Clinical trial NCT03820726
Conditions: Lung Diseases, Interstitial
Sponsor: Boehringer Ingelheim
Start date: 2019-04-16; Completion date: 2022-08-30
Enrollment: 435 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main objective is to assess long term tolerability and safety of treatment with oral nintedanib in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD) who have complete (and did not prematurely discontinue trial medication in) the phase III parent trial, INBUILD® (trial 1199.247).

Detailed description:

Arms: arm 1: Patients taking 150 milligram (mg) bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib 150 mg bid in this extension trial. Patients taking 100 mg bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib in this extension trial either at 100 mg bid or at an increased dose of 150 mg bid at the discretion of the investigator orally as soft gelatine capsule, twice daily (bid), together with a glass of water (\~250 mL), in a dose interval of 12 hours. With an optional dose reduction to 100 mg bid temporarily or permanently to manage adverse events (AEs). The treatment had a duration of 96 weeks or until nintedanib was made available to the patients outside of the clinical trial. Treatment was stopped if any reason for withdrawal was met.
Interventions: intervention 1: Nintedanib
Intervention descriptions: intervention 1: Bid

Protocol documents:
Prot_000.pdf: 




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dose
method and route of
administration
Duration of treatment
Treatment duration of at least 96 weeks or until nintedanib can be 
made available to the patient outside of the clinical trial. Treatment 
will be stopped if a reason for withdrawal is met.  
Statistical methods
Descriptive statistics of adverse events and other safety parameters, 




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Footnotes:
* In case of dose change (reduction or re-escalation) additional visits may have to be scheduled (refer to section 6.2.2)
1 The patient is required to sign informed consent prior to any trial related activities.  
2 Visit 1 will occur on the same day as EOTB in INBUILD®.  Laboratory tests, physical examination, vital signs, pregnancy test, ECG and spirometry tests are performed only 
once on that day as part of the EOTB visit in INBUILD®. 
3 Demographics will be collected from the INBUILD® database. Medical History will be collected from the INBUILD® database and may be updated with relevant new 
information.
4 Medical conditions that are occurring concomitantly at visit 1 will be recorded as baseline conditions in the eCRF, including any ongoing AEs from INBUILD® at the time 
of Visit 1.
5 Intermediate lab tests (‘a’-Visits) to be done as needed for additional safety monitoring (see sections 4.2.1.2 and 5.2.3) at the discretion of the investigator. ‘a’ visits do not 
necessarily need to be a site visit.
6 Urine pregnancy tests should be performed in all women of childbearing potential every 4-6 weeks: at least at every visit and if necessary, additionally at home or at a local 
doctor / laboratory.  If urine pregnancy test is not acceptable to local authorities, a blood test can be done at a local laboratory.  Women of childbearing potential will be 
instructed accordingly.
7 Visit X stands for Visit 9, Visit 10 etc. Visits should be repeated every 12 weeks until at least visit 12 (Week 96).  Thereafter, visits will be repeated every 12 weeks until 
the patient’s end of trial (see section 3.3.4).
8 End of Treatment (EOT) Visit to be performed for all patients, as soon as possible after last drug intake in this extension trial (refer to section 3.3.4 and 6.2.2).
9 A follow-up (FU) visit should be planned for 28 days (+ 7 days window) after last drug intake in case trial medication had to be discontinued permanently due to adverse 
events.  This visit may be conducted by telephone.
10 After the individual patient’s end of the trial the investigator should report only any occurrence of cancer, related SAEs and related AESIs of which the investigator may 
become aware of and only via the SAE form, please see section 5.2.5.2.1.


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOWCHART.........................................................................................................................4
TABLE OF CONTENTS ........................................................................................................6
ABBREVIATIONS..................................................................................................................9
1.
INTRODUCTION...............................................................................................12
1.1
MEDICAL BACKGROUND.............................................................................12
1.2
DRUG PROFILE................................................................................................13
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................17
1.4
BENEFIT - RISK ASSESSMENT.....................................................................17
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................19
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........19
2.1.1
Main objectives....................................................................................................19
2.1.2
Primary endpoint(s)............................................................................................19
2.1.3
Secondary endpoint(s) ........................................................................................19
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................20
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................20
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................20
3.3
SELECTION OF TRIAL POPULATION .......................................................20
3.3.1
Main diagnosis for trial entry ............................................................................21
3.3.2
Inclusion criteria .................................................................................................21
3.3.3
Exclusion criteria ................................................................................................21
3.3.4
Withdrawal of patients from treatment or assessments..................................22
3.3.4.1
Discontinuation of trial treatment .........................................................................22
3.3.4.2
Withdrawal of consent to trial participation .........................................................23
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................23
4.
TREATMENTS...................................................................................................24
4.1
INVESTIGATIONAL TREATMENTS ...........................................................24
4.1.1
Identity of the Investigational Medicinal Products..........................................24
4.1.2
Selection of doses in the trial and dose modifications......................................24
4.1.3
Method of assigning patients to treatment groups...........................................25
4.1.4
Drug assignment and administration of doses for each patient......................25
4.1.5
Blinding and procedures for unblinding...........................................................25
4.1.5.1
Blinding.................................................................................................................25
4.1.5.2
Unblinding and breaking the code ........................................................................25
4.1.6
Packaging, labelling, and re-supply...................................................................26




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7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................45
7.3
PLANNED ANALYSES.....................................................................................45
7.3.1
Primary endpoint analyses.................................................................................46
7.3.2
Secondary endpoint analyses .............................................................................46
7.3.4
Safety analyses.....................................................................................................46
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................47
7.4
INTERIM ANALYSES ......................................................................................47
7.5
HANDLING OF MISSING DATA ...................................................................47
7.6
RANDOMISATION ...........................................................................................47
7.7
DETERMINATION OF SAMPLE SIZE .........................................................47
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........48
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................48
8.2
DATA QUALITY ASSURANCE ......................................................................49
8.3
RECORDS...........................................................................................................49
8.3.1
Source documents ...............................................................................................49
8.3.2
Direct access to source data and documents.....................................................50
8.3.3
Storage period of records ...................................................................................50
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................50
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........51
8.6
TRIAL MILESTONES.......................................................................................51
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................51
9.
REFERENCES....................................................................................................53
9.1
PUBLISHED REFERENCES............................................................................53
9.2
UNPUBLISHED REFERENCES......................................................................54
10.
APPENDICES.....................................................................................................55
10.1
1199.247 (INBUILD®) EXCLUSION CRITERIA (BASED ON FINAL 
PROTOCOL VERSION 2 DATED 21 DEC 2016)..........................................55
10.2
CREATININE CLEARANCE...........................................................................56
10.3
VISIT MODIFICATION IN EXCEPTIONAL CIRCUMSTANCES ...........57
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................58
11.1
GLOBAL AMENDMENT 1 ..............................................................................58


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALK
Alkaline Phosphatase
ALAT
Latin American Thoracic Association
ALT
Alanine Aminotransferase
ALCOA
Attributable Legible Contemporaneous Original Accurate
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Transaminase 
ATS/ERS
American Thoracic Society / European Respiratory Society
AUC
Area under the Curve
AZA
Azathioprine 
bid
Bis In Die (twice daily dosing)
BI
Boehringer Ingelheim
CA
Competent Authority
CHP
Chronic fibrosing Hypersensitivity Pneumonitis
CK
Creatine Kinase
Cmax
Maximum Concentration
CML
Clinical Monitor Local
CNS
Central Nervous System
CRA
Clinical Research Associate
CrCL
Creatinine Clearance
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract / Clinical Research Organization
CT
Computed Tomography
CTD
Connective Tissue Disorder
CTD-ILD
Connective Tissue Disorder- associated Interstitial Lung Disease
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP3A4
Cytochrome P450 3A4
DDI
Drug Drug Interaction
DILI
Drug Induced Liver Injury
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EOT
End of Treatment
ERS
European Respiratory Society
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FEV1
The Forced Expiratory Volume In One Second
FGFR
Fibroblast Growth Factor Receptor
FU
Follow Up
FVC
Forced Vital Capacity
GCP
Good Clinical Practice


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GGT
Gamma-Glutamyl Transferase
GI
Gastro Intestinal
GMP
Good Manufacturing Practice
Hb
Haemoglobin
Hct
Haematocrit
HR
Hazard Ratio
HRCT
High Resolution Computerised Tomography
IB
Investigator’s Brochure
ICH
International Council on Harmonization
ICH M3 
(R2)
International Council on Harmonization: Guidance on M3 (R2) Nonclinical 
Safety Studies 
IEC
Independent Ethics Committee
IIPs
Idiopathic Interstitial Pneumonias
ILD
Interstitial Lung Disease
INR
International Normalised Ratio
iNSIP
Idiopathic Nonspecific Interstitial Pneumonia
IPF
Idiopathic Pulmonary Fibrosis
IPV
Important Protocol Violation
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
I.U.
International Units
IV
Intravenous
JRS
Japanese Respiratory Society
Lck
Lymphocyte-specific Tyrosine-protein Kinase
LDH
Lactate Dehydrogenase
LPLT
Last Patient Last Treatment
MACE
Major Adverse Cardiac Events
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
Milligrams
mL
Millilitres
MMF
Mycophenolate Mofetil
NAC
N-Acetylcysteine
nRTK
Non-Receptor Tyrosine Kinase
OCS
Oral Corticosteriods
OPU
Operative Unit
PAH
Pulmonary Arterial Hypertension
p.o.
per os (oral)
PDGFR
Platelet-Derived Growth Factor Receptor
P-gp
P-glycoprotein
PF-ILD
Progressive Fibrosing-Interstitial Lung Disease
PK
Pharmacokinetics 
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
QoL
Quality of Life
RA-ILD
Rheumatoid Arthritis-associated Interstitial Lung Disease
RA/CTD
Rheumatoid Arthritus/Connective Tissue Disease
RBC
Red Blood cell Count


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REP
Residual Effect Period
RTK
Receptor Tyrosine Kinase
s.c.
Subcutaneous
SAE
Serious Adverse Event
SMQ
Standard MedDRA Query
SOC
System Organ Class
SOP
Standard Operating Procedure
Src
Proto-oncogene tyrosine-protein kinase src
SSc-ILD
Systemic Sclerosis-associated Interstitial Lung Disease
SUSAR
Suspected Unexpected Serious Adverse Reaction
TCM
Trial Clinical Monitor
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UIP
Usual Interstitial Pneumonia
ULN
Upper Limit of Normal
VEGF/R
Vascular Endothelial Growth Factor / Receptor 
WHO GCP
World Health Organization Handbook For Good Clinical Practice
WOCBP
Woman Of Childbearing Potential 


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Based on clinical experience, there is a group of patients who, independent from the 
interstitial lung disease (ILD) classification, at some point in time, develop a progressive 
fibrosing phenotype. In this group of patients, the natural history appears to follow a course 
similar to idiopathic pulmonary fibrosis (IPF) with worsening of respiratory symptoms, lung 
function, quality of life (QoL) and functional status, as well as early mortality despite 
treatment with currently available non-approved immunomodulatory therapies. The proposed 
terminology for describing this group is progressive fibrosing interstitial lung disease (PF-
ILD).
Based on expert consensus, the main fibrosing ILDs in which progressive behaviour is 
present include:
∀
Idiopathic Interstitial Pneumonias (IIPs): mainly IPF, idiopathic non-specific 
interstitial pneumonia (iNSIP) and unclassifiable IIP
∀
Chronic fibrosing hypersensitivity pneumonitis (CHP)
∀
Autoimmune ILDs: connective tissue disease- ILD (CTD-ILD) (mainly rheumatoid 
arthritis-associated ILD (RA-ILD) and systemic sclerosis-associated ILD (SSc-ILD)) 
and idiopathic pneumonia with autoimmune features
∀
Environmental/occupational fibrosing lung disease
The scientific working hypothesis is that the response to lung injury in these ILDs includes 
the development of fibrosis which becomes progressive, self-sustaining and independent of 
the original clinical association or trigger. It is postulated that, at this stage, targeted 
antifibrotic therapy is required to slow the progression of the disease.
Based on the similarity in both, the biologic and clinical behaviours i.e. self-sustaining 
fibrosis and progressive decline in lung function and early mortality, it is considered justified 
to group patients with PF- ILDs together regardless of their original ILD diagnosis.
Nintedanib is a kinase inhibitor indicated for the treatment of IPF, which has been shown to 
slow the progression of IPF. The rationale for development of nintedanib in PF-ILD is 
supported by the pre-clinical data indicating that nintedanib impacts fundamental processes 
of lung fibrosis and that the anti-fibrotic activity of nintedanib is independent of the cause of 
the fibrosing lung disease (P14-02860, P14-17410, P15-02392, P15-06100). Based on the 
similarity in both the underlying pathophysiology and clinical course of PF-ILD and IPF, it is 
anticipated that nintedanib will elicit similar effects in PF-ILD as it demonstrated in IPF. 
The efficacy and safety of nintedanib in patients with PF-ILD was investigated in the 
INBUILD® trial (BI trial 1199.247; EudraCT no. 2015-003360-37), the parent trial to this 
extension trial. Patients remained in the parent trial on blinded treatment (part B) until 
unblinded data were available from the first database lock (after last randomised patient 
reached the 52-week time point) of the parent trial. If further exposure was justified by these 
initial results of INBUILD®, the patients were offered to participate in this extension trial 
without treatment interruption.


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Based on the INBUILD® results, nintedanib offers a long term antifibrotic maintenance 
treatment option for patients with PF-ILD, a medical indication with high unmet medical 
need. The current trial is aimed to establish the tolerability and safety of nintedanib in 
patients with PF-ILD over a longer duration of treatment.
1.2
DRUG PROFILE
Nintedanib is a small molecule that inhibits a distinct spectrum of receptor tyrosine kinases 
(RTKs) and non-receptor tyrosine kinases (nRTKs) including VEGFR (vascular endothelial 
growth factor receptor), PDGFR (platelet-derived growth factor receptor), FGFR (fibroblast 
growth factor receptor), and Src family kinases (Src, Lck and Lyn belonging to a family of 
proto-oncogene tyrosine-protein kinases).
All of these growth factor pathways and their down-stream signal cascades have been 
demonstrated to be involved in the pathogenesis of fibrotic tissue remodelling.
Nintedanib inhibited the proliferation and migration of human lung fibroblasts from patients 
with IPF. It demonstrated anti-fibrotic and anti-inflammatory activity in three animal models 
of lung fibrosis and in more specific models of SSc-ILD and RA-ILD. Although the initiation 
of the fibrotic lung pathology in these model systems is different, progressive fibrotic lung 
pathology with proliferation, migration and transformation of fibroblasts to the pathogenic 
myofibroblast is the final common pathway. These similarities and the mode of action of 
nintedanib directed against the proliferation, migration and transformation of fibroblasts 
strongly support the rationale for the use of nintedanib in the treatment of patients with PF-
ILD (U06-1451, U06-1479, U12-2437-01, U12-2066-01, n00239669, n00247887).
Pharmacokinetics
A soft gelatin capsule formulation of nintedanib is used in humans. Maximum plasma 
concentrations occur between 2 - 4 hours after oral administration. Steady state is latest 
reached within one week of dosing. After food intake, a trend towards an increased systemic 
exposure (around 20%) and a delayed absorption was observed compared to administration 
under fasted conditions. Nintedanib is preferentially distributed in plasma with a blood to 
plasma ratio of 0.87 and the terminal half-life is in the range of 7 to 19 hours. The absolute 
bioavailability of nintedanib was slightly below 5%.
Nintedanib is mainly eliminated via faeces.
Co-administration of nintedanib with the P-glycoprotein (P-gp) inhibitor ketoconazole 
increased exposure to nintedanib by 60-70% based on area under the curve (AUC) and by 
80% based on a maximum measured concentration of the analyte in plasma (Cmax) in a 
dedicated drug-drug interaction (DDI) trial. 
In a DDI trial with the P-gp inducer rifampicin, exposure to nintedanib decreased to 50.3% 
based on AUC and to 60. 3% based on Cmax upon coadministration with rifampicin 
compared to administration of nintedanib alone. 
Based on population pharmacokinetic (PK) analysis, age and body weight were correlated 
with nintedanib exposure. However, their effects on exposure are not sufficient to warrant an 
a priori dose adjustment. There was no influence of sex or mild and moderate renal 
impairment (creatinine clearance (CrCL) > 30 mL/min) on the exposure of nintedanib. In a 
dedicated single dose phase I study and compared to healthy subjects, exposure to nintedanib 
was approximately 2-fold higher in volunteers with mild hepatic impairment (Child Pugh A) 


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and approximately 8-fold higher in volunteers with moderate hepatic impairment (Child Pugh 
B). Subjects with severe hepatic impairment (Child Pugh C) have not been studied.
The Residual Effect Period (REP) of nintedanib is 28 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
Data from clinical studies
Nintedanib (trade name: Ofev) is approved for the treatment of IPF and for the treatment of 
SSc-ILD in the US, EU, Japan and a large number of additional countries. Nintedanib is 
recently also approved in the US, EU, Japan, Canada and a number of other countries for the 
treatment of (chronic) fibrosing ILDs with a progressive phenotype.
Summary of clinical efficacy results in IPF: The clinical efficacy of nintedanib has been 
studied in over 1400 patients with IPF in one phase II dose finding trial (TOMORROW) 
including four different doses of nintedanib, and two replicate phase III trials (INPULSIS® 1 
and 2). These were randomised, double-blind, placebo-controlled trials comparing treatment 
with nintedanib twice daily to placebo for 52 weeks. A statistically significant reduction in 
the annual rate of decline of forced vital capacity (FVC) (in mL) was demonstrated in 
patients receiving nintedanib 150 mg twice daily (bid) compared to patients receiving 
placebo. The treatment effect of nintedanib compared to placebo on FVC was consistent in 
all 3 studies, i.e. a relative reduction of decline of approximately 50%. Supporting the effect 
of nintedanib on slowing disease progression, nintedanib 150 mg bid significantly reduced 
the risk of first acute exacerbation compared with placebo in INPULSIS®-2 and in the 
TOMORROW trial and  reduced the risk of acute exacerbations (adjudicated) by 68% in a 
pre-specified sensitivity analysis of  pooled data from the INPULSIS® trials (P14-07514; 
P11-11216).
Summary of clinical safety results in IPF: The safety profile of nintedanib in patients with 
IPF has been investigated comprehensively in clinical Phase II/III trials. The most commonly 
reported AEs were gastrointestinal disorders. Of those, the most frequent events were 
diarrhoea, nausea, vomiting and abdominal pain. Most of these events were of mild or 
moderate intensity, reported as non-serious, and were managed by symptomatic treatment 
and/or temporary interruption and/or reduction of the nintedanib dose. Diarrhoea, nausea, 
vomiting may lead to dehydration and/or electrolyte disturbances. Weight decreased and 
appetite decrease are also considered adverse drug reactions of nintedanib treatment.
Administration of nintedanib was associated with elevations of liver enzymes (ALT, AST, 
ALK, GGT). Administration of nintedanib was also associated with elevations of bilirubin.
The dosing regimen, that includes dose reduction and dosing interruptions, was effective in 
the management of liver enzyme and bilirubin elevations (see section 4.2.1). Cases of drug-
induced liver injury (DILI) have been observed with nintedanib treatment. In the post-
marketing period, non-serious and serious cases of drug-induced liver injury, including 
severe liver injury with fatal outcome, have been reported. The majority of hepatic events 
occur within the first three months of treatment.
Based on data from clinical trials and post-marketing and supported by population 
pharmakokinetic models, patients with low body weight (<65 kg), Asian and female patients 
have a higher risk of liver enzyme elevations with nintedanib treatment.
Patients at known risk for bleeding or who required fibrinolysis, full-dose therapeutic 
anticoagulation, or high dose antiplatelet therapy were excluded from participation in the 


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nintedanib in IPF trials, and initiation of any of these therapies during the course of the trials 
required discontinuation of the study medication. In the IPF phase III trials, bleeding events 
were slightly more frequently reported in patients treated with nintedanib than in those 
receiving placebo. In the post-marketing period non-serious and serious bleeding events, 
some of which were fatal, have been observed. Considering that VEGFR inhibition might 
potentially be associated with an increased risk of bleeding, patients with full-dose 
anticoagulation should only be treated with nintedanib if the anticipated benefit outweighs the 
potential risk.
Thromboembolic events were more frequently reported in the nintedanib group than in the 
placebo group. This difference was due to arterial thromboembolic events, specifically due to
myocardial infarction. The proportion of patients with cardiac adverse events and cardiac 
SAEs, and especially AEs reflecting ischaemic heart disease, was balanced between the 
nintedanib and placebo groups. Based on the available clinical data, and considering the 
mechanism of action of nintedanib, no definitive conclusion on the risk of thromboembolic 
events can be drawn. Arterial thromboembolism is considered an important potential risk of 
nintedanib treatment in IPF.
A slightly increased frequency of arterial hypertension, which is considered an adverse drug 
reaction, was observed with nintedanib in the IPF clinical trials.
Based on cumulative post-marketing safety data bleeding, pancreatitis and thrombocytopenia 
are included as adverse drug reactions.
In the INPULSIS trials no increased risk of gastrointestinal perforation was observed in 
nintedanib treated patients. Due to the mechanism of action nintedanib patients might have an 
increased risk of gastrointestinal perforations. Cases of gastrointestinal perforations have 
been reported in the post-marketing period. Gastrointestinal perforations are considered an 
important potential risk of nintedanib treatment.
Summary of clinical efficacy in patients with progressive fibrosing ILD: (INBUILD® study 
[c26471552])
The INBUILD® study was a multicentre, randomised, placebo-controlled, double-blind Phase 
III clinical trial to investigate the efficacy and safety of nintedanib in patients with 
progressive fibrosing ILDs over 52 weeks. 663 patients were randomised, stratified by HRCT 
fibrotic pattern: ‘UIP-like pattern only’ (412 patients) or ‘Other fibrotic patterns’ (251 
patients). Treatment with nintedanib reduced the adjusted annual rate of decline in FVC by 
106.96 mL/year (95% CI 65.42, 148.50; p < 0.0001) in the overall population and by 128.20 
mL/year (95% CI 70.81, 185.59; p < 0.0001) in patients with HRCT with UIP-like fibrotic 
pattern compared with placebo. Consistent results were observed in the complementary 
population of patients with other HRCT fibrotic patterns (adjusted difference 75.28 mL/year; 
95% CI 15.54, 135.01). The treatment effect was independent of HRCT pattern (interaction 
p-value 0.2268).
Secondary and further lung function endpoints (such as categorical changes in relative FVC 
% predicted and absolute change from baseline in FVC % predicted) supported the primary 
endpoint. Time-to-event endpoints further evidenced the treatment benefit of nintedanib vs. 
placebo and suggested that the reduction in FVC decline translated into a reduction of 
clinically meaningful outcome events. Over the whole trial (Part A+B), treatment with 
nintedanib reduced the risk of first ILD exacerbation or death by 33% compared with 


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placebo, as indicated by the HR of 0.67 (95% CI 0.46, 0.98), and numerically reduced the 
risk of death by 22% compared with placebo (HR 0.78; 95% CI 0.50, 1.21).
Summary of clinical safety results in patients with PF-ILD (INBUILD® study [c26471552])
In the overall population over 52 weeks, adverse events in the SOC 'gastrointestinal disorders' 
were the most common AEs and were reported more frequently in the nintedanib group 
(80.7%) than in the placebo group (45.0%). The difference was mainly driven by the PTs 
diarrhoea (nintedanib: 66.9%, placebo: 23.9%), nausea (28.9% vs. 9.4%), vomiting (18.4% 
vs. 5.1%), and abdominal pain (10.2% vs. 2.4%). Almost all of these events were non-serious 
and of mild or moderate intensity; they led to premature treatment discontinuation in less than 
10% of patients. In line with the findings for gastrointestinal disorders, the proportions of 
patients with decreased appetite reported as AE and weight loss reported as AE or measured 
as body weight were higher for nintedanib than for placebo. 
Elevations of hepatic enzymes are a known side effect of nintedanib treatment. The 
frequencies of patients with AEs in the safety topic 'hepatic enzyme increased' were about 
four times higher in the nintedanib group (22.6%) than in the placebo group (5.7%). Most of 
the liver laboratory AEs were non-serious. In the pooled INPULSIS® trials, the frequencies of 
patients with AEs related to liver enzyme elevations were about five times higher in the 
nintedanib group than in the placebo group [U13-2683-01/ c02153150-02]. In trial 1199.247, 
all patients with serious hepatobiliary or liver laboratory AEs in the nintedanib group, except 
for 1 patient with hepatic cirrhosis, recovered from these events, in most cases after drug 
withdrawal or dose reduction. Clinical liver failure in terms of hepatic decompensation was 
not reported. The reported hepatic laboratory changes were in line with the observed liver 
laboratory AEs.
In the INBUILD® trial, the incidence of hypertension, a labelled side effect of nintedanib in 
IPF, was comparable in both treatment groups. Serious and non-serious cardiovascular AEs 
were reported with similar frequencies in both treatment groups. No imbalances were 
observed for fatal or non-fatal MACE. AEs in the safety topic 'myocardial infarction' were 
reported for 0.9% of patients in both treatment groups.
The proportion of patients with AEs in the safety topic 'bleeding' was similar in the 
nintedanib group (11.1%) and in the placebo group (12.7%). Like in the INPULSIS® trials 
the majority of bleeding events in trial 1199.247 were non-serious cases, and SAEs were 
reported for very few patients only.
In conclusion, the observed safety profile of nintedanib in patients with progressive fibrosing 
ILD comprised risks that were manageable or occurred at a low frequency. The most 
frequently reported AEs were gastrointestinal disorders, in particular diarrhoea, nausea, and 
vomiting. Common AEs were mostly mild or moderate in intensity. In addition, treatment 
with nintedanib was associated with elevations in liver enzymes. The large majority of liver 
enzyme elevations normalised upon treatment interruption, dose reduction, treatment 
discontinuation, or spontaneously with continued treatment. There were no new or 
unexpected safety concerns identified in this trial. Overall, a positive benefit-risk profile for 
nintedanib in patients with progressive fibrosing ILD was shown.


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For a more detailed description of the nintedanib profile, please refer to the current 
Investigator’s Brochure (IB) for nintedanib in IPF, Systemic Sclerosis and PF-ILD 
(c01783972-11).
1.3
RATIONALE FOR PERFORMING THE TRIAL
This trial is an extension trial of the 1199.247 parent trial, INBUILD® All patients still 
receiving blinded treatment at the end of part B of the parent trial had the possibility to 
receive open label nintedanib in this extension trial.
The aim of this extension trial is to evaluate long term tolerability and safety of nintedanib in 
patients with PF-ILD. 
1.4
BENEFIT - RISK ASSESSMENT
In the group of patients with PF-ILD the natural history of the disease appears to follow a 
course similar to IPF with worsening of respiratory symptoms, lung function, quality of life 
(QoL) and functional status, as well as early mortality. With the exception of nintedanib and 
pirfenidone, which were available for patients with IPF, there was no approved therapy for 
PF-ILD at the start of this trial.
Based on the efficacy and safety shown in IPF patients, and considering the similarity of the 
pharmacological rationale between IPF and PF-ILD, the same dose regimen of 150 mg 
nintedanib bid is considered appropriate.
This extension trial only started recruiting when the results from the initial database lock (i.e. 
the efficacy and safety results after 52 weeks of treatment) of the INBUILD® trial had been 
reviewed and justified the start of this extension study. This meant that the nintedanib-treated 
patients showed a lesser decline in lung function compared to the placebo-treated group, and 
that the safety and tolerability was acceptable with no new relevant safety issues identified 
that influenced the existing benefit-risk assessment. The first day of this extension trial was
on the same day as the last visit of the parent trial to allow continuous treatment. 
All patients receive active treatment in this trial.
The risks of treatment with nintedanib have been well delineated in patients with the fibrotic 
lung disease IPF. These risks are primarily related to the gastrointestinal tract (diarrhoea, 
nausea, vomiting, abdominal pain), and are usually managed with supportive therapy and 
with temporary or permanent dose reduction to 100 mg bid. In some cases, temporary 
interruption or permanent drug discontinuation is necessary. A reduction in appetite and 
weight decrease has also been reported in patients treated with nintedanib. 
The potential for drug-induced liver injury (DILI) is under constant surveillance by sponsors 
and regulators. Cases of drug-induced liver injury (DILI) have been observed with nintedanib 
treatment. The majority of patients presented with mild to moderate liver enzyme elevation, 
which was in most cases transient upon dose reduction or treatment discontinuation. 
However, severe DILI with fatal outcome has also been reported. Therefore, this trial requires 
timely detection, evaluation, and follow-up of laboratory alterations in selected liver 
laboratory parameters to ensure patients´ safety. Nintedanib must be dose-reduced, or
interrupted in the event of hepatic toxicity and further treatment withheld until recovery of 
the abnormal laboratory parameters (see also section 4.2.1.2 and 5.2.5.1.4).


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Concomitant therapies with a known overlap in side effects with nintedanib (e.g. 
gastrointestinal [GI] adverse events, increase of AST, ALT, bilirubin) or concomitant use of 
therapies that interact with metabolism of nintedanib (through UGT1A1 and P-gp) should be 
used with caution and patients should be closely monitored (see section 4.2.2.2).
Potential risks of nintedanib treatment also include gastrointestinal perforations and
thromboembolism. Hypertension, thrombocytopenia and bleeding are considered side effects 
of nintedanib treatment in IPF. Therefore, the use of full dose therapeutic anticoagulation, 
fibrinolysis or high-dose antiplatelet therapy is not recommended during the trial, and 
patients requiring such a treatment should only be treated with nintedanib if the anticipated 
benefit outweighs the potential risks.
The mode of action of nintedanib indicates a high potential for teratogenicity and 
embryotoxicity, including fetotoxicity and lethality. In women of childbearing potential 
receiving nintedanib, contraceptive measures must be employed 28 days before treatment 
initiation, during the treatment and for a period of 3 months after last drug intake.
The underlying diseases should be managed in accordance with current standard management 
practices.  In some of the underlying diseases, immunosuppressive agents as well as of non-
immunosuppressive therapies are commonly used to treat organ-specific manifestations, and 
need to be considered although appropriate randomised-controlled data for these therapies are 
lacking. Cautionary notes are included in the protocol (section 4.2.2.2) with regard to such 
therapies whose safety profile could interfere with that of nintedanib.
Safety will be closely monitored at site visits, including physical examinations, safety 
laboratory and specific monitoring procedures, to follow-up potential hepatic enzyme 
elevation and exclusion of pregnancy. In addition, safety laboratory results will be monitored 
at intermediate lab visits in the first year. In patients who develop severe symptoms of 
gastrointestinal toxicity not amenable to symptomatic treatment with standard measures or 
severe liver enzyme elevations or other severe adverse events as specified in section 3.3.4, 
treatment with nintedanib must be discontinued and appropriate therapeutic measures taken.
Based on the pharmacological mechanism, existing non-clinical, clinical and post-marketing 
data there is no indication that treatment with nintedanib may increase the risk for infection 
with SARS-CoV-2 or for worsening the disease course of COVID-19. It is currently 
unknown whether PF-ILD conveys a higher risk for adverse outcomes in case of COVID-19.
The trial related risk to the COVID-19 pandemic situation is the general risk of travelling to 
site and being at site for assessments with increased infection risk for lung function testing. 
Risk mitigation and possible modifications are described in Section 6.1 and in Appendix 10.3
In conclusion, the benefit-risk profile is considered appropriate for this stage of clinical 
development.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective is to assess long term tolerability and safety of treatment with oral 
nintedanib in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD) who 
have completed (and did not prematurely discontinue trial medication in) the phase III parent 
trial, INBUILD® (trial 1199.247).
2.1.2
Primary endpoint(s)
The primary endpoint is the incidence of overall adverse events over the course of this 
extension trial.
2.1.3
Secondary endpoint(s)
No secondary efficacy endpoints are defined.


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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 
estimated that approximately 480 patients with PF-ILD will complete the INBUILD® trial 
1199.247 (part A and part B) on blinded treatment. These patients will be eligible for 
enrolment in this extension trial. Patients who withdrew treatment prematurely in the 
INBUILD® trial will not be eligible for the open label extension trial (INBUILD®-ON).
At the time point when the data from the INBUILD® trial for patients with PF-ILD are 
available, and justify the start of the extension trial, all patients on blinded treatment at the 
end of the parent trial can be offered participation in the current rollover study. 
After signing Informed Consent, and if all eligibility criteria are met, patients will initiate 
treatment with nintedanib (Visit 1) (refer to section 4.1.3). Patients will receive active drug at 
a dose of 150 mg bid or 100 mg bid, depending on their last dose of blinded medication in the 
parent trial. Patients whose last dose of blinded medication in the parent trial was 150 mg bid 
will receive nintedanib 150 mg bid in the extension trial.  Patients who dose reduced to 
100mg bid in the parent trial, can either receive nintedanib 100 mg bid or be offered 
nintedanib at the dose of 150 mg bid based on the judgement of the investigator.
In order to collect long-term safety data in patients with PF-ILD, all patients will be requested 
to stay in the trial for 96 weeks (until visit 12). At week 96, patients who can be treated with 
nintedanib outside the clinical trial will have their EOT visit. The remaining patients will 
continue in the trial until nintedanib can be made available to them outside the clinical trial. 
Treatment will be stopped if a reason for withdrawal is met (refer to section 3.3.4). Overall, 
the trial is estimated to last a total of approximately 36 months.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The trial will be conducted as a prospective, open-label trial. This design is appropriate for 
assessing the long-term tolerability and safety of nintedanib in patients with PF-ILD.
All patients eligible for this extension study will have completed the parent trial, i.e. were 
treated with blinded study drug (nintedanib or placebo) for at least 52 weeks and did not 
prematurely discontinue blinded treatment. All patients in the extension study will receive 
active treatment as prolonged use of placebo would not be appropriate.
3.3
SELECTION OF TRIAL POPULATION
It is anticipated that approximately 480 patients, from approximately 160 sites in about 15 
countries, will complete the INBUILD® trial and will consent to participate (and thus receive 
treatment) in this extension trial. At the start of the open label extension trial it is not known 
which treatment the patients have received in INBUILD®. Patients previously on active 
treatment will continue treatment with nintedanib, patients who received placebo will initiate 
treatment with nintedanib for the first time at Visit 1 of the extension trial.


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A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF).
If a patient is entered in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
Only patients with PF-ILD who have completed the parent trial (INBUILD®) on treatment 
(i.e. did not early discontinue treatment) are eligible and will be included in this trial if they 
fulfil all the inclusion and do not present any of the exclusion criteria.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Male or female patients who completed the INBUILD® trial as planned and who did not 
prematurely discontinue blinded treatment.
2. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
3. Women of childbearing potential (WOCBP)1 must continue to use highly effective 
methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% 
per year when used consistently and correctly, as well as one barrier method, for 28 days 
prior to and 3 months after nintedanib administration. A list of contraception methods 
meeting these criteria is provided in the patient information and in section 4.2.2.4.
3.3.3
Exclusion criteria
1. Any disease that may put the patient at risk when participating in this trial.  Reconsider 
carefully all exclusion criteria of the INBUILD® trial (see Appendix 10.1). However, 
patients may qualify for participation even though exclusion criteria may have been met 
during the course of participation in INBUILD®, if the investigator’s benefit-risk 
assessment remains favourable.
2. Patients who must or wish to continue the intake of restricted medications (see section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial
3. Patient not compliant in parent trial (INBUILD®), with trial medication or trial visits, 
according to investigator’s judgement. 
4. Previous enrolment in this trial.
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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5. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
the patient an unreliable trial participant or unlikely to complete the trial.
6. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”); please see sections 3.3.4.1 and 3.3.4.2 below.
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If the reason for discontinuation is
death, this should be reported on the SAE form as well, regardless of causal relationship.  
These data will be included in the trial database and will be reported.
3.3.4.1
Discontinuation of trial treatment
An individual patient will permanently discontinue trial treatment if:
∀
The patient experiences signs of hepatic injury, defined in section 5.2.5.1.4
∀
In the opinion of the investigator, the patient experiences unacceptable adverse events 
despite dose adjustments and supportive care.
∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
∀
The patient needs to take prohibited concomitant medication as defined in section 4.2.2
“Restrictions”.
∀
The patient can no longer receive nintedanib for medical reasons 
∀
Pregnancy: if a patient becomes pregnant during the trial, nintedanib needs to be stopped 
and the patient should be followed up until birth or otherwise termination of the 
pregnancy.  The data of the patient will be collected and reported in the clinical trial 
report (CTR) until patient’s last visit and any events thereafter will be reported in the BI 
drug safety database.  Refer to section 5.2.5.2.4 for detailed information on event 
reporting in case of pregnancy.
In the following cases discontinuation of nintedanib is highly recommended. Only in special 
circumstances, the investigator, upon thorough assessment of all available clinical data and 
taking into consideration the potential risks associated with administration of nintedanib, may 
decide not to withdraw the trial medication, even though one or more of the below mentioned 
criteria are fulfilled. In such a case, continuation of treatment with trial medication should be 
discussed with the patient, and the decision and reasoning documented in the source data.
∀
Major surgery, including any abdominal or intestinal surgery.
∀
Anti-coagulation. Patients who require full-dose therapeutic anticoagulation (e.g. vitamin 
K antagonists, heparin, hirudin, direct thrombin inhibitors, factor Xa inhibitors etc.), or 
high-dose antiplatelet therapy. (Prophylactic low dose heparin or heparin flush as needed 
for maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. per 
day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 


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325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other antiplatelet therapy 
is allowed.).
∀
Major thrombo-embolic events e.g. stroke, deep vein thrombosis, pulmonary embolism, 
myocardial infarction.
In case of a temporary interruption, trial treatment should be restarted if medically justified, 
please see section 4.2.1.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the options for continued follow up outside of the trial after trial 
discontinuation, please see section 3.3.4.1 above.
Given the patient’s agreement, the patient will undergo the procedures for trial 
discontinuation and follow up (if applicable) as outlined in the Flowchart and section 6.2.3.
3.3.4.3
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 invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
2. Patients have alternative access to nintedanib, for example via an alternative clinical trial, 
marketed product, an expanded access program, named patient use program, 
compassionate use protocol or other means based on local regulation.
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
All patients will be treated with nintedanib in this trial; there is no active comparator or 
placebo.
Substance:
Nintedanib
Pharmaceutical formulation:
Soft gelatine capsule
Source:
BI Pharma GmbH & Co. KG
Unit strength:
150mg, 100mg
Posology:
Bid
Route of administration:
Oral (swallowed)
4.1.2
Selection of doses in the trial and dose modifications
Based on the efficacy, safety and dose-finding from trials investigating nintedanib in IPF, a 
dose of 150 mg bid is selected for the PF-ILD program. With 150 mg bid, acceptable 
tolerability in PF-ILD patients is expected based on the risk profile seen in IPF patients.  
However to manage adverse events, the dose may be reduced to 100 mg bid temporarily or 
permanently (see section 4.2.1 and section 6.2.2).
The objective of INBUILD® was to assess the efficacy and safety of a dose of 150 mg bid 
compared to placebo. Patients were randomised either to blinded nintedanib or to blinded 
placebo 150 mg bid.  
Patients taking 150 mg bid blinded study medication (active drug or placebo) at the end of 
INBUILD® will start treatment with nintedanib 150 mg bid in the current extension trial.
Patients taking 100 mg bid blinded study medication (active drug or placebo) at the end of 
INBUILD® will start treatment with nintedanib in the current extension trial either at 100 mg 
bid or at an increased dose of 150mg bid at the discretion of the investigator.
For patients who receive nintedanib 100 mg bid in the extension study, at the time of 
unblinding (final database lock) of the INBUILD® trial, it is allowed to increase the dose to 
150 mg bid at the discretion of the investigator, based on the unblinding information.  In this 
situation, dose increase will need to be assigned through IRT, and an additional visit might be 
required (refer to section 6.2.2).
Nintedanib can be interrupted or reduced without prior interruption, i.e., immediately 
stepping down from 150 mg bid to 100 mg bid at the discretion of the investigator to manage 
adverse events.  Dose adjustments might require a special trial visit according to the 
procedures in section 6.2.2.


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4.1.3
Method of assigning patients to treatment groups
All patients will receive treatment with nintedanib.  Interactive Response Technology (IRT) 
will be used to assign medication numbers to eligible patients. Distribution of nintedanib to 
sites will be triggered by IRT. Details on the IRT system are provided in the ISF.
4.1.4
Drug assignment and administration of doses for each patient
The treatment for an individual patient will be assigned by means of an IRT contact during 
Visits 1, 3, 5, 6, 7, 8 to X.  Each patient will receive active drug at a dosage of 150mg bid or 
100mg bid.  
Trial medication will consist of 1 capsule twice daily throughout the trial.  Wallets covering
30 days + 5 days reserve treatment will be dispensed to the patient:
∀
1 wallet at Day 1 (Visit 1) (30 days plus 5 days reserve)
∀
2 wallets at Visit 3 (60 days plus 10 days reserve)
∀
3 wallets at Visit 5, Visit 6, Visit 7, Visit 8 and Visit X (90 days plus 15 days reserve)
Nintedanib will be administered orally on a twice daily basis (bid).  The patients should 
swallow the trial medication unchewed together with a glass of water (~250mL), and should 
observe a dose interval of 12 hours.  Nintedanib needs to be taken at the same times every 
day (between 06:00 and 11:00 in the morning, and between 18:00 and 23:00 in the evening).  
Because nintedanib may cause stomach discomfort, it is recommended to take the trial 
medication with food.
A forgotten dose should be skipped if the time window to the next dose is less than 8 hours.  
The next dose should be taken as scheduled.
Nintedanib should only be dispensed to participating patients according to the protocol by 
authorised personnel as documented in the form “Trial Staff List”.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
In this open-label trial, treatment allocation will not be concealed throughout the trial. The 
CRF will contain information on actual treatment.
The previous treatment received in INBUILD® (active drug or placebo) will remain unknown 
to the investigator and patient until after the final database lock of INBUILD®. No individual 
unblinding regarding treatment received in INBUILD® should occur prior to this time.
4.1.5.2
Unblinding and breaking the code
Not applicable.


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4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated clinical 
research organisation (CRO). They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice (GMP). Initial supply and re-supply to the sites 
will be managed via an IRT system, which will also monitor expiry dates of supplies 
available at the sites, and assign treatment kits to each patient.
For details of packaging and the description of the label, refer to the ISF.
Primary trial material will be capsules containing 150 mg of nintedanib (or 100 mg of 
nintedanib if dose is reduced). All trial medication will be packaged in blister cards. Each 
blister card will contain 10 capsules. Seven blisters cards will be packaged into one child-
resistant tamper-evident wallet (i.e. 70 capsules/wallet). Each wallet will be labelled with a 
multi-language booklet according to the requirements of the participating countries.
One wallet provides for one month of treatment.
Re-supplies of trial medication are planned due to the short expiry date and the long duration 
of the trial. The medication for re-supply will be packaged in an identical manner as the 
medication for initial supply.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by a clinical 
research organisation (CRO) appointed by the sponsor when the following requirements are 
fulfilled:
∀
Approval of the clinical trial protocol by the institutional review board (IRB) / ethics 
committee (EC),
∀
Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational site,
∀
Approval/notification of the regulatory authority, e.g. competent authority,
∀
Availability of the curriculum vitae of the Principal Investigator,
∀
Availability of a signed and dated clinical trial protocol,
∀
In countries where it is required, availability of the proof of a medical license for the 
Principal Investigator,
∀
In the US, availability of FDA Form 1572.


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Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee 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 warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal.
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor or appointed CRO, the investigator or designee 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.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Rescue medications to reverse the action of nintedanib are not available.
There are no special emergency procedures to be followed.
Dose reduction (from 150 mg bid to 100 mg bid) or treatment interruption should be 
considered to manage adverse events. No further dose reduction is possible for patients on the 
100 mg bid dose. In case of persistent adverse events observed at this dose, or severe effects 
at 150 mg bid, permanent treatment discontinuation should be considered.
Dose reduction from 150 mg bid to 100 mg bid was possible at Visit 1 if required to manage 
adverse events identified at the end of the INBUILD® trial.
Treatment interruption and reduction and re-escalation are repeatedly possible.
Table 4.2.1: 1
Allowed treatment reduction / interruption periods
AEs considered drug related
AEs or other events not 
considered drug related
Maximum interruption
4 weeks
12 weeks
Recommended restart
with reduced dose (100 mg bid)
with the same dose (100 mg bid or 
150 mg bid)
Re-escalation
Any time to 150 mg bid
----


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4.2.1.1
Management of diarrhoea
Diarrhoea is a known side effect of nintedanib treatment (see section 1.2).  However, 
potential causes for diarrhoea other than study medication should always be considered and 
treated accordingly (e.g. viral infections, bacterial overgrowth, antibiotic treatment).
Diarrhoea should be managed as early as possible after onset of first symptoms with standard 
antidiarrhoeal symptomatic treatment, e.g. loperamide.
If diarrhoea persists despite optimal symptomatic treatment, treatment interruption and dose 
reduction of nintedanib should be considered based on the recommendations described in 
table 4.2.1.1:1.
Table 4.2.1.1: 1
Management of diarrhoea (considered related to trial medication)
Description
Symptomatic Treatment*
Action with trial medication
Diarrhoea with 
increase of <4 stools 
per day over baseline1.
Initiate anti-diarrhoeal medicines 
at first signs of symptoms (e.g. 
4 mg loperamide followed by 
2 mg after each loose stool or 
every 2-4 hours to a maximum of 
16 mg/day) until bowel 
movements cease for 12 hours.
Continue same trial medication 
dose.
Diarrhoea with 
increase of 4 to 6 
stools per day over 
baseline1.
Initiate/continue anti-diarrhoeal 
medicines;
If diarrhoea of this severity 
persists for ≥48 to 72 hours assess 
for dehydration and electrolyte 
imbalance; 
In addition, consider IV fluids and 
electrolyte replacement as 
clinically indicated.
If diarrhoea persists for ≥48 to 72 
hours despite optimal symptomatic 
care:
1.
Interrupt trial medication until 
recovery.
2.
Reduce dose to 100 mg bid 
after recovery. 
3.
Re-escalate to 150 mg bid 
within 4 weeks if deemed 
clinically appropriate.
Diarrhoea with 
increase of ≥7 stools 
per day over baseline1; 
stool incontinence, 
or
life threatening 
consequences.
Follow recommendations above.
In addition, consider stool work-
up to exclude infectious colitis; 
adequate IV fluid replacement 
≥24 hours, hospitalisation as 
clinically indicated; consider 
referral to a GI specialist to rule 
out potential differential 
diagnoses.
1.
Interrupt trial medication until 
recovery.
2.
Reduce dose to 100 mg bid 
after recovery.
3.
Consider re-escalation within 4 
weeks to 150 mg bid if deemed 
clinically appropriate.
In case of reoccurrence of diarrhoea 
of this severity despite optimal 
symptomatic treatment and dose 
reduction, treatment with trial 
medication should be permanently 
discontinued.
Footnotes:
* Other causes for diarrhoea should always be considered and treated accordingly (e.g. viral infections, bacterial overgrowth, 
antibiotic treatment)
1 Baseline defined as usual stools/day prior to visit 1.


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4.2.1.2
Management of liver enzyme elevation
Evaluate the concomitant use of other drugs known to cause liver enzyme elevations. For a 
detailed guidance on how to manage liver enzyme elevations, please refer to Table 4.2.1.2: 1.
Table 4.2.1.2: 1
Management of liver enzyme elevations
AST or ALT increase to
Signs of hepatic injury* 
(section 5.2.5.1.4)
>1.5x to <3x
ULN
≥3x to <5x
ULN and no 
signs of  
hepatic injury
(section 
5.2.5.1.4)
≥5x to <8x
ULN and no 
signs of  
hepatic injury
(section 
5.2.5.1.4)
Continue as 
planned1
Reduce dose or 
interrupt trial 
medication 2
Interrupt trial 
medication 
Permanently discontinue / 
interrupt trial medication
CLINICAL 
EVALUATION OF 
HEPATIC INJURY4
(section 5.2.5.1.4) 
Close 
observation3
After 2 weeks 
or any time 
later
Close 
observation3
After 2 weeks 
or any time 
later
<3x ULN
≥3x ULN
< 3x ULN
≥3x ULN
Reduced: return 
to initial dose.
Interrupted: 
restart at reduced 
dose.
Monitor every 2 
weeks for at least 
8 weeks
Permanently 
discontinue 
trial medication
Close 
observation3
Restart at 
reduced dose
Monitor 
weekly for 4 
weeks, then 
every 2 weeks
for at least 8 
weeks
Permanently discontinue 
trial medication.
Close observation3
Footnotes:
*Signs of hepatic injury are defined as
∀
ALT and/or AST ≥8 fold ULN
∀
ALT and/or AST ≥3 fold ULN and total bilirubin ≥2 fold ULN 
∀
ALT and/or AST ≥3 fold ULN and unexplained INR >1,5
∀
ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%)
∀
ALT and/or AST ≥3 fold ULN and appearance of fatigue, nausea, vomiting, right upper abdominal quadrant pain 
or tenderness, fever and/or rash
1 According to visit schedule. Consider additional control visits as adequate.
2 To be decided by Investigator, based on individual risk assessment.
3 Close observation: Re-test ALT and AST, alkaline phosphatase, total bilirubin, and eosinophils within 48 to 72 hours, then 
after approximately 7 days and after approximately 2 weeks by using intermediate visit lab kit.
4If clear evidence for alternative cause for hepatic injury was identified and resolved (i.e. relation to trial medication 
excluded, hepatic injury confirmed to have alternative explanation [other than use of IMP]): return to trial 
medication would be possible, after consultation with the sponsor. Prior to restart, liver laboratory values must be 
normal. Monitor weekly for first 4 weeks of re-introduction and every 2 weeks for the following 8 weeks.


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Initial assessment and blood sampling for liver enzyme elevation follow up should be 
performed at the investigational site. Blood samples for additional monitoring may be 
collected at the investigational site, primary care physician or external laboratory with 
specific trial lab kits and sent to the central laboratory for analysis.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Investigational therapy is not allowed during the entire study period of this open label 
extension trial. 
There are no further restrictions for treatment of the underlying disease or other treatments 
for the ILD, thus allowing the underlying disease to be managed according to current 
standard practice (see cautionary notes below).
4.2.2.2
Cautionary notes
As nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4, concomitant use of 
P-gp and CYP3A4 inhibitors (e.g. erythromycin) with nintedanib may increase exposure to 
nintedanib. Patients taking potent P-gp inhibitors (e.g. ketoconazole, erythromycin or 
ciclosporine) should be monitored closely for tolerability of nintedanib.  Management of 
adverse events may require interruption, dose reduction, or discontinuation of therapy with 
nintedanib.
Concomitant use of P-gp and CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin, 
and St. John’s wort) with nintedanib may decrease exposure to nintedanib and should be 
avoided.
As the most common side effects known for nintedanib are GI effects, the concomitant use of 
medication with an overlapping safety profile (e.g. methotrexate, mycophenolate mofetil) 
should be carefully considered.
Nintedanib is associated with increases in liver enzymes and bilirubin. If in addition to the 
trial medication, a treatment is introduced that is known to induce AST/ALT elevations (e.g. 
methotrexate, bosentan), additional measurements of liver enzymes (ALT and AST, alkaline 
phosphatase, total bilirubin, and eosinophils) are recommended every 2 weeks for 
approximately 6 weeks, by using the intermediate (a-visit) trial lab kit.
The concomitant use of full dose therapeutic anticoagulation or high dose antiplatelet therapy 
(e.g. acetyl salicylic acid >325 mg/day, or clopidogrel >75 mg/day, or equivalent doses of 
other antiplatelet therapy) is not recommended (see note section 3.3.4.1).
4.2.2.3
Restrictions on diet and life style
There are no restrictions on diet and lifestyle.


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4.2.2.4 
Contraception requirements
WOCBP (for the definition please refer to section 3.3.2) must continue to use two medically 
approved methods of birth control throughout the trial, and for a period of at least 3 months
after last trial drug intake. They must use one barrier method, i.e. condom or occlusive cap 
with spermicide, or vasectomised partner, and one highly effective non-barrier method 
including oral, injected or implanted hormonal contraceptives, intrauterine device or system
or bilateral tubal occlusion.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on capsule counts, treatment compliance will be calculated as the number of capsules 
taken, divided by the number of capsules which should have been taken according to the 
scheduled period, multiplied by 100. Compliance will be verified by the on-site monitor 
authorised by the sponsor.
Treatment compliance (%) =
Number of capsules actually taken # 100
Number of capsules which should have been taken
If the number of doses taken is not between 80-120%, site personnel will explain the patient 
the importance of treatment compliance.


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5.
ASSESSMENTS


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5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination, including body weight, will be performed at the time 
points specified in the Flowchart. It includes at a minimum general appearance, neck, lungs, 
cardiovascular system, abdomen, extremities, and skin. 
Measurement of height will be performed at Visit 1. 
All abnormal findings at baseline (Visit 1) in the extension trial will be recorded on the 
Baseline Condition eCRF page.  New abnormal findings or worsening of baseline conditions 
in the extension trial detected at subsequent physical examinations, if judged clinically 
relevant, will be recorded as adverse events on the appropriate eCRF page.
5.2.2
Vital signs
Systolic and diastolic blood pressure and pulse rate will be measured at the time points 
specified in the Flowchart, ideally prior to blood sampling and with the patient seated after 
having rested.  All abnormal findings at baseline (Visit 1) in the extension trial will be 
recorded on the Baseline Condition eCRF page.  New abnormal findings or worsening of 
baseline conditions in the extension trial detected at subsequent physical examinations, if 
judged clinically relevant, will be recorded as adverse events on the appropriate eCRF page.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3:1. For the sampling time 
points please see the Flowchart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 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 lab and detailed documentation 
(Laboratory Manual) will be included in the ISF.
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to section 5.2.5.2).


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In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see section 5.2.5.1.4 and the DILI Checklist provided in the ISF). The 
amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
The laboratory tests at regular site visits (Visit 1, Visit 3, Visit 5, Visit 6, Visit 7, Visit 8 to X) 
will include: 
Table 5.2.3: 1
Laboratory tests
Category
Laboratory test 
Haematology
Red blood cell count (RBC)
Haemoglobin (Hb)
Haematocrit (Hct)
Mean corpuscular volume
White blood cell count including differential
Platelet count
Biochemistry 
Aspartate aminotransferase (AST)
Alanine transaminase (ALT)
Gamma-glutamyl transferase  (GGT)
Alkaline phosphatase (ALK)
Creatine kinase (CK)
Lactate dehydrogenase (LDH)
Total protein
Total bilirubin
Creatinine
Glucose (non fasting)
Uric acid
Thyroid stimulating hormone (at V1 then every 48 weeks and at EOT)
Electrolytes
Sodium
Potassium
Calcium
Chloride
Inorganic phosphorus
Coagulation
International normalised ratio (INR)
Partial thromboplastin time (PTT)
Prothrombin time  (PT)
Local Urine dipstick pregnancy test in all women of childbearing potential. If urine test is not 
acceptable to local authorities, a blood test must be done at a local laboratory.


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The laboratory tests at Visit 2, Visit 4, Visit 5a, Visit 6a and Visit 7a will include:
Table 5.2.3: 2
Laboratory tests at Visit 2, Visit 4, Visit 5a, Visit 6a and Visit 7a
Category
Laboratory test 
Biochemistry
Total protein, creatinine, electrolytes (sodium, potassium, calcium, chloride, 
inorganic phosphorus) and liver function (AST, ALT, GGT, alkaline 
phosphatase, and total bilirubin)
Local Urine dipstick pregnancy test in all women of childbearing potential. If urine test is not 
acceptable to local authorities, a blood test must be done at a local laboratory.
The laboratory samples taken at intermediate ‘a’ visits (Visits 5a, 6a and 7a) and any samples 
taken for additional safety monitoring (see section 4.2.1.2) may be collected at the office of a 
local doctor using trial specific lab kits that will be sent to a central laboratory for analyses.  
These kits will be provided to patients at study visits as applicable.
Creatinine clearance will be calculated based on serum creatinine according to Cockcroft and 
Gault (R96-0690), Appendix 10.2).  
If laboratory values indicate abnormality, adequate and more frequent blood sampling may be 
performed at the discretion of the Investigator. Dependent on concomitant treatments, 
additional safety monitoring should be considered at the discretion of the investigator.  
In case of liver function value elevations, close monitoring must be ensured by the 
Investigator. Refer to section 4.2.1.2 for monitoring elevations and section 3.3.4 for 
withdrawal criteria.
5.2.4
Electrocardiogram
Resting 12-lead electrocardiograms (ECGs) will be conducted during the trial with site’s own 
equipment.  The 12-lead ECGs must be administered by a qualified technologist and results 
will be recorded as scheduled in the Flowchart. The investigator or a designee will evaluate 
whether the ECG is normal or abnormal and assess clinical relevance. ECGs may be repeated 
for quality reasons and a repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at Visit 1) or otherwise as AEs and will be followed up and/or treated as medically 
appropriate.


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5.2.5
Assessment of adverse events
5.2.5.1
Definitions of AEs 
5.2.5.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable
according to the criteria in section 5.2.5.1.2):
∀Worsening of the underlying disease or of other pre-existing conditions 
∀Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, including adverse events that 
started during the parent trial, INBUILD®, and that are still ongoing at the time of Visit 1 of 
the extension trial, they will be considered as baseline conditions and should be collected on 
the Baseline Condition eCRF only.
5.2.5.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation,
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
For Japan only:
The following events will be handled as “deemed serious for any other reason”. AEs which 
possibly lead to disability will be reported as SAEs.


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5.2.5.1.3
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.5.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the electronic data capture (eDC) 
system. A copy of the latest list of “Always Serious AEs” will be provided upon request.
These events should always be reported as SAEs as described above.
5.2.5.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.5.2.2.
Adverse events relating to gastrointestinal perforation and hepatic injury will be considered
AESIs.
Hepatic injury
In this trial protocol, signs of hepatic injury are defined as:
∀
ALT and/or AST ≥8 fold ULN
∀
ALT and/or AST ≥3 fold ULN and total bilirubin ≥ 2 fold ULN* 
∀
ALT and/or AST ≥3 fold ULN and unexplained INR > 1,5*
∀
ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%)*
∀
ALT and/or AST ≥3 fold ULN and appearance of fatigue, nausea, vomiting, right 
upper abdominal quadrant pain or tenderness, fever and/or rash
* in the same blood draw sample.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to immediately stop the trial medication and need to be followed up 
according to the “drug-induced liver injury (DILI) checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are


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analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
5.2.5.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.5.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug.
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced.
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).
∀
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∀
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.


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5.2.5.2
Adverse event collection and reporting
5.2.5.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial: 
all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for new AEs but should only 
report on the SAE form, any occurrence of cancer and related SAEs and related AESIs of 
which the investigator may become aware of by any means of communication, e.g. phone 
call.  Those AEs should however not be reported in the CRF.
5.2.5.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours ) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
5.2.5.2.3
Information required
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been assessed as “chronic” or “stable”, or no further 
information can be obtained.
5.2.5.2.4
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).


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As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.5.2.5    Safety monitoring and adverse events with additional information collection
Additional details (on top of standard AE and SAE reporting) will be collected in the eCRF 
for the adverse event ‘Diarrhoea’ and the adverse events in the subordinate Standard 
MedDRA Query (SMQ) ‘Haemorrhage terms, excluding laboratory terms’.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Not applicable
5.3.2
Methods of sample collection
Not applicable
5.3.3
Analytical determinations
Not applicable
5.3.4
Pharmacokinetic – pharmacodynamic relationship
Not applicable
5.4
ASSESSMENT OF BIOMARKER(S)
Not applicable
5.5
BIOBANKING
Not applicable
5.5.1
Methods and timing of sample collection
Not applicable
5.6
OTHER ASSESSMENTS
Not applicable.


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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 Flowchart.
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 Flowchart. Some flexibility 
is allowed in scheduling the visits according to visit time windows as specified in the 
Flowchart. The trial medication kits contain sufficient medication to allow for these time 
windows. If any visit has to be rescheduled, subsequent visits should follow the original visit 
date schedule (calculated from Visit 1). All deviations from the planned visit schedule will be 
documented.  In case of a missed visit, the investigator should contact the local clinical 
monitor, these will be addressed on a case by case basis.
All patients that complete the INBUILD® trial and did not prematurely discontinue blinded 
treatment may be eligible for this trial. After giving informed consent (at the latest before any 
procedure related to this study 1199-0248 is performed), and if all inclusion criteria and none 
of the exclusion criteria are met, patients enter the trial on the same day as the EOTB visit in 
the parent trial, INBUILD®.
Patients will be requested to stay in the trial for 96 weeks (until visit 12). At week 96, patients 
who can be treated with nintedanib outside the clinical trial will have their EOT visit. The 
remaining patients will continue in the trial until nintedanib can be made available to them 
outside the clinical trial. Treatment will be stopped if a reason for withdrawal is met (refer to 
section 3.3.4). 
In exceptional circumstances, when it is impossible to conduct study visits at the study site, 
study visits may be performed at the patient’s home or remotely (via telephone and/or 
internet based means of communication). The visit may also be performed as a hybrid of 
home and remote visit. All home/remote visits need to be discussed and approved by the 
sponsor’s trial team. Local regulatory and legal requirements of the participating country still 
apply. The trial team’s decision will be based on a thorough benefit-risk evaluation.
The procedures performed during a home/remote visit may be adjusted as compared to a 
regular visit, as detailed in Appendix 10.3.
If blood sampling for central lab at the trial site is not possible, safety lab analyses can be 
performed at a local lab. The results of the lab tests must be transferred to the investigator 
who ensures medical review and proper documentation in the eCRF. Minimum required 
safety lab parameters are AST, ALT, GGT, ALK and Total bilirubin.  For patients who have 
been in the trial for at least 36 weeks, the maximum interval between two lab measurements 
for these parameters is 16 weeks.  If the interval is more than 16 weeks, trial treatment should 
be interrupted (refer to section 4.2.1).  These measures relating to lab sampling were not 
possible early in the trial when frequent monitoring was mandatory.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The investigations and assessments will be performed as outlined in the Flowchart and as
per the descriptions listed below.


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6.2.1
Screening and run-in period(s)
Visit 1 will be conducted on the same day as EOTB of the parent trial, INBUILD® so that 
there is no interruption of treatment. The trial will be explained to all patients who completed 
INBUILD® (who didn’t discontinue treatment) and are willing to continue or start treatment 
with nintedanib.  This may be done prior to Visit 1, however no trial related procedure or data 
collection should be performed until the patient has signed the Informed Consent for the 
extension trial at Visit 1.  
Upon obtaining informed consent, the investigator will register the patient in the IRT system 
and the patient will receive a trial identification card.
Assessments conducted as part of EOTB of the INBUILD® trial do not need to be repeated for 
Visit 1 of this extension trial.  
If the patient has been determined eligible by the investigator to enter the trial (refer to 
section 3.3), medication will be assigned to the patient via the IRT system (refer to section
4.1.3).  First dose of nintedanib within INBUILD®-ON will be administered in the clinic at 
Visit 1. Data from the EOTB assessments will be transferred to INBUILD®-ON as baseline 
data.  All AEs ongoing at the EOTB visit of INBUILD® will be recorded as baseline 
conditions in INBUILD®-ON.
6.2.2
Treatment period(s)
Subsequent clinic visits will be scheduled after 2, 4, 8, 12, 24, 36 and 48 weeks of treatment 
(Visits 2- 8).  After the first 48 weeks of treatment (Visit 8), complete clinic visits will be 
scheduled every 12 weeks until at least Week 96 (Visit 12) and thereafter until the patient’s 
end of trial.  
Intermediate lab tests (‘a’ visits) will be performed if needed at 18, 30 and 42 weeks (Visits 
5a, 6a and 7a) at the discretion of the investigator.  The laboratory samples taken at these
visits and any samples taken for additional safety monitoring (see sections 4.2.1.2 and 5.2.3)
may be collected at the office of a local doctor using trial specific lab kits that will be sent to 
a central laboratory for analyses.  These kits will be provided to patients at study visits as 
applicable.
If possible, ECG should be performed prior to blood draw.  
For detailed description of the trial procedures at each visit and dispensing schedule, please 
refer to section 5 and the Flowchart.
Dose Modification Visit
If the dose is reduced or increased (refer to section 4.1.3) patients may need to come to the 
investigational site for a dose modification visit where the following will be performed:
∀
Physical examination including weight
∀
Vital signs


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∀
Assessment of adverse events and concomitant therapy since last visit
∀
Assignment of new dose in IRT and trial medication dispensation
∀
Trial medication will be collected and drug accountability and treatment compliance 
will be reviewed
End of Treatment (EOT)
If a reason for drug discontinuation is met or when the trial is terminated due to one of the 
reasons mentioned in section 3.3.4, an End of Treatment Visit (EOT) should be scheduled as 
soon as possible after last drug intake for all patients.  Reason for discontinuation must be 
documented in the eCRF.  IRT should always be notified on end of treatment (EOT).
Adverse events that are ongoing at EOT should be followed up according to section 5.2.5.2.3.
For detailed description of the trial procedures at the EOT visit, please refer to the Flowchart. 
6.2.3
Follow up period and trial completion
A follow-up (FU) visit must be conducted 28 days after last drug intake if trial medication 
was discontinued permanently due to adverse events. A FU visit does not need to be 
conducted for patients who stop for any other reason.
For detailed description of the trial procedures at the FU visit, please refer to the Flowchart.
If the reason for removal of a patient from the treatment is an adverse event, the patient must 
be followed until complete resolution or stabilization of the event for at least 28 days after the 
onset of the event or until follow-up is considered adequate by the investigator and clinical 
monitor. 
A patient will be 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.
For patients who permanently discontinue nintedanib due to adverse events, the FU Visit will 
be the trial completion visit.  For all other patients the EOT visit will be the trial completion 
visit.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a multi-centre, multi-national, open-label clinical trial to investigate the long-term 
tolerability and safety of nintedanib in patients with Progressive Fibrosing Interstitial Lung 
Disease (PF-ILD) previously treated in a double-blind phase III placebo controlled trial 
(INBUILD®).
As the main objective of this extension trial is to study long-term tolerability and safety, only 
descriptive statistics will be used. Some limitations due to the nature of the extension trial 
should be considered when interpreting the data (bias in the selection of the population, no 
comparative arm). Further endpoints are considered as exploratory only.
This statistical paragraph deals with the analyses to be performed on the extension trial only. 
Although data of the parent trial will not be described in the scope of these analyses, they will 
be taken into account for adverse events analyses, as well as other evaluations.
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
All evaluations will be based on the treated set (TS), unless otherwise stated. The TS will 
consist of all patients who are documented to have received and taken at least one dose of 
open-label trial 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, restricted medications and inadequate 
follow-up of hepatic events.
Patients will be analysed according to their randomised treatment group in the previous trial 
(INBUILD®) and overall.
Values collected at Visit 1 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 
during the on treatment period. 


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7.3.1
Primary endpoint analyses
The primary objective of the study is to assess the tolerability and safety of nintedanib, so 
please refer to section 7.3.4. Number of patients and % will be presented over the extension 
trial by category for adverse events overall.
7.3.2
Secondary endpoint analyses
Not applicable.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 28 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
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) at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.


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Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Not applicable.
7.4
INTERIM ANALYSES
Interim analyses could be performed upon request from Health Authorities or for publication 
purpose. All the above mentioned analyses may be presented at each interim analysis.
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.
Missing or incomplete data for survival are managed by censored data analyses. No specific 
procedures need to be specified to handle them.
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 who have completed INBUILD® and did not 
prematurely discontinue trial medication, who fulfil the eligibility in this trial and are willing 
to participate.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC)
and the harmonised standards for Medical Devices (ISO 14155, current version).
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) and other relevant regulations. Investigators and site staff 
must adhere to these principles.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, 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 investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 


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The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Source documents in addition to the patient file are:
∀
∀
Laboratory reports


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


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8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the 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
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined as 
the date on which the last patient in the whole trial is administered the last dose of trial 
treatment (as scheduled per protocol or prematurely). Individual investigators will be notified 
of SUSARs occurring with the trial medication until 30 days after LPLT at their site. Early 
termination of the trial is defined as the premature termination of the trial due to any reason 
before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 


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Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF.     
BI has appointed a Trial Clinical Monitor (TCM), responsible for coordinating all required 
activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Local Clinical Monitors (CML), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, 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.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, 
and an IRT vendor will be used in 
this trial. Details will be provided in the Central Laboratory Manual, Spirometry Manual and
IRT Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
c26471552
BI investigational product: Nintedanib (BIBF 1120). Page: 1 of 13. Report 
date: 15 Aug 2019. Trial no./Doc. no.: 1199.247 / c26471552-02. Dates of 
trial:.
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.
P11-07084
Raghu G, et al, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary     
Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary 
fibrosis: evidence-based guidelines for diagnosis and management. Am J 
Respir Crit Care Med 183 (6), 788 - 824 (2011).
P11-11216
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 365 (12), 1079 - 1087 (2011)
P14-02860
Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Anti-fibrotic and 
anti-inflammatory activity of the tyrosine kinase inhibitor, nintedanib, in 
experimental models of lung fibrosis. J Pharmacol Exp Ther 349, 209 - 220 
(2014)
P14-07514
Richeldi L, et al, INPULSIS Trial Investigators. Efficacy and safety of 
nintedanib in idiopathic pulmonary fibrosis. New England Journal of 
Medicine, published on May 18, 2014, doi: 10.1056/NEJMoa1402584 N 
Engl J Med 2014. 370(22):2071-2082.
P14-17410
Hostettler KE, Zhong J, Papakonstantinou E, Karakiulakis G, Tamm M, 
Seidel P, Sun Q, Mandal J, Lardinois D, Lambers C, Roth M. Anti-fibrotic 
effects of nintedanib in lung fibroblasts derived from patients with idiopathic 
pulmonary fibrosis. Respir Res (Lond) 15, 157 (2014)
P15-02392
Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, Kolb 
M. Mode of action of nintedanib in the treatment of idiopathic pulmonary 
fibrosis. Eur Respir J 45 (5), 1434 - 1445 (2015)
P15-06100
Huang J, Beyer C, Palumbo-Zerr K, Zhang Y, Ramming A, Distler A, Gelse 
K, Distler O, Schett G, Wollin L, Distler JHW. Nintedanib inhibits fibroblast 
activation and ameliorates fibrosis in preclinical models of systemic 
sclerosis. Ann Rheum Dis 75 (5), 883 - 890 (2016)
R96-0690
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976. 16(1):31-41.


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9.2
UNPUBLISHED REFERENCES
c01783972-11
Investigator’s Brochure (IB) for nintedanib in IPF, Systemic Sclerosis and 
PF-ILD
n00239669
 Evaluation of Nintedanib in preclinical model systems of 
systemic sclerosis. Study number Dist-GvHD-Tsk-1-Fra-2. 26 September 
2014. This was submitted to IND 124707 on January 15, 2015 (Sequence 
0001/Serial Number Not Applicable), Module 4.2.1.1.
n00247887
 Evaluation of the therapeutic efficacy of 
Nintedanib in a model of rheumatoid arthritis-associated intersitial lung 
disease. 11 Feb 2016.
U06-1451
 Dose-dependent effects of BIBF 1120 ES on bleomycininduced 
lung fibrosis in rats. 1 Jun 2006.
U06-1479
 Effect of 50 mg/kg BIBF 1120 ES on bleomycin-induced lung 
fibrosis in rats using a delayed treatment model. 14 Jun 2006
U12-2066-01
 Effect of nintedanib (BIBF 1120) on silica-induced lung 
inflammation and fibrosis. 31 July 2012.
U12-2437-01
 Effect of nintedanib (BIBF 1120) on bleomycin-induced lung 
inflammation and fibrosis. 19 October 2012.   
U13-2683-01/ 
c02153150-02
Clinical Overview Nintedanib (BIBF 1120) Treatment of idiopathic 
pulmonary fibrosis (IPF) and to slow disease progression. 07 Apr 2014 


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10.
APPENDICES
10.1
1199.247 (INBUILD®) EXCLUSION CRITERIA (BASED ON FINAL 
PROTOCOL VERSION 2 DATED 21 DEC 2016)
1. AST, ALT > 1.5 x ULN at Visit 1
2. Bilirubin > 1.5 x ULN at Visit 1
3. Creatinine clearance <30 mL/min calculated by Cockcroft–Gault formula at Visit 1 
(refer to Appendix 10.2).
4. Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic 
impairment).
5. Previous treatment with nintedanib or pirfenidone.
6. Other investigational therapy received within 1 month or 6 half-lives (whichever was 
greater) prior to screening visit (Visit 1).
7. Use of any of the following medications for the treatment of ILD: azathioprine (AZA), 
cyclosporine, MMF, tacrolimus, oral corticosteroids (OCS) >20mg/day and the 
combination of OCS+AZA+NAC within 4 weeks of Visit 2, cyclophosphamide within 
8 weeks of Visit 2, rituximab within 6 months of Visit 2.
Note: Patients whose RA/CTD is managed by these medications should not be 
considered for participation in the current study unless change in RA/CTD medication 
is medically indicated 
8. Diagnosis of IPF based on ATS/ERS/JRS/ALAT 2011 Guidelines (P11-07084).
9. Significant Pulmonary Arterial Hypertension (PAH) defined by any of the following:
a.
Previous clinical or echocardiographic evidence of significant right heart failure
b. History of right heart catheterization showing a cardiac index ≤ 2 l/min/m²
c.
PAH requiring parenteral therapy with epoprostenol/treprostinil
10. Primary obstructive airway physiology (pre-bronchodilator FEV1/FVC < 0.7 at 
Visit 1).
11. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
12. Major extrapulmonary physiological restriction (e.g. chest wall abnormality, large 
pleural effusion)
13. Cardiovascular diseases, any of the following:
a.
Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 
6 month of Visit 1
b. Myocardial infarction within 6 months of Visit 1
c.
Unstable cardiac angina within 6 months of Visit 1
14. Bleeding risk, any of the following:
a.
Known genetic predisposition to bleeding.
b.
Patients who require 
i. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, 
direct thrombin inhibitors, heparin, hirudin)
ii. High dose antiplatelet therapy. 
[Note: Prophylactic low dose heparin or heparin flush as needed for 
maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. 
per day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic 


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acid up to 325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other 
antiplatelet therapy) are not prohibited].
c.
History of haemorrhagic central nervous system (CNS) event within 12 months of 
Visit 1.
d.
Any of the following within 3 months of Visit 1:
i. Haemoptysis or haematuria
ii. Active gastro-intestinal (GI) bleeding or GI – ulcers
iii. Major injury or surgery (Investigators judgment).
e.
Coagulation parameters: International normalized ratio (INR) >2, prolongation of 
prothrombin time (PT) and activated partial thromboplastin time (aPTT) by >1.5 x 
ULN at Visit 1.
15. History of thrombotic event (including stroke and transient ischemic attack) within 12 
months of Visit 1.
16. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin)
17. Patients with peanut allergy.
18. Other disease that may interfere with testing procedures or in the judgment of the 
Investigator may interfere with trial participation or may put the patient at risk when 
participating in this trial.
19. Life expectancy for disease other than ILD < 2.5 years (Investigator assessment).
20. Planned major surgical procedures.
21. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
22. Women of childbearing potential not willing or able to use highly effective methods of 
birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year 
when used consistently and correctly as well as one barrier method for 28 days prior to 
and 3 months after nintedanib administration. A list of contraception methods meeting 
these criteria is provided in the patient information.
23. In the opinion of the Investigator, active alcohol or drug abuse.
24. Patients not able to understand or follow trial procedures including completion of self-
administered questionnaires without help.
10.2
CREATININE CLEARANCE
Creatinine clearance calculation is done according to Cockcroft and Gault (R96-0690).
∀
Creatinine clearance = (140 - age) x (Weight in kg) x (0.85 if female) / (72 x serum 
creatinine in mg/dL)


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10.3
VISIT MODIFICATION IN EXCEPTIONAL CIRCUMSTANCES
INITIAL 
MODIFIED or ADDED 
Face-to-face patient visit performed 
by a physician/under the 
responsibility of a physician on site.
Remote or home visit performed by the  investigational site physician/under the responsibility of the 
investigational site physician to ensure the wellbeing of a patient and to collect at least: Adverse Events / 
Concomitant Treatments and Drug Interruption 
Regular on-site safety lab test using 
central lab kits:
∀
Haematology, Biochemistry, 
Electrolytes, Coagulation, 
Urinalysis every 12 weeks; 
additional liver enzyme 
monitoring optional in between
∀
Pregnancy every 4-6 weeks 
(possible at home)
∀
Under treatment with nintedanib, regular liver enzyme monitoring is required and needs to be ensured by the 
investigational site, but can be done at a local lab / local doctor.  The investigator has to ensure medical review 
and proper documentation in the eCRF.  Minimum required safety lab parameters are AST, ALT, GGT, ALK 
and Total bilirubin.
∀
Urine pregnancy tests (for women of childbearing potential only) are regularly required and may be done at 
local lab / local doctor, or at home. 
∀
For patients who have been in the trial for at least 36 weeks, the maximum interval between two lab 
measurements for these parameters is 16 weeks.  If the interval is more than 16 weeks, trial treatment should 
be interrupted.  These measures relating to lab sampling were not possible early in the trial when frequent 
monitoring was mandatory.  Decision whether to continue nintedanib treatment should be made based on an 
individual risk assessment for that individual patient and weigh up the benefits of an extended lab interval to 
maximum 16 weeks versus an interruption of treatment.
∀
Medical decision has to be documented in patient’s source notes.
If remote patient visits and/or local liver enzyme monitoring cannot be performed, nintedanib treatment needs to 
be interrupted.
If liver function tests are out of the 
range, the per protocol rules apply => 
dose reduction
If the patient cannot come to site to receive new dose treatment and/ or patient safety and follow up safety lab 
testing cannot be guaranteed, treatment needs to be interrupted.
Dispensation of study treatment on 
site
∀
Site / depot to patient IMP shipments
∀
Patients must consent to providing contact details for shipping purposes 
∀
Patients should retain all unused IMP and packaging, and return it when they are able to return to the site.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
01 Sep 2020
EudraCT number
EU number
2018-000525-32
BI Trial number
1199-0248
BI Investigational Medicinal 
Product(s)
Nintedanib
Title of protocol
An open-label extension trial of the long-term 
safety of nintedanib in patients with Progressive 
Fibrosing Interstitial Lung Disease (PF-ILD)
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
1. Introduction
Description of change
Section 1 was updated to ensure that current 
knowledge and recent data are reflected in the 
indroduction section. 
Rationale for change
New data of pivotal trial (1199-0248) available.
Section to be changed
1.4 Benefit Risk Assessment 
Description of change
Risk assessment due to COVID-19 pandemic 
situation added
Rationale for change
New information on benefit/risk due to COVID-19 
pandemic situation.
Section to be changed
4.2.1
Other treatment and emergency procedures
Description of change
Clarification that dose reduction is possible at Visit 
1 if required to manage adverse events identified at 
the end of the INBUILD® trial.
Rationale for change
Clarification that dose reduction rules also apply to 
Visit 1.
Section to be changed
4.2.1.2 Management of liver enzyme elevations
Description of change
The wording regarding withdrawal and interruption 
of trial medication was revised for clarification. 
Furthermore it was added that trial medication may 
be resumed in the case that clear evidence for an
alternative cause for the hepatic injury was 
identified and resolved. It was specified that this is 
only possible after consultation with the sponsor 
and if prior to restart, liver laboratory values are 
normal. Liver laboratory values should be 




 
 
 
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Technical Version Number:
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Title: 
                                                                                                                   
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
001-MCS-50-415_RD-01 (1.0) / Saved on: 03 Dec 2018
 
TRIAL STATISTICAL ANALYSIS PLAN
c30127921-03
BI Trial No.:
1199-0248 (INBUILD®-ON)
Title:
An open-label extension trial of the long-term safety of nintedanib 
in patients with Progressive Fibrosing Interstitial Lung Disease 
(PF-ILD)
Investigational
Product:
Nintedanib
Responsible trial 
statistician:
Phone:
Date of statistical 
analysis plan:
18 MAY 2022 REVISED
Version:
3
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.






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10.
HISTORY TABLE..............................................................................................56


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LIST OF TABLES
Table 6.2: 1
Important protocol deviations...........................................................................27
Table 6.7: 2
Time windowing rules for physical exam and vital signs ................................35
Table 6.7: 3
Time windowing rules for laboratory measurements (and pregnancy test) .....36
Table 7.2.2: 1 Concomitant therapy outputs over the whole trial............................................39
Table 7.2.2: 2 Concomitant therapy outputs over 48 weeks and over 96 weeks.....................39
Table 7.8.1: 1 Protocol-specified AESI...................................................................................42
Table 9.3: 1
List of potentially relevant MedDRA preferred terms .....................................50
Table 10: 1
History table .....................................................................................................56


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALK
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
auto
Autoimmune ILDs
BI
Boehringer Ingelheim
BIcMQ
Boehringer Ingelheim customised MedDRA Query
bid
bis in die (twice a day)
bpm
Beats per Minute
CDG
Customised Drug Groupings
CRF
Case Report Form
CSD
Company Standard Displays
CTCAE
Common Terminology Criteria for Adverse Events
CT
Computed Tomography
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Data Base Lock
DMARD
Disease-Modifying Anti-Rheumatic Drugs
ECG
Electrocardiogramm
eCRF
Electronic Case Report Form
EMA
European Medicines Agency
EoT
End-of-Text
FEV1
Forced Expiratory Volume in 1 second
GGT
Gamma-Glutamyl-Transferase
GLI
Global Lungs Initiative
HRCT
High-Resolution Computer Tomography
HP
Hypersensitivity pneumonitis


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Term
Definition / description
IC
Informed Consent 
ICH
International Conference on Harmonisation
ILD
Interstitial Lung Disease
IMP
Investigational Medicinal Product
INR
International Normalised Ratio
iNSIP
Idiopathic nonspecific interstitial pneumonia
iPD
Important Protocol Deviation
IRT
Interactive Response Technology
LLN
Lower Limit of Normal
LLT
Lowest Level Term
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MQR
Medical and Quality Review 
PD
Protocol Deviation
PF-ILD
Progressive Fibrosing Interstitial Lung Disease
PN
Preferred Name
pred
Predicted
PT
Preferred Term
qd
quaque die (once a day)
SAE
Serious Adverse Event
SAS
Statistical Analyses Software as developed by SAS Institute
SCS
Screened Set
SD
Standard Deviation
SDG
Standardised Drug Grouping
SGOT
Aspartate Aminotransferase
SGPT
Alanine Aminotransferase
SOC
System Organ Class
TS
Treated Set
TS150S
Treated Set – 150 mg bid starting dose


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Term
Definition / description
TSAP
Trial Statistical Analysis Plan
uIIP
Unclassifiable idiopathic interstitial pneumonia
UIP
Usual Interstitial Pneumonia
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1) the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomisation.
INBUILD®-ON is the open-label extension of INBUILD® trial 1199.0247 which is also called 
parent trial throughout this document. Therefore, this TSAP also assumes familiarity with the 
TSAP of INBUILD® trial 1199.0247.
Unless stated otherwise SAS® Version 9.4 or later will be used for all analyses.




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5.
ENDPOINTS
For endpoints or other variables where derived “last contact date” is utilised, e.g. time-to-
event analyses, the following will apply:
The derived last contact date when the subject was known to be alive is defined as the latest 
date recorded in the electronic Case Report Form (eCRF) from the dates listed below (in case 
a date is planned to be imputed for the analysis, the imputed date will also be used): 
∀
Last visit date,
∀
Last reported Adverse Event (AE) date (excluding end dates when outcome is fatal or 
unknown), 
∀
Last reported concomitant therapy date, 
∀
Last laboratory sample date,
∀
Last reported nintedanib intake date (non-imputed), 
∀
Last reported dose change / interruption date, 
∀
∀
Last contact date as collected on the end of study eCRF page (if reason for non-
completion is not “Death”). 
5.1
PRIMARY ENDPOINT
The primary endpoint is the incidence of overall adverse events over the course of this 
extension trial.
5.2
SECONDARY ENDPOINTS
Not applicable.
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
Not applicable.


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5.4
OTHER VARIABLES
5.4.1
Demographics and baseline characteristics
5.4.1.1
Demographic data 
∀
Gender (Male; Female)
∀
Ethnicity (Hispanic/Latino; Not Hispanic/Latino)
Note: For this study collection of ethnicity was not allowed at sites in France as per 
French law.
∀
Race: single race respondents, multiple race respondents (all combinations ticked), 
and all race categories regardless of how many race categories were ticked 
Note: For this study collection of race was not allowed at sites in France as per French 
law.
∀
Age [years] at time of informed consent (IC) in extension trial (transferred by IRT) as 
continuous variable and in categories:
<30 years; >=30 to <45 years; >=45 to <60 years; >=60 to <75 years; >=75 years


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∀
Age [years] at time of IC in parent trial (transferred by IRT) as continuous 
variable and in categories:
<30 years; >=30 to <45 years; >=45 to <60 years; >=60 to <75 years; >=75 years
∀
Weight [kg] (at inclusion in extension trial, i.e. Visit 1) as continuous variable and in 
categories: <30 kg; >=30 to <60 kg; >=60 to <90 kg; >=90 kg
∀
Height [cm] (at inclusion in extension trial, i.e. Visit 1) as continuous variable
∀
Body mass index [kg/m²] (at inclusion in extension trial, i.e. Visit 1), calculated as
ℎ []
!ℎ ["] ∗!ℎ ["]
as a continuous variable and in categories:
< 18.5 kg/m²; >=18.5 to <25 kg/m²; >=25 to <30 kg/m²; >=30 kg/m²
∀
Smoking status (Never; Current; Former)
∀
Pack years (for subjects with smoking status “Current” or “Former”) as continuous 
variable and in categories: <20 pack years; >=20 to <40 pack years; >= 40 pack years
∀
Duration of exposure to trial drug in parent trial will be calculated based on first and 
last trial drug intake in parent trial in days as 
Date of last trial drug intake– Date of first trial drug intake + 0.5 days,
assuming that only one capsule was taken on day of last trial drug intake. In case of 
first trial drug intake was at 2:30 p.m. or later another half day will be subtracted.
Duration in months will then be calculated as 
+,-./0 /1 23/4,- / -.5 6-, 0 3.-0 -.5 [6.74]
30.5
Duration of exposure to trial drug in parent trial will be summarised as continuous 
variable [months] and in categories:
o
<=12 months
(365 days); 
o
>12 to <=18 months (547 days); 
o
>18 to <=24 months (730 days); 
o
>24 to <=30 months (912 days); 
o
>30 months


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5.4.1.3
Baseline characteristics for lung function
∀
FVC [mL] (at inclusion in extension trial, i.e. Visit 1)
∀
FVC [% pred] (at inclusion in extension trial, i.e. Visit 1)
∀
FEV1/FVC (at inclusion in extension trial, i.e. Visit 1)
5.4.2
Compliance
Only compliance in the extension trial will be considered.
5.4.2.1
Over the whole trial
Compliance [%] will be calculated as:
?,"@- /1 >.34,54 .>,.557 .0
?,"@- /1 >.34,54 Aℎ>ℎ4ℎ/,56 ℎ.B @0 .0 × 100%
The number of capsules which should have been taken over the whole trial will be calculated 
as:
( Duration of exposure over the whole trial) × 2,


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using duration of exposure as defined in Section 5.4.3.1 below. In case of dose reduction to 
100 mg bid, the number of capsules taken per day is still 2, so the calculation of compliance 
remains the same. Only treatment interruptions not due to AE will be considered as a 
compliance issue, i.e. duration of interruptions due to AE will be subtracted from the duration 
of the treatment period for compliance calculation.
Compliance [%] will be summarised as continuous variable and in categories:
<50%; >=50 to <80%; >=80 to <=120%; >120%.
If the amount of capsules taken is not reported for at least one expected visit or no final 
compliance assessment on or after the day of last trial drug intake is available the compliance 
will not be calculated.
5.4.2.2
Over 48 weeks and over 96 weeks
The number of capsules which should have been taken over 48 weeks and over 96 weeks 
respectively will be calculated as:
(Date of last nintedanib intake[1] – Date of first nintedanib intake + 1) × 2
[1] Or Week 48/Week 96 compliance assessment, if earlier.
In case of last nintedanib intake happened until Week 48/Week 96 compliance assessment, 
half a day will be subtracted assuming that only one capsule was taken on day of last 
nintedanib intake.
5.4.3
Exposure
Only exposure in the extension trial will be considered.
5.4.3.1
Over the whole trial
Duration of exposure [days] over the whole trial will be calculated as
Date of last nintedanib intake – Date of first nintedanib intake + 0.5 days,
assuming that only one capsule was taken on day of last nintedanib intake. Treatment 
interruptions will not be subtracted from this duration of exposure.
Duration of exposure [weeks] will be calculated as
+,-./0 /1 23/4,- [6.74]
7
Duration of exposure [months] will be calculated as
+,-./0 /1 23/4,- [6.74]
30.5


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Duration of exposure will be summarised as continuous variable [months] and in categories:
∀
<=3 months
(91 days); 
∀
>3 to <=6 months
(182 days); 
∀
>6 to <=12 months
(365 days); 
∀
>12 to <=18 months
(547 days); 
∀
>18 to <=24 months
(730 days); 
∀
>24 to <=36 months
(1095 days); 
∀
>36 months
Further categories might be defined if needed.
Duration of exposure on actual dose (100 or 150 mg bid) [months] will be calculated as
M," /1 .>ℎ>/00,/,4 6,-./0 /1 23/4,- / 100/150 " @6 [6.74]
30.5
This duration of exposure will be adjusted for treatment interruptions, dose reductions and 
dose increases and will be summarised as continuous variable and in categories:
∀
No 100/150 mg
∀
<=3 months
(91 days); 
∀
>3 to <=6 months
(182 days); 
∀
>6 to <=12 months
(365 days); 
∀
>12 to <=18 months
(547 days); 
∀
>18 to <=24 months
(730 days); 
∀
>24 to <=36 months
(1095 days); 
∀
>36 months 
Off-treatment duration [weeks] will be calculated as
M," /1 .>ℎ>/00,/,4 6,-./0 /1 /11 −-."0 3-/64 [6.74]
7
Total dose [g] will be calculated as
Duration of exp. on 100 mg [days] * 0.2 g + Duration of exp. on 150 mg [days] * 0.3 g.
Dose intensity [%] will be calculated as
Q/.5 6/4 []
0.3  × +,-./0 /1 23/4,- [6.74] × 100%


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Dose intensity [%] will be summarised as continuous variable and in categories:
∀
<=30%; >30 to <=50%; >50 to <=90%; >90 to <100%; =100%.
∀
<=90%, >90%
5.4.3.1.1
Exposure-related time-to-event analyses
Exposure-related time-to-event analyses will be performed for the following items:
∀
Time to first dose reduction [days]
∀
Time to first treatment interruption [days]
∀
Time to premature treatment discontinuation [days]
∀
Time to first dose reduction or treatment interruption [days]
Time-to-event [days] for exposure-related analyses is derived based on first nintedanib intake 
in extension trial as
Date of event/censoring – Date of first nintedanib intake + 1 day
For the above mentioned time-to-event analyses subjects with no such event occurred during 
the extension trial will be censored according to the mechanism for censoring as described in 
Table 5.4.3.1.1: 1.


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These time-to-event analyses will also be summarised in categories:
∀
<=1 month
(31 days) 
∀
>1 to <=3 months
(91 days) 
∀
>3 to <=6 months
(182 days) 
∀
>6 to <=12 months
(365 days) 
∀
>12 to <=18 months
(547 days) 
∀
>18 to <=24 months
(730 days) 
∀
>24 to <=36 months
(1095 days) 
∀
>36 months
∀
Censored
Further categories might be defined if needed.
5.4.3.2
Over 48 weeks and over 96 weeks
Duration of exposure [days] over 48 weeks and over 96 weeks respectively will be calculated 
as
Date of last nintedanib intake[1] – Date of first nintedanib intake + 1 day
[1] Or Week 48/Week 96 time point (Day 379/Day 715, i.e. 378/714 days after date of Visit 1), if earlier.
In case of last nintedanib intake happened until Week 48/Week 96 time point, half a day will 
be subtracted assuming that only one capsule was taken on day of last nintedanib intake.
Treatment interruptions will not be subtracted from this duration of exposure.
Other variables relative to exposure, such as for example duration of exposure [months] or 
duration off-treatment, total dose or dose intensity will be derived as defined in 
Section 5.4.3.1. However, last category for duration of exposure and duration of exposure on 
actual dose will be “>12 months” for the analyses over 48 weeks and “>18 months” for the 
analyses over 96 weeks.
5.4.4
Liver enzyme and bilirubin elevations
Liver enzyme and bilirubin elevations will be reported using the following definitions: 
∀
(ALT and/or AST >=3 fold ULN) and bilirubin >=2 fold ULN [1]
∀
ALT >=5 fold ULN and/or AST >=5 fold ULN
∀
ALT >=3 fold ULN and/or AST >=3 fold ULN
[1] within a time window of 30 days i.e. the elevation of  bilirubin should appear within 30 days after the 
elevation of AST and/or ALT


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The proportion of subjects presenting signs of hepatic injury will be summarised, based on the 
following definition for signs of hepatic injury:
∀
ALT and/or AST >=8 fold ULN
∀
ALT and/or AST >=3 fold ULN and total bilirubin >=2 fold ULN [2]
∀
ALT and/or AST >=3 fold ULN and unexplained INR >1.5 [2]
∀
ALT and/or AST >=3 fold ULN and unexplained eosinophilia (>5%) [2]
∀
ALT and/or AST >=3 fold ULN and appearance of fatigue, nausea, vomiting, right 
upper abdominal quadrant pain or tenderness, fever and/or rash within +/- 7 days of 
the abnormal ALT and/or AST laboratory test result (please refer to Table 9.3: 1 for
the list of relevant MedDRA preferred terms to support the derivation of a potential 
hepatic injury)
[2] in the same blood draw sample
In addition, maximum individual elevations based on worst value on treatment will be defined 
as:
∀
>=3 fold ULN; >=5 fold ULN; >=8 fold ULN 
for AST and ALT and AST and/or ALT
∀
>=1.5 fold ULN; >=2 fold ULN for Bilirubin
∀
>=1.5xULN; >=2 fold ULN for alkaline phosphatase (ALK)
∀
>=3xULN for Gamma-Glutamyl-Transferase (GGT)
Note: ULN refers to the Upper Limit of Normal from the central or local laboratory analysing 
samples from this extension trial.
5.4.4.1
Time-to-event analyses for liver enzyme elevations
Time to first occurrence in extension trial of the above described liver enzyme elevations 
[days] will be analysed as
Date of event/censoring – Date of first nintedanib intake + 1 day
Subjects with no such event occurred during the trial will be censored according to the 
mechanism for censoring as described in Table 5.4.4.1: 1.


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These times to onset of first event in extension trial will also be summarised in categories:
∀
<=1 month
(31 days)
∀
>1 to <=3 months
(91 days) 
∀
>3 to <=6 months
(182 days) 
∀
>6 to <=12 months
(365 days) 
∀
>12 to <=18 months
(547 days) 
∀
>18 to <=24 months
(730 days) 
∀
>24 to <=36 months
(1095 days) 
∀
>36 months
∀
Censored
Further categories might be defined if needed.
5.4.5
Marked changes in vital signs
A marked increase in vital signs is defined as: 
∀
Systolic Blood Pressure >150 mmHg and increase >=25 mmHg above baseline
∀
Diastolic Blood Pressure >90 mmHg and increase >=10 mmHg above baseline
∀
Pulse Rate >100 bpm and increase >=10 bpm above baseline,
at any visit.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For treatment specifications, please refer to CTP Section 4.
The different periods of interest, as per CTP flow chart, are the following:
Note: the last day of each of the periods is excluded from the period. It defines the first day of 
the subsequent period.
∀
Post-IC period (optional[a]): From date of informed consent to first nintedanib intake.
∀
Treatment period: From first nintedanib intake (or re-start of treatment if interruption) 
to last nintedanib intake (or day before start date of interruption if interruption) plus 
one day.
∀
Off-treatment (optional[a]): From start date of interruption to re-start of treatment.
∀
Residual effect period[b]: From last nintedanib intake plus one day to last nintedanib 
intake plus 28 days plus one day.
∀
Follow-up period (optional[a]): From last nintedanib intake plus 28 days plus one day 
(after residual effect period) to last contact date (as collected on the end of study eCRF 
page) plus one day. This period is only created if last nintedanib intake took place 
more than 28 days before last contact date (as collected on the end of study eCRF 
page).
∀
Post-study period (optional[a]): From last nintedanib intake plus 28 days plus one day 
or from last contact date (as collected on the end of study eCRF page) plus one day, 
whichever occurs later.
[a] This period is optional insofar as it does not necessarily exist for all subjects.
[b] In addition, a residual effect period of 7 days will be used for safety analyses to more closely reflect the 
period of time after the last nintedanib intake.
For subjects who did not receive any dose of nintedanib in extension trial, Post-IC period is 
the only period defined.
For subjects who died during the trial, periods with above defined start date after date of death 
do not exist and last existing period is defined until date of death plus one day only.
For safety analyses (Section 7.8), data from the treatment period, possible off-treatment 
periods and residual effect period will be considered as on-treatment.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
No per protocol set analysis will be performed for this study; however, the following list in 
Table 6.2: 1 below defines the different categories of potentially important protocol deviations 
(iPD), and it shows whether subjects will potentially be excluded from evaluations performed 
in this trial. Potentially iPDs will be handled according to BI standards (3). The proportion of 
subjects with iPDs will be presented for completeness purposes and to demonstrate the 
adherence to the CTP.
Table 6.2: 1
Important protocol deviations
Category/Code
Description
Requirements
Excluded from
A
Eligibility Criteria
A1
Potential risk related to 
fetotoxicity
a) Women who are 
pregnant, nursing, or who 
plan to become pregnant 
while in the trial 
b) Women who are of 
childbearing potential not 
willing or able to use 
highly effective methods of 
birth control per ICH M3
a) (exclusion criterion 6 met)
b) (inclusion criterion 3 not met)
and subject entered the trial
Automatic iPD
Additional note:
In the CTR Table it should show which 
criteria are violated; however, deviations 
of multiple sub-categories will only 
count once towards the overall category.
None
A2
Subjects with other 
underlying diseases or 
conditions that may put the 
subject at risk when 
participating in the trial
Exclusion criterion 1 met
and subject entered the trial
Automatic iPD
None
B
Informed Consent
B1
Informed consent not given
Inclusion criterion 2 not met
Automatic iPD
All
B2
Informed consent given too 
late
eCRF date of informed consent is after 
date of Visit 1
Automatic iPD
Additional note:
Signature of the wrong IC version, and 
later signature of the correct one will 
also be part of this iPD category. This 
can however only be determined via a 
manual process.
None


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Table 6.2: 1
Important protocol deviations (continued)
Category/Code
Description
Requirements
Excluded from
C
Trial Medication and 
Randomization
C1
Trial medication not 
interrupted
a) when ALT or AST >= 5 
fold ULN
b) or dose reduced when 
ALT or AST >= 3fold to < 
5 fold ULN
Based on eCRF dose interruption and lab 
values between first drug intake and 
EOT
Manual iPD based on MQR outputs 
Additional note:
In the CTR Table it should show which 
criteria are violated; however, deviations 
of multiple sub-categories will only 
count once towards the overall category.
None
C2
Trial medication not 
permanently discontinued 
after signs of liver enzyme 
elevations were observed 
that 
a) are indicative of hepatic 
injury as defined in Section 
5.2.5.1.4 and 4.2.1.2 of the 
CTP
b) correspond to ALT or 
AST >= 3 fold ULN 
despite dose reduction or 
treatment interruption for 2 
weeks or more
All subjects where signs of liver enzyme 
elevations are not dealt with according to 
the requirements of the CTP.
Manual iPD based on MQR outputs
Additional note:
In the CTR Table it should show which
criteria are violated; however, deviations 
of multiple sub-categories will only 
count once towards the overall category.
None
C3
Compliance > 120%
In case calculated overall compliance is 
missing: If the answer to the question 
“Did the patient take trial medication as 
instructed?” of the eCRF is “No” at at 
least one of the visits where the 
compliance cannot be calculated, then an 
iPD will be flagged. Otherwise no iPD 
although calculated overall compliance is 
missing.
Manual iPD with review of MQR listings
None
C4
Incorrect trial medication 
taken
a) 150 mg capsules used 
instead of 100 mg capsules
b) 100 mg capsules used 
instead of 150 mg capsules
c) qd instead of bid
To be discussed on a case by case basis 
to determine if iPD
Manual iPD with review of MQR listings
Additional note:
In the CTR Table it should show which 
criteria are violated; however, deviations 
of multiple sub-categories will only 
count once towards the overall category.
None


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Table 6.2: 1
Important protocol deviations (continued)
Category/Code
Description
Requirements
Excluded from
C5
Trial medication 
interrupted more than 4 
weeks for drug-related 
liver enzyme or bilirubin 
related AE with duration of 
more than 4 weeks
To be discussed on a case by case basis 
to determine if iPD
Manual iPD with review of MQR listings
None
C6
More than 16 weeks 
between ALT, AST or 
BILI lab tests without trial 
medication interruption
To be discussed on a case by case basis 
to determine if iPD
Manual iPD with review of MQR listings
None
D
Concomitant Medication
D1
Subjects who received any 
other investigational drug 
during the entire duration 
of their study participation
Any occurrence of such concomitant 
therapy is to be flagged as iPD.
Manual iPD with review of MQR outputs
Additional note:
In the CTR Table it should show which 
medication was taken; however, 
deviations regarding multiple 
medications will only count once 
towards the overall category.
None
Automatic PDs are those detected via an automated programming process using SAS®.
6.3
SUBJECT SETS ANALYSED
∀
Screened Set (SCS):
This subject set includes all subjects having signed informed consent.
∀
Treated Set (TS):
This subject set includes all subjects who were dispensed trial medication (nintedanib) 
and were documented to have taken at least one dose of open-label trial medication
(nintedanib).
∀
Treated Set – 150 mg bid starting dose (TS150S)
This subject set includes all subjects who were dispensed trial medication (nintedanib) 
and were documented to have taken nintedanib 150 mg bid as starting dose of open-
label trial medication.
All evaluations will be based on the treated set (TS), unless otherwise stated. 
Subjects will be analysed according to their randomised treatment group in the parent trial 
(Placebo or Nintedanib) and overall (Total column). 


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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in a statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Primary endpoint
Missing or incomplete AE dates will be imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (6).


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6.6.3
Other variables
6.6.3.2
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. Imputed end dates must not be after date of death or last 
contact date as collected on the end of study eCRF page.


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6.6.3.3 Exposure
6.6.3.3.1
Permanent trial drug discontinuation
A missing or incomplete date of last nintedanib intake will be imputed that the derived date is 
the latest possible date which is on or before date of death, and on or before last contact date 
from end of study eCRF page.
6.6.3.3.2
Treatment interruptions
For the definition of off-treatment periods an incomplete start or end date for a treatment 
interruption will be imputed the same way as specified for time-to-event analyses in 
Section 6.6.2.2. . For duration of interruption no imputation will be applied, i.e. interruptions 
with missing or incomplete start or end date will have duration missing. Overall duration of 
interruptions per subject will be missing in these cases as well.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
As a general rule, the last assessment/measurement before or on the date of Visit 1 will be 
used as baseline.
Visit windowing will be performed as described in Tables 6.7: 1, 6.7: 2 and 6.7: 3, in order to 
assign data to the relevant study visit based on the actual day of the assessment. Data will be 
analysed using the re-calculated visits in the statistical tables. However, in the listings, all 
visits performed will be displayed (even if outside time-window), along with the re-calculated 
visit. No time-windowing will be performed for the follow-up visit, i.e. follow-up visit will be 
displayed in listings (where applicable) whenever it was performed. A follow-up visit is only 
scheduled for subjects who prematurely discontinued nintedanib due to adverse event. 


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Table 6.7: 2
Time windowing rules for physical exam and vital signs
Time window of actual day [1]
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned day of 
the visit
1
1
1
1
Baseline
1
2
22
21
2
2 weeks
15
23
43
21
3
4 weeks
29
44
71
28
4
8 weeks
57
72
127
56
5
12 weeks
85
128
211
84
6
24 weeks
169
212
295
84
7
36 weeks
253
296
379
84
8
48 weeks
337
380
463
84
9
60 weeks
421
464
547
84
10
72 weeks
505
548
631
84
11
84 weeks
589
632
715
84
12 (p)
96 weeks
673 (RS)
RS + 1
+ RSTU −RS
2
RSTU
+ RSTV −RSTU
2
RSTV −RS
2
3 + 1
…
RSTU
= RS + 12 × 7
…
…
…
…
Every 12 
weeks 
thereafter
…
RS denotes the planned day of the visit
[1] Date of Visit 1 in extension trial is taken into account as a reference to calculate time windows


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Table 6.7: 3
Time windowing rules for laboratory measurements (and pregnancy test)
Time window of actual day [1]
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned day of 
the visit
1
1
1
1
Baseline
1
2
22
21
2
2 weeks
15
23
43
21
3
4 weeks
29
44
71
28
4
8 weeks
57
72
106
35
5
12 weeks
85
107
148
42
5a [2]
18 weeks
127
149
190
42
6
24 weeks
169
191
232
42
6a [2]
30 weeks
211
233
274
42
7
36 weeks
253
275
316
42
7a [2]
42 weeks
295
317
379
63
8
48 weeks
337
380
463
84
9
60 weeks
421
464
547
84
10
72 weeks
505
548
631
84
11
84 weeks
589
632
715
84
12 (p)
96 weeks
673 (RS)
RS + 1
+ RSTU −RS
2
RSTU
+ RSTV −RSTU
2
RSTV −RS
2
3 + 1
…
RSTU
= RS + 12 × 7
…
…
…
…
Every 12 
weeks 
thereafter
…
RS denotes the planned day of the visit
[1] Date of Visit 1 in extension trial is taken into account as a reference to calculate time windows
[2] Intermediate lab tests (‘a’-Visits) to be done as needed for additional safety monitoring at the discretion of the 
investigator and do not necessarily need to be a site visit.
If after windowing of visits at baseline, two values fall within the same baseline interval, then 
the last value will be taken into account. If after windowing of post-baseline visits, two visits 
fall in the same interval, then the measurement closest to the planned day of the visit will be 
taken into account. In case two measurements are equidistant from the planned day of the
visit, then the last one will be picked.


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7.
PLANNED ANALYSIS
Unless otherwise specified, all analyses described in this section will be done on the Treated 
Set.
The labelling and display format of statistical parameters will follow BI standards (9). For 
End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median / 
Max. In descriptive statistics tables, mean, SD and median will be rounded to one additional 
digit than the raw individual value. In case some endpoints show some extreme data outside 
the expected range, quartiles and percentiles will be presented additionally.
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 subjects in the respective subject
set whether they have non-missing values or not). The precision for percentages should be one 
decimal point. The category missing will be displayed only if there are actually missing 
values.
Unless otherwise specified, all analyses will be provided by randomised treatment group in 
the parent trial (Placebo or Nintedanib) and overall (Total column).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
A table in the CTR will present the number of subjects screened, entered and treated. 
The completion status of subjects will be summarised by frequency counts with regards to 
planned treatment period as well as planned (trial) observation period together with 
corresponding reasons for non-completion. For potential interim analyses the number of 
subjects who are still ongoing in the trial will be presented in addition.
A similar summary will be provided regarding the first 48 weeks or the first 96 weeks only, 
i.e. until Week 48/Week 96 time point (Day 379/Day 715, i.e. 378/714 days after date of 
Visit 1).
Descriptive statistics as well as frequency counts will be provided for all demographic and 
baseline characteristics depicted in Section 5.4.1.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
7.2.1
Baseline conditions and cardiovascular medical history
Baseline conditions will be coded using the current Medical Dictionary for Regulatory 
Activities (MedDRA) version in use at BI at the time of (interim) database lock. They will be 
summarised by MedDRA system organ class (SOC) and preferred term (PT). The CTR table 
will show the counts of subjects with a baseline condition in each SOC (SOC sorted by 
standard European Medicines Agency (EMA) order) and then the conditions (preferred terms) 
under that SOC in descending order of overall prevalence (Total column). 
The relevant cardiovascular medical history will be summarised, with particular focus on 
myocardial infarction, transient ischemic attacks, stroke, cardiac arrhythmia and heart failure.
7.2.2
Concomitant therapies
Concomitant therapies will be coded using the current World Health Organization Drug 
Dictionary (WHO-DD) version in use at BI at the time of (interim) database lock.
Concomitant therapies will be assigned to the following categories:
∀
Previous therapies: All therapies with a stop date before date of Visit 1 in extension 
trial.
∀
Baseline therapies: All therapies with a start date before date of first nintedanib intake 
in extension trial and a stop date after or on the day of Visit 1 in extension trial (or 
ongoing after completion of extension trial).
∀
On-treatment concomitant therapies: All therapies with a start date after or on the day 
of first nintedanib intake in extension trial and before or on the day of last nintedanib 
intake in extension trial.
∀
Post-study drug discontinuation therapies: All therapies with a start date after last 
nintedanib intake in extension trial and before or on the last contact as collected on the 
end of study eCRF page.
Concomitant therapies will be described over the entire duration of the extension trial. Similar 
summaries will be provided regarding the first 48 weeks or the first 96 weeks only, i.e. until 
Week 48/Week 96 time point (Day 379/Day 715, i.e. 378/714 days after date of Visit 1).
Table 7.2.2: 1 and Table 7.2.2: 2 summarise the concomitant therapy outputs which will be 
provided for analyses over the whole trial, over 48 weeks and over 96 weeks respectively, for 
each category of concomitant therapy created.


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Summaries by Anatomical Therapeutic Chemical (ATC) classification and preferred name 
(PN) will use the ATC3 levels, and will be sorted by alphabetical ATC class and by 
decreasing order of overall prevalence (Total column) of PN within ATC class.
Summaries by Customised Drug Grouping (CDG) and PN will be sorted by alphabetical CDG 
name and by decreasing order of overall prevalence (Total column) of PN within CDG. CDGs 
are built using WHO-DD Standardised Drug Groupings (SDG), Sub-SDGs and ATC4 levels. 
CDGs are listed in Section 9.2.
Table 7.2.2: 1 Concomitant therapy outputs over the whole trial
By ATC and PN
By CDG and PN
Baseline therapies
X
X
On-treatment concomitant therapies
X
X
All baseline and on-treatment 
concomitant therapies
X
X
All baseline and on-treatment 
concomitant therapies with an 
incidence greater than 2% (in at least 
one treatment arm)
X
Not required
Post-study drug discontinuation 
therapies
Not required
Not required
Table 7.2.2: 2 Concomitant therapy outputs over 48 weeks and over 96 weeks
By ATC and PN
By CDG and PN
Baseline therapies
Not required
Not required
On-treatment concomitant therapies
X
X
All baseline and on-treatment 
concomitant therapies
X
X
All baseline and on-treatment 
concomitant therapies with a an 
incidence greater than 2% (in at least 
one treatment arm)
X
Not required
Post-study drug discontinuation 
therapies
Not required
Not required
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. The evaluations will be 
done over the whole trial. A similar summary will be provided regarding the first 48 weeks or 
the first 96 weeks only.


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7.4
PRIMARY ENDPOINT
The primary objective of the trial is to assess the safety of Nintedanib, so please refer to 
Section 7.8.1.4 for detailed analyses.
7.5
SECONDARY ENDPOINTS
This section is not applicable as no secondary endpoint has been specified in the protocol.
7.7
EXTENT OF EXPOSURE
Exposure will be summarised over the whole trial. Similar summaries will be provided 
regarding the first 48 weeks or the first 96 weeks only.


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A summary table showing the duration on treatment in extension trial in months (both, mean 
and frequency in categories, see Section 5.4.3) will be presented together with duration of 
exposure in patient-years, total dose (mean) and dose intensity (both, mean and frequency in 
categories, see Section 5.4.3).
Besides, a summary table showing the duration on actual treatment dose in months (both,
mean and frequency in categories, see Section 5.4.3) and off-treatment duration in weeks 
(mean) will be performed. This will take into account the actual dose following dose 
reductions or increases. Furthermore, the proportion of subjects on each dose actually taken as 
first dose in 1199-0248 will be presented.
A summary of dose reductions will be performed including number of subjects with at least 
one dose reduction, number of dose reductions (total and per subject) and reasons for dose 
reduction, as well as time to first dose reduction in extension trial (both, quartiles from 
Kaplan-Meier curve and frequency in categories, see Section 5.3.3.3). Dose intensity of 
subjects with at least one dose reduction will be summarised in addition. A similar summary 
will be performed for treatment interruptions. Additionally, the (total) duration of 
interruptions per subject will be summarised. For dose increases to 150 mg only number of 
subjects with at least one increase and total number of increases will be summarised.
Time to first dose reduction will only be calculated for subjects with first dose in extension 
trial 150 mg (see Section 6.3 for further information on this analysis set).
As for the other exposure-related time-to-event analyses, time to premature treatment 
discontinuation and time to first dose reduction or treatment interruption will be summarised
over the whole trial on the Treated Set according to both, quartiles from Kaplan-Meier curve 
and frequency in categories (see Section 5.4.3.1.1).
Separate Kaplan-Meier plots will be presented by randomised treatment group in the parent 
trial (Placebo or Nintedanib) and overall (total group) for all exposure-related time-to-event 
analyses. No statistical tests will be performed. Kaplan-Meier plots present data over the 
whole trial. Kaplan Meier estimates and confidence intervals (using Greenwood variance 
formula) for the cumulated time-to-event rate will be calculated at 48 weeks (378 days after 
date of first nintedanib intake), at every further 48 weeks (336 days) and over the whole trial.
7.8
SAFETY ANALYSIS
All safety analyses will be performed over the whole trial on the treated set. Similar 
summaries will be provided regarding the first 48 weeks or the first 96 weeks only.
The analysis of safety data will be based on the concept of treatment emergent AEs or 
measurements. That means that, for analyses over the whole trial, all AEs/laboratory or vital 
sign measurements occurring between first nintedanib intake till last nintedanib intake + 28 
days will be assigned to the on-treatment period. For analyses over 48 weeks and 96 weeks 
respectively the on-treatment period is defined from date of first nintedanib intake until date 
of last nintedanib intake + 28 days, or until Week 48/Week 96 time point (Day 379/ Day 715, 
i.e. 378/714 days after date of Visit 1), if earlier.


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All analyses will be performed according to randomised treatment group in the parent trial 
and overall.
7.8.1
Adverse Events
Adverse events will be coded using the current Medical Dictionary for Regulatory Activities 
(MedDRA) version in use at BI at the time of database lock. Unless otherwise specified, the 
analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and NOT on the number of AEs.
For analysis multiple AE occurrence data on the eCRF will be collapsed into an AE provided 
that all of the following applies:
∀
All AE attributes are identical (Low Level term ((LLT), intensity, action taken, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AESI, 
CTCAE if applicable)
∀
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence).
For further details on summarization of AE data, please refer to (6, 7). 
All AEs occurring before first nintedanib intake will be assigned to ‘Post-IC period’ and all 
AEs occurring after the residual effect period will be assigned to ‘follow-up’ or ‘post-study’ 
(for listings only). All adverse events occurring between the start and the end of an 
interruption of nintedanib will be assigned to ‘off-treatment’ period in the listings. For details on 
the treatment definition, see Section 6.1.
According to ICH E3 (2), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and AEs with 
(i) ‘action taken = DRUG WITHDRAWN’ or ‘action taken = DOSE REDUCED’, or 
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy.
Summary tables will be produced for non-serious adverse events meeting part (i) of the 
definition. Part (ii) of the definition will be covered by the analysis of laboratory data. Please 
refer to Section 7.8.2 for further information.
Adverse events related to gastrointestinal perforation and hepatic injury will be considered as 
protocol-specified AEs of special interest (AESIs), and ticked as such in the eCRF.
Table 7.8.1: 1 Protocol-specified AESI 
Protocol-specified AESI
AE type
Gastrointestinal perforation
AEs established for other tyrosine kinase 
inhibitors as possible adverse reactions
Hepatic injury
Other AEs of interest


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An overall summary of AEs will be presented, by treatment group in the parent trial and 
overall.
The frequency of subjects with adverse events, will be summarised by randomised treatment 
group in parent trial (and overall), primary system organ class (SOC) and preferred term (PT). 
This will be repeated for subjects with adverse events occurring with an incidence in preferred 
term greater than 5% (in at least one treatment arm). For analyses over the whole trial, time at 
risk and exposure-adjusted incidence rates with 95% confidence intervals will be presented in 
addition. Please refer to Section 7.8.1.1 for further details on the derivation of time at risk and 
exposure-adjusted incidence rates.
Separate tables will be provided for subjects with
∀
serious AEs (SAEs)
∀
severe AEs
∀
other significant AEs (as defined by point (i) of the ICH E3 definition indicated 
above)
∀
AEs leading to dose reduction
∀
AEs leading to permanent treatment discontinuation
∀
investigator defined drug-related AEs
∀
AEs leading to death
∀
protocol-specified AEs of special interest (AESIs) 
(as ticked on the AE page of the eCRF)
∀
investigator defined drug-related SAEs. 
The system organ classes (SOC) will be sorted according to the standard sort order specified 
by EMA, preferred terms will be sorted by decreasing frequency in the total column (within 
SOC).
7.8.1.1
Exposure adjusted analysis of adverse events
Exposure adjusted analysis of AEs will be presented for analyses over the whole trial. Time at 
risk and incidence rates per 100 patient-years will be calculated based on the first onset of an 
AE in the extension trial.
For a specific AE, the total AE time at risk [years] is defined as
∑" . -4 [6.74].>>-/44 .55 >/0-@,0 4,@Y>4
365.25
with for each subjects the time at risk [days] defined as follows:
∀
Date of first onset of the AE – date of first nintedanib intake in extension trial +1 day
for subjects with the specific AE


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∀
End of time at risk – date of first nintedanib intake in extension trial + 1 day
for subjects without the specific AE. 
The end of time at risk is the minimum of either “date of last nintedanib intake + 28 days”,
date of last contact date as collected on the end of study eCRF page, date of death or date of 
the (interim) database lock.
The AE incidence rate [1/100 patient-years (pt-yrs)] will be calculated as
?,"@- /1 4,@Y>4 Aℎ43>1> Z[
Q/.5 43>1> Z[ " . -4 [7.-4] × 100
The 95% confidence intervals for incidence rates are derived using the method described by 
Rothman and Greenland (2008) (12).
7.8.1.2
Additional analysis of adverse event groupings by system
Further adverse event groupings by safety topic have been defined outside the trial protocol, 
which will be continuously updated at project level (11). These safety topics are deemed of 
particular importance, and these definitions can be based on selection of coded terms based on 
MedDRA. The latest approved version of the project level overview archived prior to 
(interim) DBL will be used in the CTR.
The frequency of subjects with adverse events within these groupings will be summarised by 
system, safety topic, subcategory (if applicable) and preferred term. These displays will focus 
on subjects with any adverse event, subjects with serious adverse events and subjects with 
investigator defined drug-related adverse events. For analyses over the whole trial, time at risk 
and exposure-adjusted incidence rates with 95% confidence intervals will be presented in 
addition. Please refer to Section 7.8.1.1 for further details on the derivation of time at risk and 
exposure-adjusted incidence rates.
Systems will be presented in alphabetical order. Safety topics, subcategories (if applicable) 
and preferred term will be sorted by decreasing frequency in the total column (within system, 
safety topic or subcategory).
7.8.1.3
Adverse events with additional information collection
Diarrhoea, bleeding and ILD are AEs with additional AE-specific information collected on 
the eCRF. These are investigator reported on the eCRF and will be identified using this 
information for this analysis. That is if the diarrhoea information has been completed for an 
adverse event then the adverse event will be considered as diarrhoea for this analysis 
regardless of subsequent MedDRA coding of the verbatim term. Likewise, if the bleeding 
information has been completed for an adverse event then the adverse event will be 
considered as bleeding for this analysis regardless of subsequent MedDRA coding of the 
verbatim term. The same applies to ILD.
The frequency of subjects with AEs with additional information collection will be 
summarised by randomised treatment group in the parent trial (and overall), primary SOC and 


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PT separately for diarrhoea, bleeding and ILD. The additional information collected will also 
be summarised at the AE level (occurrence level) rather than at the subject level separately for 
diarrhoea, bleeding and ILD. 
For the time to first onset of diarrhoea, bleeding or ILD, respectively, in extension trial
Kaplan-Meier plots by treatment will be created. The same censoring rules and categories as 
for time to first liver enzyme elevation in extension trial will be used. See Section 5.4.4.1 for 
details. 
7.8.1.4
Analysis of the primary endpoint
Only descriptive analyses will be performed. The same methods (i.e. number and frequency 
of subjects with adverse events, time at risk and exposure-adjusted incidence rates with 95% 
CI) as described in Section 7.8.1 and  Section 7.8.1.1 will be used. The primary endpoint will 
be assessed on data collected over the whole trial and regardless of randomised treatment 
group in the parent trial. .
7.8.2
Laboratory data
7.8.2.1
Standard laboratory analyses
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(8). Please refer to CTP Section 7.3.4. Laboratory measurements and their corresponding 
reference range will be used as they were transmitted from the central laboratory or entered in 
the eCRF for local laboratory data, except for measurements not reported in the standard unit. 
Such measurements and corresponding reference ranges will be transposed into the standard 
unit for the analysis. For INR measurements, no reference range is transmitted by the central 
laboratory, because the central laboratory does not have information on concomitant 
medication taken by the subjects, and the reference range for INR depends on whether a 
subject is taking anticoagulants. The reference ranges for INR will therefore by imputed with 
0.8 for the lower limit of normal (LLN) and with 1.2 for the ULN, which correspond to the 
reference range defined by the central laboratory for subjects not taking anticoagulants and 
which is more conservative than the range for subjects taking anticoagulants (LLN=2, 
ULN=3).
7.8.2.2 
Liver enzyme and bilirubin elevations
A thorough description of liver enzymes and bilirubin elevations, as defined in Section 5.4.4,
will be given over the whole trial by randomised treatment group in the parent trial and 
overall, including:


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∀
Summary table of liver enzyme elevation
∀
Summary table of individual maximum liver enzyme and bilirubin elevations
∀
Time to first onset in extension trial and number of subjects with liver enzyme 
elevation. The time to onset of first liver enzyme and bilirubin elevation [days] will be 
summarised according to both, quartiles from Kaplan-Meier curve and frequency in 
categories (see Section 5.4.4.1).
∀
Kaplan-Meier plot of time to first liver enzyme elevation in extension trial. No 
statistical test will be performed. Separate plots will be presented by randomised 
treatment group in the parent trial and overall.
∀
Single time course profiles of liver enzymes for subjects having liver enzyme 
elevations (ALT and/or AST >= 3 fold ULN)
∀
Graphical displays of potential Hy’s law cases
7.8.3
Vital signs
Summary statistics will be presented for observed values and change from baseline by visit
over extension trial (please refer to Table 6.7: 2 for time windowing definition). The 
frequency of subjects with marked changes in vital signs at any visit during the extension trial 
will also be summarised by randomised treatment group in the parent trial and overall 
according to the definitions in Section 5.4.5 of this document. Furthermore, minimum relative 
change from baseline in weight will be summarised (both, mean and frequency in categories, 
see Section 5.4.5). Categorised relative change in weight over the extension trial will also be 
described according to Body mass index at inclusion in extension trial in categories (<18.5 
kg/m², >=18.5 to <25 kg/m², >=25 to <30kg/m², >=30 kg/m²).
7.8.4
ECG
Not applicable (ECG findings are reported as adverse events).


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7.8.5
Others
Not applicable.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, Note For 
Guidance on Statistical Principles for Clinical Trials, current version.
2.
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, EMA webpage.
3.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD)", current version; KMED.
4.
001-MCS-50-415_RD-03: “Clinical Trial Analysis Decision Log (template) Decision Log”, current 
version, Group “Biostatistics & Data Sciences”, KMED.
5.
BI-KMED-BDS-HTG-0023: “Standard Table Shells for Inferential and Descriptive Company Standard 
Displays (CSD-Catalogue)”, current version; KMED.
6.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current version; KMED.
7.
BI-KMED-BDS-HTG-0066: “ Analysis and Presentation of Adverse Event Data from Clinical Trials”, 
current version; KMED.
8.
BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, current version; 
KMED.
9.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project Summaries”, current 
version; KMED.
10.
BI-KMED-BDS-HTG-0046: “Trial Statistical Analysis Plan (TSAP) Process and Timelines”, current 
version; KMED.
11.
Specifications for adverse event groupings by safety topic for Nintedanib:
Nintedanib / Clinical / Systemic sclerosis/ Project Data Management and Statistics / Section 8 PSAP and 
Programming / 8-07-other-safety-topic-definition, current version; BIRDS.
12.
Rothman KJ, Greenland S, Lash TL. Modern epidemiology. 3rd ed. Philadelphia: Lippincott Williams & 
Wilkins, 2008. [R10-1239]
13.
Philip H. Quanjer, Multi-ethnic reference values for spirometry for the 3–95 year age range: The global 
lung function 2012 equations. [R15-0845]


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9.
ADDITIONAL SECTIONS


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9.3
LIST OF POTENTIAL TERMS FOR HEPATIC INJURY DERIVATION
The table below shows the list of potentially relevant MedDRA preferred terms to support the 
derivation of a potential hepatic injury.
Table 9.3: 1
List of potentially relevant MedDRA preferred terms
Symptom
Selection via
MedDRA decode
MedDRA code
Vomiting 
Preferred Term
Vomiting
10047700
Fatigue
Preferred Term
Fatigue
10016256
Nausea
Preferred Term
Nausea
10028813
Right upper abdominal 
quadrant pain or tenderness
High Level Term
Gastrointestinal and abdominal 
pains (excl oral and throat)
10017926
Fever
Preferred Term
Pyrexia
10037660
Rash
BIcMQ
Skin rash potentially related to 
drug use (BIcMQ) (narrow)
30000087


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c30127921-03
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Table 10: 1
History table (continued)
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
3
11-MAY-2022
4
5.4.3.1.1
7
Wording for “Time to permanent 
treatment discontinuation” adapted to 
“Time to premature treatment 
discontinuation” in order to better reflect 
what is actually meant. “Permanent” 
wanted to differentiate from temporary 
interruptions but is misleading for 
treatment completers who should not be 
considered “events” here.
5
Last spirometry assessment added to list 
of dates used for derived last contact 
date when the subject was known to be 
alive.
7.1
7.2.2
7.3
7.7
7.8
Specific analyses “over 48 weeks” and 
“over 96 week” respectively are not 
restricted to the corresponding interim 
analysis anymore but will also be 
provided for the final analysis.