Clinical trial NCT05262751
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2022-03-28; Completion date: 2022-11-30
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this trial is to assess single dose drug exposure of several newly developed formulation prototypes of Nintedanib compared to Ofev® following oral administration.

Detailed description:

Arms: arm 1: Each participant received: Nintedanib formulation 1: Monolithic Nintedanib Modified Release Tablet (MR1) as two Prototypes (MR1-1 and MR1-2), compared to the reference (R) treatment: Nintedanib formulation 3: Ofev®. arm 2: Nintedanib formulation 2: Polyox Nintedanib Modified Release Tablet (MR2) as two Prototypes (MR2-1 and MR2-2) compared to the reference (R) treatment: Nintedanib formulation 3: Ofev®.
Interventions: intervention 1: Ofev® intervention 2: Nintedanib formulation 1 intervention 3: Nintedanib formulation 2
Intervention descriptions: intervention 1: Ofev® intervention 2: Nintedanib formulation 1: Monolithic Nintedanib Modified Release Tablet (MR1) as two Prototypes (MR1-1 and MR1-2). intervention 3: Nintedanib formulation 2: Polyox Nintedanib Modified Release Tablet (MR2) as two Prototypes (MR2-1 and MR2-2).

Protocol documents:
Prot_000.pdf: 




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Test product (TP) 1
Nintedanib Modified Release 1 (MR1)1, Prototype 1 Tablet (MR1-1)
dose
mg (1 tablet) as single dose
mode of admin.
Oral with 240 mL of water after light breakfast
Test product 2
Nintedanib MR11, Prototype 2 Tablet (MR1-2)
dose
 mg (1 tablet) as single dose
mode of admin.
Oral with 240 mL of water after light breakfast
Test product 3
Nintedanib MR22, Prototype 1 Tablet (MR2-1)
dose
 mg (1 tablet) as single dose
mode of admin.
Oral with 240 mL of water after light breakfast
Test product 4
Nintedanib MR22, Prototype 2 Tablet (MR2-2)
dose
 mg (1 tablet) as single dose
mode of admin.
Oral with 240 mL of water after light breakfast
Test product 5, optional
Nintedanib selected MRX³, Prototype 34 Tablet (MRX-3)
dose
 to 
 mg (approximate dose range, 1 tablet) as single dose
mode of admin.
Oral with 240 mL of water after light breakfast
Test product 6, optional
Nintedanib selected MRX, Prototype 44 Tablet (MRX-4)
dose
to 
mg (approximate dose range, 1 tablet) as single dose
mode of admin.
Oral with 240 mL of water after light breakfast
Test product 7, optional
Nintedanib selected MRX, Prototype 54 Tablet (MRX-5)
dose
to 
mg (approximate dose range, 1 tablet) as single dose
mode of admin.
Oral with 240 mL of water after light breakfast
Reference product (RP)
Ofev®
 mg soft capsules5
dose
 mg (1 capsule) twice per day (b.i.d.)
mode of admin.
Oral with 240 mL of water after light breakfast/dinner
1 MR1 = Monolithic Nintedanib Modified Release Prototype Tablet
2 MR2 = Polyox Nintedanib Modified Release Prototype Tablet
3 MRX = Placeholder for Polyox and/or Monolithic Nintedanib Modified Release Prototype Tablet
4 Further prototypes will be selected from a design space describing formulation variables. Each prototype will 
be given a number assigned sequentially as dosed
5 Immediate Release


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Duration of treatment
One day (single dose) for each treatment:
Trial part 1
Trial part 1A (cohort 1, n=15)
∀
RP (Ofev®
 mg soft capsules) b.i.d.: 
 mg Nintedanib b.i.d. after 
light breakfast and dinner, respectively
∀
TP1 (Nintedanib MR1, Prototype 1):
 mg Nintedanib after light 
breakfast
∀
TP2 (Nintedanib MR1, Prototype 2): 
 mg Nintedanib after light 
breakfast
Trial part 1B (cohort 2, n=15)
∀
RP (Ofev®
 mg soft capsules) b.i.d.:
 mg Nintedanib b.i.d. after 
light breakfast and dinner, respectively
∀
TP3 (Nintedanib MR2, Prototype 1): 
 mg Nintedanib, after light 
breakfast
∀
TP4 (Nintedanib MR2, Prototype 2): 
 mg Nintedanib, after light 
breakfast
Decision point: either (a) stop here or (b) proceed to trial part 2 with one 
selected formulation.
Trial part 2 (optional, cohort 3, n=15)
∀
RP (Ofev®
 mg soft capsules) b.i.d.: 
 mg Nintedanib b.i.d. after 
light breakfast and dinner, respectively
∀
TP5 (Nintedanib selected MRX, Prototype 3): 
-
 mg Nintedanib, 
after light breakfast 
∀
TP6 (Nintedanib selected MRX, Prototype 4): 
-
 mg Nintedanib, 
after light breakfast 
Decision point: either (a) stop here or (b) proceed to trial part 3 with one 
selected formulation. 
Trial part 3 (optional, cohort 4, n=14)
∀
RP (Ofev®
 mg soft capsules) b.i.d.:
 mg Nintedanib b.i.d. after 
light breakfast and dinner, respectively
∀
TP7 (Nintedanib selected MRX, Prototype 5): 
-
 mg Nintedanib, 
after light breakfast 
In any trial part, there will be a washout period of at least 14 days between 
treatments, i.e. the morning dose in the preceding treatment period and the morning 
dose in the following treatment period will be separated by at least 14 days.


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Statistical methods
Preliminary pharmacokinetic analyses and simulations will be performed between 
trial part 1 and 2 as well as between part 2 and 3, if appropriate.
Relative bioavailability will be estimated by the ratios of the geometric means (test/ 
reference) for primary, secondary and further selected 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, subject nested within sequence, 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 - REFERENCE TREATMENT OFEV® IR 
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
-28 to -1
Screening (SCR)1
A
x
x
1/2/3 (2 or 3 periods separated by a wash-out of at least 14 days)
2 or 3 
or 4*
-1
-12:00
20:00
Admission to trial site
x5
x
-11:30
20:30
Snack (voluntary)
1
-1:30
06:30
Allocation to treatment2
(visit 2 only)
B2
x2
x2
x2
x2
-0:30
07:30
Light breakfast
0:00
08:00
Drug administration (with 240 mL 
fluid intake)
1:00
09:00
x
2:00
10:00
240 mL fluid intake
x
x
x
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x 
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
10:00
18:00
x
11:30
19:30
Dinner
12:00
20:00
Drug administration 
x8
x
13:00
21:00
x
14:00
22:00
x
x
15:00
23:00
x
2
16:00
00:00
x
x
18:00
02:00
x
20:00
04:00
x
22:00
06:00
x
24:00
08:00
Breakfast (voluntary)3
B
x
x
x
x
28:00
12:00
Lunch (voluntary)
31:00
15:00
Snack (voluntary)
34:00
18:00
Dinner (voluntary)3
x
x
3
48:00
08:00
Breakfast (voluntary)3
x
x
52:00
12:00
Lunch (voluntary)
55:00
15:00
Snack (voluntary)
58:00
18:00
Dinner (voluntary)3
x
x
4
72:00
08:00
Breakfast (voluntary)3
Discharge from trial site
B
x
x
x
x
EoT
5
15 to 22
End of trial (EoT) examination4
A
x
x
x
*Visit 4 only applicable for trial parts 1 and 2
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 (BP, PR), ECG, safety laboratory (including drug 
screening and virology), 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.


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4.
At the end of trial visit the EoT examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. 
5.
Only urine drug screening and alcohol breath test will be done at this time
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.
Letter A and B define different sets of safety laboratory examinations (for details refer to Table 5.2.3: 1)
8.
Blood sampling within 5 minutes before drug administration (for trough estimation)


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FLOW CHART - TEST TREATMENT NINTEDANIB MR1-4
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
-28 to -1
Screening (SCR)1
A
x
x
1/2/3 (2 or 3 periods separated by a wash-out of at least 14 days)
2 or 3 
or 4*
-1
-12:00
20:00
Admission to trial site
x5
x
-11:30
20:30
Snack (voluntary)
1
-1:30
06:30
Allocation to treatment2
(visit 2 only)
B2
x2
x2
x2
x2
-0:30
07:30
Light breakfast
0:00
08:00
Drug administration (with 240 mL 
fluid intake)
1:00
09:00
x
2:00
10:00
240 mL fluid intake
x
x
x
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x 
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
10:00
18:00
x
11:30
19:30
Dinner
12:00
20:00
x
x
14:00
22:00
x
x
15:00
23:00
x
2
16:00
00:00
x
x
17:00
01:00
x
18:00
02:00
x
20:00
04:00
x
22:00
06:00
x
24:00
08:00
Breakfast (voluntary)3
B
x
x
x
x
28:00
12:00
Lunch (voluntary)
31:00
15:00
Snack (voluntary)
34:00
18:00
Dinner (voluntary)3
x
x
3
48:00
08:00
Breakfast (voluntary)3
x
x
52:00
12:00
Lunch (voluntary)
55:00
15:00
Snack (voluntary)
58:00
18:00
Dinner (voluntary)3
x
x
4
72:00
08:00
Breakfast (voluntary)3
Discharge from trial site
B
x
x
x
x
EoT
5
15 to 22
End of trial (EoT) examination4
A
x
x
x
*Visit 4 only applicable for trial parts 1 and 2
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 (BP, PR), ECG, safety laboratory (including drug 
screening and virology), 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 2 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.


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4.
At the end of trial visit the EoT examination includes physical examination, body weight, vital signs, ECG, safety 
laboratory, recording of AEs and concomitant therapies. 
5.
Only urine drug screening and alcohol breath test will be done at this time
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.
Letter A and B 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 - REFERENCE TREATMENT OFEV® IR ........................6
FLOW CHART - TEST TREATMENT NINTEDANIB MR1-4...................8
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION.................................................................................... 17
1.1
MEDICAL BACKGROUND............................................................................17
1.2
DRUG PROFILE...............................................................................................17
1.2.1
Human pharmacokinetic profile in healthy volunteers.....................18
1.2.2
Clinical experience with Nintedanib in healthy volunteers...............18
1.2.3
Human pharmacokinetic profile in NSCLC patients........................20
1.2.4
Clinical experience with Nintedanib in NSCLC patients..................20
1.2.5
Residual Effect Period..........................................................................22
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................22
1.4
BENEFIT – RISK ASSESSMENT...................................................................22
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 25
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......25
2.1.1
Main objectives......................................................................................25
2.1.2
Primary endpoints ................................................................................25
2.1.3
Secondary endpoint ..............................................................................25
2.2.2.2
Safety and tolerability..............................................................26
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 27
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................27
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................30
3.2.1
Discussion of study design....................................................................30
3.2.2
Rationale for decision rules..................................................................30
3.3
SELECTION OF TRIAL POPULATION ......................................................30
3.3.1
Main diagnosis for trial entry..............................................................31
3.3.2
Inclusion criteria...................................................................................31
3.3.3
Exclusion criteria ..................................................................................32
3.3.4
Withdrawal of subjects from treatment or assessments ...................34
3.3.4.1
Discontinuation of trial treatment............................................34


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3.3.4.2
Withdrawal of consent to trial participation ............................35
3.3.4.3
Discontinuation of the trial by the sponsor..............................35
3.3.5
Replacement of subjects .......................................................................35
4.
TREATMENTS........................................................................................ 37
4.1
INVESTIGATIONAL TREATMENTS ..........................................................37
4.1.1
Identity of the Investigational Medicinal Products ...........................37
4.1.2
Selection of doses in the trial and dose modifications........................38
4.1.3
Method of assigning subjects to treatment groups ............................38
4.1.4
Drug assignment and administration of doses for each subject .......39
4.1.5
Blinding and procedures for unblinding ............................................40
4.1.6
Packaging, labelling, and re-supply ....................................................41
4.1.7
Storage conditions.................................................................................41
4.1.8
Drug accountability ..............................................................................41
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................42
4.2.1
Other treatments and emergency procedures....................................42
4.2.2
Restrictions............................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment .........................42
4.2.2.2
Restrictions on diet and life style.............................................42
4.3
TREATMENT COMPLIANCE.......................................................................43
5.
ASSESSMENTS....................................................................................... 44
5.1
ASSESSMENT OF EFFICACY.......................................................................44
5.2
ASSESSMENTS OF SAFETY..........................................................................44
5.2.1
Physical examination ............................................................................44
5.2.2
Vital signs...............................................................................................44
5.2.3
Safety laboratory parameters..............................................................44
5.2.4
Electrocardiogram................................................................................46
5.2.5
Other safety parameters.......................................................................47
5.2.6
Assessment of adverse events...............................................................47
5.2.6.1
Definitions of adverse events...................................................47
5.2.6.1.1 Adverse event ............................................................47
5.2.6.1.2 Serious adverse event ................................................47
5.2.6.1.3 AEs considered ‘Always Serious’.............................48
5.2.6.1.4 Adverse events of special interest .............................48
5.2.6.1.5 Intensity (severity) of AEs.........................................49
5.2.6.1.6 Causal relationship of AEs ........................................49
5.2.6.2
Adverse event collection and reporting ...................................50
5.2.6.2.1 AE collection.............................................................50
5.2.6.2.2 AE reporting to the sponsor and timelines ................51
5.2.6.2.3 Information required..................................................51
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................51
5.3.1
Assessment of pharmacokinetics .........................................................51


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5.3.2
Methods of sample collection...............................................................51
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................51
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................52
5.4
ASSESSMENT OF BIOMARKER(S) .............................................................52
5.5
BIOBANKING ...................................................................................................52
5.6
APPROPRIATENESS OF MEASUREMENTS.............................................52
6.
INVESTIGATIONAL PLAN.................................................................. 53
6.1
VISIT SCHEDULE............................................................................................53
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................53
6.2.1
Screening period....................................................................................53
6.2.2
Treatment periods.................................................................................53
6.2.3
Follow-up period and trial completion ...............................................54
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 55
7.1
STATISTICAL DESIGN – MODEL ...............................................................55
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................55
7.3
PLANNED ANALYSES....................................................................................55
7.3.1
Primary endpoint analyses...................................................................56
7.3.2
Secondary endpoint analyses ...............................................................57
7.3.4
Safety analyses.......................................................................................58
7.4
INTERIM ANALYSES .....................................................................................59
7.5
HANDLING OF MISSING DATA ..................................................................59
7.5.1
Safety......................................................................................................59
7.5.2
Pharmacokinetics..................................................................................59
7.6
RANDOMISATION ..........................................................................................59
7.7
DETERMINATION OF SAMPLE SIZE ........................................................60
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 62
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................62
8.2
DATA QUALITY ASSURANCE .....................................................................63
8.3
RECORDS..........................................................................................................63
8.3.1
Source documents .................................................................................63
8.3.2
Direct access to source data and documents.......................................64
8.3.3
Storage period of records.....................................................................64
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................64


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8.5
URGENT SAFETY MEASURES ....................................................................64
8.6
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......65
8.6.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................65
8.7
TRIAL MILESTONES .....................................................................................65
8.8
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................66
9.
REFERENCES......................................................................................... 67
9.1
PUBLISHED REFERENCES...........................................................................67
9.2
UNPUBLISHED REFERENCES.....................................................................67
10. APPENDICES .......................................................................................... 70
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 71
11.1
GLOBAL AMENDMENT 1 .............................................................................71




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ECG
Electrocardiogram
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
EoT
End of trial
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
FDA
Food and Drug Administration
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GGT
Gamma-GT
gMean
Geometric mean
HIV
Human Immunodeficiency Virus
IB
Investigator’s brochure
ILD
Interstitial lung disease
IEC
Independent Ethics Committee
IMPD
Investigational Medicinal Product Dossier
IPD
Important protocol deviation
IPF
Idiopathic pulmonary fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare products Regulatory Agency
MR
Modified release
MTD
Maximum tolerated dose
NSCLC
Non-small cell lung cancer
PCR
Polymerase chain reaction
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter analysis 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


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REP
Residual effect period
RNA
Ribonucleic acid
RP
Reference product
SAC
Safety advisory committee
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
ss
(at) steady state
T
Test treatment
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TP
Test product
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vss
Apparent volume of distribution at steady state after intravascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
XTC
Ecstasy 


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1.
INTRODUCTION
Nintedanib is approved for 4 indications in 2 different therapeutic areas: IPF, progressive 
fibrosing ILD, and SSc-ILD in the respiratory therapeutic area as Ofev® and NSCLC for 
oncology as Vargatef®. In most countries, nintedanib is marketed under the trade name Ofev®
for the respiratory indications and as Vargatef® for oncology (NSCLC). Ofev® has been 
approved for treatment of idiopathic pulmonary fibrosis (IPF) since 2015 with a standard 
therapeutic dose of
 mg twice daily. Each treatment includes one
 mg Nintedanib soft 
capsule with an immediate release (IR) profile, which releases the total drug amount at once 
in the gut. Since the rapid local drug exposure is associated with increased gut toxicity and
adverse drug reactions, dose reduction to 
 mg twice daily is often necessary. Alteration in 
the capsule’s composition can lead to a modified release (MR) profile with a preferable 
steadier increase of local drug exposure. This is postulated to reduce local toxicity and 
increase overall tolerability of Nintedanib. Therefore, several MR formulations for 
Nintedanib have been developed and are planned to be tested in this clinical trial in healthy 
volunteers.
1.1
MEDICAL BACKGROUND
The major abnormality in fibrosing interstitial lung diseases (ILDs) is the disruption of the 
distal lung parenchyma. Although the pathogenesis, especially of the interstitial idiopathic 
pneumonias (including IPF), remains unknown, it is generally agreed that some form of 
injury of the alveolar epithelial cells initiates an inflammatory response coupled with 
inappropriate repair mechanisms. The initiating injury can be introduced via the airways (e.g. 
inhalation of mineral fibres or dust as in occupational diseases or sensitisation to inhaled 
allergens as in hypersensitivity pneumonitis) or via the circulation (e.g. connective tissue 
disease and drug-induced ILDs). The injury-repair process is reflected pathologically as 
inflammation, fibrosis or a combination of both. Fibrosing ILD, including IPF, is 
characterised by alveolar epithelial cell injury and subsequent dysregulated repair, 
characterised by excessive deposition of extracellular matrix and loss of normal parenchymal 
architecture and lung function. In IPF fibroblasts exhibit unregulated proliferation and 
differentiate into myofibroblasts. The latter is considered the hallmark cell in the 
development and establishment of lung fibrosis. Several growth factors are implicated in the 
proliferation, migration and transdifferentiation of the fibroblast and myofibroblast pool in 
pulmonary fibrosis.
For details on medical background refer to the current version of the Investigator’s Brochure
(IB) [c01783972].
1.2
DRUG PROFILE
Nintedanib is an oral small molecule triple receptor tyrosine kinase inhibitor that potently 
blocks vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1 
and 3, platelet derived growth factor receptor α/β, lymphocyte-specific tyrosine-protein 
kinase, tyrosine-protein kinase lyn, proto-oncogene tyrosine-protein kinase src, and colony 
stimulating factor 1 receptor. Nintedanib imparts its therapeutic effects through receptor 


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engagement and blockage of intracellular signal transmission, which reduces fibrogenesis in 
interstitial lung tissue of IPF and interstitial lung disease patients. 
For a detailed description of the non-clinical pharmacology, pharmacokinetics (in animals)
and toxicology of Nintedanib please refer to the current IB [c01783972] and to the Summary 
of Product Characteristics (SmPC) of Ovef® [R21-3511].
1.2.1
Human pharmacokinetic profile in healthy volunteers
Table 1.2.1: 1 shows human PK parameters and Tables 1.2.1: 2 and 1.2.1: 3 show drug
exposure after single dose in healthy volunteers for Ofev® in fed state [R21-3511], 
[c01783972], [U06-1411] and Vargatef® [c08883821].
Table 1.2.1: 1
Human pharmacokinetic parameters for 
 mg Ofev® in
healthy volunteers (SmPC and IB Ovef®)
Parameter
Value
F [%]
4.69 (+ 20% when fed)
Vss [L]
1,050 
CL [mL/min]
1,390
tmax [h]
2.0 (fasted) - 4.0 (fed)
t1/2,eff [h]
10 – 15 (> 90% recovery after 4 d)
1.2.2
Clinical experience with Nintedanib in healthy volunteers
Nintedanib has been given as single doses of up to 
 mg (immediate release as marketed)
to healthy volunteers in 9 Phase I trials. In addition to the studies listed in the IB for fibrotic 
lung diseases [c01783972], one clinical bioequivalence trial (1199-0237; [c08883821]) was 
performed with oncologic Vargatef® (Nintedanib). In that trial, 70 healthy male volunteers 
were administered 2 single doses of 
 mg Nintedanib in fed state. Over all 9 trials, 
Nintedanib was given to approximately 240 healthy volunteers (including also study 
1199-0237 [c08883821]; excluding liver-impaired subjects in trial 1199-0200 [c03149997]). 
Single doses of Nintedanib were generally safe and well tolerated in healthy subjects. All 


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investigator-defined drug-related adverse events (AEs) after treatment with single doses of 
Nintedanib were mild or moderate and fully reversible. Headache and gastro-intestinal side 
effects (e.g. diarrhea, abdominal discomfort, nausea or vomiting) were the most common 
drug-related AEs.
Table 1.2.2: 1
Completed phase I trials with Nintedanib in healthy volunteers and 
subjects with investigator-reported drug-related AEs.
Indication
Study No. / 
Doc No.
Doses of 
Nintedanib [mg]
Healthy subjects 
treated with 
Nintedanib [N]
Drug-related 
AEs1 [number of 
subjects]
Food effect
1199-0017
[c01787137]
 mg, 1 single 
dose, p.o.
15
Diarrhea (7), 
abdominal 
discomfort (3), 
nausea (1)
ADME
1199-0020
[c01787114]
 mg, 1 single 
dose, p.o.
8
Nausea (1), 
asthenia (1)
Relative BA
1199-0021
[c01798932]
 mg, 2 or 3 
single doses, p.o.
36
Diarrhea (14), 
headache (8), 
nausea (2), 
vomiting (1), 
dizziness (1), 
fatigue (1), dry 
mouth (1)
Absolute BA
1199-0075
[c01789568]
, , or  mg (i.v.), 
single dose;
 mg (p.o.), 
single dose
24
Diarrhea (1)
DDI with 
ketoconazole
1199-0161
[c02036462]
 mg, 2 single 
doses, p.o.
31
Headache (4), 
back pain (2), 
fatigue (1)
DDI with 
rifampin
1199-0162
[c01801263]
 mg, 2 single 
doses, p.o.
26
Diarrhea (7), 
headache (2)
Liver 
impairment
1199-0200
[c03149997]
 mg, 2 single 
doses, p.o.
172
Nausea (2), 
vomiting (1), 
headache (1)
BE3
1199-0237
[c08883821]
 mg, 2 single 
doses, p.o.
70
Diarrhea (24), 
nausea (7), 
abdominal 
discomfort (3), 
abdominal pain 
upper (1), 
headache (9), 
dizziness (3), 
fatigue (1)
DDI with 
bosentan
1199-0239
[c09412738]
 mg, 2 single 
doses, p.o.
13
Headache (2), 
diarrhea (1)






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1.2.5
Residual Effect Period
The Residual Effect Period (REP) is the period after the last dose with measurable drug levels 
and/or pharmacodynamic effects still likely to be present. 
For this trial using 1 day treatment of 
 to (potentially) 
 mg Nintedanib in healthy male 
volunteers, a REP of 14 days is used, i.e. the individual subject’s end of trial is on day 15 
following dosing at the earliest and the washout between periods is at least 2 weeks (see 
Flow Chart).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Ofev® soft capsules dissolve instantly within the gut environment and thus show an IR 
profile. However, the rapid increase of local drug exposure is associated with increased gut 
wall toxicity and gastro-intestinal adverse drug reactions such as diarrhoea. In contrast, a 
constant drug release over a longer period of time is hypothesized to improve gastro-
intestinal tolerability. Alteration in the shell’s composition may lead to such release profiles 
of Nintedanib and improve tolerability. Hence, several different tablets are to be 
manufactured to accomplish a MR of Nintedanib over 24 hours and match the equivalent 
drug exposures to that of the standard Ofev® treatment. Equivalent drug exposure can be 
presumed, if the MR formulation is within the same exposure corridor as Ofev®, i.e. equal 
total drug exposure (AUC0-24,ss), non-inferior minimum drug concentration (Cmin,ss) and non-
superior (Cmax,ss) peak drug concentration at steady state. Consequently, sufficient efficacy 
for the MR formulation can be assumed without explicit testing. Since only single dose 
administration is planned for the MR formulations, the concentration after 24 hours post dose 
will be measured (C24), while Cmin,ss as well as Cmax,ss for steady state may be simulated in a 
respective model at the end of trial (e.g. after database lock).
1.4
BENEFIT – RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to improve overall tolerability and 
treatment success of patients with IPF and ILD. The subjects are exposed to the risks of the 
study procedures and the 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.
The total volume of blood withdrawn per subject during the entire study will not exceed a 
volume of 550 mL in a 4-week period. No health-related risk to healthy subjects is expected 
from withdrawal of this volume of blood.
Electrocardiogram (ECG) stickers on the subjects’ chests and limbs may cause some local 
irritation and may be uncomfortable to remove but subjects will be closely monitored to 
ensure any local irritation does not persist.




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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.
General risk mitigation against COVID-19 will be implemented in accordance with 
 monitoring and prevention control measures.
COVID-19 testing may be performed based on current infection rates and availability of tests. 
If required, testing will comprise an antibody blood test performed at screening, and an 
antigen polymerase chain reaction (PCR) test or other antigen test performed at screening, the 
day before admission to each treatment period, and discharge or the day before discharge 
from each treatment period. Testing time points may be changed and additional time points 
may be added throughout the study as required. The decision on COVID-19 testing and the 
definition of the testing time points will be agreed by the study team and documented in the 
Investigator Site File (ISF) via the Clinical Kick-Off Meeting minutes. The risk mitigation 
measures, where applicable, will be amended based on emerging government guidance.
COVID-19 Vaccine-Related Risk
Approved (including health authority conditional marketing optimization) COVID-19 
vaccines eg killed, inactivated, peptide DNA and RNA vaccines may be permitted according 
to the investigator’s discretion and as per local guidance. Based on the mechanism of action 
of Nintedanib, as a tyrosine kinase inhibitor, there is no perceived impact on the safety of the 
study subjects or on the study objectives for subjects who may receive these vaccines (either 
first or second doses). It is also very unlikely that administration of Nintedanib would 
interfere with COVID-19 vaccination response; however, no specific preclinical or clinical 
investigations have been conducted at this point with Nintedanib.
The emerging safety and efficacy data from millions of vaccinated people, many of whom are 
elderly and with underlying health conditions and taking multiple concomitant medications, 
indicate that these vaccines have an excellent safety and efficacy record. In the broader 
interests of society and to limit the extent of the global pandemic, it is important that subjects 
should receive a vaccine when it is offered to them.
Summary of benefit-risk assessment
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, 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 assess single dose drug exposure of several newly 
developed MR formulations of Nintedanib (MR1 and MR2 prototypes) compared to 
mg 
of Ofev® IR, twice daily (Reference, R) following oral administration.
In trial part 1, four MR prototypes of Nintedanib (prototypes 1 and 2, each with a fast and 
slow in-vitro dissolution rate) will be tested. Based on pharmacokinetic results, one MR 
formulation may be selected for subsequent optimisation in dissolution and dose rate to 
ultimately match exposure corridor of Ofev® IR. The optimised MR formulation will then be 
evaluated in optional trial part 2. If the pre-selected MR formulation is still not matching the 
Ofev® IR exposure corridor, an optional trial part 3 is conducted after further optimisation of 
dissolution profile and dose. 
Plasma drug exposure and PK parameters will be assessed after each trial part and MR 
formulations adjusted accordingly (e.g. coating compositions, drug dose) for the following 
trial part.
2.1.2
Primary endpoints
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 [first dose] extrapolated to infinity which includes also the 
second Nintedanib dose of the day)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter 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 within the 24h 
dosing interval)
∀
C24 (concentration of the analyte in plasma 24 h after the (first) dose)


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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 in healthy male subjects as an open-label, randomised, single-
dose study in up to three trial parts in order to compare each of the test treatments (MR1, 
MR2, MRX) to the respective reference treatment R. The subjects will be randomly allocated 
to three treatment sequences in trial part 1 and 2 (Latin square design). There will be a 
washout period of at least 14 days between the treatments, i.e. the morning dose in the 
preceding treatment period and the morning dose in the following treatment period are 
separated by at least 14 days.
For illustration of the overall study design, refer to Figure 3.1: 1. 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.
Trial part 1
Trial part 1 (n=30) will be performed with two parallel groups (cohort 1 and 2, each n=15), 
each in a randomised three-period crossover design in order to compare MR1 test treatments 
to the reference treatment R (for trial part 1A) as well as MR2 test.
These treatments will be administered after light fed conditions (light breakfast, additionally 
light dinner in Reference) and in one of the following three sequences for each group:
For Trial part 1A:
R
 MR1-1
 MR1-2
MR1-2 R
 MR1-1
MR1-1 MR1-2
 R


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For Trial part 1B:
R 
 MR2-1
 MR2-2 
MR2-2 R 
 MR2-1 
MR2-1 MR-2
 R
A single dose (test treatments) and a b.i.d. dose for one day (reference treatments), 
respectively will be administered as depicted in Figure 3.1: 1 above and Table 4.1.4: 1.
Decision point: either (a) stop here or (b) proceed to trial part 2 with one selected formulation 
MR1 or MR2 and release profile in order to optimise dose.
In-study decisions will be made by the safety advisory committee (SAC), which will always 
comprise the investigator, the sponsor’s representative medical monitor or the sponsor’s 
medically qualified designee who is familiar with the study protocol and IB, and a PK expert 
where appropriate. Formulation and dose selection will only be made after a complete review 
of all data collected from the previous dose group. 
The following in-study decisions will be made:
∀
Formulation selection
∀
Dose selection (please see Section 4.1.2)
Decision rules: The decision will be based on data of all evaluable subjects (see Section 7.3
PKS definition) in each of trial parts 1A as well as 1B and will include the assessment of (i) 
safety parameters (e.g., AE, ECG, vital signs and safety laboratory data) up to 72 h post-dose, 
(ii) preliminary pharmacokinetic analysis up to 72 h post-dose.
Criteria to stop particular MR formulation after trial part 1 will be in case one of the below 
points holds true:
∀
MR formulation is considered not to be safe (see Section 3.3.4.3 for stopping criteria)
∀
the 90% confidence interval (CI) of the AUC0-∞gMean ratio between a MR 
formulation and Ofev® IR lies completely outside of 95-105% and further 
optimisation of the formulation with regards to dose and dissolution rate is not 
expected to improve pharmacokinetic properties, accordingly
∀
the lower 90% CI of the Cmax gMean ratio between a MR formulation and Ofev® IR is 
>105% and further optimisation of the formulation with regards to dose and 
dissolution rate is not expected to improve pharmacokinetic properties, accordingly
∀
the upper 90% CI of the C24 gMean ratio between a MR formulation and Ofev® IR is 
<95% and further optimisation of the formulation with regards to dose and dissolution 
rate is not expected to improve pharmacokinetic properties, accordingly
In case no MR formulation fulfils the criteria above the following rule will help in deciding
which MR formulation to develop further:
∀
for AUC0-∞, Cmax and C24 the adjusted gMean ratios for each MR formulation as well 
as the gSE of the difference will be calculated coming from the defined ANOVA 
model in Section 7.3.1.
∀
for an adjusted gMean ratio >1 the decision value (DV) is defined by gMean 
ratio*gSE


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∀
for an adjusted gMean ratio ≤1 the decision value (DV) is defined by gMean 
ratio/gSE
∀
the MR formulation with DV values for AUC0-∞, Cmax and C24 closest to 1 will be 
chosen for further development
Decision outcome: If optimisation is considered possible for at least one of the two MR 
formulations, further optimisation will be done on the selected formulation(s) and tested in 
trial part 2. 
Trial part 2 (optional)
Trial part 2 (cohort 3, n=15) will be performed as a randomised three-period crossover design 
in order to compare further prototypes to the reference treatment R.
These treatments will be administered after light fed conditions (light breakfast, additionally 
light dinner in Reference) and in one of the following three sequences:
R
 MRX-3
 MRX-4
MRX-4  R
 MRX-3
MRX-3  MRX-4
 R
A single dose (test treatments) and a b.i.d. dose for one day (reference treatment), 
respectively will be administered as depicted in Figure 3.1: 1 above and Table 4.1.4: 1.
Decision point: either (a) stop here or (b) proceed to trial part 3 with the optimised 
formulation in order to optimise release rate and dose.
In-study decisions will be made by the SAC.
Decision rules: The decision will be based on data of all evaluable subjects and will include 
the assessment of (i) safety parameters (e.g. AE, ECG, vital signs and safety laboratory data) 
up to 72 h post-dose, (ii) preliminary pharmacokinetic analysis up to 72 h post-dose.
Criteria to stop or to continue particular MR formulation after trial part 2 will be the same as 
for Part 1 (see above).
Decision outcome: If further optimisation is considered necessary and possible for the 
selected MR formulation(s) tested in part 2, another prototype will be developed and further 
tested in trial part 3.
Trial part 3 (optional)
Trial part 3 (cohort 4, n=14) will be performed as a randomised two-period crossover design 
in order to compare test treatment to the reference treatment R.
These treatments will be administered after light fed conditions (light breakfast, additionally 
light dinner in Reference) and in one of the following two sequences:
R
 MRX-5
MRX-5  R


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A single dose (test treatment) and a b.i.d. dose for one day (reference treatment), respectively
will be administered as depicted in Figure 3.1: 1 and Table 4.1.4: 1.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
3.2.1
Discussion of study design
The Clinical Trial Authorisation (CTA) application for this study describes a flexible protocol 
design using the concept of formulation design space to allow decision-making in response to 
interim pharmacokinetic (PK) observations. The principles of a flexible protocol were 
discussed and agreed with the Medicines and Healthcare products Regulatory Agency 
(MHRA) at a Scientific Advice Meeting between the MHRA and 
formerly 
Pharmaceutical Profiles).
Based upon the concept of formulation design space/a bracketed dose approach, specific 
IMPs are not detailed within the Investigational Medicinal Product Dossier (IMPD) but rather 
a defined dose range of formulation inputs and corresponding performance outputs are 
described and justified based on in vitro studies. The chosen formulation from within the 
approved design space for the first prototype to be dosed will be documented in a decision 
document and approved by the sponsor and a 
representative ahead of manufacture.
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analyte.
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between formulations is based 
on an intra-subject comparison, thus removing inter-subject variability from the comparison 
between formulations [R94-1529].
3.2.2
Rationale for decision rules
The rationale for performing this trial is to identify an MR formulation that still results in 
Nintedanib exposure within the corridor of standard Ofev® IR treatment.
Rules, described in Section 3.1, allow to make a decision whether one of the tested 
formulations meets the requirements after trial part 1, or whether it can be improved within 
this trial in part 2 and/ or part 3. Rules would also guide the termination of the process, either 
after trial part 1 or trial part 2, if no successful formulation was to be achieved.
3.3
SELECTION OF TRIAL POPULATION
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. It is planned that 30 or 59 (optional) healthy male subjects will enter the study. They 
will be recruited from the volunteers' pool of the trial site. 


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 must have a full medical history from each subject’s general practitioner 
(GP) within the last 24 months, prior to enrolment in the study. Before subjects are admitted 
to the clinical unit, The Over Volunteering Prevention System (TOPS) will be checked to 
ensure that each subject has not participated in a study at another site within at least 90 days 
of the dosing date.
As this is a Phase I study assessing the PK, relative bioavailability and safety of Nintedanib, 
the most relevant population is healthy volunteers. Subjects who are non-smokers without a 
history of alcohol or drug abuse or regular co-medication are proposed to avoid interaction on 
drug metabolism and to avoid non-compliance. 
Considering the teratogenic potential of Nintedanib, only male subjects will be included. 
(refer also to [R21-3511]).
3.3.1
Main diagnosis for trial entry
The study 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:
1. Healthy male subjects (Caucasian and Black only) according to the investigator’s 
assessment, 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) and absolute body weight of at least 65 kg
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
5. Non-smokers for at least 6 months
6. Subjects who are sexually active must use with their partner, highly effective 
contraception from the time of administration of trial medication until 30 days after 
administration of trial medication. Adequate methods are:
∀
Condoms plus use of hormonal contraception by the female partner that started at 
least 2 months prior to administration of trial medication (e.g., implants, injectables, 
combined oral or vaginal contraceptives, intrauterine device) or
∀
Condoms plus surgical sterilization (vasectomy at least 1 year prior to enrolment) or
∀
Condoms plus surgically sterilised partner (including hysterectomy) or
∀
Condoms plus intrauterine device or
∀
Condoms plus partner of non-childbearing potential (including homosexual men)


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Subjects are required to use condoms to prevent unintended exposure of the partner (both, 
male and female) to the study drug via seminal fluid. Male subjects should use a condom 
throughout the study and for 30 days after last IMP administration. Alternatively, true 
abstinence is acceptable when it is in line with the subject’s preferred and usual lifestyle. If a 
subject is usually not sexually active but becomes active with their partner, they must comply 
with the contraceptive requirements detailed above.
Male subjects should not donate sperm for the duration of the study and for at least 30 days 
after last IMP administration.
Male subjects with pregnant or lactating partners are allowed.
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. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or 
human immunodeficiency virus (HIV) antibody results
5. Liver enzymes (AST and ALT) above upper limit of normal at the screening examination 
6. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
7. Clinically significant gastrointestinal, hepatic, renal, respiratory, cardiovascular, 
metabolic, immunological, dermatological or hormonal disorders. Subjects with Gilbert’s 
syndrome are not permitted.
8. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
9. Significant diseases of the central nervous system (including but not limited to any kind 
of seizures [febrile seizures are acceptable] or stroke), and other relevant neurological or 
psychiatric disorders 
10. History of relevant orthostatic hypotension, fainting spells, or blackouts
11. Relevant chronic or relevant acute infections


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12. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
13. Use of drugs (excluding Covid-19 vaccination, within 7 days) 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). Ibuprofen up to 1200 mg per 
day is allowed.
14. Intake of an investigational drug in another clinical trial within 90 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
15. Alcohol abuse (consumption of more than 21 units per week)
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
18. Subjects who do not have suitable veins for multiple venepunctures/cannulation as 
assessed by the investigator or delegate at screening
19. Intention to perform unaccustomed excessive physical activities within one week prior to 
the administration of trial medication or during the trial
20. Inability to comply with the dietary regimen of the trial site
21. 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 
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
24. Subjects who have previously been administered IMP in this study. Subjects who have 
taken part in one trial part are not permitted to attend to any following trial part.


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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 1.2.3), 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:
∀
The subject wants to discontinue trial treatment, without the need to justify the decision
∀
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.
∀
The subject has a concurrent illness 
 or needs to take 
concomitant medication that interferes with the investigational medicinal product or other 
trial treatment
∀
The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
∀
The subject experiences a serious or severe AE including but not limited to:
∀
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
∀
corrected QT interval by Fridericia’s formula (QTcF) of >500 msec or increase in 
QTcF interval of >60 msec from baseline (confirmed following a repeat ECG)
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.


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Even if the trial treatment is discontinued, the subject remains in the trial and, given his 
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
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 
or halted 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, or if severe non-serious adverse reactions (i.e. severe non-serious AE 
considered as at least possibly related to the IMP administration) in two subjects in the 
same cohort, independent of within or not within the same system organ class. 
Relatedness to IMP will be determined by the investigator.
3. Violation of GCP, or the CTP, or the contract with BI impairing the appropriate conduct 
of the trial
4. The sponsor decides to discontinue the further development of the investigational product
If the study is halted, a temporary halt will be submitted to the Medicines and Healthcare 
products Regulatory Agency (MHRA) and ethics committee (EC) in the form of a substantial 
amendment. The study may be resumed or terminated; however, it will not be resumed until a 
further substantial amendment to resume the study is submitted and approved by MHRA and 
EC.
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than 3 subjects in one of the parallel groups of trial part 1 or in trial parts 2 and 
3 do not complete the trial, the Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 


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replaced. A replacement subject will be assigned a unique trial subject number and will be 
assigned to the same treatment as the subject he replaces.
It is planned to have at least 12 evaluable subjects per crossover part. Up to 3 replacement 
subjects may be used per cohort. The maximum number of subjects that may be dosed is 18, 
the cohort size of 15 plus 3 replacements.












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investigator or designee must verify that all unused or partially used drug supplies have been 
returned by the clinical trial subject and 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.
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 or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
Drugs with a known hepatotoxicity profile (e.g., paracetamol or diclofenac) or medication 
with an increased risk for bleeding (e.g. acetylsalicylic acid) should be avoided during the 
entire study; if necessary, short term use of ibuprofen is acceptable.
Known inhibitors or inducers of P-gp and CYP3A activity should be avoided during the 
entire study due to drug-drug interaction potential with Nintedanib. Drugs that cause QT/QTc 
interval prolongation should also be avoided.
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 4 h after drug intake in the 
morning.
From 1 h before drug intake in the morning until lunch, fluid intake is restricted one cup of 
water without sugar served with breakfast (see Section 4.1.4), the water administered with the 
drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all subjects). 
From lunch until 24 h post-dose, total fluid intake is restricted to 3000 mL.
Poppy-seeds containing foods should not be consumed starting 3 days before screening and
admission to each treatment period to avoid false-positive results in the drug screen.


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Alcoholic beverages are not permitted from 3 days before first drug administration until the 
end of trial examination.
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.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed during inhouse stays.
Smoking is not allowed during in-house confinement.
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.
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 
of trial medication 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
ASSESSMENTS OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results 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 (including drug screening), 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 including determination of weight.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor (e.g., 
DASH 4000) 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. If required, vital signs assessment 
can be repeated.
In addition, oral body temperature may be measured at any time at the discretion of the 
investigator. These measurements will not be recorded in the eCRF.
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 
10 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
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
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; Lymphocytes/Leukocytes 
--
--
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
Manual differential 
WBC (only if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils Bands; 
Neutrophils Bands, absol.; Eosinophils/Leukocytes; Eosinophils, 
absol.; Basophils/ Leukocytes; Basophils, absol.; Monocytes/ 
Leukocytes; Monocytes, absol.; Lymphocytes/Leukocytes; 
Lymphocytes, absol.
X
X
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
INR (International Normalization Ratio)
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
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) 
X
X
X
X
X
X
--
X
X
X
X
X
Electrolytes
Sodium
Potassium
Chloride
X
X
X
X
X
X
Urinalysis (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 sediment 
(microscopic examination 
if erythrocytes, 
leukocytes nitrite or 
protein are abnormal in 
urine)
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) and Visit 5 (EOT examination)
B: parameters to be determined at Visit 2, 3 and 4 (for time points refer to Flow Chart)


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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., Lion 
Alcolmeter 500) 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 an Alere Drug 
Screen Test Cup, respectively, or comparable test systems. Urinalysis assessments also will 
be performed at the trial site using, e.g., Combi-Screen® Urine Test Strips. If urine 
microscopy is required, a sample will be shipped to 
” for analysis.
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 (e.g., Mortara ELI 250c) 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.


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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. 
All ECGs will be stored as paper copies.
5.2.5
Other safety parameters
Not applicable.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
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.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
∀
Results in death
∀
Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe
∀
Requires inpatient hospitalisation
∀
Requires prolongation of existing hospitalisation
∀
Results in persistent or significant disability or incapacity


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∀
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
5.2.6.1.3
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in Section 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.
These events should always be reported as SAEs as described above.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
∀
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
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. 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 


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test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
5.2.6.1.6
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 
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)


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∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial (written informed consent), 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)
o
The only exception to this rule are AEs (serious and non-serious) 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 of which the 
investigator may become aware of by any means of communication, e.g. 
phone call. Those AEs should, however, not be reported in the CRF.


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5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, and non-serious AEs which are relevant for the reported 
SAE, on the BI SAE form via fax immediately to the sponsor’s unique entry point (country 
specific contact details will be provided in the ISF). The same timeline applies if follow-up 
information becomes available. In specific occasions the Investigator could inform the 
sponsor upfront via telephone. This does not replace the requirement to complete and fax the 
BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
5.2.6.2.3
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 / 
time intervals indicated in the Flow Chart. The actual sampling times will be recorded and 
used for determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of Nintedanib concentrations in plasma, approximately 2.7 mL of blood 
will be drawn from an antecubital or forearm vein into an K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venepuncture with a metal needle. The first 0.5 mL withdrawn by an indwelling cannula 
will be discarded.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed in less than 60 min with interim storage of blood samples and aliquots in ice water 
or on ice. The time each aliquot was placed in the freezer will be documented. Until transfer 
on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 


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the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g. for stability testing or assessment of metabolites. However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the CTR is 
archived.
5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
5.4
ASSESSMENT OF BIOMARKER(S) 
Not applicable.
5.5
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 vital 
signs, standard laboratory values, and ECG parameters 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 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, the end of trial examination, and measurements and 
assessments scheduled to occur ‘before’ trial medication administration in the morning of 
Day 1 are provided in the Flow Chart.
If not stated otherwise in the Flow Chart, the general acceptable deviation from the scheduled 
time for vital signs, ECG, and laboratory tests will be ± 30 min.
The acceptable deviations from the nominal urine sampling time points for urinalysis are:
∀
The pre-dose urine sample will be the first void of the day or a sample collected ≤3 h 
before dosing
∀
Post-dose urine samples will be taken ± 2 h from the nominal urine sampling time
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.
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.
6.2.2
Treatment periods
Each subject is expected to participate in 3 treatment periods (part 1, optional part 2) or in 2 
treatment periods (optional part 3) (Days -1, 1, 2, 3, and 4 in each period). At least 14 days
will separate drug administrations in each treatment periods.
In the evening before drug administration, study participants will be admitted to the trial site 
and kept under close medical surveillance for at least 72 h following drug administration in 
the morning of Day 1. The subjects will then be allowed to leave the trial site after formal 


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assessment and confirmation of their fitness. No ambulatory appointments are planned during 
treatment periods.
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 EoT 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 EoT Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained.
For definition of ‘end of the trial’ refer to Section 8.6.


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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 several MR 
formulations of Nintedanib (Test, T) compared to 
mg of Ofev® IR, twice daily 
(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.
A further objective is to evaluate and compare further pharmacokinetic parameters between 
the treatments. These pharmacokinetic parameters will be assessed by descriptive statistics.
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 each of the MR formulations compared with 
mg of Ofev®
IR 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 for each crossover part will be based on the following analysis sets:
∀
Treated set (TS): The treated set includes all subjects who were randomised 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 DV domain sheet, 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
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 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 violations 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 experiences emesis at any time during the labelled dosing interval. 
∀
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
Each of the crossover parts will be analysed separately according to bellows description.
Primary analyses
The statistical model used for the analysis of the primary endpoint 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,(3),
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
&j = the jth period effect, j = 1, 2, (3),
∋k = the kth treatment effect, k = 1, 2, (3),
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 endpoint
(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.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoint but with 
all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, ‘treatment’) 
considered as fixed effects.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.3.2
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the relevant 
internal BI procedures and will be assessed statistically using the same methods as described 
for the primary endpoint.


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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 
Blinded 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, those between first trial medication intake and end of 
REP (see Section 1.2.3) will be assigned to the 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.


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7.4
INTERIM ANALYSES
Prior to start of a next study part (Part II or III) a preliminary analysis on PK parameters 
(AUC0-∞, C24 and Cmax) will be performed as described in Section 3.1.
The pharmacokinetic parameters AUC0-∞, Cmax and C24 for Nintedanib will be calculated 
according to relevant internal procedures. The non-compartmental analysis will be performed 
using a validated software program such as Phoenix WinNonlinTM software (version 6.3 or 
higher, 
 or SAS® Version 9.4 (or later version). A 
quality check of the preliminary data will be performed.
In contrast to the final PK calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows. Therefore, minor deviations may occur between preliminary and final results. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values. The preliminary results will be distributed to the 
investigator and the trial team. 
Depending on the results of available preliminary PK analyses and the tolerability and safety 
of the compound, changes to the formulation and additional PK preliminary analysis may be 
performed if requested by the Clinical Trial Leader, the investigator, Trial Statistician or Trial 
Clinical Pharmacokineticist. Preliminary PK results will not be reported in the CTR.
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 internal procedures.
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
For each of the three-way crossover part subjects will be randomised to one of the 3 treatment 
sequences in a 1:1:1 ratio. Within the two-way crossover part, 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. 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).






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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 Medicines 
for Human Use (Clinical Trials) Regulations SI 2004, No 1031, as amended 2006 (SI No. 
1928 and No. 2984), 2008 (SI No 941) and 2019 (SI No. 744) 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. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a general rule, no trial results should be published prior to 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 Independent Ethics Committee (IEC) and competent authority 
(CA) according to national and international regulations. The same applies for the 
implementation of changes introduced by substantial 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.
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.
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, 
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


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∀
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.
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.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
URGENT SAFETY MEASURES
If
or any of its staff or contractors becomes aware of an actual or potential urgent 
safety issue, then the sponsor must be immediately contacted so that appropriate urgent safety 


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measures can be agreed. An urgent safety issue is defined as: • An immediate hazard to the 
health or safety of subjects participating in a clinical study • A serious risk to human health or 
potentially a serious risk to human health An urgent safety issue may include issues with an 
investigational drug or comparators, study procedures, inter-current illness (including 
pandemic infections), concomitant medications, concurrent medical conditions or any other 
issues related to the safe conduct of the study or that pose a risk to study subjects. In 
exceptional circumstances of imminent hazard and in order to safeguard the health or safety 
of individuals,
may take urgent safety measures before informing the sponsor, but 
the sponsor must be informed immediately after the hazard has resolved. The Sponsor is 
responsible for informing appropriate competent authorities, and the EC; the task of reporting 
will be delegated to 
8.6
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.
8.6.1
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 banking 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
8.7
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.


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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 country 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.
8.8
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at
, 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 Clinical Trial Managers (CTM), 
Clinical Research Associates, and investigators of participating trial sites
The trial medication will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany (Reference product only) and 
, 
 (test products only).
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.
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
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R21-1406
Guidance for industry: assessing the effects of food on drugs in INDs and 
NDAs - clinical pharmacology considerations (draft guidance) (this 
guidance document is being distributed for comment purposes only) 
(February 2019, clinical pharmacology). Source: 
https://www.fda.gov/media/121313/download (access date: 13 April 2021); 
U.S. Department of Health and Human Services Food and Drug 
Administration, Food and Drug Administration, Center for Drug Evaluation 
and Research (CDER); 2019.
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
R21-3511
European Medicines Agency. Ofev
 mg, 
 mg soft capsules 
(Boehringer Ingelheim) (summary of product characteristics, 
manufacturer(s) responsible for batch release, conditions or restrictions 
regarding supply and use, other conditions and requirement of the 
marketing authorisation, conditions or restrictions with regard to the safe 
and effective use of the medicinal product, labelling and package leaflet, 
scientific conclusions and grounds for the variation to the terms of the 
marketing autorisation(s), last updated: 02/09/2021). 
Website:ema.europa.eu/en/documents/product-information/Ofev-epar-
product-information_en.pdf (access date: 15 October 2021); 2021.
9.2
UNPUBLISHED REFERENCES
c01783972
Investigator’s Brochure Nintedanib (BIBF 1120). Project 1199.p3, P10, 
P16. Current Version.
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
 1199-0200. 
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.
c08883821
 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
Influence of bosentan on the pharmacokinetics of nintedanib in healthy 
male subjects. Clinical Trial Report 1199-0239. Nov 2016.
U13-1506
 Clinical Overview: Nintedanib 
(BIBF 1120) soft capsules, 100 mg, 150 mg. 02 September 2013.
U05-2191
 An open label dose 
escalation study of BIBF 1120 administered orally for four weeks in 
patients with advanced solid tumours with repeated administration in 
patients with clinical benefit. Clinical Trial Report 1199-0001. Nov 2009.
U06-1697
A Phase I open label dose escalation 
study of continuous once-daily oral treatment with BIBF 1120 in patients 
with advanced solid tumours. Clinical Trial Report 1199-0003. Jan 2013.


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U06-1411
 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. Clinical Trial Report 1199-0017. Jun 2011.


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10.
APPENDICES
According to FDA Guidance for Industry, a low-fat meal contains total of 400-500 kcal, 
including 11-14 g fat (equals 100-125 kcal or 25 % of total calories). Table 10: 1 and 10: 2
show exemplary light (low-fat, low calorie) breakfast [R21-1406].
Table 10: 1
Exemplary composition of the low-fat, low-calorie meal
Ingredients
50 g Corn Flakes
One Butter Croissant
One portion Jam (20 g)
240 ml Skimmed milk (0,1 % fat) 
This low-fat breakfast contains 545,8 kcal and has 14 grams of fat
Table 10: 2
Exemplary composition of the low-fat, low-calorie meal
Ingredients
One bread roll 
15 g butter
One sliced cheese (40 g Gouda)
One sliced sausage (20 g turkey breast)
One cup of water or decaffeinated coffee without sugar
This low-fat breakfast contains 430 kcal


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol
11.1
GLOBAL AMENDMENT 1
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
Product(s)
Title of protocol
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
Description of change
Rationale for change

SAP_001.pdf: 


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................8
5.
ENDPOINTS..........................................................................................................9
5.1
PRIMARY ENDPOINT........................................................................................9
5.2
SECONDARY ENDPOINTS ...............................................................................9
5.2.1
Key secondary endpoints ......................................................................................9
5.2.2
Secondary endpoints .............................................................................................9
5.3
FURTHER ENDPOINTS.....................................................................................9
5.4
OTHER VARIABLES ........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS...........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED ...........................................................................14
6.5
POOLING OF CENTRES..................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................16
7.
PLANNED ANALYSIS ......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........18
7.2
CONCOMITANT DISEASES AND MEDICATION......................................19
7.3
TREATMENT COMPLIANCE ........................................................................19
7.4
PRIMARY ENDPOINTS ...................................................................................19
7.4.1
Primary analysis of the primary endpoints ......................................................19
7.5
SECONDARY ENDPOINTS .............................................................................21
7.5.1
Key secondary endpoints ....................................................................................21
7.5.2
(Other) Secondary endpoints .............................................................................21
7.7
EXTENT OF EXPOSURE .................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse Events ....................................................................................................22
7.8.2
Laboratory data...................................................................................................23
7.8.3
Vital signs.............................................................................................................24
7.8.4
ECG ......................................................................................................................24
7.8.5
Others ...................................................................................................................24
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............25
9. 
REFERENCES ....................................................................................................26


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11.
HISTORY TABLE..............................................................................................28


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LIST OF TABLES
Table 6.1: 1 
Treatments and labels used in the analysis – Part 1 .........................................12
Table 6.3: 1
Subject sets analysed ........................................................................................15
Table 11: 1
History table .....................................................................................................28


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
ALT
Alanine Aminotransferase
ANOVA
Analysis of variance
AST
Aspartate Aminotransferase
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
b.i.d.
Bis in die: twice per day
BMI
Body mass index
C24
Concentration of the analyte in plasma 24 h after the (first) dose
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma within the 24h 
dosing interval
CV
Arithmetic Coefficient of Variation
DILI
Drug induced liver injury
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
IR
Immediate release
Max
Maximum
Min
Minimum
MR
Modified release
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PKS
PK parameter analysis set
Q1
1st quartile
Q3
3rd quartile
QD
Quaque die, once daily
R
Reference treatment
RAGe
Report Appendix Generator system


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Term
Definition / description
SD
Standard Deviation
T
Test treatment
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomization.
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
The trial was prematurely terminated during recruitment of subjects in trial part 1 since the 
first analysis of part 1 was not as expected and further development has stopped.
Consequently, only data from trial part 1 (n=7/15 for cohort 1, n=14/15 for cohort 2) will be 
analysed. For part 1, all analyses as planned in the CTP will be performed and are described 
in more detail in this TSAP.




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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)
5.4
OTHER VARIABLES
Section 5.2.1 of the CTP:
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results 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 (including drug screening), 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 including determination of weight.
Age [years] will be determined as the difference between year of informed consent and year 
of birth.
BMI will be calculated as weight [kg] / (0.01 * height [cm])2.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment groups, 
selection of doses, refer to CTP Sections 3 and 4. 
The study was originally planned to consist of up to three trial parts aiming to assess and 
optimize different modified release (MR) formulations of oral Nintedanib. 
Section 3.1 of the CTP:
The study will be performed in healthy male subjects as an open-label, randomised, single-
dose study in up to three trial parts in order to compare each of the test treatments (MR1, 
MR2, MRX) to the respective reference treatment R. The subjects will be randomly allocated 
to three treatment sequences in trial part 1 and 2 (Latin square design) and two sequences in
trial part 3 (optional). There will be a washout period of at least 14 days between the 
treatments, i.e. the morning dose in the preceding treatment period and the morning dose in 
the following treatment period are separated by at least 14 days.
Each trial part was planned as a randomised crossover trial, details are provided below:
In trial part 1, it was planned to assign 30 healthy male subjects to two parallel groups (trial 
part 1A and 1B, each n=15). In each parallel group, subjects were randomised to one of three 
treatment sequences:
Trial part 1A (Cohort 1):
R / MR1-1 / MR1-2 
MR1-2 / R / MR1-1
MR1-1 / MR1-2 / R
Trial part 1B (Cohort 2):
R / MR2-1 / MR2-2
MR2-2 / R / MR2-1
MR2-1 / MR2-2 / R
For details of dosage and formulation see Table 6.1: 1 below:




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Based on this, 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 
first drug administration in treatment period 1.
∀
On treatment (labelled (in Part 1): “R”, “MR1-1”, “MR1-2”, “MR2-1”, “MR2-2”)
o
Ranging from the administration time of first respective drug administration in 
this period until 14 days (12 AM on day 14) thereafter OR until next drug 
administration of the following period, whatever occurs first.
∀
Follow-up (labelled “F/U R”, “F/U MRX-Y”, with X=1,2, Y=1,2))
o
Ranging from 14 days (12 AM on day 14) after administration time of first 
drug administration of that period until the next drug administration of the 
following period OR until trial termination, whatever occurs first.
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:
In Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) of the 
CTR displays, the on treatment phase will be analysed (labelled with the short label of the 
study treatment). The screening and follow-up phases will not be included in this analysis.
The following totals will be provided in addition for Section 15.3:
∀a total over all on treatment phases from cohort 1 (“Total Cohort 1”)
∀a total over all on treatment phases from cohort 2 (“Total Cohort 2”)
∀a total over all on treatment phases from trial part 1 (“Total”)
In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays, the screening period, as 
well as the follow-up phases will additionally be included and no totals will be provided.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) 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 


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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 DV domain sheet, 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 (DV domain) (3) and in the decision log (4). The iPD specification 
file will be stored within the TMF in EDMS.
The iPDs will be summarized and listed in the CTR.
6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:
Statistical analyses for each crossover part will be based on the following analysis sets:
∀
Treated set (TS): The treated set includes all subjects who were randomised 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.
(…)
Pharmacokinetics
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 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 violations 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


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Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example
∀
The subject experiences emesis at any time during the labelled dosing interval. 
∀
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).
Table 6.3: 1
Subject sets analysed
Subject analysis set
Class of endpoint
TS
PKS
Analyses of PK endpoints 
X
Disposition
X
Demographic/baseline parameters
X
Important protocol deviations
X
Exposure
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.


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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.
Missing or incomplete AE dates are imputed according to BI standards (see BI-KMED-BDS-
HTG-0035) (5).
Missing data and outliers of PK data are handled according to BI standards (see BI-KMED-
TMCP-MAN-0012 (6) and BI-KMED-TMCP-MAN-0014 (7).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before drug administration in each 
treatment period.
Section 6.1 of the CTP:
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening, the end of trial examination, and measurements and 
assessments scheduled to occur ‘before’ trial medication administration in the morning of 
Day 1 are provided in the CTP Flow Chart.
If not stated otherwise in the CTP Flow Chart, the general acceptable deviation from the 
scheduled time for vital signs, ECG, and laboratory tests will be ± 30 min.
The acceptable deviations from the nominal urine sampling time points for urinalysis are:
∀
The pre-dose urine sample will be the first void of the day or a sample collected ≤3 h 
before dosing
∀
Post-dose urine samples will be taken ± 2 h from the nominal urine sampling time
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
Each of the three possible trial parts was planned to be analysed separately. Cohort 1 and 
cohort 2 of trial part 1 will be presented in one table, but the reference group will be stratified 
to R (Cohort 1) and R (Cohort 2).
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 Translational Medicine and Clinical Pharmacology (TMCP) at BI and will be 
presented in Section 15.6 of the CTR and in Appendix 16.1.13.5.
The format of the listings and tables will follow the BI standards (see BI-KMED-BDS-HTG-
0045 (8)) with the exception of those generated for PK-calculations following BI standards 
for PK/PD analysis (9).
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 and PK parameters, the following descriptive statistics will 
additionally be calculated:
Nobs 
number of observations
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
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 


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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 available in 
the CRF and will display the number of observations in a category, as well as the percentage 
(%). Percentages will be rounded to one decimal place and will be based on all subjects in the 
respective subject set whether they have non-missing values or not. The category 'missing' 
will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in brackets (e.g. 
(mg)).
Exclusion of PK parameters
The ADS “ADPP” (PK parameters) contains column variables APEX and APEXCO 
indicating inclusion/exclusion (APEX) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters only if they are not 
flagged for exclusion, that is APEX is equal to “Included”.
Exclusion of PK concentrations
The ADS “ADPC” (PK concentrations per time-point or per time-interval) contains column 
variables ACEX and ACEXCO indicating inclusion/exclusion (ACEX) 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.
Further details are given in BI-KMED-TMCP-MAN-0014 “Noncompartmental 
Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” (7) and BI-KMED-
TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD Data Files” (10).
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.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
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 will 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
Section 4.3 of the CTP:
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 
of trial medication will provide additional confirmation of compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM and described in the CTR.
7.4
PRIMARY ENDPOINTS
The relative bioavailability of several MR formulations of Nintedanib compared to Ofev® IR 
will be investigated on the basis of the primary PK endpoint AUC0-∞(see Section 5.1).
Each of the crossover parts will be analysed separately.
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 endpoint 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 


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k in period j,
# = the overall mean,
∃i = the ith sequence effect, i = 1, 2,(3),
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
%j = the jth period effect, j = 1, 2, (3),
&k = the kth treatment effect, k = 1, 2, (3),
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where  ~ (0, 
) i.i.d.,  ~ (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 endpoint 
(see Section 5.1) 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 ENDPOINTS
The relative bioavailability of several MR formulations of Nintedanib compared to Ofev® IR 
will also be investigated on the basis of the secondary PK endpoint AUC0-tz, Cmax and C24 (see 
Section 5.2.2).
Each of the crossover parts will be analysed separately.
7.5.1
Key secondary endpoints
This section is not applicable, as no key secondary endpoint has been specified in the 
protocol.
7.5.2
(Other) Secondary endpoints
Section 7.3.2 of the CTP:
The secondary endpoints (refer to Section 5.2.2) will be calculated according to the relevant 
internal BI procedures and will be assessed statistically using the same methods as described 
for the primary endpoint.
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 administration will be listed for each subject.


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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.
7.8.1
Adverse Events
AEs will be coded using MedDRA. The coding version number will be displayed as a 
footnote in the respective output.
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] (11) and [BI-KMED-BDS-HTG-
0066] (12) 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. The ‘on-treatment’ and ‘follow-up’ AEs will be analysed based on actual 
treatments, as defined in Table 6.1: 1.
According to the clinical study protocol, 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 the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
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. 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.
According to ICH E3 (13), 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 


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adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced 
or interrupted).
An overall summary of adverse events 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 system organ class (SOC) and preferred 
term (PT).
The system organ classes will be sorted by default alphabetically, PTs will be sorted by 
frequency (within SOC).
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.
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] (14). Analyses will be based on normalised values.
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).


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7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate). In the listing the change from baseline will also be 
displayed.
For vital signs, descriptive statistics will be calculated by planned time point based on the last 
value of the subject at that planned time point (or assigned to that planned time point). Time 
courses of vital signs presenting means and standard deviations per time point and treatment 
group will be provided.
Clinically relevant findings 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.
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.
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 trial 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 released for interim analysis as specified in the CTP 
Section 4.1.5.
The treatment information will be loaded into the trial database after completion of enrolment
for the respective trial parts, 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, Group “Clinical Operations”, IDEA for CON.
3.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, current version, KMED.
4.
001-MCS-50-415_RD-03: “Clinical Trial Analysis Decision Log (template) Decision 
Log”, current version, Group “Biostatistics & Data Sciences”, IDEA for CON.
5.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current
version; KMED.
6.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
7.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; KMED.
8.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project 
Summaries”, current version; KMED.
9.
BI-KMED-TMCP-OTH-0003: “Graphs and Tables for Clinical Pharmacokinetics and
Pharmacodynamic Noncompartmental Analyses”, current version, KMED.
10. BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; KMED.
11. BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
12. BI-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from clinical trials”,
current version, KMED.
13. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version, EMA webpage.
14. 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 
25-AUG-2022
None
This is the final TSAP 
2
28-FEB-2023
Sections 
4, 6.1, 7, 
7.8.3
Update of cohort labels, description of 
premature trial termination, figures for 
vital signs added