital signs, 
pregnancy test (cont’d)
...
...
...
...
Every 16 
weeks 
thereafter
Vp+2
...
...
...
...
...
Vp+...
[1] First trial drug intake date is taken into account as a reference to calculate time windows [2] Depending on 
the last assessment before first trial drug intake (included), refer to Section 6.7 for baseline definition
Table 6.7: 2
Time windowing rules for laboratory measurements
Time window of actual day [1]
Allocated to
Start (Sn) day
End (included) 
(En) day
Length of 
the time-
window
[days]
Visit number
Visit name
Planned day 
of the visit
(Vn)
1
1
1
1 or 2 [2]
Baseline
1
2
22
21
3
2 weeks
15
23
36
14
4
4 weeks
29
37
64
28
5
6 weeks
43
65
106
42
6
12 weeks
85
107
148
42
6a
18 weeks
127
149
190
42
7
24 weeks
169
191
232
42
7a
30 weeks
211
233
274
42
8
36 weeks
253
275
316
42
8a
42 weeks
295
317
365
49
9
48 weeks
337 


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Table 6.7: 2
Time windowing rules for laboratory measurements (cont’d)
366
421
56
9a
56 weeks
393
422
Vp + (Vp+1-Vp)/2 
= 477
Ep-Sp +1
10
64 weeks
449 (Vp)
Vp + 1+ 
(Vp+1-Vp)/2
Vp+1 + (Vp+2-
Vp+1)/2
Ep+1-Sp+1
+1
10a
72 weeks
505 (Vp+1)
...
...
...
...
Every 16 
weeks 
thereafter
Vp+2
...
...
...
...
...
Vp+...
[1] First trial drug intake date is taken into account as a reference to calculate time windows   [2] Depending on 
the last assessment before first trial drug intake (included), refer to Section 6.7 for baseline definition
For all endpoints, if two post-baseline visits fall in the same time interval after windowing 
has been applied, 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.
If after windowing of visits at baseline, two values fall within the same baseline interval, then 
the last value will be taken into account.
The same rules will be applied for laboratory measurements.


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max. 
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.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
According to the CTP, there are fewer restrictions in concomitant therapies in 1199.33 as 
compared to parent trial. No comparison is therefore possible between parent and extension 
trial, even for placebo-randomized patients in parent trial.
Baseline therapies will be defined as treatments with a start date before first trial drug intake 
in extension trial and taken after or on the day of the first trial drug intake in extension trial.
On-treatment concomitant therapies are defined as treatments with a start date after or on the 
day of first trial drug intake in extension trial and before or on the day of last trial drug intake 
in extension trial.
A summary of all on-treatment concomitant therapies (including baseline CTs) will be 
provided by randomised treatment in parent trial , ATC3 codes and Preferred Name (PN) 
(sorted by alphabetical ATC class and decreasing frequency of preferred names within ATC 
class).
Post-study drug discontinuation therapies are defined as treatments started between last trial 
drug intake and the latest between trial completion and last drug intake + 28 days (included). 
They will be summarized by randomised treatment in parent trial, ATC3 codes and Preferred 
Name (PN). This aims at flagging concomitant treatments taken by patients after they have 
stopped the study drug.
Relevant groups of therapies have been defined as Special Search Categories (SSC) or 
Standardised Drug Groupings (SDG). These are listed in Section 9.3.
The summary of all on-treatment concomitant therapies (baseline CTs and on-treatment CTs)
will also be performed by Special Search Category (SSC) or Standardised Drug Groupings 
(SDG) and Preferred Name (PN) (sorted by alphabetical SSC or SDG and decreasing 
frequency of preferred names within SSC).


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Only descriptive statistics are planned for this section of the report.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINT(S)
There is no primary endpoint as the primary objective of the trial is to assess the safety of 
Nintedanib, so please refer to Section 7.8. 
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
(Other) Secondary endpoint(s)
This section is not applicable as no secondary endpoint has been specified in the protocol.


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7.7
EXTENT OF EXPOSURE
The data will be analysed on the Treated Set.
A summary table showing the duration on treatment (both mean and frequency in classes, see 
Section 5.4.3) will be performed. 
A table displaying the disposition of patients and the conclusion of patients’ participation,
and a table displaying the primary reason for non-inclusion will be provided. 
The proportion of patients on each dose actually taken at visit 2 will be displayed according 
to:
-
randomized treatment group in parent trial (by parent trial and both combined)
-
the dose actually taken at the end of parent trial (by parent trial and both 
combined)
-
the dose actually taken at the end of 1199.33 extension trial
A summary of treatment interruption will be performed including number of patients with at 
least one interruption, number and reason of interruptions, as well as time to first treatment 
interruption in 1199.33. A similar summary will be performed for dose change.
Besides, a summary table showing the duration on actual treatment dose (both mean and 
frequency in classes, see Section 5.4.3) and off-treatment duration will be performed by 
randomized group of the parent trial. This will take into account the actual dose following 
dose reductions or increases.
Kaplan-Meier plots of time to permanent treatment discontinuation will be drawn by 
randomised treatment in parent trial and overall. Similarly, Kaplan-Meier plots will be
performed for time to first dose reduction and for time to first treatment interruption by 
randomised treatment in parent trial and overall. No statistical tests will be performed.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the Treated Set. 
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature and
will be based on BI standards (2). 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
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 in 1199.33 
until 28 days after last drug intake in 1199.33 will be assigned to the on-treatment period and 
described according to randomised treatment in parent trial. All adverse events occurring 
before first drug intake in 1199.33 will be assigned to ‘screening’ and all adverse events 
occurring after last drug intake + 28 days will be assigned to ‘post-treatment’, ‘post-study’ or 
‘follow-up’ (for listings only). Some queries will be edited in case some adverse events are 
incorrectly reported in 1199.33 instead of parent trial, in order to report these in parent trial 
instead (before parent trial DBL). Also, all adverse events 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 (3), 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 summarised by randomised treatment 
in parent trial, primary system organ class and preferred term. Separate tables will be 
provided for patients with other significant adverse events according to ICH E3 (3), for 


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patients with serious adverse events, for patients with adverse events occurring with an 
incidence in preferred term greater than 5% (in at least one treatment arm), for patients with 
protocol specified significant adverse events (as ticked in the AE page of the CRF), for 
patients with related adverse events, for patients with adverse events leading to dose 
reduction and for patients with adverse events leading to treatment discontinuation.
The system organ classes will be sorted according to the standard sort order specified by 
EMA, preferred terms will be sorted by descending frequency over the total column (within 
system organ class).
Specific tables will be created in order to describe selected adverse events of particular note, 
such as diarrhoea events:
-
Display of the diarrhoea specific page of the CRF
-
Summary of diarrhoea events including time to onset, number and duration of 
episodes
-
Summary of diarrhoea adverse events including seriousness, clinical 
consequences (dose -reduction, drug discontinuation or drug interruption) and 
outcome
-
Kaplan-Meier plots of time to first diarrhoea event, by randomised treatment in 
parent trial and overall
Specific summary tables including seriousness, clinical consequences and outcome will also 
be presented to describe the following adverse events of particular note: nausea, vomiting, 
dehydration and weight decrease 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 plots of time to first event, by randomised treatment in 
parent trial and overall, may also be produced with and without a y-axis cut-off at 70%.
Topics or syndromes that are medically relevant to the clinical development program are 
specified in Table 7.8.1: 1. The frequency of patients with AEs within these topics or 
syndromes will be summarised by treatment, topic or syndrome and preferred term. A 
separate table will be provided for patients with serious AEs (SAEs), by treatment, topic or 
syndrome and preferred term.
Table 7.8.1:1
Aggregated adverse events by topic or syndrome
Organ system
Topic or Syndrome
Term selection
Gastrointestinal 
disorders
Pancreatitis
SMQ Acute pancreatitis
Perforation
SMQ Gastrointestinal 
perforation (narrow)
Hepatobiliary 
disorders


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Table 7.8.1:1
Additional aggregated adverse events by topic or syndrome (cont’d)
Liver enzyme and bilirubin 
elevations
SMQ Drug related hepatic disorders –
comprehensive search (narrow);
SMQ Liver related investigations, signs 
and symptoms (broad);
SMQ Cholestasis and jaundice of hepatic 
origin (narrow);
SMQ Hepatitis, non-infectious (narrow).
Hepatic injury
SMQ Hepatic failure, fibrosis and cirrhosis 
and other liver damage-related conditions 
(narrow)
Vascular disorders
Bleeding
SMQ Haemorrhage terms (excl laboratory 
terms) (narrow)
Venous thromboembolism
SMQ Embolic and thrombotic events, 
venous (narrow)
Arterial thromboembolism
SMQ Embolic and thrombotic events, 
arterial (narrow);
SMQ Myocardial infarction (narrow).
Stroke
SMQ Ischaemic central nervous system 
vascular conditions (narrow); 
SMQ Haemorrhagic central nervous 
system vascular conditions (narrow).
Cardiac disorders
Cardiac failure
SMQ Cardiac failure (narrow)
QT prolongation
SMQ Torsade de pointes/QT prolongation 
(narrow)
MACE
Renal disorders
Renal failure
SMQ Acute renal failure (narrow)
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (4).
Specific tables will be presented to describe liver enzyme elevations as defined in Section


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5.4.4:

Summary table of liver enzyme elevation including time to first onset and number of 
episodes

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 timecourse profile of liver enzyme for patients having liver enzyme and bilirubin 
elevation
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report, including calculation of 
the change from baseline.
7.8.4
ECG
Not applicable (ECG findings are reported as adverse events).
7.8.5
Others
Not applicable.


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8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
2
001-MCG-156: "Analysis and Presentation of Adverse events Data from Clinical 
Trials", current version; IDEA for CON.
3
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
4
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.
5
CPMP/ICH/361/96: “Statistical principles for clinical trials”, ICH Guideline Topic 
E9; Note For Guidance on Statistical principles for clinical trials, current version


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10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Final
14-June-13
None
This is the final TSAP without any 
modification
Revised
29-
September-
15
4
As the protocol has been revised, the term 
“On trial survival” has already been changed 
into “Time to death”
5.2.2
In accordance with new SOP, endpoints are 
now classified as further endpoints and not 
as secondary endpoints anymore.
6.2
Precision added for IPV A2.1
6.6
A reference to the CTP has been added for 
the handling of missing data.
7.5.2
In accordance with new SOP, endpoints are 
now classified as further endpoints and not 
as secondary endpoints anymore.
7.7, 7.8.1
Precision that KM plots will  also be 
performed overall groups and with 70% cut-
off for y-axis for AEs of particular note
General
Reference section numbers have been 
updated or removed due to new classification 
of endpoints and for consistency purposes 
with revised CTP based on Global 
amendment 2.


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Table 10: 1
History table (cont’d)
Revised
19-
September-
16
6.3
The definition of the Treated Set has been 
updated in order to specify that the Treated 
Set only includes patients from parent trials 
1199.32/34 (and not transitioned patients 
from study 1199.35).
Revised
25-Jul-17
7.2
The definition of baseline therapies was 
clarified. 
A summary of post-study drug 
discontinuation therapies has been added in 
order to display the proportion of patients 
having taken commercial nintedanib after 
trial drug discontinuation.
7.8
Some specific AE tables by Topic or 
syndrome were added, as judged medically 
relevant for the project.