Clinical trial NCT04938453
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2021-07-14; Completion date: 2021-08-30
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main objective of this trial is to investigate the relative bioavailability of 100 mg nintedanib given as four capsules of 25 mg nintedanib compared with one capsule of 100 mg nintedanib.

Detailed description:

Arms: arm 1: first test (T), then reference (R) treatment arm 2: first reference (R), then test (T) treatment
Interventions: intervention 1: nintedanib 25 mg intervention 2: nintedanib 100 mg
Intervention descriptions: intervention 1: soft gelatin capsule intervention 2: soft gelatin capsule

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c35094875-03
EudraCT No.
2021-001052-34
BI Trial No.
1199-0463
BI Investigational
Medicinal Product
Ofev®, nintedanib
Title
Relative bioavailability of 100 mg nintedanib (Ofev®) given as 
four capsules of 25 mg compared to one capsule of 100 mg 
following oral administration in healthy male subjects (an open-
label, randomised, single-dose, two-period, two-sequence 
crossover study)
Lay Title
A study in healthy men to test whether four capsules of 25 mg 
nintedanib are taken up in the body in the same way as one 100 
mg capsule
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax:
Principal 
Investigator
Phone: 
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 1))
Version and Date
Version: 2.0
Date: 02 June 2021
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© 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
21 April 2021
Revision date
02 June 2021
BI trial number
1199-0463
Title of trial
Relative bioavailability of 100 mg nintedanib (Ofev®) given as four capsules of 25 
mg compared to one capsule of 100 mg following oral administration in healthy 
male subjects (an open-label, randomised, single-dose, two-period, two-sequence 
crossover study)
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
This trial is intended to characterize the pharmacokinetics of a new dose strength, 
25 mg nintedanib soft gelatin capsules in plasma. For this purpose, the relative 
bioavailability of 4 nintedanib soft gelatin capsules à 25 mg vs. 1 soft gelatin 
capsule à 100 mg is investigated in healthy volunteers. The data are intended to 
supplement in vitro data of the new 25 mg dose strength.
Trial objective
The main objective of this trial is to investigate the relative bioavailability of 
100 mg nintedanib given as four capsules of 25 mg nintedanib (Test, T) compared 
with one capsule of 100 mg nintedanib (Reference, R) following oral 
administration.
Trial design
Randomised, open-label, two-way crossover design
Trial endpoints
Primary endpoints: AUC0-tz and Cmax of nintedanib
Secondary endpoints: AUC0-! of nintedanib
Number of subjects 
total entered
20
each treatment
20
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 55 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product
Nintedanib soft gelatin capsule 25 mg (T)
dose
100 mg (4 capsules à 25 mg nintedanib)
mode of admin.
Oral with 240 mL of water after a breakfast


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Reference product
Nintedanib soft gelatin capsule 100 mg (R)
dose
100 mg (1 capsule)
mode of admin.
Oral with 240 mL of water after a breakfast
Duration of treatment
One day (single dose) for each treatment
Statistical methods
Relative bioavailability will be estimated by the ratios of the geometric means 
(test/reference) for the primary and secondary endpoints. Additionally, their two-
sided 90% confidence intervals (CIs) will be provided. This method corresponds to 
the two one-sided t-test procedure, each at a 5% significance level. Since the main 
focus is on estimation and not testing, a formal hypothesis test and associated
acceptance range is not specified. The statistical model will be an analysis of 
variance (ANOVA) on the logarithmic scale including effects for sequence, subjects 
nested within sequences, period and treatment. CIs will be calculated based on the 
residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to 
drug administration)
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory 7
PK blood
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
A
x
x
1/2 (two identical periods separated by a wash-out of at least 7
days
2/3
1
-2:00
06:00
Admission to trial site2; 
allocation to treatment2 (visit 2 only)
B2,5
x2
x2
x2
x2
-0:30
07:30
Standard breakfast
0:00
08:00
Drug administration
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
2:30
10:30
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake
x
5:00
13:00
x
6:00
14:00
240 mL fluid intake, lunch3
x
x
8:00
16:00
Snack (voluntary)3
x
10:00
18:00
x
11:00
19:00
Dinner
12:00
20:00
x
x
2
24:00
08:00
Breakfast3 (voluntary),
discharge from trial site
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x
4
72:00
08:00
Ambulatory visit
B
x
x
FU
4
8 to 14
End of trial (EoTrial) examination4
C
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria.
 
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies.
5.
Including urine drug screening and alcohol breath test
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
Letters A, B, and C define different sets of safety laboratory examinations (for details refer to Table 5.2.3: 1)


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................5
ABBREVIATIONS.............................................................................................9
1.
INTRODUCTION.................................................................................... 11
1.1
MEDICAL BACKGROUND............................................................................11
1.2
DRUG PROFILE...............................................................................................11
1.2.1
Residual Effect Period..........................................................................14
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................14
1.4
BENEFIT - RISK ASSESSMENT ...................................................................14
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 17
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......17
2.1.1
Main objectives......................................................................................17
2.1.2
Primary endpoints ................................................................................17
2.1.3
Secondary endpoint ..............................................................................17
2.2.2.2
Safety and tolerability..............................................................18
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 19
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................19
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................19
3.3
SELECTION OF TRIAL POPULATION ......................................................19
3.3.1
Main diagnosis for trial entry..............................................................19
3.3.2
Inclusion criteria...................................................................................19
3.3.3
Exclusion criteria ..................................................................................20
3.3.4
Withdrawal of subjects from treatment or assessments ...................21
3.3.4.1
Discontinuation of trial treatment ............................................21
3.3.4.2
Withdrawal of consent to trial participation ............................22
3.3.4.3
Discontinuation of the trial by the sponsor..............................22
3.3.5
Replacement of subjects .......................................................................22
4.
TREATMENTS........................................................................................ 23
4.1
INVESTIGATIONAL TREATMENTS ..........................................................23
4.1.1
Identity of the Investigational Medicinal Products ...........................23


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4.1.2
Selection of doses in the trial................................................................23
4.1.3
Method of assigning subjects to treatment groups ............................23
4.1.4
Drug assignment and administration of doses for each subject .......24
4.1.5
Blinding and procedures for unblinding ............................................24
4.1.6
Packaging, labelling, and re-supply ....................................................24
4.1.7
Storage conditions.................................................................................25
4.1.8
Drug accountability ..............................................................................25
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................26
4.2.1
Other treatments and emergency procedures....................................26
4.2.2
Restrictions............................................................................................26
4.2.2.1
Restrictions regarding concomitant treatment .........................26
4.2.2.2
Restrictions on diet and life style.............................................26
4.3
TREATMENT COMPLIANCE.......................................................................27
5.
ASSESSMENTS....................................................................................... 28
5.1
ASSESSMENT OF EFFICACY.......................................................................28
5.2
ASSESSMENT OF SAFETY............................................................................28
5.2.1
Physical examination ............................................................................28
5.2.2
Vital signs...............................................................................................28
5.2.3
Safety laboratory parameters..............................................................28
5.2.4
Electrocardiogram................................................................................30
5.2.5
Other safety parameters.......................................................................31
5.2.6
Assessment of adverse events...............................................................31
5.2.6.1
Definitions of adverse events...................................................31
Adverse event ............................................................31
Serious adverse event ................................................31
AEs considered ‘Always Serious’.............................32
Adverse events of special interest .............................32
Intensity (severity) of AEs.........................................33
Causal relationship of AEs ........................................33
5.2.6.2
Adverse event collection and reporting ...................................34
AE collection.............................................................34
AE reporting to the sponsor and timelines ................35
Information required..................................................35
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................35
5.3.1
Assessment of pharmacokinetics .........................................................35
5.4
BIOBANKING ...................................................................................................36


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5.6
APPROPRIATENESS OF MEASUREMENTS.............................................36
6.
INVESTIGATIONAL PLAN.................................................................. 38
6.1
VISIT SCHEDULE............................................................................................38
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................38
6.2.1
Screening period....................................................................................38
6.2.2
Treatment periods.................................................................................38
6.2.3
Follow-up period and trial completion ...............................................39
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 40
7.1
STATISTICAL DESIGN – MODEL ...............................................................40
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................40
7.3
PLANNED ANALYSES....................................................................................40
7.3.1
Primary endpoint analyses...................................................................41
7.3.2
Secondary endpoint analyses ...............................................................42
7.3.4
Safety analyses.......................................................................................43
7.4
INTERIM ANALYSES .....................................................................................43
7.5
HANDLING OF MISSING DATA ..................................................................44
7.5.1
Safety......................................................................................................44
7.5.2
Pharmacokinetics..................................................................................44
7.6
RANDOMISATION ..........................................................................................44
7.7
DETERMINATION OF SAMPLE SIZE ........................................................44
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 45
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................45
8.2
DATA QUALITY ASSURANCE .....................................................................46
8.3
RECORDS..........................................................................................................46
8.3.1
Source documents .................................................................................46
8.3.2
Direct access to source data and documents.......................................47
8.3.3
Storage period of records.....................................................................48
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................48
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......48
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................48
8.6
TRIAL MILESTONES .....................................................................................49
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................49


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9.
REFERENCES......................................................................................... 51
9.1
PUBLISHED REFERENCES...........................................................................51
9.2
UNPUBLISHED REFERENCES.....................................................................52
10. APPENDICES .......................................................................................... 54
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 55


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials Database
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
IB
Investigator’s brochure
IEC
Independent Ethics Committee


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ILD
Interstitial lung disease
iPD
Important protocol deviation
IPF
Idiopathic pulmonary fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
SSc-ILD
Systemic sclerosis associated interstitial lung disease
T
Test product or treatment
TKI
Tyrosine kinase inhibitore
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
VEGFR
Vascular endothelial growth factor receptor
XTC
Ecstasy 


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1.
INTRODUCTION
Nintedanib (Ofev®) soft gelatin capsules at dose strengths 100 mg and 150 mg are indicated 
for treatment of idiopathic pulmonary fibrosis (IPF), chronic fibrosing interstitial lung 
diseases (ILD) with a progressive phenotype, and systemic sclerosis associated interstitial 
lung disease (SSc-ILD) in adult patients. Development for fibrosing interstitial lung disease
in children and adolescents (6 to 17 years old) is ongoing. 
To accommodate pediatric age groups, a 25 mg nintedanib soft gelatin capsule has been 
developed. This current study aims at characterizing the pharmacokinetics (PK) of 25 mg 
nintedanib soft gelatin capsules via relative bioavailability comparison with 100 mg capsules. 
For this purposes, two treatments will be compared in this trial: Reference Treatment (R) 
consists of one single dose of 100 mg nintedanib, and Test Treatment (T) consists of one 
single dose of 4 capsules à 25 mg nintedanib, i.e. 100 mg nintedanib.
The results of this study are intended to support the submission of nintedanib for pediatric 
indications.
1.1
MEDICAL BACKGROUND
In addition to above-described adult indications, clinical development of nintedanib (Ofev®) 
in children and adolescents (6 to 17 years old) with various forms of clinically significant 
chronic fibrosing lung diseases (trial 1199-0337) is ongoing.
Although the classification of paediatric interstitial lung disease is distinct from that of adult 
ILD, similar to adults with PF-ILD, some patients with children’s interstitial lung disease 
develop chronic lung fibrosis that is associated with significant morbidity and mortality. 
However, there are currently no approved therapies for the treatment of fibrosing interstitial 
lung disease in children. Building on the scientific working hypothesis of the PF-ILD 
programme that lung fibrosis can become progressive, self-sustaining, and independent of the 
original clinical association or trigger, it is postulated that targeted antifibrotic therapy may 
also provide therapeutic benefit in children with fibrosing lung disease.
For details on medical background refer to the current version of the Investigator’s Brochure 
[c01783972].
1.2
DRUG PROFILE
For details of drug profile refer to the current version of the Investigator’s Brochure 
[c01783972].
Mode of action
Nintedanib is a tyrosine kinase inhibitor (TKI) targeting fibroblast growth factor receptor 
1–3, platelet-derived growth factor receptor α and β, and vascular endothelial growth factor 
receptor (VEGFR) 1–3 involved in fibrotic mechanisms active in patients with fibrosing 
interstitial lung diseases. In addition, nintedanib inhibits lymphocyte-specific tyrosine-protein 
kinase, tyrosine-protein kinase lyn, proto-oncogene tyrosine-protein kinase (Src) [P08-08684] 
and colony-stimulating factor 1 receptor kinases [P18-00197]. Nintedanib binds 


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competitively to the Adenosine Triphosphate binding pocket of these kinases and blocks the 
intracellular signalling cascades, which have been demonstrated to be involved in the 
pathogenesis of fibrotic tissue remodelling in interstitial lung diseases. Nintedanib inhibited 
migration, proliferation and transformation of human lung and skin fibroblasts from patients 
with IPF and SSc-ILD and the release of extracellular matrix protein [P14-07999, P14-17410, 
P15-06100, P14-02860, P16-05905, P17-06049, P18-05607]. In addition nintedanib 
attenuated cellular processes assumed to be involved in the initiation and progression of 
fibrosis, the release of pro-fibrotic mediators from peripheral blood monocytic cells (PBMC) 
[P17-06052] and the polarisation of macrophages to alternatively activated pro-fibrotic 
macrophages [P17-06049]. Nintedanib was effective in attenuating the progressive fibrotic 
lung pathology in animal models of lung fibrosis independent of the initial trigger, chemical, 
environmental, immunologic or transcriptional [P17-03310, P14-02860, P15-06100, P17-
10564, P18-02512] suggesting a preclinical rationale to treat patients with lung fibrosis 
related to different underlying diseases.
Single dose toxicity studies in rats and mice indicated low acute toxic potential of nintedanib.
In repeat dose toxicology studies in rats, adverse events (e.g. thickening of epiphyseal plates,
lesions of the incisors) were mostly related to the mechanism of action of nintedanib (i.e.
VEGFR-2 inhibition). Changes occurring during bone growth phases were reversible after
discontinuation, while alterations in tooth structure and function were irreversible. These
findings are considered class effects and may be particularly relevant for growing children
with regards to development and growth of skeleton and teeth. Diarrhoea and vomiting,
accompanied by reduced food consumption and loss of body weight, were observed in
toxicity studies in non-rodents. There was no evidence of liver enzyme increases in rats,
dogs, and cynomolgus monkeys. Mild liver enzyme increases were only observed in rhesus
monkeys. Nintedanib is non-mutagenic. Embryo-foetal lethality and teratogenic effects in rats 
were observed at dose level resulting in plasma drug concentrations comparable or below 
those in humans. As nintedanib may cause foetal harm, women of childbearing potential
should be advised to avoid becoming pregnant while receiving nintedanib treatment. The use 
of male contraception especially condoms by male patients receiving nintedanib is not 
mandatory and female partners of male patients receiving nintedanib are not required to
follow contraceptive guidelines. Based on preclinical investigations, there is no evidence for 
impairment of male fertility.
Key pharmacokinetic characteristics
A soft gelatin capsule formulation of nintedanib is used in humans. Maximum plasma 
concentrations (Cmax) occur between 2 to 4 hours after oral administration. Steady state is 
reached at the latest within one week of dosing. The absolute bioavailability of nintedanib is 
slightly below 5%. After food intake, a trend towards an increased systemic exposure (around 
15-20%) and a delayed absorption (median tmax around 4 h) is observed compared to 
administration under fasted conditions. Nintedanib is recommended to be taken with food to 
improve gastrointestinal tolerability. Nintedanib is preferentially distributed in plasma with a 
blood to plasma ratio of 0.87; the terminal half-life varied between 7 and 19 h. Nintedanib is 
mainly eliminated via faeces (~93%), with minimal renal excretion (0.7%).


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1.2.1
Residual Effect Period
For this trial using two single doses of 100 mg nintedanib in adult healthy volunteers, a 
Residual Effect Period (REP) of 7 days is used. This is a conservative estimate of the period 
after the last single dose with measurable drug levels and/or pharmacodynamic effects is still 
likely to be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Nintedanib (Ofev®) 100 and 150 mg capsules are indicated for treatment of fibrotic diseases 
in adult populations. In addition to these dose strengths, a 25 mg nintedanib capsule has been 
developed. All three dose strengths are being investigated in trial 1199-0337 evaluating 
nintedanib in fibrosing ILD in pediatric age groups. This current trial has the purpose to 
characterize the pharmacokinetics of the 25 mg nintedanib capsule in plasma. For this 
purpose, the relative bioavailability of 4 capsules à 25 mg nintedanib (100 mg in total; 
treatment Test [T]) vs. 1 capsule à 100 mg nintedanib (treatment reference [R]) is 
investigated in healthy male volunteers. 
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance to generate further information on 
bioavailability of the nintedanib 25 mg capsule to supplement in vitro data of this new 
formulation used in the clinical development programme of nintedanib in children and 
adolescents (6 to 17 years old) with various forms of clinically significant chronic fibrosing 
lung diseases. Subjects are exposed to risks of study procedures and risks related to the 
exposure to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.


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The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
Nintedanib, as tyrosine kinase inhibitor with an anti-angiogenic mechanism of action, has 
been administered only short term to healthy volunteers. No undue risk is expected with short 
term administration. Nintedanib has been given in single doses to 240 healthy volunteers (see 
Section 1.2) and has been generally safe and well tolerated. The most common drug-related 
adverse events were gastrointestinal effects and headache. All drug-related adverse events 
were mild or moderate and fully reversible. The highest dose given so far to healthy 
volunteers was 200 mg; this was given (two single doses of 200 mg each separated by a 
wash-out phase) to 70 healthy male volunteers in trial 1199-0237 [c08883821-01]. 
The current trial uses two single doses of 100 mg which is well below maximal doses given 
to healthy volunteers so far, separated by an appropriate wash-out phase.
Intake with food improves the tolerability of nintedanib, therefore nintedanib should be taken 
with food. Accordingly, in this trial the study medication will be given after a standardized 
breakfast.
Subject selection criteria and pre-dose measurements are suitable to select the appropriate 
healthy population for this trial. Post-dose safety laboratory includes parameters to assess 
potential side effects reported after multiple-dose treatment in patient populations.
COVID-19 pandemic
Based on the pharmacological mechanism and existing non-clinical, clinical and post-
marketing data there is no indication that treatment with nintedanib may increase the risk of
infection with or progression of SARS-CoV-2 infection. Participation in this trial may 
increase the risk of COVID-19 exposure due to travels to the study site and completion of 
protocol-defined procedures at the site. A risk management plan has been set up at the 
clinical site that details precautionary measures (e.g., hygiene rules, wearing of face masks, 
physical distancing) and screening for SARS-CoV-2 infection. 
Drug-induced liver injury surveillance
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.6.1.4, adverse events of special interest.
Summary of benefit-risk assessment
This trial is required to generate further information on bioavailability of the nintedanib 
25 mg capsule to supplement in vitro data of this new formulation used in the clinical 
development programme of nintedanib in children and adolescents (6 to 17 years old) with 


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various forms of clinically significant chronic fibrosing lung diseases. Taking into account 
the safety profile of nintedanib, the safety measures in this trial, and the need for effective 
treatment of fibrosing interstitial lung diseases in children and adolescents (6 to 17 years old), 
the expected benefit of this trial outweighs the potential risks and justifies exposure of 
healthy human subjects.


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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 of this trial is to investigate the relative bioavailability of 100 mg 
nintedanib given as four capsules of 25 mg nintedanib (Test, T) compared with one capsule 
of 100 mg nintedanib (Reference, R) following oral administration.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for nintedanib:
∀
AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)
∀
Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for nintedanib:
∀
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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2.2.2.2
Safety and tolerability
Safety and tolerability of nintedanib will be assessed based on:  
∀
Adverse events (including clinically relevant findings from the physical examination)
∀
Safety laboratory tests
∀
12-lead ECG
∀
Vital signs (blood pressure, pulse rate)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, open-label, two-way crossover trial in healthy 
male subjects in order to compare the test treatment (T) to the reference treatment (R). The 
treatments will be 100 mg nintedanib given as 4 capsules à 25 mg (T) administered to 
subjects in the fed state and 100 mg nintedanib given as 1 capsule à 100 mg (R) administered 
to subjects in the fed state. The subjects will be randomly allocated to the 2 treatment 
sequences (T-R or R-T). For details, refer to Section 4.1.
There will be a washout period of at least 7 days between the treatments.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between treatments is based on 
an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529].
The open-label treatment is not expected to bias results, since the trial endpoints are derived 
from measurement of plasma concentrations of the analyte. Analyte plasma concentrations 
are not expected to be affected by knowledge of treatment.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 20 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site.
Considering the teratogenic potential of nintedanib, only male subjects will be included in the 
trial.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:


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1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests
2. Age of 18 to 55 years (inclusive)
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Relevant chronic or acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients, including also peanut and soy)
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation) or any (re-)vaccination within 30 days before first trial medication or 
planned during the trial
12. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 24 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial


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18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
21. Body weight lower than 65 kg
22. Increased bleeding risk, including known genetic predisposition to bleeding, use of 
medication that could relevantly increase bleeding risk (e.g. low-molecular weight 
heparin; recent use of non-steroidal anti-inflammatory drugs is allowed), history of 
haemorrhagic central nervous system event within 12 months of planned first study 
medication, or any of the following within 3 months of planned first study medication: 
Haemoptysis or macrohaematuria, active gastro-intestinal bleeding or gastro-intestinal 
ulcers, or major injury or surgery (investigator judgement)
23. During Covid-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 
discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.1), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 
and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject 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.


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3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
6. An AE or clinically significant laboratory change or abnormality occurs that the 
investigator assesses as warranting discontinuation of treatment. This may include:
∀
The subject has an elevation of AST and/or ALT ≥3-fold ULN
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
if more than 50% of the subjects have drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least 1 drug-related serious adverse event is 
reported
3. Violation of GCP or the CTP impairing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational product
3.3.5
Replacement of subjects
In case more than 2 subjects do not complete the trial (including non PK evaluable subjects), 
the CT Leader together with the Trial Pharmacokineticist and the Trial Statistician are to 
decide, if and how many subjects will be replaced. A replacement subject will be assigned a 
unique trial subject number, and will be assigned to the same treatment as the subject he or 
she replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products will be supplied by BI Pharma GmbH & Co. KG. 
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
Nintedanib
Pharmaceutical formulation: Soft gelatin capsule
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg
Posology:
4-0-0
Route of administration:
oral
Duration of use:
One single dose
The characteristics of the reference product are given below:
Substance:
Nintedanib
Pharmaceutical formulation: Soft gelatin capsule
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
One single dose
4.1.2
Selection of doses in the trial
The doses selected for this trial are suitable to assess PK of 4 capsules à 25 mg nintedanib in 
comparison to one capsule à 100 mg nintedanib. 
4.1.3
Method of assigning subjects to treatment groups
The randomisation list will be provided to the trial site in advance.
According to the planned sample size, 2 cohorts are planned. Prior to the start of the study, 
subjects willing to participate will be recruited to cohorts according to their temporal 
availability. In the morning of Day 1 (Visit 2), subjects will be allocated to treatment 
sequences prior to the first administration of trial medication. For this purpose, numbers of 
the randomisation list will be allocated to the subjects by drawing lots. Subjects are then 
assigned to a treatment sequence according to the randomisation list.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.6.


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4.1.4
Drug assignment and administration of doses for each subject
This trial is a 2-way crossover study. All subjects will receive the 2 treatments in randomised 
order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T (Test)
Nintedanib
Soft gelatin 
capsule
25 mg
4 capsules, single dose, fed
100 mg
R (Reference)
Nintedanib
Soft gelatin 
capsule
100 mg
1 capsule, single dose, fed
100 mg
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a standing position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
After an overnight fast starting 10 h before drug administration, a standardized continental 
breakfast will be served 30 min before drug administration. The subjects must completely 
consume the meal prior to drug intake.
Subjects will be kept under close medical surveillance until 24 h after drug administration. 
During the first 6 h after drug administration, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture).
The treatments will be separated by a wash-out phase of at least 7 days.
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.


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The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
Packaging and labelling will be performed in such a way that reserve samples as per 
21CFR320 are available for storage by the investigational site and that the trial materials can 
be chosen in a random way by the Investigator.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the IRB / ethics committee
∀
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  
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
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 subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant therapies will be recorded 
(including time of intake on study days) on the appropriate pages of the CRF.
In case of e.g. headache ibuprofen is allowed. 
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 6 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the fluid given with the
breakfast, the water administered with the drug, and an additional 240 mL of water at 2 h,
4 h, and 6 h post-dose (mandatory for all subjects). From lunch until 24 h post-dose, total 
fluid intake is restricted to 3000 mL.
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of the study is collected.
Alcoholic beverages are not permitted from 48 h before study drug administration until the 
last PK sample of each study period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 10 h before until 24 h after each administration of trial 
medication.
Smoking is not allowed during in-house confinement while admitted to the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.


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4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations
will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results of alcohol history not mandatory to be entered into CRF 
or to be reported), relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a 
physical examination. At the end of trial examination, it will include review of vital signs, 12-
lead ECG, laboratory tests, and a physical examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (Dinamap Pro 100, 
) at the 
times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine 
position. All recordings should be made using the same type of blood pressure recording 
instrument on the same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 9 h. 
For retests, at the discretion of the investigator or designee, overnight fasting is not required. 
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; 
Basophils/ Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is
abnormal)
Neut. Poly (segs) /Leukocytes; Neut. Poly (segs), absol.; 
Neutrophils Bands/Leukocytes;  Neutrophils Bands, absol.;
Eosinophils/Leukocytes; Eosinophils, absol.; Basophils/ 
Leukocytes; Basophils, absol.; Monocytes/ Leukocytes; 
Monocytes, absol.; Lymphocytes/Leukocytes; 
Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
INR (International Normalization Ratio)
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
X
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)
Cholesterol, total
Triglyceride
X
X
X
X
X
X
X
X
--
--
X
X
--
--
--
--
--
X
X
X
X
X
--
--
Electrolytes
Sodium
Potassium
X
X
--
--
X
X
Urinalysis1 (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment1
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 2 and 3 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 4 (end of trial examination)
1 Microscopic examination (urine sediment) if erythrocytes, leukocytes, nitrite or protein are abnormal in urinalysis.


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The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and prior to each treatment period.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alco True 
M®,
) will be performed prior to each treatment period, 
and may be repeated at any time during the study at the discretion of an investigator or 
designee. The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
, with the exception of 
drug screening tests. These tests will be performed at the trial site using Surestep Urine Drug 
test or M-10/14-PDT Surestep Multiline test, or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, 
 
) at the times provided in the Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (
). Electrode placement will be performed according to the 


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method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
Not applicable
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
∀
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 pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
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


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∀
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 
upon appropriate medical judgment 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
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 trial medication and must be reported 
as described in 5.2.6.2, 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 eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
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 5.2.6.2.2.
The following are considered as AESIs:
∀
Hepatic injury
A hepatic injury is defined by 
o ALT and/or AST ≥8 fold ULN
o ALT and/or AST ≥3 fold ULN and total bilirubin ≥ 2 fold ULN* 
o ALT and/or AST ≥3 fold ULN and unexplained INR > 1,5*
o ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%)*


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o 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 subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF or eDC system. 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 that these parameters are analysed, if necessary in an 
unscheduled blood test. Should the results meet the criteria of hepatic injury alert, the 
procedures described in the DILI checklist should be followed.s
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
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
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 


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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
5.2.6.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
∀
From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.
∀
After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 


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communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
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 contact details will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions the 
Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and 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.
Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 


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5.4
BIOBANKING
Not applicable.
5.6
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in 
standard laboratory values that might occur as a result of administration of trial medication. 
The safety assessments are standard, are accepted for evaluation of safety and tolerability of 


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an orally administered drug, and are widely used in clinical trials. The pharmacokinetic 
parameters and measurements outlined in Section 5.3 are generally used assessments of drug 
exposure. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening, study measurements and assessments scheduled to 
occur ‘before’ trial medication administration on Day 1, and the end of trial examination are 
provided in the Flow Chart.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for laboratory tests will be ± 2 h.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
Starting from planned time of 48 hours after drug administration (and beyond) a time window 
of +/- 120 minutes will be allowed for all procedures.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.4.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.5).
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Days 1, 2, 3, and 4 in each 
period). At least 7 days will separate drug administrations in the first and second treatment 
periods.
On Day 1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration. The 
subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness. On all other study days, subjects will be treated in an ambulatory fashion.


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For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.1 to 5.2.6.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained. 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the relative bioavailability of 100 mg 
nintedanib given as 4 capsules à 25 mg (Test, T) compared with 100 mg nintedanib given as 
1 capsule à 100 mg (Reference, R) following oral administration on the basis of the primary 
and secondary pharmacokinetic endpoints, as listed in Section 2.1.2 and 2.1.3. The trial is 
designed to allow intra-subject comparisons and will be evaluated statistically by use of a 
linear model for logarithmically transformed PK endpoints.
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of 4 capsules à 25 mg nintedanib compared with 1 capsule à 
100 mg nintedanib will be estimated by the ratios of the geometric means (test/reference),
and their corresponding 2-sided 90% confidence intervals (CIs) will be provided. This 
method corresponds to the two one-sided t-test procedure, each at the 5% significance level. 
Since the main focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:
∀
Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for safety 
analyses.
∀Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he/she 
contributes only one PK parameter value for one period to the statistical assessment.
Descriptive and model based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(iPD) categories will be suggested in the iPD specification file, iPDs will be identified no 
later than in the Report Planning Meeting, and the iPD categories will be updated as needed.


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Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for nintedanib will be calculated 
according to the to the relevant BI internal procedures.
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be
∀
Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to
∀
Incorrect dose of trial medication taken
∀
Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example
∀
The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis)
∀
A predose concentration is >5% Cmax value of that subject
∀
Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.3.1
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: sequence, subjects within 
sequences, period and treatment. The effect 'subjects within sequences' will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation:
yijkm = # + ∃i + sim + %j + &k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment 
k in period j,


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# = the overall mean,
∃i = the ith sequence effect, i = 1, 2,
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., 20
%j = the jth period effect, j = 1, 2,
&k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means).
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
7.3.2
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the relevant 
BI internal procedures. and will be assessed statistically using the same methods as described 
for the primary endpoints.


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7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, and those between trial medication intake and end of 
REP (see Section 1.2.1) will be assigned to the respective treatment period. Events occurring 
after the REP but prior to next intake or end of trial termination date will be assigned to 
’follow-up’. In case of two or more treatments, the follow-up will be summarized according 
to the previous treatment. These assignments including the corresponding time intervals will 
be defined in detail in the TSAP. Note that AEs occurring after the last per protocol contact 
but entered before final database lock will be reported to Pharmacovigilance only and will not 
be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No interim analysis is planned.


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7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures.
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Subjects will be randomised to one of the 2 treatment sequences in a 1:1 ratio. The block size 
will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
The sample size determination is not based on a power calculation, but assures a precise 
estimation of the relative bioavailability. For this trial a precision of 1.25 has been considered 
necessary and sufficient by the project team. Thereby, precision is defined as ratio of upper 
confidence interval limit to the relative BA estimate. 
The observed intra-individual coefficient of variation (gCV) for nintedanib in previous trials 
[c09412738-01] was roughly 27% for Cmax and 12% for AUC0-tz.
Assuming an intra-individual variability of 30% for nintedanib, the trial will need 18 subjects 
in order to achieve two-sided 90% confidence intervals that have a precision of at least 1.25
with a probability of 95%. As an example, for the above stated assumptions and an expected 
ratio of geometric means (T/R) of 1.00, the expected two-sided 90% confidence interval will 
range from (0.80, 1.25).
Accounting for up to 2 non PK evaluable subjects, a total of N = 18+2 = 20 subjects are 
planned to be entered into the trial.
The calculation was performed as described by Julious [R11-5230, Chapter 8] using R 
Version 4.0.2.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
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, 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 subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects 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. As a general rule, no trial results should be 
published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the  subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT 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 a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’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 subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject 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.


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The consent and re-consenting process should be properly documented in the source 
documentation.
For subjects enrolled during the Covid-19 pandemic: In addition to the study-specific 
informed consent, separate written consent will be obtained for testing on SARS-CoV-2 
infection.
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 subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the
– the 
validated ClinBaseTM system is used for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as data base. Instead of being entered into CRFs, selected data are directly 
entered into the system.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. 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.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 


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and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:
∀
Subject identification: sex, year of birth (in accordance with local laws and 
regulations)
∀
Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)
∀
Dates of subject’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
AEs and outcome events (onset date [mandatory], and end date [if available])
∀
SAEs (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)
∀
ECG results (original or copies of printouts)
∀
Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)
∀
Prior to allocation of a subject 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 subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data are entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
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 Clinical Research Associate, 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.


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8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial.
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.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject 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 subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’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.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular
∀
Sample and data usage has to be in accordance with the informed consent
∀
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.
∀
An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place
∀
A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage
∀
A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
∀
Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF


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8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’).
Early termination of the trial is defined as the premature termination of the trial for 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 EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
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).
The trial will be conducted at the 
 
, under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
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 Trial Managers, Clinical 
Research Associates, and investigators of participating trial sites
The trial medication will be provided by the 
Safety laboratory tests will be performed by the local laboratory of the trial site (
).
Analyses of nintedanib concentrations in plasma will be performed at 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.


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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.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P08-08684
Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase 
inhibitor with sustained receptor blockade and good antitumor efficacy. 
Cancer Res. 2008;68:4774-82.
P14-02860
Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Antifibrotic and 
anti-inflammatory activity of the Tyrosine Kinase inhibitor Nintedanib in 
Experimental Models Of Lung Fibrosiss. J Pharmacol Exp Ther 
2014;349(2):209-220.
P14-07999
Wollin L, Ostermann A, Wex E, Herrmann FE, Doods H. Nintedanib 
attenuates motility of lung fibroblasts from patients with idiopathic 
pulmonary fibrosis. ATS 2014, 110th Int Conf of the American Thoracic 
Society (ATS), San Diego, 16 - 21 May 2014. Am J Respir Crit Care Med 
2014;189:A2008.
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) 2014 ; 15; 157.
P15-06100
Huang J, Beyer C, Palumbo-Zerr K, et al. Nintedanib inhibits fibroblast 
activation and ameliorates fibrosis in preclinical models of systemic 
sclerosis. Ann Rheum Dis 2016;75(5):883-890.
P16-05905
Wollin L, Schuett J, Ostermann A, Herrmann F. The effect of nintedanib on 
platelet derived growth factor-stimulated contraction of human primary 
lung fibroblasts. ATS 2016, 112th Int Conf of the American Thoracic 
Society (ATS), San Francisco, 13 - 18 May 2016. Am J Respir Crit Care 
Med 2016;193:A2384.
P17-06049
Tandon K, Herrmann F, Ayaub E, et al. Nintedanib attenuates the 
polarization of profibrotic macrophages through the inhibition of tyrosine 
phosphorylation on CSF1 receptor. ATS 2017, 113th Int Conf of the 
American Thoracic Society (ATS), Washington, 19 - 24 May 2017. Am J 
Respir Crit Care Med 2017;195:A2397.
P17-06052
Wollin L, Ostermann A, Brauchle V, Williams C. Nintedanib inhibits 
profibrotic mediators with relevance in connective tissue disease-associated 
interstitial lung diseases. ATS 2017, 113th Int Conf of the American 
Thoracic Society (ATS), Washington, 19 - 24 May 2017. Am J Respir Crit 
Care Med 2017;195:A2450.
P17-03310
Ackermann M, Kim YO, Wagner WL, et al. Effects of nintedanib on the 
microvascular architecture in a lung fibrosis model. Angiogenesis 
2017;20(3):359-372.


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P17-10564
Huang J, Maier C, Zhang Y, et al. Nintedanib inhibits macrophage 
activation and ameliorates vascular and fibrotic manifestations in the Fra2 
mouse model of systemic sclerosis. Ann Rheum Dis 2017;76(11):1941-
1948.
P18-00197
Hilberg F, Tontsch-Grunt U, Baum A, et al. Triple angiokinase inhibitor 
nintedanib directly inhibits tumor cell growth and induces tumor shrinkage 
via blocking oncogenic receptor tyrosine kinases. J Pharmacol Exp Ther 
2018;364(3):494-503.
P18-02512
Redente EF, Aguilar MA, Black BP, et al. Nintedanib reduces pulmonary 
fibrosis in a model of rheumatoid arthritis-associated interstitial lung 
disease. Am J Physiol Lung Cell Mol Physiol 2018;314(6):L998-L1009
P18-05607
Akter T, Atanelishvili I, Noguchi A, Wollin L, Silver RM, Bogatkevich GS. 
Molecular evidences for antifibrotic potential of nintedanib in interstitial 
lung disease associated with systemic sclerosis. Source: ATS 2018, 114th 
Int Conf of the American Thoracic Society (ATS), San Diego, 18 - 23 May 
2018. Am J Respir Crit Care Med 2018 ; 197; A4638.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
c01783972
Investigator’s Brochure Nintedanib (BIBF 1120). Project 1199.p3, P10, 
P16. Current Version.
c08883821-01
Bioequivalence of 1 soft 
gelatine capsule containing 200 mg nintedanib compared to 2 soft gelatine 
capsules containing 100 mg nintedanib following oral administration in 
healthy male subjects. Clinical Trial Report 1199-0237. Jun 2016.
c09412738-01
Influence of bosentan on the pharmacokinetics of nintedanib in healthy 
male subjects. Clinical Trial Report 1199-0239. Nov 2016.
c01787114
1199.2. 
Metabolism and pharmacokinetics of [14C]-BIBF 1120 after administration 
of single doses of 100 mg [14C]-BIBF 1120 oral solution in healthy male 
volunteers. 03 Aug 2006
c01787137
 1199.17. Safety and 
pharmacokinetics/bioavailability of a single dose of 150 mg BIBF 1120 
administered as soft gelatine capsules with and without food to healthy 
male volunteers in an open, randomised intra-individual crossover 
comparison design. 15 Jun 2011


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c01798932
 
1199.21. Safety and relative bioavailability of a single dose of 150 mg 
BIBF 1120 administered as soft gelatine capsules charge 1 compared to 
BIBF 1120 soft gelatine capsules charge 2 compared to BIBF 
1120...30 Mar 2009
c01789568
 1199.75. Safety and tolerability of single rising doses of 
1 mg, 3 mg, 10 mg, and 20 mg of BIBF 1120 as intravenous infusion 
(single-blind, placebo-controlled at each dose group) and absolute 
bioavailability of 100 mg BIBF 1120...11 Jan 2010
c02036462
1199.161. Relative bioavailability of 
nintedanib given alone and in combination with ketoconazole at steady state 
in healthy male volunteers (an open-label, randomised, two-way cross-over 
clinical Phase I study). 04 Jul 2013
c01801263
1199.162. Relative 
bioavailability of a single oral dose of nintedanib given alone and in 
combination with multiple oral doses of rifampicin in healthy male 
volunteers (an open-label, two-period, fixed-sequence Phase I trial). 
08 Aug 2013
c03149997
1199.2. Pharmacokinetics, 
safety and tolerability of nintedanib single oral dose in male and female 
patients with different degrees of hepatic impairment (Child-Pugh 
classification A and B) as compared with nintedanib administration to male 
and female healthy subjects (a nonblinded, parallel group study of Phase I). 
20 May 2015


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1 
Date of amendment
02 June 2021
EudraCT number
2021-001052-34
BI Trial number
1199-0463
BI Investigational Medicinal 
Product
Ofev®, nintedanib
Title of protocol
Relative bioavailability of 100 mg nintedanib 
(Ofev®) given as four capsules of 25 mg compared 
to one capsule of 100 mg following oral 
administration in healthy male subjects (an open-
label, randomised, single-dose, two-period, two-
sequence crossover study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Section 3.3.3
2. Section 3.3.4.1
3. Section 5.2.3
Description of change
1. Exclusion criterion no. 11 amended to exclude
(re-)vaccination as concomitant medication
2. Additional treatment discontinuation criterion for
individual subjects introduced
3. Typos corrected in footnote 2 and 3 of Table 
5.2.3.1 
Rationale for change
1. Content change as requested by IEC/CA
2. Content change to address question raised by 
IEC/CA
3. Correction of inconsistency to Flow Chart


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Boehringer Ingelheim 
Page 2 of 2
Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c36860477-01
BI Trial No.:
1199-0463
Title:
Relative bioavailability of 100 mg nintedanib (Ofev®) given as
four capsules of 25 mg compared to one capsule of 100 mg
following oral administration in healthy male subjects (an open-
label, randomised, single-dose, two-period, two-sequence crossover 
study)
(Revised Protocol including Amendment 1 [c35094875-03])
Investigational
Product(s):
Ofev®, nintedanib
Responsible trial 
statistician(s):
Phone: 
Fax:
Date of statistical 
analysis plan:
29 SEP 2021 SIGNED
Version:
final
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! 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................3
2.
LIST OF ABBREVIATIONS...............................................................................4
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................7
5.
ENDPOINTS(S).....................................................................................................8
5.1
PRIMARY ENDPOINT(S)...................................................................................8
5.2
SECONDARY ENDPOINT(S).............................................................................8
5.2.1
Key secondary endpoint(s) ...................................................................................8
5.2.2
Secondary endpoint(s)...........................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS...........................................................10
6.1
TREATMENT(S) ................................................................................................10
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................11
6.3
SUBJECT SETS ANALYSED ...........................................................................12
6.5
POOLING OF CENTRES..................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................13
7.
PLANNED ANALYSIS ......................................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........16
7.2
CONCOMITANT DISEASES AND MEDICATION......................................16
7.3
TREATMENT COMPLIANCE ........................................................................17
7.4
PRIMARY ENDPOINT(S).................................................................................17
7.4.1
Primary analysis of the primary endpoints ......................................................17
7.5
SECONDARY ENDPOINT(S)...........................................................................19
7.5.1
Key secondary endpoint(s) .................................................................................19
7.5.2
Secondary endpoint.............................................................................................19
7.7
EXTENT OF EXPOSURE .................................................................................19
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse Events ....................................................................................................20
7.8.2
Laboratory data...................................................................................................21
7.8.3
Vital signs.............................................................................................................21
7.8.4
ECG ......................................................................................................................21
7.8.5
Others ...................................................................................................................22
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............23
9. 
REFERENCES ....................................................................................................24


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11.
HISTORY TABLE..............................................................................................26
LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................10
Table 6.3: 1
Subject sets analysed ........................................................................................13
Table 11: 1
History table .....................................................................................................26


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Aspartate transaminase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BMI
Body mass index
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CSD
Company Standard Displays
CV
Arithmetic coefficient of variation
F/U
Follow Up
gCV
Geometric coefficient of variation
gMean
Geometric mean
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PKS
PK parameter analysis set
Q1
1st quartile
Q3
3rd quartile
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RPM
Report Planning Meeting
SD
Standard deviation


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Term
Definition / description
SOC
System organ class
TS
Treated set
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 Trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on trial objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher, 
).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP.


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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
Section 2.1.2 of the CTP: 
The following pharmacokinetic parameters will be determined for nintedanib:
∀
AUC0-tz (area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point)
∀
Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoint(s)
Section 2.1.3 of the CTP: 
The following pharmacokinetic parameters will be determined for nintedanib:
∀
AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
Safety and tolerability endpoints
Section 2.2.2.2 of the CTP: Safety and tolerability of nintedanib will be assessed based on:
∀
Adverse events (including clinically relevant findings from the physical examination)
∀
Safety laboratory tests
∀
12-lead ECG
∀
Vital signs (blood pressure, pulse rate)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on investigational products and selection of doses, please see 
CTP Sections 3 and 4.
The study will be performed as a randomised, open-label, two-way cross-over trial. The 
treatments will be 100 mg nintedanib given as 4 capsules à 25 mg (T) administered to subjects 
in the fed state and 100 mg nintedanib given as 1 capsule à 100 mg (R) administered to 
subjects in the fed state. In total, it was planned to assign 20 healthy male subjects to the 2 
treatment sequences RT or TR. 
There will be a washout period of at least 7 days between the treatments.
For details of dosage and formulation see Table 6.1: 1 below:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
R
Nintedanib, 1 capsule à 100 mg, qd, fed
NIN 1*100mg 
T
Nintedanib, 4 capsules à 25 mg, qd, fed
NIN 4*25mg
Section 1.2.1 of CTP: For this trial using two single doses of 100 mg nintedanib in adult 
healthy volunteers, a Residual Effect Period (REP) of 7 days is used. This is a conservative 
estimate of the period after the last single dose with measurable drug levels and/or 
pharmacodynamic effects is still likely to be present.
The following study phases will be defined for the analysis of adverse events (AEs):
∀
Screening
o
Ranging from 0:00h on day of informed consent until administration time of 
nintedanib in treatment period 1.
∀
On treatment (labelled “NIN 1*100mg”, “NIN 4*25mg”)
o
Ranging from the administration time of nintedanib until 7 days (168 h) 
thereafter OR until next administration of nintedanib, whatever occurs first.
∀
Follow-up (labelled “F/U NIN 1*100mg”, “F/U NIN 4*25mg”)
o
Ranging from the end of REP until the next administration of nintedanib OR 
until trial termination, whatever occurs first.


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Section 7.3.4 of the CTP: Note that AEs occurring after the last per protocol contact but
entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
The following AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) of the 
CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the 
study treatment (short label)). Screening and follow-up periods will not be included in 
this analysis. 
The following total will be provided in addition (Section 15.3 only):
∀a total over all on treatment phases included in this analysis ("Total")
B) Section 15.4 of the CTR displays:
∀Screening 
∀On treatment (labelled with the name of the study treatment (short label))
∀Follow-up phases (labelled “F/U NIN 1*100mg”, “F/U NIN 4*25mg”)
For detailed information on the handling of the treatments refer to Technical TSAP ADS plan 
and Analysis Data Reviewers guide.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, all 
manual deviations identified at the sites by the CRAs and deviations too complex to program 
will be reviewed by the trial team to decide which are considered important. For definition of 
important protocol deviations (iPD), and for the process of identification of these, refer to the 
Boehringer Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" 
(2).
Section 7.3 of the CTP: Important protocol deviation (iPD) categories will be suggested in 
the iPD specification file, iPDs will be identified no later than in the Report Planning 
Meeting, and the iPD categories will be updated as needed.
If any iPDs are identified, they are to be summarised into categories and will be captured in
the iPD specification file and the decision log. The iPD specification file (e.g. the DV domain 
specifications) will be stored within the TMF in EDMS.
The iPDs will be summarized and listed in the CTR.


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6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:
∀
Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for safety 
analyses.
∀
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he/she 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model based analyses of PK parameters will be based on the PKS.
[…]
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be
∀
Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to
∀
Incorrect dose of trial medication taken
∀
Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example
∀
The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis)
∀
A predose concentration is >5% Cmax value of that subject
∀
Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Analyses of PK endpoints 
X
Safety parameters 
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
X
Exposure
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see BI-KMED-BDS-
HTG-0035) (4).
Missing data and outliers of PK data are handled according to BI standards (see BI-KMED-
TMCP-MAN-0012 (5) and BI-KMED-TMCP-MAN-0014 (6).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before administration of nintedanib in 
each treatment period. 
Section 6.1 of the CTP: The acceptable time windows for screening, study measurements 
and assessments scheduled to occur ‘before’ trial medication administration on Day 1, and 
the end of trial examination are provided in the CTP Flow Chart.
If not stated otherwise in the Study Protocol Flow Chart, the acceptable deviation from the 
scheduled time for laboratory tests will be ± 2 h.


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For planned blood sampling times, refer to the CTP Flow Chart. Starting from planned time 
of 48 hours after drug administration (and beyond) a time window of +/- 120 minutes will be
allowed for all procedures.
Adherence to time windows will be checked via the consistency check listings at the RPM.
Unscheduled measurements of laboratory data and vital signs data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement. 


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Section 7.4 and Section 7.5.2) will
also be performed by 
and will be presented in Section 15.5 of 
the CTR and in Appendix 16.1.13.3.
Descriptive data analysis of PK endpoints and concentrations will be performed by the 
department of 
 at 
and will be 
presented in Section 15.6 of the CTR.
The format of the listings and tables will follow the BI standards with the exception of those 
generated for PK-calculations following BI standards for PK/PD analysis (7).
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number and visit. The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile


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The data format for descriptive statistics of concentrations will be identical to the data format 
of the respective concentrations. The descriptive statistics of PK parameters will be calculated 
using the individual values with the number of decimal places as provided by the evaluation 
program. Then the individual values as well as the descriptive statistics will be reported with 
three significant digits in the CTR.
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, unless the denominator is smaller 
than 100 (in all treatment columns), in which case percentages are given in integer numbers. 
The category missing will be displayed only if there are actually missing values.
Exclusion of PK parameters
The ADS “ADPP” (PK parameters) contains column variables APEXC and APEXCO 
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for 
exclusion, that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS “ADPC” (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC and ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by treatment sequence and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report, based on the TS.


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Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
It is not intended to list the compliance separately. Any deviation from complete intake will 
be addressed in the RPM (see Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINT(S)
For nintedanib, the relative bioavailability will be investigated on the basis of the primary PK 
endpoints AUC0-tz and Cmax (see Section 5.1).
7.4.1
Primary analysis of the primary endpoints
Section 7.3.1 of the CTP:
The statistical model used for the analysis of the primary endpoints will be an analysis of
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include
effects accounting for the following sources of variation: sequence, subjects within sequences, 
period and treatment. The effect 'subjects within sequences' will be considered as random, 
whereas the other effects will be considered as fixed. The model is described by the following 
equation:
yijkm 
= μ + ζi + sim + πj + τk + eijkm, where
yijkm
= logarithm of response measured on subject m in sequence i receiving 
treatment k in period j,
μ
= the overall mean,
ζi
= the ith sequence effect, i = 1, 2,
sim
= the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., 20
πj
= the jth period effect, j = 1, 2,
τk
= the kth treatment effect, k = 1, 2,
eijkm
= the random error associated with the mth subject in sequence i who received 
treatment k in period j.


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where sim ~ N(0, 
) i.i.d., eijkm ~ N(0, 
 ) i.i.d. and sim, eijkm are independent random
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see CTP Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
The implementation for this analysis will be accomplished by using the CSD macros based on 
PKS. The following SAS code can be used:
PROC MIXED DATA=indata METHOD=REML; 
CLASS subject treatment sequence period; 
MODEL logpk = treatment sequence period / DDFM=KR; 
RANDOM subject(sequence); 
LSMEANS treatment / PDIFF CL ALPHA=0.1;
RUN;
   


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable, as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoint
The secondary endpoint […] AUC0-∞will be calculated according to the relevant BI internal 
procedures. and will be assessed statistically using the same methods as described for the 
primary endpoints.
Safety and tolerability endpoints
Refer to Section 7.8 for a description of the analysis of safety and tolerability.
7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administrations will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. 
The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.


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7.8.1
Adverse Events
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. BI 
standards as presented in “Analysis and Presentation of Adverse Event Data from Clinical 
Trials – Display Template” [BI-KMED-BDS-HTG-0041] (9) and [BI-KMED-BDS-HTG-
0066] (10) will be applied. 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to ‘screening’, ‘on-treatment’ or ‘follow-up’ phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
According to the CTP, adverse events of special interest (AESI) will be analysed:
Section 5.2.6.1.4 of the CTP: The following are considered as AESIs:
∀
Hepatic injury
A hepatic injury is defined by
o ALT and/or AST ≥8 fold ULN
o ALT and/or AST ≥3 fold ULN and total bilirubin ≥ 2 fold ULN*
o ALT and/or AST ≥3 fold ULN and unexplained INR > 1,5*
o ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%)*
o 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.
According to ICH E3 (11), in addition to deaths and serious adverse events, ‘other significant’ 
AEs need to be listed in the clinical trial report. These will be any non-serious adverse event 
that led to an action taken with study drug (e.g. discontinuation or dose reduced or 
interrupted).
An overall summary of AEs will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with 
serious AEs, for subjects with drug-related AEs, for subjects with drug-related serious adverse 
events and for subjects with AESIs. In addition, the frequency of subjects with AEs will be 
summarised by treatment, worst intensity, primary SOC and PT.
The SOCs and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.


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For disclosure of adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:
∀
Adverse Events per arm for disclosure on EudraCT
∀
Non-serious Adverse Events for disclosure on EudraCT
∀
Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
[BI-KMED-BDS-HTG-0042] (12). 
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possibly 
clinically significant will be flagged in the data listings.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significantly 
abnormal or not (at the RPM at the latest). 
Descriptive statistics of laboratory data including change from baseline will be calculated by 
planned time point based on the worst value of the subject at that planned time point (or 
assigned to that planned time point).
7.8.3
Vital signs
Vital signs (blood pressure and pulse rate) will only be listed.
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as AEs (when they 
occurred during treatment), and will be analysed as such.
No separate ECG listing will be provided.


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7.8.5
Others
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition
(i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. 
No separate listing or analysis of physical examination findings will be prepared.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be loaded into the trial database after completion of enrolment, 
i.e. the randomisation has been completed.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, IDEA for CON.
3.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, current version, KMED. 
4.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version; KMED.
5.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
6.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; KMED.
7.
BI-KMED-TMCP-OTH-0003: “Graphs and Tables for Clinical Pharmacokinetics and 
Pharmacodynamic Noncompartmental Analyses”, current version, KMED.
8.
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; KMED.
9.
BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
10. BI-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from clinical 
trials”, current version, KMED.
11. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version.
12. BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1
29-SEP-21
None
This is the final TSAP