The Effect of Multiple Oral Doses of BI 1015550 on the Pharmacokinetics of Nintedanib and Pirfenidone Administered Single Dose to Healthy Male Subjects (Open-label, Two-period, Fixed-sequence Crossover Trial)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

Clinical Trial Protocol
 
Document Number:
c41830059-03
EUCT No.
Universal Trial No.
2023-505522-34-00
U1111-1292-0376
BI Trial No.
1305-0034
BI Investigational
Medicinal Product
BI 1015550
Title
The effect of multiple oral doses of BI 1015550 on the 
pharmacokinetics of nintedanib and pirfenidone administered 
single dose to healthy male subjects (open-label, two-period,
fixed-sequence crossover trial)
Lay Title
A study in healthy men to test whether BI 1015550 influences 
the amount of nintedanib and pirfenidone in the blood
Clinical Phase
I
Clinical Trial Leader
Phone: +
Fax: +
Investigator
Phone: +
Fax: 
Current Version, Date
Version 3.0, 05 October 2023
Original Protocol Date
31 May 2023
Page 1 of 76
Proprietary confidential information
© 2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
31 May 2023
Revision date
05 October 2023
BI trial number
1305-0034
Title of trial
The effect of multiple oral doses of BI 1015550 on the pharmacokinetics of 
nintedanib and pirfenidone administered single dose to healthy male subjects (open-
label, two-period, fixed-sequence crossover trial)
 Investigator
Trial site
Clinical phase
I
Trial rationale
Nintedanib (NIN) and pirfenidone (PIR) are the only drugs registered for the 
treatment of idiopathic pulmonary fibrosis (IPF). Nintedanib is also registered for 
systemic sclerosis interstitial lung disease (SSc-ILD) and progressive fibrosing 
ILDs. As BI 1015550 is developed for treatment of IPF and other forms of 
progressive pulmonary fibrosis, it is very likely that it may be used on top of NIN or 
PIR in clinical practice. Therefore, it is crucial to investigate if there is any effect of 
BI 1015550 on the kinetics of and NIN or PIR when administered together.
Trial objective
The main objective is to investigate the effect of multiple oral doses of 18 mg of 
BI 1015550 bid on the pharmacokinetics of single oral doses of NIN or PIR. 
Trial endpoints
Primary endpoints:       AUC0-tz , AUC0-∞and Cmax of nintedanib 
                                      AUC0-tz , AUC0-∞and Cmax of pirfenidone
Trial design
Open-label, two-period fixed sequence crossover design trial
Number of subjects 
total entered
14
in each treatment
14
Diagnosis
Not applicable
Main inclusion criteria
Healthy male subjects, age of 18 to 55 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Trial product 1
BI 1015550, 18 mg film-coated tablets
dose
2 x 1 tablet (= 36 mg BI 1015550 daily)
mode of admin.
Oral with 240 mL of water

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Trial product 2
Nintedanib (Ofev®) 100 mg soft capsules
dose
1 capsule (= 100 mg nintedanib), single dose
mode of admin.
Oral with 240 mL of water, after a standardised breakfast
Trial product 3
Pirfenidone (Esbriet®) 267 mg film-coated tablets
dose
1 tablet (= 267 mg pirfenidone), single dose
mode of admin.
Oral with 240 mL of water, after a standardised breakfast
Duration of treatment
Treatment Period Reference (R):
1 x 1 tablet Esbriet® (single dose) on Day 1 of Period 1 and
1 x 1 capsule Ofev® (single dose) on Day 2 of Period 1
Treatment Period Test (T):
1 tablet BI 1015550 twice daily for 10 days (Day -6 to Day 4) together with
1 tablet Esbriet® (single dose) in the morning of Day 1 of Period 2 
1 capsule Ofev® (single dose) in the morning of Day 2 of Period 2
Statistical methods
The effect of steady state BI 1015550 on the pharmacokinetics of nintedanib or 
pirfenidone will be estimated by the ratios of the geometric means (T/R) for the 
primary 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 ‘subject’ and ‘treatment’, with ‘subject’ as random and 
‘treatment’ as fixed effect. 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 
Period
Visit
Day
Planned time (relative to the 
first drug intake [h:min])
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory7
PK blood BI 1015550
PK blood pirfenidone
PK blood nintedanib
Suicidality assessment
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-14 to -2
Screening (SCR)1
A
x
x
1 (Treatment Reference) 
2
-1
-12:00
20:00
Admission9
x5
x
1
-1:00
07:00
treatment allocation2
x2
x2
-0:30
07:30
Standard breakfast
0:00
08:00
Pirfenidone administration
x8
x8
x8
0:30
08:30
x
1:00
09:00
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, Lunch3
x
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
10:00
18:00
x
11:00
19:00
Dinner, all subjects together
12:00
20:00
x
x
2
23:30
07:30
Standard breakfast3
x2
x2
24:00
08:00
Nintedanib administration
x8
x8
x8
x8
24:30
08:30
x
25:00
09:00
x
25:30
09:30
x
26:00
10:00
240 mL fluid intake
x
x
27:00
11:00
x
28:00
12:00
240 mL fluid intake, Lunch3
x
x
30:00
14:00
x
32:00
16:00
Snack (voluntary)3
x
34:00
18:00
x
35:00
19:00
Dinner, all subjects together
36:00
20:00
x
x
3
48:00
08:00
Breakfast (voluntary) 3 and 
discharge
x
x
60:00
20:00
Ambulatory visit
x10
x10
4
72:00
08:00
Ambulatory visit
x10
x10
5
96:00
08:00
Ambulatory visit
B10
C10
x10
x10

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FLOW CHART – TEST 
Period
Visit
Day
Planned time (relative to the 
first drug intake [h:min])
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory7
PK blood BI 1015550
PK blood pirfenidone
PK blood nintedanib
Suicidality assessment
ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Wash-out of at least 72 h to last study drug administration in period 1
2 (Treatment Test)
3
-6
-144:00
08:00
BI 1015550 administration11
x2
x2
x2
-132:00
20:00
BI 1015550 administration11
x2
-5
-120:00
08:00
BI 1015550 administration11
x2
-108:00
20:00
BI 1015550 administration11
x2
-4
-96:00
08:00
BI 1015550 administration11
x2
-84:00
20:00
BI 1015550 administration11
x2
-3
-72:00
08:00
BI 1015550 administration11
B2
x2
-60:00
20:00
BI 1015550 administration11
x2
-2
-48:00
08:00
BI 1015550 administration11
x2
-36:00
20:00
BI 1015550 administration11
x2
-1
-24:00
08:00
BI 1015550 administration11
x2
-14:00
18:00
Admission9
x5
-12:00
20:00
BI 1015550 administr.
x2
1
-0:30
07:30
Standard breakfast3
B2
x2
x2
0:00
08:00
BI 1015550 + pirfenidone 
x8
x8
x8
0:30
08:30
x
1:00
09:00
x
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, lunch3
x
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
10:00
18:00
x
11:00
19:00
Dinner, all subjects together
12:00
20:00
BI 1015550 administr. (after PK)
x
x
2
23:30
07:30
Standard breakfast3
x2
x2
x2
24:00
08:00
BI 1015550 + nintedanib 
x8
x8
x8
x8
24:30
08:30
x
25:00
09:00
x
x
25:30
09:30
x
26:00
10:00
240 mL fluid intake
x
x
x
27:00
11:00
x
x
28:00
12:00
240 mL fluid intake, lunch3
x
x
x
30:00
14:00
x
32:00
16:00
Snack (voluntary)3
x
34:00
18:00
x
35:00
19:00
Dinner, all subjects together
36:00
20:00
BI 1015550 administr. (after PK)
x
x
3
48:00
08:00
BI 1015550 administr. (after PK),
breakfast (voluntary)3 , discharge 
x
x
x2
x2
60:00
20:00
Ambulatory visit, BI 1015550 
administration (after PK) 10
x10
x10

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FLOW CHART – TEST, (CONT.)
Period
Visit
Day
Planned time (relative to the 
first drug intake [h:min])
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory7
PK blood BI 1015550
PK blood pirfenidone
PK blood nintedanib
Suicidality assessment
ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
4
72:00
08:00
Ambulatory visit, BI 1015550 
administration (after PK) 10
x10
x10
84:00
20:00
Ambulatory visit, BI 1015550 
administration10
x10
5
96:00
08:00
Ambulatory visit
x10
x10
FU
4
11-25
End of study (EoS) examination4
D
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, suicidality assessment, concomitant therapy, review of inclusion/exclusion criteria. 
2.
The time is approximate; the procedure is to be performed and completed within 3 h prior to next drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of study (synonym for end of trial), the EoS examination includes physical examination, suicidality 
assessment, vital signs, ECG, safety laboratory, recording of AEs and concomitant therapies.
5.
Urine drug screening and alcohol breath test.
6.
AEs and concomitant therapies will be recorded throughout the trial but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
Letters A, B C and D define different sets of safety laboratory examinations (for details refer to Section 5.2.3).
8.
To be done within 15 min prior to study drug dosing.
9.
The time is approximate. Procedures are to be performed no later than 10 h prior to the next drug administration in 
period 1 and within 2 hours prior to next study drug administration in period 2.
10.  After discharge from 
 in the morning of Day 3 the tolerance time for all subsequent procedures is ± 60 min.
11. The tolerance time for ambulatory dosing on Day -6 to Day -1 in Treatment Test is ± 2 hours.
For details of suicidality assessment, refer to Section 5.2.5.1.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART - REFERENCE.......................................................................4
FLOW CHART – TEST.....................................................................................5
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS AND DEFINITIONS..................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................14
1.2.1
BI 1015550 .............................................................................................14
1.2.1.1
Pharmacokinetic properties......................................................14
1.2.1.2
Clinical safety in healthy subjects............................................16
1.2.2
Nintedanib (NIN) ..................................................................................17
1.2.2.1
Pharmacokinetic properties......................................................17
1.2.2.2
Clinical safety in healthy subjects............................................18
1.2.3
Pirfenidone (PIR)..................................................................................18
1.2.3.1
Pharmacokinetic properties......................................................19
1.2.3.2
Clinical safety in healthy subjects............................................19
1.2.4
Residual Effect Period..........................................................................20
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................20
1.4
BENEFIT - RISK ASSESSMENT ...................................................................20
1.4.1
Benefits...................................................................................................20
1.4.2
Risks .......................................................................................................20
1.4.3
Discussion...............................................................................................27
1.4.3.1
Risks of drug-drug-interaction.................................................27
1.4.3.2
Overall assessment...................................................................28
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 29
2.1
MAIN OBJECTIVE AND PRIMARY ENDPOINTS....................................29
2.1.1
Main objective.......................................................................................29
2.1.2
Primary endpoints ................................................................................29
2.2.2.2
Safety and tolerability..............................................................30
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 31
3.1
OVERALL TRIAL DESIGN............................................................................31

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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................31
3.3
SELECTION OF TRIAL POPULATION ......................................................32
3.3.1
Main diagnosis for trial entry..............................................................32
3.3.2
Inclusion criteria...................................................................................32
3.3.3
Exclusion criteria ..................................................................................32
3.3.4
Withdrawal of subjects from treatment or assessments ...................34
3.3.4.1
Withdrawal from trial treatment ..............................................35
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 .......................................................................36
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................................................................38
4.1.3
Method of assigning subjects to treatment groups ............................38
4.1.4
Drug assignment and administration of doses for each subject .......38
4.1.5
Blinding and procedures for unblinding ............................................39
4.1.6
Packaging, labelling, and re-supply ....................................................39
4.1.7
Storage conditions.................................................................................40
4.1.8
Drug accountability ..............................................................................40
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................40
4.2.1
Other treatments and emergency procedures....................................40
4.2.2
Restrictions............................................................................................41
4.2.2.1
Restrictions regarding concomitant treatment .........................41
4.2.2.2
Restrictions on diet and life style.............................................41
4.3
TREATMENT COMPLIANCE.......................................................................41
5.
ASSESSMENTS....................................................................................... 42
5.1
ASSESSMENT OF EFFICACY.......................................................................42
5.2
ASSESSMENT OF SAFETY............................................................................42
5.2.1
Physical examination ............................................................................42
5.2.2
Vital signs...............................................................................................42
5.2.3
Safety laboratory parameters..............................................................42
5.2.4
Electrocardiogram................................................................................44
5.2.5
Other safety parameters.......................................................................45
5.2.5.1
Suicidality assessment .............................................................45
5.2.6
Assessment of adverse events...............................................................46
5.2.6.1
Definitions of adverse events...................................................46

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5.2.6.1.1 Adverse event ............................................................46
5.2.6.1.2 Serious adverse event ................................................47
5.2.6.1.3 AEs considered ‘Always Serious’.............................47
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 ...................................49
5.2.6.2.1 AE collection.............................................................49
5.2.6.2.2 AE reporting to the sponsor and timelines ................50
5.2.6.2.3 AE reporting from suicidality assessment.................50
5.2.6.2.4 Female partner pregnancy .........................................51
5.2.6.2.5 SUSAR reporting by the sponsor ..............................51
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................52
5.3.1
Assessment of pharmacokinetics .........................................................52
5.3.2
Methods of sample collection...............................................................52
5.3.2.1
Blood sampling for pharmacokinetic analysis of nintedanib...52
5.3.2.2
Blood sampling for pharmacokinetic analysis of pirfenidone .52
5.3.2.3
Blood sampling for pharmacokinetic analysis of BI 1015550.53
5.4
ASSESSMENT OF BIOMARKERS................................................................54
5.5
BIOBANKING ...................................................................................................54
5.6
OTHER ASSESSMENTS .................................................................................55
5.6.1
Pharmacogenomic evaluation..............................................................55
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................55
6.
INVESTIGATIONAL PLAN.................................................................. 56
6.1
VISIT SCHEDULE............................................................................................56
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................56
6.2.1
Screening................................................................................................56
6.2.2
Treatment period ..................................................................................56
6.2.3
Follow-up period and trial completion ...............................................57
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 58
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................58
7.2
PLANNED ANALYSES....................................................................................58
7.2.1
General considerations.........................................................................58
7.2.1.1
Analysis sets.............................................................................58

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7.2.1.2
Pharmacokinetics.....................................................................58
7.2.2
Primary endpoint analyses...................................................................59
7.2.3
Secondary endpoint analyses ...............................................................60
7.2.5
Safety analyses.......................................................................................60
7.2.6
Interim analyses ....................................................................................61
7.3
HANDLING OF MISSING DATA ..................................................................61
7.3.1
Safety......................................................................................................61
7.3.2
Pharmacokinetics..................................................................................61
7.4
RANDOMISATION ..........................................................................................61
7.5
DETERMINATION OF SAMPLE SIZE ........................................................61
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 63
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................63
8.2
DATA QUALITY ASSURANCE .....................................................................64
8.3
RECORDS..........................................................................................................64
8.3.1
Source documents .................................................................................64
8.3.2
Direct access to source data and documents.......................................65
8.3.3
Storage period of records.....................................................................65
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................66
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......66
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................66
8.6
TRIAL MILESTONES .....................................................................................66
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................67
9.
REFERENCES......................................................................................... 69
9.1
PUBLISHED REFERENCES...........................................................................69
9.2
UNPUBLISHED REFERENCES.....................................................................70
10. APPENDICES .......................................................................................... 73
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 74
11.1
GLOBAL AMENDMENT 1 .............................................................................74

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ABBREVIATIONS AND DEFINITIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
bid
Twice a day
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
C-SSRS
Columbia Suicide Severity Rating Scale
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
CYP
Cytochrome P450
DDI
Drug Drug Interaction
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid

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EoS
End of Study (synonym for End of Trial)
ESR
Erythrocyte Sedimentation Rate
FDA
Food and Drug Administration
FEED
Fertility and early embryonic development
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
HR
Heart rate
IB
Investigator’s brochure
ICH
International Council for Harmonisation
IGRA
Interferon Gamma Release Assays
IEC
Independent Ethics Committee
ILD
Interstitial lung disease
IPD
Important protocol deviation
IPF
Idiopathic pulmonary fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
!z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
MRTpo
Mean residence time of the analyte in the body after oral administration
NIN
Nintedanib
PD
Pharmacodynamic(s)
PDE
Phosphodiesterases
PIR
Pirfenidone
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QT
Peak-trough swing
QT interval
ECG interval from the start of the QRS complex to the end of the T wave
QTc interval
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB)
R
Reference treatment

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REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
ss
(at) steady state
T
Test product or treatment
t1/2
Terminal half-life of the analyte in plasma
TB
Tuberculosis
TBA
Trial Bioanalyst
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration

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1.
INTRODUCTION
BI 1015550, an oral preferential inhibitor of the phosphodiesterase 4B (PDE4B) isoenzyme 
which hydrolyses and inactivates cyclic adenosine monophosphate (cAMP), is being 
developed by Boehringer Ingelheim (BI) for the treatment of idiopathic pulmonary fibrosis 
(IPF) and other forms of progressive pulmonary fibrosis.
1.1
MEDICAL BACKGROUND
Idiopathic Pulmonary Fibrosis is a specific form of chronic, progressive fibrosing interstitial 
pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and 
associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia 
(UIP) [P11-07084]. 
While IPF is considered a prototypical form of progressive pulmonary fibrosis, there is a
group of patients with different underlying clinical interstitial lung disease (ILD) diagnoses 
who develop a phenotype similar to patients with IPF during the course of their disease [P17-
10582, P18-04729, P19-01738, R19-0854, P20-01299], which is characterised by increasing 
extent of pulmonary fibrosis on imaging, declining lung function, worsening respiratory 
symptoms and quality of life despite disease management considered appropriate in clinical 
practice, and, ultimately, early mortality [P17-10582, P18-04729, P19-01738, R19-0854, 
P20-01299].
Nintedanib and pirfenidone are the only drugs registered for the treatment of IPF and both 
treatments are recommended in the recent ATS/ERS/JRS/ALAT Clinical Practice Guideline 
for the Treatment of Idiopathic Pulmonary Fibrosis [P15-07539]. Nintedanib is also 
registered for the treatment of adults with other chronic fibrosing ILDs with a progressive 
phenotype and Systemic Sclerosis-associated ILD. However, despite existing treatment, there 
remains a high unmet need for new treatments for IPF and other fibrosing ILDs that have 
greater efficacy and fewer side effects than existing therapies [P18-06345].
BI 1015550 is an oral preferential inhibitor of the PDE4B with broad anti-inflammatory and 
antifibrotic activities. Based on its mode of action, as well as available pre-clinical and 
clinical data, BI 1015550 is hypothesised to have complementary activity to current therapies 
in IPF and other forms of progressive pulmonary fibrosis.
1.2
DRUG PROFILE
1.2.1
BI 1015550
1.2.1.1
Pharmacokinetic properties
Absorption
BI 1015550 plasma exposure had a dose proportional 
increase following both single- and multiple-dose administration. Following multiple-dose 
administration of BI 1015550 
under fed conditions over 14 days in 

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Combined administration of NIN and PIR in IPF patients did not provide any signal of a 
relevant PK-interaction between both drugs [R23-1847].
1.2.2.2
Clinical safety in healthy subjects
Up to the present nintedanib has been administered to more than 200 healthy subjects. In 
clinical trials single oral doses of up to 200 mg nintedanib were well tolerated. Gastro-
intestinal side effects and headache were the most common drug related adverse events.
In 1199.17, single doses of 150 mg nintedanib were administered to 15 healthy subjects. 
Drug related AEs were diarrhoea (reported in 7 cases), abdominal discomfort (reported in 3 
cases) and nausea (reported by 1 subject) [U06-1411-02].
In 1199.20, a single oral dose of 100 mg nintedanib was administered to 8 healthy subjects. 
Two drug related adverse events have been reported – nausea (N= 1) and asthenia (N=1) 
[U06-1724].
In 1199.21, two single oral doses of 150 nintedanib were given to 36 healthy volunteers. 
Drug related AEs comprised diarrhoea (N=14), headache (N=8), nausea (N=2), vomiting 
(N=1), dizziness (N=1), fatigue (N=1) and dry mouth (N=1) [U07-1736-02].
In 1199.75, thirty subjects were treated with single doses of intravenous (1, 3 or 6 mg) or oral 
(100 mg) NIN or placebo. The only drug-related AE was diarrhoea (1x) [U10-1400-02].
In 1199.161, a single dose of 50 mg nintedanib was given alone and in combination with
steady state ketoconazole to 34 healthy subjects. Drug related AEs (referring to the intake of 
NIN alone or in combination with ketoconazole) were headache (reported by 5 subjects), 
upper abdominal pain and fatigue (each reported by 1 subject) [U13-1925-01].
In 1199.162, a single dose of 150 mg nintedanib was given alone and in combination with 
steady state rifampin to 26 healthy subjects. Drug related AEs (referring to nintedanib alone 
or in combination with rifampin) were diarrhoea (8x) and headache (2x) [U13-1478-01].
In 1199.237 single doses of 200 mg NIN were given in three trial periods to 70 healthy male 
subjects. Drug related AEs were reported by 33 subjects and comprise loose stool (24x), 
nausea (7x), abdominal discomfort (3x), upper abdominal pain (1x), headache (9x), dizziness 
(3x) and fatigue (1x). All drug related AEs were of mild or moderate intensity and resolved 
without treatment. NIN had no relevant effects on safety lab and vital signs [c08883821-01]. 
For a more detailed description of the nintedanib profile, please refer to the current SmPC 
[R23-1847].
1.2.3
Pirfenidone (PIR)
Pirfenidone is used for the treatment of mild to moderate Idiopathic Pulmonary Fibrosis (IPF) 
in adults. The mechanism of action of pirfenidone in the treatment of IPF has not been 
established.

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1.2.3.1
Pharmacokinetic properties
After single oral-dose administration of a 801 mg pirfenidone tablet to healthy subjects, mean 
tmax was achieved after 1 h and 2 h under fasted and fed conditions. Food decreased the rate 
and extent of absorption by about 40% and 20%. The elimination half-life was about 2.77 and 
2.74 hours in fasted and fed state [R17-3055].   
Pirfenidone is mainly metabolised (70-80%) by cytochrome P450 1A2 and to a minor extent 
by CYP2C9, 2C19, 2D6 and 2E1. Pirfenidone is excreted predominantly (about 80% of an 
oral dose) in the urine.
Co-administration with the strong CYP1A2 inhibitor fluvoxamine increased exposure to 
pirfenidone by approximately 4-fold in non-smokers and 7-fold in smokers. Co-
administration with ciprofloxacin (moderate inhibitor of CYP1A2) increased the exposure to 
pirfenidone by 81%.
1.2.3.2
Clinical safety in healthy subjects
In clinical trials, the most frequent adverse events reported by healthy subjects were
gastrointestinal disorders (e.g. nausea, abdominal pain, vomiting) and dizziness. To reduce 
the incidence of nausea and dizziness a fed intake is recommended.
In a dose-escalation study single doses of 200, 400 and 600 mg pirfenidone (fasted intake) 
and multiple doses of 400 mg tid (for 5 days, fed intake) have been tested in healthy male and 
female Chinese subjects. Adverse events were reported by 8 of 48 subjects and comprise 
dizziness (7 cases), nausea (4 cases), vomiting, stomach upset and cold sweat (each in 1 
case). AEs generally occurred 0.5 h to 2 h after pirfenidone intake. Incidence of adverse 
events was higher in the highest dose group (5 cases) and in females (7 of 8 cases). No AEs 
were reported in the low dose group and in the multiple dose part[R23-1844]. 
In another trial single doses of 200 mg and 600 mg pirfenidone (randomised cross-over 
design, fasted intake, cohort 1 with N=10) and 400 mg pirfenidone (single dose followed by 
tid dosing for 6 days, fed intake, group 2 with N=10) have been tested in healthy male and 
female Chinese subjects. Drug related adverse events have been reported by 6 subjects and 
comprise dizziness (3 cases), stomach discomfort (2 cases), intermittent headache, nausea, 
belching, drowsiness and decreased haemoglobin (1 case each). Incidence of AEs was higher 
in females (5 subjects) and in the multiple dose group (5 subjects). All Adverse events were 
of mild intensity and recovered without treatment. No AEs were reported after single dose 
administration of 200 mg and 400 mg pirfenidone. There were no significant changes from 
baseline regarding ECG and vital signs and [R23-1846]. 
In a four-period cross-over trial the bioequivalence of an 801 mg tablet versus 3 capsules 
containing 267 mg pirfenidone have been investigated under fasted and fed conditions in 44 
healthy subjects. Adverse events have been reported by 22 subjects, predominantly in fasted 
treatments. Most frequent AEs comprise nausea (13x), dizziness (8x), constipation (4x), 
headache (4x), vomiting (2x) and dyspepsia (2x). All adverse events were of mild intensity 
[R17-3055].
Rubino et al investigated the effect of antacids on single dose kinetics of 801 mg pirfenidone 
under fasted and fed conditions in 16 healthy elderlies. AEs were reported by 12 subjects. 

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Most commonly reported AEs comprise nausea (7x) and dizziness (6x), which more 
frequently occurred in the fasted state. All AEs were of mild or moderate intensity. There 
were no significant ECG changes or laboratory abnormalities [R23-1845].
For a more detailed description of the pirfenidone profile, please refer to the current SmPC 
[R23-1848].
1.2.4
Residual Effect Period
This is the period after the last 
dose during which measurable drug levels are still likely to be present.
The REP of nintedanib for single dose is 3 days.
The REP of pirfenidone is 12 hours.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Nintedanib and pirfenidone are the only drugs registered for the treatment of idiopathic 
pulmonary fibrosis (IPF). Nintedanib is also registered for SSc-ILD and progressive fibrosing 
ILDs. As BI 1015550 is developed for treatment of IPF and other forms of progressive 
pulmonary fibrosis, it is very likely that it may be used on top of nintedanib or pirfenidone in 
clinical practice.
This trial investigates the potential impact BI 1015550 on the pharmacokinetics of nintedanib 
or pirfenidone. The results will provide further rationale for development of the drug label 
with regards to restriction of concomitant medication.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 1015550, 
which may help to treat patients suffering from idiopathic pulmonary fibrosis.
1.4.2
Risks
Subjects are exposed to risks of trial procedures and risks related to the exposure to the trial 
medication. 
Potential side effects of BI 1015550 will be under continuous evaluation during clinical 
development. Vasculitis and foetal loss are considered as important potential risks based on 
nonclinical findings. The risks shown in the table 1.4.2:1 below are hypothetical in nature; 
these are not limited to data from BI 1015550 but also derived from general safety 
considerations of immunomodulatory drugs and from preclinical and clinical data of 
compounds with a comparable mode of action. 
In addition to the data from trials in healthy volunteers as described above (sections 1.2.2, 
1.2.3), the safety profile as summarized in the current SmPCs of nintedanib and pirfenidone 
is based on a substantial number of clinical trials in patients and post-marketing experience, 
mainly after long-term treatment. Overall, the most frequently reported adverse reactions 

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associated with the use of nintedanib included diarrhoea, nausea and vomiting, abdominal 
pain, decreased appetite, weight decreased and hepatic enzyme increased. The most 
frequently reported adverse reactions during clinical study experience with pirfenidone were 
nausea, diarrhoea, dyspepsia, anorexia, headache, and photosensitivity reaction. 
In the evaluation of risks, it is of note that only single doses of nintedanib and pirfenidone 
will be administered in the current trial to healthy male  subjects.    
An overview of trial-related risks is given in Table 1.4.2: 1.
Table 1.4.2: 1
Overview of trial-related risks for this trial
Possible or known risks 
of clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product: BI 1015550
Vasculitis
∀
Vasculopathy is an established 
preclinical toxicity of PDE4 
inhibitors
∀
Close clinical monitoring (AE 
questioning, lab values) in 
order to early detect potential 
signs of vasculitis.
∀
Treatment of a subject is 
discontinued in case of any 
suspected vasculitis event.
Major Adverse
Cardiovascular Events 
(MACE) and 
tachyarrhythmia
∀
Important potential risk for 
marketed PDE4 inhibitor 
apremilast.
∀
In clinical trials with BI 
1015550 no relevant findings 
were observed.
∀
These risks will be addressed 
by careful safety monitoring 
(AE-questioning) and safety 
measures (vital signs, ECG)

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Table 1.4.2: 1
Overview of trial-related risks for this trial, (cont.)
Possible or known risks 
of clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Psychiatric disorders:
depression and suicidality
∀
For the marketed PDE4 
inhibitors depression is listed as 
side effect and they are 
associated with increased risk 
of depression with some 
patients reporting suicidal 
ideation and attempts and also 
reported cases of completed 
suicide.
∀
The risk of depression and 
suicidality within the planned 
dosing period of 10 days is 
considered low 
∀
Subjects will be proactively 
screened and monitored for SIB 
in accordance with regulatory 
guidance (use of C-SSRS 
questionnaire)
∀
Exclusion of subjects with any 
suicidal ideation in the past 12 
months or any lifetime history 
of suicidal behaviour
Severe infections 
including, serious, 
opportunistic and 
mycobacterium 
tuberculosis infections
∀
Inhibition of the immune 
response due to the anti-
inflammatory mode of action of 
BI 1015550 potentially 
increases the risk of severe and 
serious infections.
∀
Serious infections were 
balanced between placebo and 
BI 1015550 in Phase II trial.
∀
Screening procedures for 
infections are defined for this 
trial. Subjects with any relevant 
chronic or acute infections are 
excluded from the trial
∀
Treatment of infections should 
be initiated promptly according 
to standards of care
∀
In case of severe acute 
infection treatment with BI 
1015550 will be stopped

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Table 1.4.2: 1
Overview of trial-related risks for this trial, (cont.)
Possible or known risks 
of clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Malignancies
∀
Inhibition of the immune 
response with an 
immunomodulatory drug may 
potentially impair immune 
defences and thus, theoretically 
decrease immune defence 
against malignancies.
∀
Subjects with active or 
suspected malignancy or
history of malignancy within 5 
years prior to screening will be 
excluded from participation in 
this trial
Gastrointestinal disorders 
(e.g., diarrhoea, nausea, 
vomiting, abdominal 
pain)
∀
Vomiting and diarrhea are 
important dose-limiting side 
effects of marketed oral PDE-4 
inhibitors.
∀
In phase I trials gastrointestinal 
disorders are frequently 
reported side effects
∀
Subjects are regularly asked for 
adverse events
∀
Gastrointestinal side effects can 
be managed in the setting of a 
phase I trial (e.g. hydration of 
subjects with diarrhoea)
Drug-induced liver injury 
(DILI)
∀
Rare but severe event, thus 
under constant surveillance by 
sponsors and regulators
∀
Timely detection, evaluation, 
and follow-up of laboratory 
alterations in selected liver 
laboratory parameters to ensure 
subjects´ safety
∀
Increased awareness and 
expedited reporting (AESI).

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Table 1.4.2: 1
Overview of trial-related risks for this trial, (cont.)
Possible or known risks 
of clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Nintedanib (NIN)
Reproductive toxicity
∀
NIN caused embryofetal 
letality in rats and rabbits.
∀
Female subjects are not 
included in this trial.
Tolerability in healthy 
subjects
∀
Gastro-intestinal side effects 
and headache were the most 
common drug related adverse 
events reported from healthy 
subjects
∀
A single low dose of 100 mg 
NIN is administered in this trial 
∀
side effects described by 
healthy subjects so far can be 
managed in the setting of a 
phase I trial
Hepatic function
∀
Liver enzyme elevation has 
been very commonly 
observed with nintedanib 
treatment, in the majority of 
cases reversible upon dose 
reduction or interruption.
∀
Cases of drug-induced liver 
injury have been observed 
with nintedanib treatment
including severe liver injury 
with fatal outcome. 
∀
Single doses will be 
administered in this trial 
rendering the risk of liver 
injury very low.
∀
Timely detection, evaluation, 
and follow-up of laboratory 
alterations in selected liver 
laboratory parameters to 
ensure subjects´ safety
∀
Increased awareness and 
expedited reporting (AESI)
Hypersensitivity to  
peanut or soya
∀
Each Ofev® 100 mg soft 
capsule contains 1.2 mg of 
soya lecithin
∀
Dietary soya products are 
known to cause allergic 
reactions including severe 
anaphylaxis in persons with 
soya allergy. 
∀
Patients with known allergy 
to peanut protein carry an 
enhanced risk for severe 
reactions to soya 
preparations.
∀
Subjects with 
hypersensitivity to peanut or 
soya will be excluded.

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Table 1.4.2: 1
Overview of trial-related risks for this trial, (cont.)
bleeding
∀
Listed side effect in the 
SmPC of Ofev®
∀
The risk of bleeding is 
considered minimal based on 
the single applications in this 
study.
∀
Nevertheless, subjects with a 
hereditary bleeding disorder 
and subjects with an out-of-
range value at screening 
indicating a bleeding risk will 
be excluded from 
participation
proteinuria
∀
Listed side effect in the 
SmPC of Ofev®
∀
The risk of proteinuria is 
considered minimal based on 
the single applications in this 
study. 
∀
Patients with proteinuria at 
screening will be excluded 
from participation. 

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Table 1.4.2: 1
Overview of trial-related risks for this trial, (cont.)
Possible or known risks 
of clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Pirfenidone (PIR)
Tolerability in healthy 
subjects
∀
Gastrointestinal disorders and 
dizziness were the most 
frequent drug related adverse 
events reported from healthy 
subjects 
∀
A breakfast will be served prior 
to PIR intake to reduce the 
incidence of nausea and 
dizziness
∀
A single low dose of 267 mg 
PIR is administered in this trial
∀
side effects described by 
healthy subjects can be 
managed in the setting of a 
phase I trial  
∀
subjects will be discharged only 
after confirmation of their 
fitness
Photosensitivity reaction 
and rash
∀
listed as Special warnings and 
precautions for use in the 
SmPC of pirfenidone
∀
a low single dose of 
pirfenidone will be given
∀
after PIR dosing subject will be 
kept inhouse for 48 hours (du-
ring this time direct exposure to 
sunlight should be avoided)
∀
half-life of PIR is about 2.8 h
angioedema
∀
listed as Special warnings and 
precautions for use in the 
SmPC of pirfenidone
∀
healthy subjects with a history 
of angioedema are excluded 
(exclusion 33)

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Table 1.4.2: 1
Overview of trial-related risks for this trial, (cont.)
Possible or known risks 
of clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Drug-induced liver injury 
(DILI) and increased 
transaminases
∀
listed as Special warnings and 
precautions for use in the 
SmPC of pirfenidone
∀
Uncommonly, elevations in 
AST and ALT were associated 
with concomitant bilirubin 
increases. Cases of severe 
drug-induced liver injury, 
including isolated cases with 
fatal outcome, have been 
reported post-marketing
∀
a low single dose of 
pirfenidone will be given
∀
half-life of PIR is about 2.8 h
∀
measurement of liver function 
tests should be performed in 
subjects who report symptoms 
that may indicate liver injury, 
including right upper 
abdominal discomfort, dark 
urine, or jaundice.
Trial procedures
Inflammation of the wall 
of the vein. Injuring of a 
nerve while inserting the 
venous catheter, 
potentially resulting in 
paraesthesia, reduced 
sensibility, and/or pain 
for an indefinite period.
General risk by venepuncture for 
blood sampling, acceptable in the 
framework of trial participation.
Evaluation of the medical 
expertise of the trial sites is part 
of site feasibility assessment. 
Trial treatment discontinuation 
criteria as well as criteria for trial 
treatment restart are implemented 
for relevant cases.
Skin irritation, redness,
itching
General risk by ECG electrodes,
acceptable in the framework of
trial participation.
Exclusion of subjects from trial
participation with known 
clinically
relevant hypersensitivity 
reactions to
adhesive tapes
The total volume of blood withdrawn per subject during the entire trial will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
1.4.3
Discussion
1.4.3.1
Risks of drug-drug-interaction

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1.4.3.2
Overall assessment
BI 1015550 is developed for the treatment of idiopathic pulmonary fibrosis (IPF) and other 
forms of progressive pulmonary fibrosis. So far NIN and PIR are the only drugs registered for 
the treatment of IPF. This trial investigates the effect of BI 1015550 on the kinetics of NIN 
and PIR to give recommendations on the safe use of BI 1015550 if administered together 
with NIN and PIR in the clinical practice. 
The safety profile of BI 1015550 has been characterized in several clinical trials including 
administration to about 190 healthy subjects so far. The observed adverse events can be 
handled in the setting of a phase I trial. There is no undue risk from the administration of BI 
1015550 to healthy subjects in this trial. 
NIN and PIR are marketed compounds that have been well tolerated by healthy subjects at 
doses that exceed the doses given in this trial thus providing a safety margin for a potential 
DDI.
 
In this trial adequate safety monitoring including safety laboratory, ECG, suicidality 
assessment and adverse events monitoring has been implemented. Taking into account these 
safety measures and considering the chosen low doses of the PIR and NIN the potential risks 
to healthy participants are considered to be low and outweighed by the benefit of a successful 
clinical development of BI 1015550 for the treatment of IPF. 

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVE AND PRIMARY ENDPOINTS
2.1.1
Main objective
The main objective of this trial is to investigate the induction effect of multiple oral doses of 
18 mg bid of BI 1015550 on the pharmacokinetics of nintedanib or pirfenidone.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for nintedanib:
∀
AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)
∀
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
∀
Cmax (maximum measured concentration of the analyte in plasma)
The following pharmacokinetic parameters will be determined for pirfenidone:
∀
AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)
∀
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
∀
Cmax (maximum measured concentration of the analyte in plasma)

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2.2.2.2
Safety and tolerability
Safety and tolerability of BI 1015550 will be assessed based on:  
∀
Adverse events (including clinically relevant findings from the physical examination)
∀
Suicidality assessment (C-SSRS)
∀
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
The trial will be performed as an open-label, two-period fixed sequence crossover design trial
in order to compare the test treatment (T) to the reference treatment (R) using the fixed 
sequence R-T. An overview of both treatments is given below, for details refer to Section 4.1.
Reference Treatment (R):
∀
267 mg pirfenidone (single dose) given orally alone on Day 1 of period 1
∀
100 mg nintedanib (single dose) given orally alone on Day 2 of period 1
Test Treatment (T)
∀
18 mg BI 1015550 given twice daily for 10 days (Day -6 to Day 4) together with
∀
267 mg pirfenidone (single dose) in the morning of Day 1 of Period 2 
∀
100 mg nintedanib (single dose) in the morning of Day 2 of Period 2
For details on drug administration, refer to Section 4.1.
There will be a washout period of at least 72 hours between the nintedanib treatment (R) and 
the first BI 1015550 administration in the test treatment period (T).
Figure 3.1:  Study Design
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For this one-sided DDI-trial (investigates the effect of the offender drug on 2 victim drugs), 
the crossover design is preferred because of its efficiency: since each subject serves as his 
own control, the comparison between treatments is based on an intra-subject comparison, 
thus removing inter-subject variability from the comparison between treatments [R94 1529].

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Because of the
different treatment schedules and in order to avoid overlapping effects, a fixed-sequence 
design is selected, in which the offender (BI 1015550) will be administered in the second 
study period only. The fixed-sequence design is not expected to lead to systematic errors in 
the estimation of the treatment effects since nonspecific time-effects are unlikely due to the 
short trial duration.
The open-label treatment is not expected to bias results, since the trial endpoints are derived 
from measurement of plasma concentrations of the analyte, that are not influenced by the 
subject`s knowledge of the treatment.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 14 healthy male subjects will enter the trial. They will be recruited from the 
volunteers' pool of the trial site.
Female subjects will not be recruited due to the teratogenic potential of nintedanib.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF, irrespective of whether they have been treated with investigational 
drug or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy subjects.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (inclusive)
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:

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1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders (including severe renal or hepatic impairment)
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Relevant chronic or acute infections
10. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin
11. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
12. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation). This includes any kind of vaccination.
13. Intake of an investigational drug in another clinical trial within 60 days or within 5 half-
lifes of the investigational drug or its metabolites (whichever is longer) of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
14. Smoker
15. Inability to refrain from smoking on specified trial days
16. Alcohol abuse (consumption of more than 24 g per day for males)
17. Drug abuse or positive drug screening
18. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
19. Intention to perform 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. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms) or any other relevant ECG finding at screening
22. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)

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23. 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 
24. Male subjects with WOCBP partner who are unwilling to use male contraception
(condom or sexual abstinence) from time point of administration of trial medication until 
90 days thereafter 
25. According to C-SSRS questionnaire at screening: any suicidal ideation in the past 12 
months or any lifetime history of suicidal behaviour 
26. History of depressive disorders 
27. History of vasculitis
28. Subjects with active tuberculosis 
29. Liver enzymes (ALT, AST, GGT) or serum creatinine above upper limit of normal range 
at screening examination, confirmed by a repeat test
30. Known hypersensitivity to peanut or soya
31. Concomitant intake of fluvoxamine
32. No intake of prescription medicine within 2 months prior to the planned administration of 
investigational drug in the current trial
33. History of angioedema
34. Thyroid dysfunction based on TSH outside the normal range confirmed by repeat test 
35. History of hereditary bleeding disorder
36. Proteinuria at screening, if confirmed by a repeat test
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may withdraw or may be removed from trial treatment or may 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, trial data will be included in the CRF and will be reported in the CTR. 
Following removal or withdrawal, a complete end-of-trial examination should be performed.
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.4, 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.

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3.3.4.1
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:
1. The subject wants to withdraw from trial treatment. The subject will be asked to explain 
the reasons but has the right to refuse to answer
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, the safety of the 
subject cannot be guaranteed as he / she is not willing or able to adhere to the trial 
requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery or 
diseases) or in case of occurrence of one AE of severe intensity or one SAE.
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
If any of the following adverse events is reported, the treatment has to be discontinued:
-
Severe or serious infections, opportunistic or mycobacterium tuberculosis 
infections
-
Vasculitis
In addition to these criteria, the investigator may discontinue subjects at any time based 
on his or her clinical judgment.
If new efficacy or safety information becomes available, Boehringer Ingelheim will 
review the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment 
for all subjects or take any other appropriate action to guarantee the safety of the trial 
subjects.
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 (if reasons 4 and/or 5 are met, the trial should be discontinued 
immediately):
1. Failure to meet expected enrolment goals overall or at a particular trial site

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2. The sponsor decides to discontinue the further development of the investigational 
products
3. Deviation from GCP, or the CTP impairing the appropriate conduct of the trial
4. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment (see Section 3.3.4.1)
5. More than 50% of the subjects show drug-related and clinically relevant adverse events of 
moderate or severe intensity, or if at least one drug-related serious adverse event is 
reported
3.3.5
Replacement of subjects
In case more than 2 subjects do not complete the trial (including subjects non-evaluable for 
PK), subjects may be replaced if considered necessary to reach the objective of the trial.
Subjects who withdraw or are withdrawn from treatment or assessments because of a drug-
related adverse event will not be replaced. The Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. A replacement subject will be assigned a unique trial subject number, and will be 
assigned to the same treatment group as the subject he replaces.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of trial product 1 are given below:
Substance:
BI 1015550
Pharmaceutical formulation: Film-coated tablets
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
18 mg
Posology:
1 – 0 – 1
Mode of administration:
Oral
Duration of use:
10 days (from Day – 6 to Day 4 in Period 2) 
The characteristics of trial product 2 are given below:
Name:
Ofev®
Substance:
Nintedanib
Pharmaceutical formulation: Soft capsules
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
100 mg
Posology:
1 – 0 – 0
Mode of administration:
Oral
Duration of use:
Single dose on Day 2 of Period 1 and Period 2
The characteristics of trial product 3 are given below:
Name:
Esbriet®
Substance:
Pirfenidone
Pharmaceutical formulation: Film-coated tablets
Source:
Unit strength:
267 mg
Posology:
1 – 0 – 0
Mode of administration:
Oral
Duration of use:
Single dose on Day 1 of Period 1 and Period 2

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4.1.2
Selection of doses in the trial
BI 1015550:
18 mg bid of BI 1015550 is the therapeutic dose that is currently used in clinical trials. In this 
trial BI 1015550 is the perpetrator drug that has to be used in the maximum dose [R20-2271].
Nintedanib:
100 mg of nintedanib is the lowest therapeutic dose which is used for safety reasons. 
Pirfenidone:
267 mg of pirfenidone is the lowest therapeutic dose which is used for safety reasons. 
4.1.3
Method of assigning subjects to treatment groups
There is only one treatment sequence investigated in this trial, and each subject will be 
allocated to the same treatment sequence (R-T). The subjects will be allocated to a trial 
subject number by drawing lots prior to first administration of trial medication in the morning 
of Day 1 of Visit 2.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
All subjects may be treated in one cohort, i.e. all subjects may receive treatment on the same 
calendar day. In case this is not feasible (e.g., due to logistical or recruitment reasons), the 
group may be split into several cohorts as required. Treatment of all subjects on the same 
calendar day is acceptable (for discussion of trial-associated risks and safety measures, see 
Section 1.4).
4.1.4
Drug assignment and administration of doses for each subject
This is a one-way crossover trial. All subjects will receive the 2 treatments in a fixed order. 
The treatments to be evaluated are summarised in Table 4.1.4: 1 below.
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
R (Reference)
Pirfenidone
Nintedanib
Film coated 
tablets
Soft capsule
267 mg
100 mg
1 x 1 tablet on Day 1 of visit 2
1 x 1 capsule on Day 2 of visit 2
T (Test)
BI 1015550
Pirfenidone
Nintedanib
Film coated 
tablets
Film coated 
tablets
Soft capsule
18 mg
267 mg
100 mg
2 x 1 tablet (from Day -6 to Day 4) 
of visit 3, together with
1 x 1 tablet on Day 1 of visit 3
1 x 1 capsule on Day 2 of visit 3

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On Day 1 and 2 of both trial periods (PK-profile days) NIN and PIR will be administered 
after a standardised breakfast. The breakfast has to be consumed within 30 min prior to study 
drug administration. In period 2 NIN and PIR will be given together with BI 1015550. The 
investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a standing position. During the 
first 4 h after drug administration, subjects are not allowed to lie down (i.e. no declination of 
the upper body of more than 45 degrees from upright posture).
Dosing of BI 1015550 is done in an ambulatory fashion on Days -6 to -1 and on Days 3-4 in 
period 2. For ambulatory dosing BI 1015550 will be administered with 240 ml water to 
subjects who are in a standing position. On ambulatory dosing days no specific restrictions 
regarding food intake have to be followed. Start of BI 1015550 dosing in period 2 should be 
separated by a wash-out phase of at least 72 hours after NIN dosing in period 1. 
For all drug administration, the so-called four-eye principle (two-person rule) should be 
applied. For this, one authorised employee of the trial site should witness the administration 
of trial medication, and – if applicable – its preparation (e.g. reconstitution), if correct dosage 
cannot be ensured otherwise.
Subjects will be kept under close medical surveillance until 48 hours after PIR intake and 
until 24 h after NIN intake. 
4.1.5
Blinding and procedures for unblinding
This non-randomised Phase I trial will be handled in an open fashion throughout. The 
treatment assignment will be available to all involved parties.
4.1.6
Packaging, labelling, and re-supply
The BI 1015550 tablets will be provided by BI. They will be packaged and labelled in 
accordance with the principles of Good Manufacturing Practice (GMP). For details of 
packing and the description of the label, refer to the ISF.
The labels will be prepared according to Regulation (EU) No 536/2014, Annex 6 omitting 
certain particulars with the following justifications:
-
The visit number is not relevant for the label because the product will remain at the 
clinical site.
-
The investigator name was omitted from the label because it is included on the Trial 
Identification Card, which will be issued to each trial participant.
-
The "keep out of reach of children" statement was omitted from the label because the 
product will remain at the clinical site.
Pirfenidone and nintedanib will be obtained by the clinical trial site from a public pharmacy.
The drugs will be dispensed out of the original, unmodified packages.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EUCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
No re-supply is planned.

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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
Clinical Research Associate (as provided in the list of contacts) is to be contacted
immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the IRB / ethics committee
∀
Approval/notification of the regulatory authority, e.g. competent authority
∀
Availability of the curriculum vitae of the Principal Investigator
∀
Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. 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.

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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 trial days) on the appropriate pages of the CRF.
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. On PK-profile days no food is allowed for at least 4 h after drug 
intake. 
On PK-profile days from 1 h before drug intake until lunch, fluid intake is restricted to the 
water provided at breakfast, to 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 12 h 
post-dose, total fluid intake is restricted to 2000 mL (thereafter subjects may drink ad 
libidum).
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sampling of the trial. 
Alcoholic beverages are not permitted starting 48 h before first trial drug administration until 
last PK sampling.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed during in-house confinement at the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Direct exposure to sun should be avoided during inhouse confinement.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial 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
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (alcohol history not mandatory to be entered into CRF or to be 
reported), relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests (including 
drug screening in all subjects), a physical examination, and assessment of suicidal ideation 
and behavior using the C-SSRS (‘baseline/screening scale’).
At the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, a physical examination, assessment of suicidal ideation and behavior using C-SSRS 
(‘since last visit scale’).
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 
(Dinamap Pro 100,
 at the times indicated in the 
Flow Chart, after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of blood pressure recording instrument on the same arm, 
if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 10 h
(for lab panel A and D; for panel B and C no specific fasting period is required). For retests, 
at the discretion of the investigator or designee, overnight fasting is not required.
The parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will 
be provided in the ISF. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
D
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
Reticulocytes, absol.
Reticulocytes/Erythrocyte
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; 
Basophils/ Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs)/Leukocytes; Neut. Poly (segs), absol.; 
Neutrophils Bands/Leukocytes; Neutrophils Bands, absol.; 
Eosinophils/Leukocytes; Eosinophils, absol.; 
Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time (Quick)
Prothrombin time – INR (International Normalization Ratio)
X
X
X
X
X
X
Enzymes
AST [Aspartate aminotransferase] /GOT, SGOT 
ALT [Alanine aminotransferase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
X
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
C-Reactive Protein (Quant)
Troponin T  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Calcium
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 HGB (qual)
Urine leucocyte esterase (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination )
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 2 on Day 5 and Visit 3 on Days -3 and 1 (also refer to Flow Chart)
C: parameters to be determined at Visit 2 on Day 5 (also refer to Flow Chart)
D: parameters to be determined at Visit 4 (end of trial examination)

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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 admission to the trial site.
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/Ecstasy
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)
QuantiFERON®-TB Gold-Plus-Test (IGRA)
To encourage compliance with alcoholic restrictions, a breath alcohol test 
will be performed prior to each admission to the trial 
during the trial 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. These tests will be performed at the trial site using 
 
or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
It is the responsibility of the Investigator to evaluate the laboratory reports. Clinically 
relevant abnormal findings as judged by the Investigator are to be reported as adverse events 
(please refer to Section 5.2.6). 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4).
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph 
at the times provided in the Flow Chart. 

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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 trial procedures scheduled 
for the same time to avoid compromising ECG quality. 
Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. For the inclusion 
or exclusion (see Section 3.3) of a subject and for the assessment of cardiac safety during the 
study, the QT and QTcF (correction according to Fridericia’s formula) values generated by 
the computerised ECG system will be used. Abnormal findings will be reported as AEs 
(during the trial) or baseline conditions (if identified at the screening visit) if assessed to be 
clinically relevant by the investigator. Any ECG abnormalities will be carefully monitored 
and, if necessary, the subject will be removed from the trial and will receive the appropriate 
medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Suicidality assessment
Based on the FDA guidance on prospective assessment of suicidality [R12-4395] suicidal 
ideation and behaviour (SIB) will be proactively evaluated as part of the drug development. 
This also refers to clinical trials in healthy volunteers with multiple dose administration of the 
IMP. 
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts
in cooperation with the FDA, assessing both suicidal behaviour and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behaviour and ideation [R08-1147].
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counsellor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behaviour, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at the screening visit (using the ‘screening / baseline’ version) with the aim to 
exclude subjects with active moderate or severe symptomatology within a specified time 
prior to the screening or baseline visit. The life time history of suicidal ideation and behavior 

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will also be recorded. The C-SSRS version used in this trial are filed in the ISF. For this trial, 
the paper version of the respective German translation will be used.
After the screening visit, the ‘since last visit’ version is used for the suicidality assessment at 
the time points indicated in the Flow Chart.
The investigator is to review all reports for plausibility and clinical relevance. Doubtful 
reports may be repeated or reports may be validated by a consulting psychiatrist. If there is a 
confirmed report of suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the 
investigator is to immediately interview the subject during the clinic visit, and/or is to consult 
a psychiatrist. If the report is confirmed, appropriate actions for the subject’s safety have to 
be initiated.
There are following types of suicidal ideation and behaviour [R12-4395]:
Suicidal ideation
1. Passive 
2. Active: nonspecific – no method, intent or plan 
3. Active: method, but no intent or plan 
4. Active: method and intent, but no plan 
5. Active: method, intent, and plan 
Suicidal behaviour
1. Completed suicide
2. Suicide attempt
3. Interrupted attempt
4. Aborted attempt
5. Preparatory actions toward imminent suicidal behaviours.
For details regarding AE reporting see Section 5.2.6.2.3
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 considered related or not.
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 

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∀
Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior 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 (except hospitalisation for routine check-up, 
diagnostic purposes only or for a planned surgery), or prolongation of existing 
hospitalisation
∀
Results in persistent or significant disability or incapacity 
∀
Is a congenital anomaly/birth defect 
∀
Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.

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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:
∀
Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters: 
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, 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.
∀
Serious infections, opportunistic or mycobacterium tuberculosis infections. 
These include Pneumocystis jirovecii, BK virus disease including polyomavirus-
associated nephropathy (PVAN), Cytomegalovirus (CMV), progressive multifocal 
leucoencephalopathy, bartonellosis (disseminated only), blastomycosis, 
toxoplasmosis, coccidioidomycosis, histoplasmosis, aspergillosis (invasive only), 
candidiasis (invasive or pharyngeal), cryptococcosis, other invasive fungi 
(mucormycosis (zygomycosis, rhizopus, mucor, lichtheimia), 
Scedosporium/Pseudallescheria boydii, fusarium), legionellosis, Listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous 
mycobacterium, salmonellosis (invasive only), HBV reactivation, herpes simplex 
(invasive only), herpes zoster, strongyloides (hyperinfection syndrome and 
disseminated forms only), paracoccidioides, Penicillium marneffei, Sporothrix 
schenckii, cryptosporidium species (chronic only), microsporidiosis, leishmaniasis 
(visceral only), Trypanosoma cruzi infection (Chagas’ disease) (disseminated only), 
campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis (invasive due 
to vibrio vulnificus), HCV progression [R17-2617]

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∀
Vasculitis
The investigator should monitor for any signs and symptoms of vasculitis at all times 
and specifically as part of the AE questioning. In case of a suspected event of 
vasculitis an additional safety lab has to be performed (general parameters: ESR, 
CRP, erythrocytes, leukocytes [incl. differential], thrombocytes) and further blood 
samples will be taken to analyse the following immunological vasculitis markers:
-
2 container (serum) for MPO-ANCA, PR3-ANCA, IL-6, anti C1q antibodies, 
antiglomerular basement membrane (GBM) antibodies, rheumatoid factor, antinuclear 
antibodies, complement C3 and C4 to be sent to 
-
1 container (serum) for CH 50. Sample processing has to be done at site. 
Centrifugation at 2000 g for 10 min. 2 aliquots of at least 1 ml serum to be frozen 
within 60 min at about -70°C. One aliquot to be sent to 
back-up 
aliquot to be stored at site until successful analysis of first aliquot has been confirmed 
by the lab.  
Number and matrix of containers may change based on requirements of
This can be implemented via non-substantial amendment.
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 whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, 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.
An adverse event for which a causal relationship to an investigational medicinal product 
cannot be ruled out has to be classified as related.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs. 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 

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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
(the End of Study (EoS) visit): 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF 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 new AEs but 
should only report any occurrence of cancer and trial treatment related SAEs
and trial treatment related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should be 
reported on the BI SAE form (see Section 5.2.6.2.2), but not on the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 
24 hours of becoming aware of the event (the only exception to this rule are SAEs and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial due to 
screening failures prior to administration of any trial medication), the country specific 
reporting process will be provided in the ISF. The same timeline applies if follow-up 
information becomes available. On specific occasions, the Investigator could inform the 
sponsor upfront via telephone. This does not replace the requirement to complete and send
the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information. 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 characterized (e.g. as 
‘chronic’ or ‘stable’), or no further information can be obtained.
5.2.6.2.3
AE reporting from suicidality assessment
Any suicidal ideation or behaviour will be reported to the sponsor. Suicidal ideation of type 
1, 2 or 3 can be reported as AE, at the discretion of the investigator. All reports should be 

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reviewed by the Investigator for clinical relevance and determination if an AE report is 
warranted.
All reports of suicidal ideation type 4 and 5 and all reports of suicidal behaviour (based on  
C-SSRS questionnaire during the trial, see section 5.2.5.1), must be reported as separate 
SAEs by the investigator. 
Suicidal ideation is given in the list of Always Serious AEs (see 5.2.6.1.3).
5.2.6.2.4
Female partner pregnancy
Potential drug exposure during pregnancy must be reported if a partner of a male trial 
participant becomes pregnant. This requires written consent of the pregnant partner. 
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner. 
The outcome of the pregnancy must be followed up and reported to the sponsor’s unique 
entry point on the Pregnancy Monitoring Form for Clinical Studies (Part B). 
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies. 
5.2.6.2.5
SUSAR reporting by the sponsor
Expedited reporting of suspected unexpected serious adverse reactions (SUSARs) will be 
performed by the Sponsor according to applicable regulations.

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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters.
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis of nintedanib
For quantification of Nintedanib concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into an K2-EDTA (dipotassium ethylenediamine-
tetraacetic 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 
venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 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 within 2 hours with interim storage of blood samples and aliquots at room 
temperature. 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 
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, barcode, subject number, 
visit, and planned sampling time. 
The back-up samples in period 2 can be used to get a profile of BI 1015550 after 
confirmation of the TBA about the successful analysis of NIN in the 1st aliquots.
5.3.2.2
Blood sampling for pharmacokinetic analysis of pirfenidone
For quantification of Pirfenidone concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into an K2-EDTA (dipotassium ethylenediamine-
tetraacetic 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 
venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 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 

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completed within 2 hours with interim storage of blood samples and aliquots at room 
temperature. 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 
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, barcode, subject number, 
visit, and planned sampling time. 
The back-up samples in period 2 can be used to get a profile of BI 1015550 after 
confirmation of the TBA about the successful analysis of PIR in the 1st aliquots.
5.3.2.3
Blood sampling for pharmacokinetic analysis of BI 1015550
For quantification of BI 1015550 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into an K2-EDTA (dipotassium ethylenediamine-
tetraacetic 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 
venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 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 within 2 hours with interim storage of blood samples and aliquots at room 
temperature. 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 
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, barcode, subject number, 
visit, and planned sampling time. 
After analysis, the plasma samples (NIN, PIR, BI 1015055) may be used for further 
methodological investigations (e.g. for stability testing or assessment of metabolites) or to 
address Health Authority questions regarding the results/methodology. 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 trial samples will be discarded after 
completion of the additional investigations but not later than 5 years after the CTR is 
archived.

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5.4
ASSESSMENT OF BIOMARKERS 
Not applicable.
5.5
BIOBANKING
Not applicable.

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5.6
OTHER ASSESSMENTS
5.6.1
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
obtained at the screening examination or during Visit 2 from each subject whose genotype 
has not been previously determined. Separate informed consent for genotyping will be 
obtained from each volunteer prior to sampling.
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. 
The gene sequences to be determined include known and likely functional variations of key 
ADME genes and incorporate more than 90% of ADME-related genetic markers identified by 
the PharmaADME group (weblink.pharmaadme.org). It is not intended to include the 
pharmacogenomic data in the CTR. However, the data may be part of the CTR, if necessary.
5.7
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 and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for vital signs, laboratory tests, ECG and for suicidality assessment will be ± 1 hour.
If scheduled in the Flow Chart at the same time as a meal, blood sampling and vital signs
recordings have to be done first. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture 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
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 trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.5.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.6).
6.2.2
Treatment period
Each subject is expected to participate in 2 treatment periods: Period 1 (Reference Treatment, 
visit 2) and Period 2 (Test Treatment, visit 3) in the fixed order R-T. At least 72 hours will 
separate the last drug administration in period 1 and the first drug administration in period 2.
Period 1: In the evening of Day -1 trial participants will be admitted to the trial site and kept 
under close medical surveillance for at least 48 h. On Day 1 a single dose of PIR will be 
administered, on Day 2 a single dose of NIN. In the morning of Day 3 the subjects will then 

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be allowed to leave the trial site after formal assessment and confirmation of their fitness.
Blood sampling until Day 5 will be performed in an ambulatory fashion.
Period 2: In period 2 subjects will be dosed with BI 1015550 twice daily for 10 days (from 
Day -6 until Day 4). Dosing is performed in an ambulatory fashion from Day -6 to Day -1. In 
the evening of Day -1 trial participants will be admitted to the trial site and kept under close 
medical surveillance for at least 48 h. On Day 1 a single dose of PIR will be administered, on 
Day 2 a single dose of NIN. In the morning of Day 3 the subjects will be dosed with BI 
1015550 and thereafter they will be allowed to leave the trial site after formal assessment and 
confirmation of their fitness. Further dosing of BI 1015550 until the evening of Day 4 and 
further blood sampling until Day 5 will be performed in an ambulatory fashion.
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. AEs and concomitant therapy will be assessed 
continuously from obtaining subject’s written informed consent until the end of trial 
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, suicidality assessment 
and physical examination during the follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoS Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS
Visit for continued safety monitoring.
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 EoS Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of PIR and NIN given alone and together with BI 1015550 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.
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:
∀
Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial 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 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.
Descriptions of additional analysis sets may be provided in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the IPD categories will be updated as needed.
7.2.1.2
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for nintedanib or pirfenidone 
will be calculated according to the relevant BI internal procedures.
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the  Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Important protocol deviations may be

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∀
Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to
∀
Incorrect dose of trial medication taken
∀
Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example
∀
The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis), 
∀
A predose concentration is >5% Cmax value of that subject
∀
Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which are 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). 
7.2.2
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: subjects and treatment. The effect 
'subjects' will be considered as random, whereas the effect 'treatment' will be considered as 
fixed. The model is described by the following equation:
ykm = # + sm + ∃k + ekm, where
ykm
= logarithm of response measured on subject m receiving treatment k,
#
= the overall mean,
sm
= the effect associated with the mth subject, m = 1, 2, ..., n, 
∃k
= the kth treatment effect, k = 1, 2,
ekm
= the random error associated with the mth subject who received treatment k
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.

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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 will be highlighted in the listings. Additionally, differences from baseline will be 
evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.2.6
Interim analyses
No interim analysis is planned.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures. Concentration data identified as NOS (no sample available), NOR (no valid 
result) or NOA (not analysed) are not considered in the evaluation (graphs and calculations).  
However, they are listed in the respective tables of the CTR. PK parameters that cannot be 
reasonably calculated based on the available drug concentration-time data will not be 
imputed.
7.4
RANDOMISATION
Subjects receive all treatments in the same order, thus no randomisation for the treatment 
assignment is performed.
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 14 subjects in the trial with the aim of ≥ 12 evaluable subjects, 
because this sample size is considered sufficient to achieve the aims of this exploratory trial. 
With this sample size, the following precision in estimating the ratio of geometric means 

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(test/reference) can be expected with 95% probability. Precision is defined as the ratio of 
upper CI limit to the relative BA estimate. Note that the precision is independent of the actual 
ratio of geometric means.
The observed intra-individual coefficient of variation (gCV%) for nintedanib in healthy 
subjects was roughly 30% for Cmax and 18% for AUC [1199-0161, 1199-0162, 1199-0239]. 
For pirfenidone, the observed intra-individual gCV% in IPF patients was roughly 18% for 
Cmax and 15% for AUC [1199-0229]. Given that the variability in patients is generally higher 
than those in healthy subjects, these estimates were considered to be sufficient.
For various assumptions around the gCV of 30%, Table 7.5: 1 provides an overview of the 
achievable precision for estimating the ratio of geometric means (test/reference). For 
illustrative purposes, the expected 90% confidence intervals are displayed for different values 
of the ratios T/R of geometric means.
Table 7.5: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a 2-period fixed sequence trial 
(N=12)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
25
1.273
100
78.55
127.31
25
1.273
150
117.83
190.96
25
1.273
200
157.10
254.61
30
1.334
100
74.99
133.36
30
1.334
150
112.48
200.03
30
1.334
200
149.98
266.71
35
1.396
100
71.65
139.56
35
1.396
150
107.48
209.34
35
1.396
200
143.31
279.12
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(#T)/exp(#R).
The expected 90% confidence interval limits in the table were derived by
CI limit, = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 4.2.1.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles. Deviation from the protocol, the principles of ICH GCP or applicable 
regulations will be treated as ‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to finalisation of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject 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.
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.
The consent and re-consenting process should be properly documented in the source 
documentation.

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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 or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the
Phase I unit – the 
validated ClinBase
system is used for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as database. Instead of being entered into CRFs, selected data are directly 
entered into the ClinBaseTM system.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
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:

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∀
Subject identification: gender, year of birth (in accordance with local laws and 
regulations)
∀
Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)
∀
Dates of subject’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
AEs and outcome events (onset date [mandatory], and end date [if available])
∀
SAEs (onset date [mandatory], and end date [if available])
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)
∀
ECG results (original or copies of printouts)
∀
Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)
∀
Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data are entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
8.3.2
Direct access to source data and documents
The investigator/institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. 
The accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial.

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Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular
∀
Sample and data usage have to be in accordance with the informed consent
∀
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.
∀
An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place
∀
A fit for the purpose documentation (e.g. 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
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(‘Last Subject Completed’).

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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 or a contract research 
organisation appointed 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
P11-07084
Raghu G, et al, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary 
Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic 
pulmonary fibrosis: evidence-based guidelines for diagnosis and 
management. Am J Respir Crit Care Med 2011;183(6):788-824
P15-07539
Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT 
clinical practice guideline: treatment of idiopathic pulmonary fibrosis: an 
update of the 2011 clinical practice guideline. Am J Respir Crit Care Med 
2015; 192(2): e3-e19.
P17-10582
Flaherty KR, Brown KK, Wells AU, et al. Design of the PF-ILD trial: a 
double-blind, randomised, placebo-controlled phase III trial of nintedanib 
in patients with progressive fibrosing interstitial lung disease. BMJ Open 
Respir Res 2017; 4: e000212.
P18-04729
Wells AU, Brown KK, Flaherty KR, et al. IPF Consensus Working Group. 
What's in a name? That which we call IPF, by any other name would act 
the same. Eur Respir J 2018; 51:1800692.
P18-06345
Sisson TH, Christensen PJ, Muraki Y, et al. Phosphodiesterase 4 inhibition 
reduces lung fibrosis following targeted type II alveolar epithelial cell 
injury. Physiol Rep 2018; 6(12): e13753.
P19-01738
Cottin V, Wollin L, Fischer A, et al. Fibrosing interstitial lung diseases: 
knowns and unknowns. Eur Respir Rev 2019; 28:180100.
P20-01299
Wong AW, Ryerson CJ, Guler SA. Progression of fibrosing interstitial 
lung disease. Respir Res 2020; 21(1):32.
R08-1147
Posner K. State of the science: measurement of suicidal adverse events and 
the Columbia Suicide Severity Rating Scale. 47th NCDEU Ann Mtg, Boca 
Raton, 11 - 14 Jun 2007. 2007:15
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R12-4395
Guidance for industry: suicidal ideation and behavior: prospective 
assessment of occurrence in clinical trials (draft guidance, August 2012). 
Website: 
fda.gov/downloads/Drugs/GuidanceRegulatoryInformation/Guidances/UC
M22 5130.pdf (access date: 5 October 2012); 2012.
R17-2617
Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen
P, et al. Opportunistic infections and biologic therapies in immune-
mediated inflammatory diseases: consensus recommendations for 
infection reporting during clinical trials and postmarketing surveillance. 
Ann Rheum Dis 2015;74:2107-2116.

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R17-3055
Pan L, Belloni P, Ding HT, Wang J, Rubino CM, Putnam WS. A 
pharmacokinetic bioequivalence study comparing pirfenidone tablet and 
capsule dosage forms in healthy adult volunteers. Advances in Therapy, 
Published online: 14 August 2017, doi: 10.1007/s12325-017-0594-8; 
2017. p. 2071-2082.
R19-0854
Kolb M, Vasakova M. The natural history of progressive fibrosing 
interstitial lung diseases. Respir Res 2019; 20(1):57.
R20-2271
Guidance for industry: clinical drug interaction studies - cytochrome P450 
enzyme- and transporter-mediated drug interactions (January 2020).
web page: fda.gov/media/134581/download (access date: 16 July 2020); 
U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER). 2020.
R23-1844
Shi S, Wu J, Chen H, Chen H, Wu J, Zeng F. ingle- and multiple-dose 
pharmacokinetics of pirfenidone, an antifibrotic agent, in healthy Chinese 
volunteers. J Clin Pharmacol; 2007; 47; 1268-1276.
R23-1845
Rubino CM, Bhavnani SM, Ambrose PG, Forrest A, Loutit J. Effect of 
food and antacids on the pharmacokinetics of pirfenidone in older healthy 
adults. Pulm Pharmacol Ther; 2009; 22; 279-285. 
R23-1846
Huang NY, Ding L, Wang J, Zhang QY, Liu X, Lin HD, et al. 
Pharmacokinetics, safety and tolerability of pirfenidone and its major 
metabolite after single and multiple oral doses in healthy Chinese subjects 
under fed conditions. Drug Res (Stuttg); 2013; 63; 388-395.
R23-1847
Fachinformation Ofev® Weichkapseln, Oktober 2021
R23-1848
Fachinformation Esbriet® Filmtabletten, März 2023
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
c02094779
 Investigator's Brochure BI 1015550 for 1305.P3, current 
version.
c02191718
Safety, tolerability and pharmacokinetics of multiple rising oral doses of 
BI 1015550 powder for oral solution in healthy male volunteers q.d. or bid 
for 14 days (a randomised, double-blind, placebo-controlled within dose 
groups Phase I trial). 1305.2.
c22991937
Safety, tolerability and pharmacokinetics of single and multiple rising oral 
doses of BI 1015550 in healthy subjects. 1305-0011.
c24902949
Relative bioavailability of a single oral dose of BI 1015550 when 
administered alone or in combination with multiple oral doses of 
itraconazole in healthy male subjects. 1305-0015.

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c25085412
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of 
BI 1015550 in patients with idiopathic pulmonary fibrosis (IPF) on no 
background anti-fibrotic therapy. 1305-0012.
c36151567
A Phase I, open-label, non-randomized, single-dose, single-arm, single-
period study to investigate the metabolism and pharmacokinetics of [C-14]-
labelled BI 1015550 after oral administration in healthy male subjects. 
1305-0016.
c37065416
A randomised, double-blind, placebo-controlled parallel group study in IPF 
patients over 12 weeks evaluating efficacy, safety and tolerability of BI 
1015550 taken orally. 1305-0013.
n00201897
In vitro determination of BI 1015550 protein binding in human and animal 
plasma and in human serum albumin and α1-acid glycoprotein solutions. 
(DM-11-1046).
n00201905
In vitro blood cell partitioning of 14C-BI 1015550 in rat, Göttingen 
minipig, and human blood. (DM-11-1045).
n00261666
BI 1015550: Metabolite profiling in plasma after multiple oral 
administration to healthy volunteers and metabolite exposure determination 
in human and the relevant toxicity species.
n00280519
BI 1015550: An oral (gavage) dose escalation followed by a six-week dose 
range-finding study in the monkey. BI study no. 20R145
c40607236
The effect of multiple oral doses of BI 1015550 on metabolism of 
midazolam administered orally in healthy male subjects.1305-0033 [draft 
report]
U06-1411-02
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. 1199.17. 15 Jun 2011
U06-1724
Metabolism and
pharmacokinetics of [14C]-BIBF 1120 after administration of single doses
of 100 mg [14C]-BIBF 1120 oral solution in healthy male volunteers.
1199.20. 03 Aug 2006
U07-1736-02
 
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. 1199.21. 30 Mar 2009
U10-1400-02
 
 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. 1199.75. 11 Jan 2010

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05 Oct 2023
BI Trial No.: 1305-0034
c41830059-03
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U13-1925-01
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). 1199.161. 04 Jul 2013
U13-1478-01
 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).
1199.162. 08 Aug 2013
c08883821-01
Bioequivalence of 1 soft 
gelatine capsule containing 200 mg nintedanib compared to 2 soft gelatine 
capsules containing 100 mg nintedanib following oral administration in 
healthy male subjects. 1199.237. 13 Jun 2016

Boehringer Ingelheim
05 Oct 2023
BI Trial No.: 1305-0034
c41830059-03
Trial Protocol
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10.
APPENDICES
Not applicable.

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05 Oct 2023
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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
07 August 2023
EU number
2023-505522-34-00
BI Trial number
1305-0034
BI Investigational Medicinal 
Product(s)
BI 1015550
Title of protocol
The effect of multiple oral doses of BI 1015550 on 
the pharmacokinetics of nintedanib and pirfenidone 
administered single dose to healthy male subjects 
(open-label, two-period, fixed-sequence crossover 
trial)
Substantial Global Amendment due to urgent safety reasons 
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
1.)
Synopsis, 2.1.2, 
2.)
Synopsis, 2.1.3, 7.2.1, 7.2.3
3.)
Flow Chart
4.)
Table 1.4.2:1
5.)
3.3.3
6.)
3.3.4.1
7.)
5.2.3
8.)
5.2.4
9.)
5.2.6.1.6
10.)
5.2.6.2.4
11.)
5.2.6.2.5
12.)
7.3.2
Description of change
1.)
AUC0-inf. added to primary 
endpoints
2.)
AUC0-inf. removed from secondary 
endpoints (no secondary endpoints)
3.)
Screening interval reduced to Day -
14 to -2. Safety laboratory moved 
from Period 2 / Day -6 to Period 1 / 
Day 5.
4.)
Bleeding and proteinuria added as 
drug related risks of nintedanib; 

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angioedema added as drug related 
risk of pirfenidone
5.)
Exclusion criteria 12 (vaccination 
added) and 13 (half-life of IMP), 24 
(duration of male contraception) 
adapted and new exclusion criteria 
32-36 added (intake of prescriptine 
medicine, history of angioedema, 
thyroid dysfunction, history of 
bleeding disorder, proteinuria at 
screening)
6.)
withdrawal in case of severe AE or 
SAE
7.)
inclusion of additional safety 
laboratory (urinalysis only)
8.)
use of QTcF described
9.)
assessment of causality of AEs
10.)
handling of female partner 
pregnancy
11.)
SUSAR reporting added
12.)
Handling of missing PK-data added
Rationale for change
1.-12.) 
regulatory request

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05 Oct 2023
BI Trial No.: 1305-0034
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Trial Protocol
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11.2
GLOBAL AMENDMENT 2
Date of amendment
05 October 2023
EU number
2023-505522-34-00
BI Trial number
1305-0034
BI Investigational Medicinal 
Product(s)
BI 1015550
Title of protocol
The effect of multiple oral doses of BI 1015550 on 
the pharmacokinetics of nintedanib and pirfenidone 
administered single dose to healthy male subjects 
(open-label, two-period, fixed-sequence crossover 
trial)
Substantial Global Amendment due to urgent safety reasons 
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
1)
Synopsis
2)
Flow chart
3)
5.2.3 
4)
table 5.2.3.1
5)
5.6.1
6)
6.1
Description of change
1) Change of Clinical Trial Leader
2) Tolerance for safety lab Visit 2, Day 5 was 
adjusted
3) Fed/fasted status of laboratory 
measurements was adjusted
4) Urin haemoglobin and leucocyte 
measurements were adjusted to reflect 
nomenclature of laboratory provider. 
Legend of table 5.2.3.1 was adjusted to 
reflect flow chart.
5) Visit 2 added to sampling 
6) Tolerance for ECG was included
Rationale for change
1)
Organisational change at Sponsor
2-6)
Clarification

 
 
 
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Technical Version Number:
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Meaning of Signature  
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