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
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c24519579-01
EudraCT No.
2020-005934-13
BI Trial No.
1305-0016
BI Investigational
Medicinal Product
BI 1015550
Title
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 
Lay Title
A study in healthy men to find out how BI 1015550 is taken up and 
handled by the body
Clinical Phase
I
Clinical Trial 
Leader
Phone:
Fax:
Principal 
Investigator
Phone: 
Fax:
Status
Final Protocol
Version and Date
Version: 1.0
Date: 28 January 2021
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© 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
28 January 2021
Revision date
Not applicable
BI trial number
1305-0016
Title of trial
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 
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
To characterize mass balance, metabolic profile and routes of elimination of BI 
1015550
Trial objectives
The main objective of this trial is to investigate the basic pharmacokinetics of BI 
1015550 and its metabolite BI 764333 (M480), [14C]-radioactivity, including mass 
balance, excretion pathways and metabolism following a single oral dose BI 
1015550 (C-14) administered to healthy male subjects.
The primary objective is:

To assess the mass balance recovery of [14C]-radioactivity from urine and 
faeces as well as vomit in case of occurrence after a single oral dose of BI 
1015550 (C-14) administered to healthy male subjects
The secondary objectives are:

To assess the pharmacokinetics of [C-14]-BI 1015550 and BI 1015550 as 
well as its metabolite BI 764333 in plasma following a single oral dose of 
BI 1015550 (C-14)

To assess the safety and tolerability of BI 1015550 
Trial design
Open-label, non-randomized, single-dose, single-arm, single-period design

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Trial endpoints:
Primary endpoints: 
Mass balance recovery of total [C-14] BI 1015550 radioactivity:

Amount of [14C]-radioactivity excreted as a percentage of the administered 
single oral dose of BI 1015550 (C-14) in urine (feurine, 0-t2) and faeces 
(fefaeces, 0-t2) as well as vomit (fevomit, 0-t2), if applicable
Secondary endpoints:
Pharmacokinetics:

Assessment of Cmax and AUC0-tz for [C-14]-BI 1015550 and BI 1015550 as 
well as its metabolite BI 764333 in plasma
Safety:

Percentage of subjects with treatment emergent adverse events (TEAEs)
Number of subjects 
total entered
6*
each treatment
6*
* In case a subject is discontinued from the trial an additional subject may be entered and dosed in order 
to assure a minimum of 4 evaluable subjects, i.e. the actual number of subjects entered may increase up 
to but will not exceed 8
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 65 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product
14Carbon-labelled BI 1015550 (BI 1015550 (C-14)) as oral solution (0.5 mg/mL)
Dose
18 mg of BI 1015550 (C-14) consisting of 17.16 mg unlabelled BI 1015550 mixed 
with 0.84 mg [C-14]-BI 1015550 as 36 mL of oral solution (0.5 mg/mL) containing 
a radioactive dose of 3.7 MBq (100µ Ci, corresponding to 0.2864 mSV)
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Reference product
Not applicable
Duration of treatment
Single dose on Day 1
Statistical methods
Descriptive statistics will be calculated for all endpoints.

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FLOW CHART
A, B & C: safety laboratory sets (see Table 5.2.3: 1)
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 body weight, smoking status and alcohol history), suicidality 
assessment (C-SSRS), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria.
2.
The time is approximate; the procedure is to be performed and completed within the 2 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
Visit
Day
Planned time (relative to 
drug administration)
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood / plasma 7
PK urine 8
PK faeces 9
Blood sampling for 
metabolic profiling 15
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-21 to -1
Screening (SCR)1
A
x
x
x
2
-1
-18:00
14:00
Admission to trial site
B5, 16,17
x14
x
-14:00
18:00
Dinner
-10:30
21:30
Snack (voluntary)
1
-2:00
06:00
x2,10
x2
x2
x14
x2
x
2
x2
0:00
08:00
Drug administration
▲
▲
0:30
08:30
x
│
│
0:45
08:45
x
│
│
1:00
09:00
x
│
│
x
1:30
09:30
x
│
│
2:00
10:00
240 mL fluid intake
x
│
│
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x10
x
┼
│
x
x
x
8:00
16:00
Snack (voluntary)3
x
┼
│
x
11:00
19:00
Dinner
│
│
12:00
20:00
x
┼
│
x
2
24:00
08:00
x10,16
x
┼
┼
x
x
x
36:00
20:00
x
│
│
x
3
48:00
08:00
x10
x
┼
┼
4
72:00
08:00
┼
┼
5
96:00
08:00
x
┼
┼
6
120:00
08:00
┼
┼
7
144:00
08:00
x
┼
┼
8
168:00
08:00
x10
x
┼
┼
9
192:00
08:00
x
┼
┼
10
216:00
08:00
Discharge from trial site18
B17
x
▼
▼
x
x
15
336:00
08:00
Start home collection
▲
16
360:00
08:00
Admission to trial site11,12,16
▲
┼
17
384:00
08:00
Discharge from trial site
▼
▼
22
504:00
08:00
Start home collection
▲
23
528:00
08:00
Admission to trial site11,12,16
▲
┼
24
552:00
08:00
Discharge from trial site
▼
▼
29
672:00
08:00
Start home collection
▲
30
696:00
08:00 Admission to trial site11,12,16
▲
┼
31
720:00
08:00
Discharge from trial site
▼
▼
3
11 to 31
End of trial (EoTrial)
examination4,13
C16
x
x
x

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4.
End-of-trial (EoT) examination to be performed within 1 to 7 days after last discharge from the trial site, or, if all once-
weekly 24 h sampling periods are needed, prior to discharge on Day 31. EoT examination includes physical 
examination, vital signs, ECG, safety laboratory, body weight, suicidality assessment (C-SSRS), recording of AEs and 
concomitant therapies. 
5.
Safety laboratory including urine drug screening and alcohol urine test will be performed at this time (see 
Section 5.2.3).
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.
Pharmacokinetics (PK): BI 1015550 and its metabolite in plasma (see Section 5.3.2); [C-14] BI 1015550-radioactivity 
in whole blood and plasma (see Section 5.3.2). Blood sampling for an individual subject can be stopped, if [14C]-BI 
1015550-radioactivity in plasma is below limit of detection (< LLOQ 30 dpm/mL) at two consecutive sampling time 
points for this subject (earliest stopping after Day 10).
8.
Urine collection intervals (for PK of [C-14] BI 1015550-radioactivity assessment and metabolic profiling; planned 
time): on Day -1 or Day 1 pre-dose (blank) sample, on Day 1 prior to start of urine collection voiding of the bladder, 0-
4 , 4-8, 8-12, 12-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192 and 192-216 hours after administration of 
[C-14] BI 1015550. Thereafter, if warranted, 24 h collections are to be performed every 7 days starting on Day 16.
When the release criteria for radioactivity recovery have been met then urine sampling for PK will be stopped (earliest 
stop on Day 10).
9. 
All stools (for PK and metabolic profiling) will be collected quantitatively in portions up to 216 hours (sampling 
intervals of 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192 and 192-216 hours) after drug 
administration. Thereafter, if warranted, 24 h collections are to be performed every 7 days starting on Day 16. A blank 
sample will be collected on Day -1 or Day 1 prior to drug administration. Collection of the predose faeces sample will 
start from approximately -48 h before admission (see Section 5.3.2). When the release criteria for radioactivity recovery 
have been met then faeces sampling for PK will be stopped (earliest stop on Day 10).
10. At this time point, only a sample for haematocrit measurement is collected.
11. The planned times for admission, discharge, start and end of the urine and faeces collection intervals are approximate.
The procedures are to be performed within a time window of ± 4 hours to the planned time. If not feasible due to 
logistic reasons the time window may be extended up to 8 hrs after the planned time. 
12. Subjects are to collect faeces at home within 24 h intervals before admission to once-weekly in-house collection 
intervals. Home collection intervals: Day 15-16, 22-23 and 29-30. If faeces are collected in the subsequent in-house 
collection interval, faeces collected at home will be discarded. If no faeces is collected in the subsequent in-house 
collection interval (no defecation), faeces collected at home will be used instead for analysis.
13. For definition of the individual subject’s end of trial, see Section 6.2.3.
14. Subjects will collect a pre-dose faeces sample at home or at the site on Day -1 or Day 1 in specific containers provided 
by PRA.
15. Metabolite sampling times may be adapted based on information obtained during trial conduct (e.g. levels of
radioactivity in each urine and/or plasma sample) as long as the overall blood volume stays the same.
16. PCR testing for SARS-CoV-2 will be performed on Day -1 prior to admission, on Day 2, at each admission to the trial 
site for 24-hours visits and at EOT (see Appendix 10.3).
17.  Subjects are to be fasted for at least 10 h before sample is taken.
18.  Prior to discharge from trial site on Day 10 confirmation of fitness will be performed including physical examination, 
vital signs, ECG, recording of AEs and concomitant medication, safety laboratory and C-SSRS. An additional body 
weight will be measured at this time point.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................13
1.2.1
Non-clinical pharmacokinetics ............................................................14
1.2.2
Pre-clinical safety pharmacology and toxicology...............................14
1.2.3
Residual Effect Period..........................................................................16
1.2.4
Clinical experience in humans.............................................................16
1.2.5
Clinical pharmacokinetics....................................................................17
1.2.6
Drug interactions ..................................................................................18
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................18
1.4
BENEFIT - RISK ASSESSMENT ...................................................................19
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......22
2.1.1
Main objectives......................................................................................22
2.1.2
Primary endpoint..................................................................................22
2.1.3
Secondary endpoints.............................................................................22
2.2.2.4
Safety and tolerability..............................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 26
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................26
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................27
3.3
SELECTION OF TRIAL POPULATION ......................................................27
3.3.1
Main diagnosis for trial entry..............................................................27
3.3.2
Inclusion criteria...................................................................................27
3.3.3
Exclusion criteria ..................................................................................28
3.3.4
Withdrawal of subjects from treatment or assessments ...................30

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3.3.4.1
Discontinuation of trial treatment............................................30
3.3.4.2
Withdrawal of consent to trial participation ............................31
3.3.4.3
Discontinuation of the trial by the sponsor..............................31
3.3.5
Replacement of subjects .......................................................................31
4.
TREATMENTS........................................................................................ 32
4.1
INVESTIGATIONAL TREATMENTS ..........................................................32
4.1.1
Identity of the Investigational Medicinal Products ...........................32
4.1.2
Selection of doses in the trial................................................................32
4.1.3
Method of assigning subjects to treatment groups ............................32
4.1.4
Drug assignment and administration of doses for each subject .......33
4.1.5
Blinding and procedures for unblinding ............................................33
4.1.6
Packaging, labelling, and re-supply ....................................................33
4.1.7
Storage conditions.................................................................................34
4.1.8
Drug accountability ..............................................................................34
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................35
4.2.1
Other treatments and emergency procedures....................................35
4.2.2
Restrictions............................................................................................35
4.2.2.1
Restrictions regarding concomitant treatment .........................35
4.2.2.2
Restrictions on diet and life style.............................................35
4.3
TREATMENT COMPLIANCE.......................................................................36
5.
ASSESSMENTS....................................................................................... 37
5.1
ASSESSMENT OF EFFICACY.......................................................................37
5.2
ASSESSMENT OF SAFETY............................................................................37
5.2.1
Physical examination ............................................................................37
5.2.2
Vital signs...............................................................................................37
5.2.3
Safety laboratory parameters..............................................................37
5.2.4
Electrocardiogram................................................................................40
5.2.5
Other safety parameters.......................................................................41
5.2.5.1
Suicidality assessment .............................................................41
5.2.6
Assessment of adverse events...............................................................42
5.2.6.1
Definitions of adverse events...................................................42
Adverse event ............................................................42
Serious adverse event ................................................42
AEs considered ‘Always Serious’.............................42
Adverse events of special interest .............................43
Intensity (severity) of AEs.........................................44
Causal relationship of AEs ........................................44
5.2.6.2
Adverse event collection and reporting ...................................45

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AE collection.............................................................45
AE reporting to the sponsor and timelines ................45
Information required..................................................46
Pregnancy ..................................................................46
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................46
5.3.1
Assessment of pharmacokinetics .........................................................46
5.3.2
Methods of sample collection...............................................................46
5.3.2.1
Sampling of whole blood and plasma......................................46
5.3.2.2
Sampling of whole blood and plasma for [14C]-radioactivity 
analysis and quantification of BI 1015550 and its metabolite   
in plasma..................................................................................47
5.3.2.3
Sampling of plasma for metabolic profiling and structural 
elucidation................................................................................47
5.3.2.4
Sampling of blood for hematocrit for blood cell/plasma ratio.48
5.3.2.5
Urine sampling for pharmacokinetic analysis..........................48
5.3.2.6
Sampling of faeces...................................................................48
5.3.2.7
Collection of vomit ..................................................................49
5.3.2.8
Further investigations...............................................................49
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................50
5.4
ASSESSMENT OF BIOMARKERS................................................................50
5.5
BIOBANKING ...................................................................................................50
5.6
OTHER ASSESSMENTS .................................................................................50
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................50
6.
INVESTIGATIONAL PLAN.................................................................. 51
6.1
VISIT SCHEDULE............................................................................................51
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................51
6.2.1
Screening period....................................................................................51
6.2.2
Treatment period ..................................................................................52
6.2.3
Follow-up period and trial completion ...............................................52
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 53
7.1
STATISTICAL DESIGN – MODEL ...............................................................53
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................53
7.3
PLANNED ANALYSES....................................................................................53
7.3.1
Primary endpoint analyses...................................................................54
7.3.2
Secondary endpoint analyses ...............................................................54

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7.3.4
Safety analyses.......................................................................................55
7.4
INTERIM ANALYSES .....................................................................................55
7.5
HANDLING OF MISSING DATA ..................................................................56
7.5.1
Safety......................................................................................................56
7.5.2
Pharmacokinetics..................................................................................56
7.6
RANDOMISATION ..........................................................................................56
7.7
DETERMINATION OF SAMPLE SIZE ........................................................56
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 57
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................57
8.2
DATA QUALITY ASSURANCE .....................................................................58
8.3
RECORDS..........................................................................................................58
8.3.1
Source documents .................................................................................58
8.3.2
Direct access to source data and documents.......................................59
8.3.3
Storage period of records.....................................................................59
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................59
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......59
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................60
8.6
TRIAL MILESTONES .....................................................................................60
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................61
9.
REFERENCES......................................................................................... 63
9.1
PUBLISHED REFERENCES...........................................................................63
9.2
UNPUBLISHED REFERENCES.....................................................................64
10. APPENDICES .......................................................................................... 65
10.1
RADIO BURDEN CALCULATION ...............................................................65
10.2
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)...............68
10.2.1 Columbia-Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening ................................................................................68
10.2.2 Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last 
Visit.........................................................................................................71
10.3
COVID-19 RISK ASSESSMENT AND SPECIFIC MEASURES ................74
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 76
11.1
GLOBAL AMENDMENT 1 .............................................................................76

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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
Aefaeces, 0-t2
Amount of analyte that is eliminated in faeces over the time interval from 
time 0 to the last quantifiable time point
Aefaeces, t1-t2
amount of analyte that is eliminated in faeces from the time interval t1 to 
t2
Aeurine, 0-t2
amount of analyte that is eliminated in urine over the time interval from 
time 0 to the last quantifiable time point
AESI
Adverse events of special interest
ALAT
Latin American Thoracic Association
ALT
Alanine Transaminase
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
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at 
steady state over a uniform dosing interval τ
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
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
cAMP
Cyclic adenosine monophosphate
[C-14] BI 
1015550
14Carbon-labelled BI 1015550
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
CLR, t1-t2
Renal clearance of the analyte in plasma from the time point t1 to t2
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central Nervous System
COVID-19
Coronavirus disease 2019
CRF
Case Report Form, paper or electronic 
C-SSRS
Columbia-Suicide Severity Rating Scale
CTM
Clinical Trial Monitor
CTP
Clinical trial protocol

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CTR
Clinical trial report
DDI
Drug Drug Interaction
DILI
Drug induced liver injury
ECG
Electrocardiogram
ECM
Extracellular Matrix
eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
ERS
European Respiratory Society
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
fefaeces, t1-t2
Fraction of administered drug excreted unchanged in faeces from time 
point t1 to t2
feurine, t1-t2
fraction of administered drug excreted unchanged in urine from time 
point t1 to t2
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
HIV
Human Immunodeficiency Virus
HVs
Healthy volunteers
IB
Investigator’s brochure
ICH
International Council for Harmonisation
IC50
Inhibitory concentration 50%
IEC
Independent Ethics Committee
ILD
interstitial lung disease
IMP
Investigational Medicinal Product
iPD
Important protocol deviation
IPF
Idiopathic pulmonary fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLOQ
Lower limit of quantification
LOAEL
low observed adverse effect level 
MBq
Megabecquerel
MDA
Methylenedioxyamphetamine

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MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
MRT,ex
Mean residence time of the analyte in the body, extravascular
mSV
Millisievert
PDE
Phosphodiesterase
PDE4
Phosphodiesterase 4
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
PRA
Pharmaceutical Research Associates
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
REP
Residual effect period
SAE
Serious adverse event
SARS-CoV
Severe acute respiratory syndrome coronavirus
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
Ss
(at) steady state
T
Test product or treatment
TEAEs
Percentage of subjects with treatment emergent adverse events 
TK
Toxicokinetics
TMF
Trial master file
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
TSAP
Trial statistical analysis plan
tz
Time of last measurable concentration of the analyte in plasma
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WHO
World Health Organization
XTC
Ecstasy 

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1.
INTRODUCTION
BI 1015550 is a selective inhibitor of the phosphodiesterase 4B (PDE4B) isoenzyme which
hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP) and shows broad anti-
inflammatory and anti-fibrotic activities. It is under development for the treatment of
idiopathic pulmonary fibrosis (IPF). This trial is a mass balance study to investigate the basic 
pharmacokinetics, excretion pathways as well as metabolism of BI 1015550 and its major 
metabolite BI 764333 (M480).
1.1
MEDICAL BACKGROUND
IPF is a progressive, fibrosing interstitial lung disease (ILD) characterized by decline in lung
function and worsening dyspnea [R18-2794]. IPF carries a poor prognosis, with a median
post-diagnosis survival in untreated patients of approximately 3 years [R18-1413]. IPF occurs 
worldwide. The prevalence of the disease appears to be increasing, although it is unclear 
whether this reflects increased recognition or a true increase in incidence. The incidence of 
IPF appears to be higher in North America and Europe (3 to 9 cases per 100,000 person-
years) than in South America and East Asia (fewer than 4 cases per 100,000 person-years) 
[R17-4284]. In the United States, the prevalence of IPF has been reported to range from 10 to 
60 cases per 100,000 [R16-1737], [R18-0408], [R14-2284]. Increasing rates of hospital 
admissions and deaths due to IPF also suggest an increasing burden of disease [R17-4284], 
[R14-4266], [P13-05880].
Nintedanib and pirfenidone are the only drugs registered for the treatment of IPF and
recommended in the recent ATS/ERS/JRS/ALAT Clinical Practice Guideline for the
Treatment of Idiopathic Pulmonary Fibrosis [R18-2794]. Despite the availability of these
drugs, the medical need remains high in this devastating disease.
Preclinical experiments have shown that BI 1015550 affects the fibrotic pathway and the
effects may be complementary and/or synergistic to those of nintedanib. PDE4 inhibition is 
expected to inhibit pro-fibrotic growth factors, to decrease fibroblast proliferation, 
transformation of fibroblast to myofibroblast, and fibroblast motility, as well as to promote 
cell death of fibroblasts, and to decrease synthesis, release, and function of ECM components 
[R12-5544, R12-5545, R12-5546]. Interference with pro-fibrotic factors/ inflammatory 
cascades may translate in clinical improvement of lung function, symptoms and quality of life 
in patients with IPF.
Based on this, it is postulated that BI 1015550 may provide therapeutic benefit to patients 
with IPF or other progressive fibrosing ILDs [c02094779].
1.2
DRUG PROFILE
BI 1015550 is a potent inhibitor of human PDE4 B, showing mean half-maximal inhibition
(IC50) at 10 nM with a nine-fold selectivity over phosphodiesterase 4D (PDE4 D) (mean IC50 
91 nM) without relevant known interaction with other targets, (78 receptors and 42 enzymes
tested at the very high concentration of 10 000 nM). In-vitro anti-inflammatory activity has
been confirmed for TNF-α (IC50: 12 nM) and IL-2 release (IC50: 5 nM) from purified human
peripheral blood mononuclear cells respectively.

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For a more detailed description of the BI 1015550 profile, please refer to the current 
Investigator’s Brochure (IB) [c02094779].
1.2.1
Non-clinical pharmacokinetics
Potential drug-drug interactions (DDIs) may occur for concomitantly administered
medications that are substantially metabolized by CYP3A4 due to induction of CYP3A4 by 
BI 1015550 at total steady state plasma concentrations greater than 634 nM, or at oral doses 
exceeding 16 mg. In addition, as CYP3A is predicted to contribute to ~70% of the hepatic 
metabolism of BI 1015550, concomitant therapies that are inhibitors or inducers of CYP3A 
may cause clinically significant changes in BI 1015550 exposure.
For a more detailed description of the BI 1015550 profile, please refer to the current 
Investigator’s Brochure (IB) [c02094779].
1.2.2
Pre-clinical safety pharmacology and toxicology
Safety pharmacology:
Safety pharmacology studies have been conducted to address cardiovascular, CNS, 
respiratory, renal and liver function in rats or minipigs. BI 1015550 administration did not 
result in any adverse effects on CNS, respiratory, liver, renal, and gastrointestinal functions. 
Cardiovascular telemetry studies in the minipig and electrocardiographs recorded during the 
2 week minipig toxicity study at doses of 3, 10, and 30 mg/kg indicated non-biologically 
significant changes in PR interval and heart rate, respectively. Because these changes were 
not of a significant magnitude they were not considered adverse, but may indicate a threshold 
effect for cardiovascular changes above 30 mg/kg.
Toxicology:
The toxicity profile for BI 1015550 has been assessed in safety pharmacology studies, genetic 
toxicology studies, and repeat dose studies in the rat and minipig of up to 26 and 39 weeks, 
respectively. The results of the repeat-dose toxicity studies support the 12-week Phase II 
clinical trial (1305-0013) in IPF patients with and without background antifibrotic treatment. 
No single-dose toxicity studies have been conducted with BI 1015550.
Repeat Dose Toxicology Studies:
Repeat dose administration of BI 1015550 was well tolerated in the rat when administered at 
up to 6 mg/kg/day for 13 weeks and 2 mg/kg/day for 26 weeks. Dose escalation of the 6 
mg/kg/day dose group in the 4-week study to 12 mg/kg/day resulted in morbidity and 
mortality secondary to vasculopathy. Morbidity secondary to vasculopathy was observed in 
the 13-week study at 9 mg/kg/day and in the 26-week study at 4 and 7.5 mg/kg/day. 
The early decedents observed in the 4, 13, and 26-week studies in rats, either died or were 
euthanized due to morbidity. These early deaths were predominantly a result of vasculopathy 
in the mesentery and gastrointestinal tract, although periosteal inflammation contributed to 
morbidity in the 26-week trial.

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BI 1015550 adverse findings in rats included vasculopathy in the stomach, duodenum, 
jejunum, ileum, colon, Peyer’s patches, mesentery, pancreas, and vagina and hypertrophic 
osteopathy.
In minipigs, mortality attributed to BI 1015550-related vasculopathy occurred in one 30 
mg/kg/day female in the 2-week study immediately following a toxicokinetics (TK) bleed on
Day 14. No mortality was observed in the 13-week study where dose levels up to 20 
mg/kg/day were administered. In the 39-week study, repeat-dose of 25 mg/kg/day was 
associated with overt adverse clinical signs in minipigs, including decreased activity and 
reduced food consumption, with a consequent reduction to 20 mg/kg/day in the third week of 
the 39-week study. Two animals given 25/20 mg/kg/day (dose level reduced within 3 weeks 
of dose initiation due to overt toxicity) were euthanized moribund due to clinical signs judged 
related to polyarteritis. 
In minipigs, perivascular/vascular degeneration/necrosis was observed at high dose levels in 
multiples tissues such as the mesenteric connective tissue or parenchyma of liver, gallbladder, 
kidney, urinary bladder, ovary, vagina, cervix, stomach, lungs, spleen, heart, coronary artery, 
periaortic, sciatic nerve, and connective tissues around the tarsus. 
Vasculopathy, characterized by inflammation, haemorrhage, and necrosis of blood vessels, is 
a known class effect of PDE4 inhibitors [R10-1559].
Clinical pathology changes: 
No adverse clinical pathology changes related to BI 1015550 administration were observed in 
rats administered 6 mg/kg/day for 2 or 13 weeks or 2 mg/kg/day for 26 weeks. Hematology 
changes were observed in rats following administration of 6/12, 9, or ≥4 mg/kg/day for 4, 13, 
or 26 weeks, respectively, as evidenced by increases in white blood cell, neutrophil, 
lymphocyte, and/or monocyte counts in both sexes. In the 4-week rat study at 6/12 
mg/kg/day, there was also a minimal increase in percent and absolute reticulocytes, which 
were also noted in the 26-week study at ≥4 mg/kg/day. These changes correlated with and 
were secondary to adverse vasculopathy and neutrophil infiltration seen microscopically in 
tissues. There were no adverse BI 1015550-related changes in serum chemistry observed in 
the rat in studies up to 13 weeks. In the 26-week study decreases in albumin with resultant 
decreases in albumin to globulin (A/G) ratios at 7.5 mg/kg/day and dose-dependent increases 
in fibrinogen at ≥2 mg/kg/day were observed. 
BI 1015550-related changes in clinical pathology were observed in minipigs in the 39-week 
study and included elevated white blood cell counts, neutrophils, fibrinogen, globulin, and 
decreased A/G ratio, predominantly in early death animals.
Histopathological changes:
No adverse histopathologic changes were observed following administration of 6, 3, 6, and 2 
mg/kg/day BI 1015550 to rats over 2, 4, 13 and 26 weeks, respectively. Administration to rats 
of 6/12 mg/kg/day (4 weeks), 9 mg/kg/day (13 weeks), and 4 or 7.5 mg/kg/day (26-weeks) 
resulted in adverse changes including mesenteric perivascular/vascular inflammation and 
inflammation in the following tissues: gastrointestinal tract, Peyer’s patches, pancreas, and/or 
vagina. These findings were reversible. With longer (26-week) treatment in rats, periosteal 
inflammation and new bone formation were observed, which were reversible or partially 
reversible, respectively.

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In the minipig, 30 mg/kg/day administered for 2 weeks was associated with alterations in the 
gallbladder (cholecystitis) and the arteries of the gallbladder (vasculopathy), as well as 
inflammation of the cecum, which were reversible or partially reversible. No test article 
related pathology was observed in the 13-week minipig study at dose levels up to 20 
mg/kg/day. In the 39-week minipig study, administration of 3 or 10 mg/kg/day resulted in 
effects in the lungs and/or heart of one animal per group. Changes in the lung consisted of 
vascular/perivascular degeneration/necrosis in arteries and alveolar capillaries. In the heart, 
findings noted included degeneration/necrosis in a coronary artery, its surrounding arteries, 
and arteries around the aorta, myocardial degeneration/necrosis of the left ventricular 
papillary muscle, and inflammation in adipose tissue of the coronary groove. 
At 25/20 mg/kg/day in minipigs administered for 39 weeks, vascular/perivascular 
degeneration/necrosis around the aorta, hypertrophy/hyperplasia of arteries throughout the 
heart, a thrombus in a left ventricular artery, myocardial fibrosis in the left ventricle and 
atrium, and/or myofiber degeneration designate heart as a target organ of PDE4i-related 
effects in minipigs. In early death 25/20 mg/kg/day minipigs, polyarteritis that affected 
tissues surrounding the tarsus on all limbs, around the aorta, and around the iliac artery, and 
the ovary, vagina, spleen, mesentery, and sciatic nerve were observed. The low-dose of 3 
mg/kg/day was considered a low observed adverse effect level (LOAEL) in the 39- week 
minipig study. 
Genetic toxicity:
The genetic toxicology results for BI 1015550 indicate that this compound is not genotoxic.
Phototoxicity:
The phototoxicity assessments suggest a low potential of phototoxicity for BI 1015550.
For a more detailed description of the BI 1015550 profile, please refer to the current 
Investigator’s Brochure (IB) [c02094779].
1.2.3
Residual Effect Period
The Residual Effect Period (REP) of BI 1015550 is 7 days. This is the period after the last
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
1.2.4
Clinical experience in humans
BI 1015550 was well tolerated following single dose administration up to 48 mg in healthy 
volunteers and following multiple administrations up to 18 mg bid over a treatment period of 
up to 12 weeks in patients. 
Six Phase I clinical studies have been completed with BI 1015550 in healthy volunteers 
(1305-0001, 1305-0002, 1305-0011, 1305-0015, 1305-0020, 1305-0017). The most 
commonly reported events in healthy volunteer studies were headache and gastrointestinal 
(GI) events, particularly abdominal pain and diarrhea, all of mild to moderate intensity. There 
was a trend for increased treatment emergent reporting of headache in those treated with 
verum. No apparent dose dependency has been observed for the GI treatment emergent 
adverse events (TEAEs). A trend toward weight loss in subjects treated with BI 1015550 has 

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been observed in study 1305-0011 in healthy volunteers. No severe, serious, fatal events or 
SUSARs have been reported in healthy volunteers.
One Phase Ic study has been completed in 15 patients (10 on active, 5 on placebo) with IPF 
on no background antifibrotic treatment (1305-0012) testing safety, tolerability and PK of BI 
1015550 at a dose of 18 mg b.i.d for 4 to 12 weeks. Dose escalation to 24 mg bid was 
stopped because the protocol-defined stopping criterion on exposure was met. There were no 
safety concerns. In this study, the most frequently reported TEAEs were gastrointestinal
disorders. One patient was hospitalized for two SAEs which were not deemed as related to 
the study drug but were rather related to long-term pre-existing conditions requiring elective 
surgery (anal fistula and anal incontinence).
No adverse vascular changes in humans have been reported. 
Overall, based on available data a single dose of 18 mg BI 1015550 is expected to be safe and 
well tolerated.
For a more detailed description of the BI 1015550 profile, please refer to the current 
Investigator’s Brochure (IB) [c02094779].
1.2.5
Clinical pharmacokinetics
Pharmacokinetics of BI 1015550 were investigated in healthy male volunteers given multiple 
oral doses of 6 and 12 mg bid under fed conditions over 14 days [1305-0011, c22991937] and
in patients with IPF given multiple oral doses of 18 mg bid over 14 days.
The geometric Mean of selected single and multiple dose PK parameters in HV and IPF 
patients are shown in Table 1.2.5: 1 and 1.2.5: 2. BI 1015550 was rapidly absorbed after oral 
dosing reaching peak level usually within 1.5 h - 3h. Plasma concentration/ time profiles 
showed a biphasic decline. The increase in BI 1015550 exposure (AUC and Cmax) was 
approximately dose proportional after single and multiple doses over the entire dose range 
tested (SRD 0.6 to 48 mg, MRD 6 to 12 mg). AUC and Cmax values were up to 1.85-fold 
higher at steady state with twice daily administered doses compared with single dose 
administration. Steady state was attained by Day 7 (Trial 1305-0002 and Trial 1305-0011). 
Exposure to BI 1015550 did not change relevantly when taken together with a high caloric, 
high fat breakfast.
The Cmax was slightly decreased (~20%), tmax slightly delayed, while AUC remained
unchanged (Trial 1305-0020). The PK of BI 1015550 was comparable between healthy 
volunteers and IPF patients. However, the variability of the PK parameters was higher in IPF 
patients as compared to HV.
Table 1.2.5: 1 
Selected Geometric Mean PK parameters of BI 1015550 after single 
dose in HVs 1305-0001 [U13-1792]
1305-0001 in HV, single oral dose
8 mg (n=6)
16 mg (n=6)
24 mg (n=6)
gMean
(gCV)
gMean
(gCV)
gMean
(gCV)
AUC0-∞[nmol∙h/L]
1210
(18.3)
2180
(19.9)
3650
(22.6)
Cmax [nmol/L]
176
(12.6)
292
(22.2)
542
(12.1)
tmaxa [h]
1.01
(0.500-1.50)
1.25
(1.00-2.48)
1.00
(1.00-1.50)
a: Median (min-max)

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Table 1.2.5: 2
Selected Geometric Mean PK parameters of BI 1015550 after single 
and multiple doses in HVs 1305-0011 and IPF patients 1305-0012 
[c02094779]
1305-0011 in HV
1305-0012 in IPF patients
6 mg b.i.d (n=8)
12 mg b.i.d (n=8)
18 mg b.i.d (n=10)
gMean
(gCV)
gMean
(gCV)
gMean
(gCV)
AUCτ,ss [nmol∙h/L]
1050
(25.7)
2300
(15.8)
3720
(49.5)
Cmax,ss [nmol/L]
164
(21.3)
348
(14.1)
460
(41.7)
tmax,ssa [h]
1.38
(0.500-3.00)
1.50
(0.500-1.50)
3.92
(1.47-8.00)
a: Median (min-max)
For a more detailed description of the BI 1015550 profile, please refer to the current 
Investigator’s Brochure (IB) [c02094779].
1.2.6
Drug interactions
CYP450 3A4 is regarded as the major enzyme responsible for BI 1015550 metabolism in 
human hepatocytes. CYP3A is predicted to contribute to ~70% of the hepatic metabolism of 
BI 1015550. Furthermore, non-clinical in vitro assays showed that BI 1015550 is a P-gp 
substrate, but not a P-pg inhibitor. The effect of 200 mg qd itraconazole (a strong CYP3A4/
Pgp inhibitor) at steady state (Day -3 to Day 9) on a single dose of 6 mg BI 1015550 
(administered at Day 1) was investigated in 16 HVs within DDI trial 1305-0015 [c24902949].
Itraconazole increased the exposure to BI 1015550 by 1.3-fold (Cmax) and 2.2-fold AUC. The 
metabolite BI 764333 created via the CYP3A4 pathway was not detectable when BI 1015550 
was administered together with itraconazole. Strong CYP 3A4 inhibitors are therefore 
prohibited as concomitant medication in this trial.
Based on non-clinical in vitro data BI 1015550 might be a mild to moderate CYP3A4 inducer 
and might affect co-medications that are CYP3A4 substrates at total plasma concentrations of 
BI 1015550 > 637 nM. The gMean Cmax,ss of the highest planned dose in this trial was below 
that threshold (460 nM). A clinical trial (1305-0021) to investigate the CYP 3A4 induction 
potential of BI 1015550 is planned.
1.3
RATIONALE FOR PERFORMING THE TRIAL
This trial is intended to examine the metabolism in humans, the mass-balance of excretion, 
plasma and urinary concentrations of BI 1015550 and its metabolite BI 764333 as well as the 
resulting PK parameters and [14C]-radioactivity in blood, plasma, urine and faeces as well as 
vomit, if applicable, following a single oral dose of 18 mg of [14C]-BI 1015550 containing a 
radioactive dose of 3.7 MBq (100 µCI, corresponding to 0.2864mSV) in healthy male 
volunteers.
The investigation of these processes, including the quantitative assessment of elimination 
pathways and drug metabolites, is necessary for an in-depth understanding of the 
pharmacokinetics of BI 1015550. In addition the data are required for future submission to 
regulatory authorities.

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1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 1015550. 
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication as well as to [14C]-radioactivity.
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.6.1.4, adverse events of special interest.
Potential Risks related to BI 1015550 administration

Pharmacokinetic interaction with strong CYP3A4 inhibitors:
CYP3A4 is regarded as the major enzyme responsible for the metabolism of BI 
1015550 in human hepatocytes and contributes to ~70% of its hepatic metabolism
(see Section 1.2.6) In this trial, concomitant medication is prohibited in general and 
potent CYP3A4 inhibitors specifically are a restricted medication.

Vasculitis:
Vasculopathy is an established toxicity of PDE4 inhibitors in rats. Vasculitis has been 
shown in both the rats and minipigs following oral administration of BI 1015550 and 
it has been the basis of the NOAEL (No Observable Adverse Effect Level) definition.
Vasculitis is listed as an important potential risk in the RMP (Risk Management Plan) 
for the marketed PDE4 inhibitors apremilast. In marketed PDE4 inhibitors, vasculitis 
has not been identified as an adverse drug reaction in humans. However, baseline 
condition or medical history of vasculitis is an exclusion criterion in this trial and 
increased awareness will be given to any occurrences of vasculitis including expedite 
reporting (AESI).

Gastrointestinal disorders (e.g. diarrhoea, nausea, vomiting, abdominal pain):
Vomiting and diarrhea are important dose-limiting side effects of marketed oral PDE-
4 inhibitors. Gastrointestinal events of mostly mild intensity have been reported for BI 
1015550, therefore increased awareness will be accounted to gastrointestinal 
symptoms in this trial. Hydration in patients with diarrhea will be carefully monitored 
clinically.

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
Weight decrease in underweight patients:
For the marketed PDE4-inhibitors apremilast and roflumilast weight loss in 
underweighted patients is identified as an important risk. A trend toward weight loss 
in subjects treated with BI 1015550 has been observed in study 1305-0011 in healthy 
volunteers but due to the limited strength and amount of available data has not been 
established as adverse drug reaction for the BI 1015550. However, body weight will 
be monitored in this trial and underweight subjects with a BMI <18.5 kg/m2 at 
screening visit will be excluded from trial participation.

Suicidality:
Two of the currently marketed PDE4 inhibitors are associated with increased risk of
depression with some patients reporting suicidal ideation and attempts as well as with 
reported cases of completed suicide. Subjects with any history suicidal behavior in 
their life-time and/or any suicidal ideation of type 4 or 5 in the Columbia-Suicide
Severity Ranking Score (C-SSRS) within the past 12 months prior to screening visit
will be excluded from trial participation.
Risks related to BI 764333 (M480)
Pharmacological activity of the major human metabolite M480 was evaluated in a non-
clinical study testing 13 different phosphodiesterases. At a concentration of 10 μM BI 764333
inhibited PDE4A1A, PDE4B1 and PDE4D2 for 51.9%, 77.2%, and 60.4% respectively, with 
inhibition values ≤15.5% for the other tested enzymes [n00261809]. In clinical studies the
gMean Cmax,ss exposure values of BI 764333/4 at 12 mg bid / 18 mg bid BI 1015550 are 38.7 
nM / 68.7 nM respectively, which is much lower than 10 μM. Therefore, pharmacological 
contribution of this metabolite is considered to be low.
Potential Risks related to administration of [C-14]-BI 1015550
[C-14]-BI 1015550 is labelled with the isotope [14C] which is necessary for the purposes of 
this mass balance trial. Therefore, subjects will be exposed to ionizing radiation. The 
effective dose that each subject receives from one administration of 3.7 MBq is 
approximately 0.29 mSv. The radioactive dose of 0.29 mSv proposed for administration in 
this human ADME study, is lower than the limit specified by WHO Category 1, (<0.5mSv –
within variations of natural background radioactivity) and lower than the limit proposed b 
ICRP Category 2a, (<1 mSv – risk defined as minor).
For clinical investigations to study the disposition, metabolism and excretion of new 
pharmaceutical compounds in human an effective dose of 0.1 – 1.0 mSv is considered 
acceptable [R15-3219]. For details on the radiation burden calculation please refer to
Appendix 10.1.
To minimize any risks resulting from exposure to ionizing radiation in this trial female 
subjects will be excluded from study participation. Furthermore, contraception requirements 
in this study will apply for the participating male subjects as well as their female partners.
Summary of benefit-risk assessment
The available results of completed Phase I and Phase Ic trials in HVs and IPF patients
respectively, show a favorable safety profile at single doses administered up to 48 mg in HVs 
and at up to 18 mg b.i.d administered in multiple doses over a treatment period of up to 12 

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weeks in IPF patients, in which administration of BI 1015550 was safe and well tolerated 
(Section 1.2.4). No clinically relevant findings in vital signs and ECG were observed. There
are no adverse events reported with regard to bodyweight. Gastrointestinal AEs and headache 
of mostly mild intensity have been reported. No severe, serious, fatal adverse events nor 
SUSARS have been reported in the healthy volunteers studies. 
Therefore a single oral dose of 18 mg BI 1015550 administered to healthy male volunteers is 
considered to be acceptable from both a preclinical (i.e supported by the 13 weeks toxicology 
data) and clinical point of view.
In the current trial, healthy male volunteers will receive a single oral dose of 18 mg of BI 
1015550. Therefore each participating subject will receive only one single radioactive dose. 
The risk associated with the expected maximal radiation burden of 0.29 mSv falls in ICRP 
category 2a with minor level risk and in WHO Category 1, i.e. within variations of natural 
background radioactivity and is therefore considered to be acceptable.
There is always the potential for subjects receiving medication to experience adverse events 
(AEs), and rarely also serious adverse events (SAEs). However, the risks to subjects are 
minimized and addressed by eligibility criteria, safety laboratory examinations, ECG and
vital sign measurements, in-house observation periods and verbal communication concerning 
AEs. If the investigator should have any clinical concern, the safety of the subjects will be of 
paramount importance. The investigator has the discretion to remove subjects from the study 
should there be any safety concerns or if the subject’s wellbeing is at jeopardy.
The trial design is optimized to collect as much relevant information as possible on the 
pharmacokinetics of BI 1015550 without exposing participating volunteers to undue risk.
The results of this trial are necessary for the further development of BI 1015550. Successful 
development of BI 1015550 is expected to provide a new valuable treatment to patients with 
pulmonary fibrosis. The risks of the participating volunteers are minimized and justified 
when compared to the potential benefits of this trial.
For assessment of risks associated with Covid-19 pandemic refer to Appendix 10.3.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the basic pharmacokinetics of BI 1015550 
and its metabolite BI 764333, [14C]-radioactivity, including mass balance, excretion pathways 
and metabolism following a single oral dose of 18 mg [14C]-BI 1015550 administered to 
healthy male subjects.
The primary objective is:

To assess the mass balance recovery of [14C]-radioactivity from urine and faeces as 
well as vomit in case of occurrence after a single oral dose of 18 mg BI 1015550 (C-
14) administered to healthy male subjects
The secondary objectives are:

To assess the pharmacokinetics of [C-14] BI 1015550 and BI 1015550 as well as its 
metabolite BI 764333 in plasma following a single oral dose of BI 1015550 (C-14)

To assess the safety and tolerability of BI 1015550
2.1.2
Primary endpoint
The following pharmacokinetic parameters will be determined for [C-14] BI 1015550:
Mass balance recovery of [14C]-radioactivity:

Amount of [14C]-radioactivity excreted as a percentage of the administered single oral 
dose of BI 1015550 (C-14) in urine (feurine, 0-t2) and faeces (fefaeces, 0-t2) as well as vomit 
(fevomit, 0-t2), if applicable
2.1.3
Secondary endpoints
The following pharmacokinetic parameters will be determined for [C-14] BI 1015550 and BI 
1015550 as well as its metabolite BI 764333 in plasma:
Pharmacokinetics:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
Safety:

Percentage of subjects with treatment emergent adverse events (TEAEs)

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2.2.2.4
Safety and tolerability
Safety and tolerability of BI 1015550 will be assessed based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate, body weight)

Suicidality assessment (C-SSRS)

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as an open-label, non-randomized, single-dose, single-arm, 
single-period trial in healthy male subjects in order to investigate the basic pharmacokinetics 
of BI 1015550, its metabolite BI 764333 and [14C]-radioactivity, including mass balance, 
excretion pathways and metabolism following a single oral dose of 18 mg BI 1015550 (C-
14).
For details on the investigational treatment, refer to Section 4.1.
The planned radioactive dose per subject is 3.7 MBq (100 µCi, corresponding to 0.2864 
mSv), which is equivalent to 0.0774 mSv/MBq (please refer to Appendix 10.1).
On Day 1 subjects will be administered with 18 mg BI 1015550 (C-14). Subjects will remain 
at the study site from admission on Day -1 until discharge on Day 10. Subjects will be 
readmitted to the study centre for 24 h collection intervals of urine and faeces on Days 16, 23
and 30 respectively, if release criteria have not been met in the preceding collection interval. 
Within 24 h prior to each of these once weekly in-house collection intervals, subjects are to 
collect faeces at home. This 24-h interval home collection faeces will be used for analysis in 
case no defecation occurs in the subsequent 24 h in-house collection interval or otherwise 
discarded.
For determination of whether release criteria have been met for individual subjects, [14C]-
radioactivity will be measured in excreta (urine and faeces). The actual recovery results will 
be reported as a percentage of the administered dose.
If one of the following release criteria is true (i.e., release criteria have been met), 24 h 
collection intervals after Day 10 will not be performed any longer/will be stopped: 

Greater than or equal to 90% of the administered dose has been recovered in urine and 
faeces combined over the investigational period
or 

If <1% of the dose administered has been collected in urine and faeces within 2 
separate, consecutive 24 h intervals
and 

Concentration of total radioactivity in plasma and in blood is <5% of Cmax of total 
radioactivity in plasma
If the mass balance recovery on Day 10 is less than 90%, subjects will be discharged from the 
research site but have to return to the clinic for 24 h collection of urine and faeces on Days 
16, 23 and 30 until the recovery is deemed to be sufficient for mass balance purposes. No PK 
plasma sampling will be performed at these 24 h collection intervals. If a subject is unable to 
attend one of these visits, subject may be allowed to reschedule the visit, if needed.
Irrespective of whether release criteria have been met or not after collection interval Day 30-
31, no further collections are planned.

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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
This is a standard design for a [14C]-human study for investigation of absorption, distribution,
metabolism, and excretion including determination of mass balance. Inclusion of a control 
groups is not required for this investigation.
The elimination of BI 1015550 is biphasic, therefore it cannot be excluded that prolonged
sampling is necessary in humans. Therefore, following in-house excreta collection after 
radioactive dosing on Day 1, subjects will return on a weekly basis for 24 h in-house
collection intervals for up to 4.5 weeks after last dosing as long as release criteria are not met
(Section 3.1).
Blinding does not apply for this trial as all subjects receive the same treatment.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 6 healthy male subjects will enter the study. They will be recruited from the 
volunteers' pool of the trial site or, if necessary, via external databases and advertisements. In 
case a subject is discontinued from the trial an additional subject may be entered and dosed to 
assure that a minimum of 4 evaluable subjects will complete the study as per protocol. The 
actual number of subjects entered may increase up to but will not exceed 8.
Only healthy male subjects will be included in this trial because they are an ideal population 
for the objectives of this trial, since they provide relatively stable physiological, biochemical 
and hormonal conditions, i.e. the absence of disease-related variations and relevant 
concomitant medications.
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 study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects 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 65 years (inclusive)
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 

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4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
5. Male subjects who meet any of the following criteria from screening until 90 days after 
trial completion:
-
Use of adequate contraception of the female partner, e.g. any of the following
methods plus condom: implants, injectables, combined oral or vaginal 
contraceptives, intrauterine device, which started at least two months prior to first 
study drug administration or barrier method (e.g. diaphragm with spermicide) or,
-
Sexually abstinent or,
-
A vasectomy performed at least 1 year prior to screening (with medical 
assessment of the surgical success) or,
-
Surgically sterilised female partner (including hysterectomy, bilateral tubal 
occlusion, or bilateral oophorectomy) or,
-
Postmenopausal female partner, defined as at least 1 year of spontaneous 
amenorrhea (in questionable cases a blood sample with levels of FSH above 40 
U/L and estradiol below 30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 45 to 90 mmHg, or pulse rate outside the 
range of 40 to 100 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation, potent CYP3A4 inhibitors, selective and non-selective PDE inhibitors as 
well as vaccination of any kind with or without re-vaccination required during the course 
of the trial).

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12. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Average intake of more than 21 units of alcohol per week (1 unit of alcohol equals
approximately 250 mL of beer, 100 mL of wine or 35 ml of spirits)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within 4 days prior to the administration 
of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. 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 
In addition, the following trial-specific exclusion criteria apply:
23. A medical history of vasculitis
24. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour)
25. Any suicidal ideation of type 4 or 5 in the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with intent 
but without specific plan, or active suicidal thought with plan and intent)
26. Participation in another ADME study with a radiation burden of >0.1 mSv in the period 
of 1 year prior to screening or 1.1-2.0 mSv in the past 2 years or 2.1-3.0 mSv in the past 3 
years etc.
27. Exposure to radiation for diagnostic reasons (except dental X-rays and plain X-rays of 
thorax and bony skeleton (excluding spinal column)) in the period of 1 year prior to 
screening
28. Irregular defecation pattern (less than a mean of one bowel movement every 1 or 2 days)
In addition, the following trial-specific exclusion criteria apply:
29. A positive test indicating an ongoing infection with SARS-CoV-2 and/or clinical 
symptoms suggestive of the disease.
For study restrictions, refer to Section 4.2.2.

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3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to 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 administration of trial medication, this will be documented and the reason 
for discontinuation must be recorded in the CRF; in addition, the data will be included in the 
CRF and will be reported in the CTR. At the time of discontinuation, a complete end of trial 
examination will be performed, if possible, and the information will be recorded in the CRF. 
If the discontinuation occurs before the end of the REP (see Section 1.2.3), the discontinued 
subject should if possible be questioned for AEs and concomitant therapies at or after the end 
of the REP in order to ensure collection of AEs and concomitant therapies throughout the 
REP, if not contrary to any consent withdrawal of the subject.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
6. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP<90/45 mmHg) or hypertension (BP>180/100 
mmHg) or of clinically relevant changes in ECG requiring intervention as well as 
unexplained liver enzyme elevations at any time during the trial.
7. The subject experiences a serious adverse reaction which is considered at least possibly 
related to the IMP administration
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.

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3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
if more than 50% of the subjects have drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least 1 drug-related serious adverse event is 
reported
3. Violation of GCP or the CTP or the contract with BI impairing the appropriate conduct of 
the trial
4. The sponsor decides to discontinue the further development of the investigational product
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the Clinical Trial Leader together with the 
Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects 
will be replaced. Replacement of subjects and dosing of additional subjects should always be 
done in mutual agreement with the principal investigator. A replacement subject will be 
assigned a unique trial subject number, and will be assigned to the same treatment as the 
subject he replaces.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 1015550 (C-14) is administered as oral solution. The oral solution contains a mixture of 
[C-14] BI 1015550 and non-radiolabelled BI 1015550 and is manufactured by 
 
.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Name:
BI 1015550 (C-14) oral solution
Substance:
BI 1015550 mixed with [C-14]-BI 1015550
Pharmaceutical formulation: Oral solution
Source:
Unit strength:
18 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
single dose
4.1.2
Selection of doses in the trial
The dose selected for this trial is one single oral dose of 18 mg BI 1015550, which is below 
the highest dose of BI 1015550 already tested in previous trials (1305-0011: single dosing of 
48 mg BI 1015550 in healthy volunteers and 1305-0012: multiple dosing of 18 mg BI 
1015550 over 12 weeks bid in patients see Section 1.2). In addition, this dose of 18 mg BI 
1015550 is being tested over 12 weeks bid in patients in the ongoing phase II study 1305-
0013. In healthy volunteers, a single dose of 18 mg was safe and well-tolerated (see 
Section 1.2) and is considered adequate for the objectives of this trial.
The 18 mg dose of BI 1015550 administered as oral solution will contain 3.7 MBq of [C-14]
BI 1015550. The radio-labelled dose of 3.7 MBq is required to provide sufficient analytical 
sensitivity for the quantification of radioactivity in plasma, urine, faeces and vomit, if 
applicable, at a sufficiently low level of detection. The total effective dose (radiation burden) 
amounts to 0.2864 mSv and lies below the limit of ICRP Category 2a (1.0 mSv), which is
considered acceptable for this biomedical investigation. Radiation burden calculations are 
presented in Appendix 10.1. For risk-benefit assessment, see Section 1.4.
4.1.3
Method of assigning subjects to treatment groups
This is an open-label, phase I, single-dose study. All subjects receive the same dose. Each 
subject will be assigned a subject number prior to dosing on Day 1 of Visit 2.
Once a subject number has been assigned, it cannot be reassigned to any other subject.

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4.1.4
Drug assignment and administration of doses for each subject
This trial is an open-label, single-period and single-arm study. All subjects will receive the 
same treatment. The treatment to be evaluated is outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T (Test product)
BI 1015550
Oral solution
0.5 mg/mL
36 mL (18 mg) once
18 mg
will determine both the weight of drug product and the total dose of 
[14C]-radioactivity administered for each subject.
In the morning of Day 1, all subjects will receive one single oral dose of BI 1015550 (C-14) 
as an oral solution of 0.5 mg/mL (36 mL, 3.7 MBq).
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. 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 sitting position.
For drug administration, the so-called four-eye principle (two-person rule) should be applied. 
For this, one authorised employee of the trial site should witness the administration of trial 
medication, and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot 
be ensured otherwise.
Subjects will be kept under close medical surveillance until Day 10 after drug administration. 
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) except for 
medical examination or if necessary for any medical reasons (e.g. AEs).
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout the entire conduct, including 
data cleaning and preparation of the analysis. This is considered acceptable because the 
potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
4.1.6
Packaging, labelling, and re-supply
Non-radiolabelled and radiolabelled drug substance will be manufactured and mixed by BI 
and provided to PRA. Manufacturing of the investigational medicinal product (oral solution) 

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will be provided by PRA. The investigational medicinal product will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
PRA pharmacy will deliver the investigational drugs to the investigator upon availability of a 
valid prescription from the investigator. The investigator will not order the drugs from the 
PRA pharmacy before the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.

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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
CYP3A4 is regarded as the major enzyme responsible for the metabolism of BI 1015550, 
therefore potent CYP3A4 inhibitors are specifically restricted in this trial.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake on Day 1.
On Day 1 fluid intake is restricted from 1 h before drug intake until lunch, to 240 mL of the 
water administered with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose 
(mandatory for all subjects). From lunch until 24 h post-dose, total fluid intake should be 
within about 1000 to 3000 mL.
During the days of urine collection, subjects will be advised that total fluid intake should be 
at least 1.5 liters and should not exceed 3.5 liters.
Alcoholic beverages are not allowed within 48 h before screening and before first admission 
to and during in-house confinement at the trial site. During ambulatory phases alcohol 
consumption is restricted to 2 units per day.
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of each study period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 24 h before until 24 h after administration of trial 
medication.
Consumption of poppy-seed containing products is not permitted from 72h prior to each drug 
screening (at Screening and on Day -1).
Smoking is not allowed during in-house confinement while admitted to the trial site.

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Excessive physical activity (such as competitive sport) should be avoided from 4 days before 
the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
as well as urinary and faecal excretion 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, body height and body 
weight, smoking and alcohol history (results not mandatory to be entered into CRF or to be 
reported), relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, C-SSRS and 
a physical examination. At the end of trial examination, medical examination will include 
review of vital signs, 12-lead ECG, laboratory tests, C-SSRS and a physical examination 
including determination of body weight. Furthermore on Day 10, prior to discharge from trial 
site, confirmation of fitness will be performed including vital signs, 12-lead ECG, laboratory 
tests, C-SSRS and a physical examination, including body weight. 
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (e.g. Dinamap CareScape VC 150,
) 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 4 h 
at screening and EOT visits and at least 10 h for all other time points. At the discretion of the 
investigator or designee, overnight fasting is not required for drug screening, for infectious 
serology and for retests. 
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively. 
SARS-CoV-2 specific testing will be conducted as specified in the Flow Chart.

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
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
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential WBC 
(if automatic differential 
WBC is abnormal), %
Neut. Poly (segs); Neutrophils Bands; Eosinophils; Basophils; 
Monocytes; Lymphocytes
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
Lipase
Amylase
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
X
X
X
Hormones
Thyroid Stimulating Hormone 
X
--
--
Substrates
Glucose (Serum)
Creatinine
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
C-Reactive Protein (Quant)  
Uric Acid 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
X
X
X
X
X
X
--
--

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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Electrolytes
Sodium
Potassium
Chloride
Calcium
Phosphate (as Phosphorus, Inorganic)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis1
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Haemoglobin (qual)
Urine WBC/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
1: Urine sediment
(microscopic examination if 
erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 2 on Day -1 and on Day 10 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 3 (end of trial examination)
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. It is planned to perform these tests during screening only. Drug screening will be 
performed at screening and at admission to trial site on Day -1.

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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Alcohol
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic and drug restrictions, a urine alcohol and drug test 
(eg. ADVIA Chemistry XPT system) will be performed at admission on Day -1, and may be 
repeated at any time during the study at the discretion of an investigator or designee. The 
results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
, 
. Laboratory 
data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (e.g.Mortara Eli 250 C) at the times provided in the 
Flow Chart. 
To achieve a stable heart rate at rest and to assure high quality recordings, subjects will be 
resting for at least 5 min in a supine position prior to start of measurement. The site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically. Electrode placement will be performed according to 
the method of Wilson, Goldberger and Einthoven 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 

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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
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does
not give a global score, but provides some categorical and some severity information
specifically for behavior and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, 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 behavior, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report.
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. In this trial the entire life time history of suicidal 
ideation and behavior will be recorded.
After the baseline visit the assessment ‘since last visit’ will be performed at the time points
indicated in the Flow Chart. The investigator is to review positive and negative 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 positive 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 positive report is confirmed, appropriate actions for the subject’s safety have to be
initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behaviour must 
be reported as separate SAEs by the investigator. For “Self-injurious behaviour, no suicidal 
intent” (Type 11) standard AE/SAE reporting rules are to be applied. For each negative report 
(suicidal ideation type 1, 2, or 3) after start of the trial, the investigator is to decide based on 
clinical judgment whether it represents an AE as defined in the protocol, and if it is
considered an AE then it must be reported accordingly.
The original English version can be found in Appendix 10.2.

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5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 

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as described in Section 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor 
and timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
eDC. 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.

Vasculitis
In this trial protocol vasculitis is defined as any adverse event term included in the 
MedDRA SMQ Vasculitis (broad). This includes clinical and pathological features 
related to primary or secondary vasculitis syndromes and involving any type, size, and 
location of blood vessels.

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

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5.2.6.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF by the investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific contact details will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions the 
Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.

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Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. 
Once a male subject has been enrolled in the clinical trial and has taken trial medication, and 
if a partner of the male trial participant becomes pregnant, the investigator must report any 
drug exposure during pregnancy in a partner of the male trial participant immediately (within 
24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s unique 
entry point. This requires a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Trials (Part A and Part B) as well as non-trial specific information and consent for 
the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood and urine samples will be collected at the time 
points / time intervals indicated in the Flow Chart. The actual sampling times will be 
recorded and used for determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Sampling of whole blood and plasma
Whole blood and plasma will be collected at time points shown in the Flow Chart:

To determine [14C]-radioactivity concentrations in whole blood and plasma

To determine concentrations of BI 1015550 and its metabolite BI 764333 in plasma

To identify additional metabolites of BI 1015550 in plasma

To determine the blood cell/plasma and blood/plasma ratios of [14C]-radioactivity

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5.3.2.2
Sampling of whole blood and plasma for [14C]-radioactivity analysis and 
quantification of BI 1015550 and its metabolite in plasma
Blood for quantification of BI 1015550 and its metabolite BI 764333 in plasma will be drawn 
from an antecubital or forearm vein into an K2-EDTA (dipotassium ethylenediaminetetra-
acetic acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood 
will be withdrawn by means of either an indwelling venous catheter or by venepuncture with 
a metal needle.
At each time point listed in the Flow Chart, approximately 9 mL of whole blood will be 
taken. These 9 mL divide into 3 aliquots of 3 mL each.
An aliquot of 3 mL of whole blood is required for the quantification of BI 1015550 and its 
metabolite in plasma.
Two aliquots of 3 mL of whole blood each are required for determination of [14C]-
radioactivity in whole blood and plasma.
Bioanalysis of BI 1015550 and its metabolite BI 764333 in plasma is planned to be prepared 
as long as PK blood samples are collected for determination of total radioactivity.
For a detailed description of blood sampling, sample volume, sample handling, sample
preparation, sample storage, tube labelling and sample shipment, refer to the laboratory
manual.
Premature stopping of blood sampling
In case [14C]-radioactivity in plasma samples is not detectable (<LLOQ 30 dpm/mL) at two
consecutive time points for a subject, blood sampling can be stopped for this subject. 
However, all samples until and including the 216 hrs sample have to be collected.
5.3.2.3
Sampling of plasma for metabolic profiling and structural elucidation
Additional K2-EDTA (dipotassium ethylenediaminetetraacetic acid) plasma samples for the
identification of drug metabolites will be taken. 
The blood samples will be drawn at certain time points in parallel to pharmacokinetic time 
points (see Flow Chart). Sample volume will differ between the timepoints. For timepoints at 
predose, 1 h and 2 h after drug administration, 10 mL is required for each sample. For 
timepoints at 4 h and 8 h after drug administration, the required sampling volume will be 30 
mL each. For timepoints at 12 h, 24 h and 36 h after drug administration, the sampling 
volume required will be 50 mL, 80 mL and 40 mL, respectively. Overall, 260 mL will be 
needed for metabolic analyses.
The maximum possible volume of blood will be drawn according to what is allowed 
considering all other blood samples taken for all other samples except metabolic profiling.
For exact sample volume as well detailed description of blood sampling, sample handling, 
sample preparation, sample storage, tube labelling and sample shipment refer to the 
laboratory manual.

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5.3.2.4
Sampling of blood for hematocrit for blood cell/plasma ratio
At each time point listed in the Flow Chart, a blood sample approximately 3 mL will be
drawn for measurement of hematocrit, which is needed for determination of blood 
cell/plasma ratio (see Section 2.2.2.3).
For a detailed description of blood sampling, sample volume, sample handling, sample
preparation, sample storage, tube labelling and sample shipment, refer to the laboratory
manual.
5.3.2.5
Urine sampling for pharmacokinetic analysis
During the trial urine will be collected in defined containers at time points or in intervals as 
indicated in the Flow Chart:

To determine [14C]-radioactivity concentrations in urine

To determine concentrations of BI 1015550 in urine

To investigate the metabolite profiling of BI 1015550 in urine
A blank urine sample will be collected prior to administration of trial medication.
For quantification of the collected volume, the weight of the containers has to be determined 
prior to (empty containers) and at the end of the collection interval. The urine volume (weight 
will be set equal to volume, i.e. 1 kg = 1 L, without correction for specific gravity of urine) 
for each collection interval will be documented. Volunteers will empty their bladders at the 
end of each sampling interval. The exact start and end times of the urine collection intervals 
will be recorded in the CRF.
Subjects are told to empty their bladders at the end of each sampling interval.
All samples after intake of BI 101550 (C-14) are planned to be used for determination of
[14C]-radioactivity.
Samples until 216 hrs on Day 10 are planned to be used for analysis of BI 1015550 and its 
metabolite BI 764333.
Samples to be used for metabolic profiling will be selected according to the levels of 
radioactivity in each urine sample interval.
For a detailed description of urine sampling, preparation of collection containers, sample
storage, sample handling, labelling, and sample shipment refer to the laboratory manual.
5.3.2.6
Sampling of faeces
Faeces will be collected for the analysis of [14C]-radioactivity and for metabolic profiling in 
intervals as indicated in the Flow Chart. A blank sample will be taken prior to drug 
administration.
All faeces samples after intake of BI 1015550 (C-14) are planned to be used for 
determination of [14C]-radioactivity. 
Samples to be used for metabolic profiling will be selected according to the levels of 
radioactivity in each faeces sample interval.

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All stools will be collected quantitatively in portions up to Day 10 after drug administration. 
The weight of the faeces and the exact times of faeces collection will be recorded in the 
eCRF.
For a detailed description of faeces sampling, sample preparation, sample storage, labelling, 
and sample shipment refer to the laboratory manual.
5.3.2.7
Collection of vomit 
If after trial drug administration vomiting occurs in a volunteer within 8 h after radioactive 
drug administration, the vomit will be collected for determination of weight and [14C]-
radioactivity.
For a detailed description of vomit sampling, sample preparation, sample storage, labelling, 
and sample shipment refer to the laboratory manual.
5.3.2.8
Further investigations
After completion of the trial, blood, plasma, urine, vomit and faeces samples may be used for 
further methodological investigations, e.g. for stability testing of the drug and/or drug 
metabolites, assessment of drug metabolites. However, only data related to the analyte and/or 
its metabolite(s) will be generated by these additional investigations.
All study samples will be discarded after completion of the additional investigations but not 
later than 5 years upon the final study report has been signed.

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5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
5.4
ASSESSMENT OF BIOMARKERS 
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
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 in human mass-balance trials.

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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 2 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests 
will be ± 30 min on Day 1 and ± 90 min on all subsequent days of Visit 2. The planned times 
for admission, discharge, start and end of the urine and faeces collection intervals are 
approximate. The procedures are to be performed within a time window of ± 4 hrs to the 
planned time. If not feasible due to logistic reasons the time window may be extended up to 8 
hrs after the planned time.
If several activities are scheduled at the same time point in the Flow Chart, ECG should be 
the first and meal the last activity. Vital signs will be measured after ECG and prior to 
urine/faeces collection. Furthermore, if several measurements including venepuncture are 
scheduled for the same time, venepuncture should be the last of the measurements due to its 
inconvenience to the subject and possible influence on physiological parameters. If required 
for logistical reasons, start of urine and faeces collection can be initiated after venipuncture. 
For planned blood sampling times and urine/faeces collection intervals, refer to the 
Flow Chart. While these nominal times should be adhered to as closely as possible, the actual 
sampling times will be recorded and used for the determination of pharmacokinetic 
parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.4.

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6.2.2
Treatment period
On Day -1, all study participants will be admitted to the trial site and kept under close
medical surveillance until discharge on Day 10 as indicated in the Flow Chart. Subjects will 
receive a single dose of BI 1015550 (C-14) in the morning of Day 1.
Subjects will be readmitted to the trial site for 24-hours collection intervals of urine and
faeces on Days 16, 23 and 30, if release criteria have not been met. Within 24 h prior to each 
of these once-weekly in-house collection intervals, subjects are to collect faeces at home. 
This 24-hours interval home collections will be used for analysis in case no defecation occurs 
in the subsequent 24-h in-house collection interval. Otherwise it will be discarded. 
Once release criteria are met, home collections will be stopped. If a subject is unable to attend 
one of these visits, they may be allowed to reschedule the visit, if needed. Irrespective of 
whether release criteria have been met or not after the last collection interval on Day 31, no 
further collections are planned.
For details on time points and procedures for collection of plasma, urine and faeces 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 5.3
of this protocol and in the Flow Chart. 
For details on times of all other trial procedures, refer to the Flow Chart. AEs and 
concomitant therapy will be assessed continuously from screening until the end of trial
examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.1 to 5.2.6.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained. 

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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the basic pharmacokinetics of BI 1015550 
and its metabolites, total radioactivity, including mass balance, excretion pathways and 
metabolism following a single oral dose of 18 mg of BI 1015550 (C-14) administered to 
healthy male subjects. 
The primary objective is to assess the mass balance recovery of [14C]-radioactivity from urine 
and faeces as well as vomit in case of occurrence. Secondary objectives are the evaluation of 
pharmacokinetic parameters specified in Section 2.1.3 and safety and tolerability. Further 
objectives are to evaluate further pharmacokinetic, mass balance and tolerability parameters
as specified in Section 2.2.2.
No statistical comparison will be conducted for this study. Data will be reported with
descriptive statistics.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No confirmatory analysis will be conducted for this study. Data will be reported with
descriptive statistics only.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were entered and treated 
with the single dose of the study drug. The treated set will be used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol violation 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 the subject
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(iPD) categories will be suggested in the iPD specification file, iPDs will be identified no 
later than in the Report Planning Meeting, and the iPD categories will be updated as needed.

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Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for drug BI 1015550 (C-14) as well as 
for its metabolite will be calculated according to the relevant SOP of the Sponsor 
[001-MCS-36-476].
Plasma, urine and faeces concentration data and parameters of a subject will be included in 
the statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol deviation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma and urine concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

Missing samples/concentration data at important phases of PK disposition curve
Plasma/urine concentration data and parameters of a subject which is flagged for exclusion 
will be reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.3.1
Primary endpoint analyses
All parameters will be calculated and analysed descriptively.
7.3.2
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the BI SOP 
001-MCS-36-476 (TMCP Data Analysis) and its reference documents and will be assessed 
statistically using the same methods as described for the primary endpoints.

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7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to intake of trial medication will be 
assigned to the screening period, those between trial medication intake and end of REP (see 
Section 1.2.3) will be assigned to the treatment period. Events occurring after the REP but 
prior to end of trial termination date will be assigned to ’follow-up’. These assignments 
including the corresponding time intervals will be defined in detail in the TSAP. Note that 
AEs occurring after the last per protocol contact but entered before final database lock will be 
reported to Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No interim analysis is planned.

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7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure [001-MCS-36-476].
Pharmacokinetic parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Randomisation is not applicable in this open-label, single arm clinical study. All subjects will 
receive the same treatment. Consecutive subject numbers will be assigned via the eDC 
system.
7.7
DETERMINATION OF SAMPLE SIZE
For this exploratory study, no prospective calculations of statistical power have been made.
The sample size of at least 4 evaluable subjects has been selected to provide sufficient 
information on safety, tolerability and pharmacokinetics of [C-14]-labelled BI 1015550 after 
oral administration in healthy male subjects. 

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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) and other 
relevant regulations. Investigators and site staff must adhere to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
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 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
CRF for individual subjects will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

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
AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 

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Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 

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A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at
, 
, under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial
ensure appropriate training and information of local clinical monitors (CTM), Clinical 
Research Associates, and investigators of participating trial sites
The radiolabelled drug substance will be provided by BI Pharma GmbH & Co. KG, Biberach, 
Germany.
The oral solution of trial medication will be manufactured by 
 
Safety laboratory tests including haematocrit analysis will be performed by the local 
laboratory of the trial site (
 
).
Analyses of non-radiolabelled BI 1015550 and metabolite concentrations in plasma will be 
performed at 
Analyses of [14C]-radioactivity concentrations in whole blood, plasma, urine and faeces will 
be performed at the Bioanalytical Lab of 
Metabolic identification will be performed at the 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs or a 
contract research organisation appointed by BI.

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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
P13-05880
Hassan Z, Muzaimi M, Navaratnam V, Yusoff NHM, Suhaimi FW, 
Vadivelu R, Vicknasingam BK, Amato D, Hoersten S von, Ismail NIW, 
Jayabalan N, Hazim AI, Mansor SM, Muller CP. From Kratom to 
mitragynine and its derivatives: physiological and behavioural effects 
related to use, abuse, and addiction. Neurosci Biobehav Rev;37(2):138-151. 
2013.
R10-1559
Giembycz MA. Life after PDE4: overcoming adverse events with dual 
specificity phosphodiesterase inhibitors. Curr Opin Pharmacol;5:238- 244. 
2005.
R12-5544
Insel PA, Murray F, Yokoyama U, Romano S, Yun H, Brown L, Snead A, 
Lu D, Aroonsakool N. cAMPand Epac in the regulation of tissue fibrosis. 
Br J Pharmacol 166, 447 - 456 (2012).
R12-5545
Udalov S, Dumitrascu R, Pullamsetti SS, Al-Tamari HM, Weissmann N, 
Ghofrani HA, Guenther A, Voswinckel R, Seeger W, Grimminger F, 
Schermuly RT. Effects of phosphodiesterase 4 inhibition on 
bleomycininduced pulmonary fibrosis in mice BMC Pulmonary Medicine. 
2010.
R12-5546
Cortijo J, Iranzo A, Milara X, Mata M, Cerda-Nicolas M, Ruiz-Sauri A, 
Tenor H, Hatzelmann A, Morcillo E. Roflumilast, a phosphodiesterase 4 
inhibitor, alleviates bleomycin-induced lung injury. British Journal of 
Pharmacology 156, 534–544. (2009).
R14-2284
Raghu G, Chen SY, Yeh WS, Maroni B, Li Q, Lee YC, Collard HR.
Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years 
and older: incidence, prevalence, and survival, 2001 - 11. Lancet 
Respiratory Medicine. Early Online Publication, 27 May 2014
R14-4266
Hutchinson JP, McKeever TM, Fogarty AW, Navaratnam V, Hubbard RB. 
Increasing global mortality from idiopathic pulmonary fibrosis in the  21st 
century. Annals of the American Thoracic Society, Articles in Press, 
published on 28-August-2014, doi: 10.1513/AnnalsATS.201404-145OC; p. 
1176-1185. 2014.
R15-3219
International Commission on Radiological Protection (ICRP). 2007 
Recommendations of the International Commission on Radiological 
Protection (users edition): abstract. webpage.icrp.org/publication 
.asp?id=ICRP%20Publication%20103%20(Users%20Editi on (ICRP 
Publication; 103 (Users Edition)) International Commission on 
Radiological Protection (ICRP). 2007.

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R16-1737
Esposito DB, Lanes S, Donneyong M, Holick CN, Lasky JA, Lederer D, 
Nathan SD, O'Quinn S, Parker J, Tran TN. Idiopathic pulmonary fibrosis in 
United States automated claims: incidence, prevalence, and algorithm 
validation. Am J Respir Crit Care Med 192(10):1200-1207. 2015
R17-4284
Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and 
mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir 
J 46(3):795-806. 2015
R18-0408
Raghu G, Morrow E, Collins BF, Ho LAT, Hinojosa MW, Hayes JM, et al. 
Laparoscopic anti-reflux surgery for idiopathic pulmonary fibrosis at. a 
single centre. Eur Respir J;48:826-832. 2016
R18-1413
Strongman H, Kausar I, Maher TM. Incidence, prevalence, and survival of 
patients with idiopathic pulmonary fibrosis in the UK. Advances in 
Therapy, Published online p. 724-736. 11 April 2018
R18-2794
Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, 
et al, American Thoracic Society, European Respiratory Society, Japanese 
Respiratory Society, Latin American Thoracic Society. Diagnosis of 
idiopathic pulmonary fibrosis: an official ATS/ERS/JRS/ALAT clinical 
practice guideline. Am J Respir Crit Care Med 198(5):e44-e68. 2018;
9.2
UNPUBLISHED REFERENCES
001-MCS-36-476 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c02094779
 Investigator's Brochure BI 1015550 for Idiopathic 
Pulmonary Fibrosis. Current version.
c22991937
Safety, tolerability and pharmacokinetics of single and multiple rising oral 
doses of BI 1015550 in healthy subjects 1305-0011. 15 November 2018
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. 15 March 2019
n00261809
Eurofins, In Vitro Pharmacology: Study of 16726375, Study Nr. 
100044125.11 May 2018.
s00092835
 B-R assessment_COVID-19_BI1015550. Current version.
U13-1792
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 
1015550 in healthy male volunteers (a partially randomised, single blinded, 
placebo-controlled Phase I study). Clinical Trial Report 1305.1. 21 June 
2013

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10.
APPENDICES
10.1
RADIO BURDEN CALCULATION

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10.2
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)
10.2.1
Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening

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10.2.2
Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit

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10.3
COVID-19 RISK ASSESSMENT AND SPECIFIC MEASURES
This section contains a risk assessment for study 1305-0016 with BI 1015550 due to the 
circumstances created by the coronavirus disease-19 (COVID-19) pandemic. In addition, this
section summarizes the mitigation approaches to be followed to minimize the risk of 
spreading severe acute respiratory syndrome coronavirus 2 (SARS CoV-2).
Assessment of risks associated with Covid-19 pandemic
For BI 1015550 an assessment specific to the COVID-19 pandemic has been performed 
based on the current knowledge to evaluate, if the treatment with BI 1015550 may pose a 
higher risk associated with SARSCoV-2 infection and COVID-19 disease.
Based on the pharmacological mechanism and existing nonclinical and clinical data there is 
no indication that treatment with BI 1015550 may increase the risk of severe clinical courses 
of SARS-COV-2 infection.
Even though an increased risk of SARS-CoV-2 infection, or of a more severe COVID-19 
disease in case of such an infection appears unlikely, subjects with active or recent SARS 
CoV-2 infection will not be included in the trial. 
For further details refer to benefit risk assessment BI 1015550 COVID19 [s00092835]
Every subject will be assessed thoroughly and individual benefit-risk assessments will be 
performed by the investigator prior to study participation of a subject. In respect of potential 
COVID-19, the risk for subjects participating in this trial will not differ from the current 
general risk of COVID-19 with all its consequences.
The investigator will take the totality of information related to each single subject and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon 
each subject’s (continued) participation in this trial. BI as the sponsor, where required, will 
support the investigator in their decision finding. It is acknowledged that the investigator may 
decide to implement protocol deviations where this protects the safety, well- being and/or is 
in the best interest of the subject.
Risk mitigating measures in study design
The study population for this study consists of healthy subjects with minimized risk of 
SARS-CoV-2 infection (free of COVID-19 symptoms, negative PCR tests prior to 
investigational medicinal product administration) and with minimized impact of COVID-19, 
if contracted during the study (e.g., upper age ≤65 years, upper BMI ≤29.9 kg/m2). Physical 
examination will be limited to screening, discharge on Day 10 and EoT as indicated in the 
Flow Chart. Subjects will be admitted for in-house confinement from Day -1 until Day 10
following a single dose administration on Day 1. Subjects will be readmitted to the research 
site for 24-h in-house stay at several time points as specified in the Flow Chart, if they do not 
meet the release criteria. At the time of EoT examination (Day 11 - Day 31) BI 1015550 is 
expected to be eliminated.
SARS-CoV-2 containment measures at research site
The following SARS-CoV-2 containment measures will be taken during the study: 

The study will be conducted in accordance with guidance from the Central Committee 
on Research Involving Human Subjects (CCMO [Centrale Commissie Mensgebonden 

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Onderzoek]) on conducting Phase 1 trials in Clinical Research Units in The 
Netherlands during the COVID 19 pandemic.

During the entire study, the clinical research unit will implement all recommendations 
issued by the Dutch Government, including specific guidelines related to clinical 
research executed in clinical research units with respect to minimizing the risk of 
disease spreading, e.g., social distancing, disinfection, hygiene, and wearing of 
personal protection equipment by study staff. Details on specific procedures are 
described in the Site Specific Manual.

In cases where subjects are not able to attend study visits due to the presence of a 
SARS-CoV-2 infection, the Investigator will discuss with the Sponsor potential 
mitigation approaches (including, but not limited to, extending the visit window, 
conducting evaluations via video link or phone call, allowing for safety procedures to 
be conducted at a local facility). The rationale (e.g., the specific limitation imposed by 
the SARS-CoV-2 infection that led to the inability to perform the protocol-specified 
assessment) and outcome of the discussion will be documented in the electronic case 
report form (eCRF).

Polymerase chain reaction (PCR) testing for SARS CoV-2 will be performed at the 
time points indicated in the Flow Chart:

A subject should not be admitted to the research site, if there was any contact with a 
person tested positive for SARS CoV-2 or a COVID-19 patient within the last 2 
weeks prior to admission to the clinical research center.

If a subject is tested to be positive for SARS-CoV-2 on Day -1, the subject will be 
excluded from participation in trial with reference to exclusion criterion #29, and 
referred for treatment.

If a subject becomes ill and/or is tested to be positive for SARS-CoV-2 after 
administration of study treatment, the subject will be isolated from other study 
participants and referred for treatment. The subject will be followed up in quarantine 
in the clinical research unit until complete elimination of the study compound or will 
be asked to quarantine at home according to guidelines of the Dutch government.
Conclusion of COVID-19 risk containment
Given the profile of the compound and given the study design, the COVID-19 risk
minimization strategy as described above is considered adequate. 

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
Product
Title of protocol
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Description of change
Rationale for change

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
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Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c24519579
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clinical-trial-protocol-version-01
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
Author-Trial Statistician
28 Jan 2021 13:22 CET
Author-Clinical Trial Leader
28 Jan 2021 13:25 CET
Approval-Team Member Medicine
28 Jan 2021 13:25 CET
Verification-Paper Signature
Completion
28 Jan 2021 14:25 CET
Author-Trial Clinical
Pharmacokineticist
28 Jan 2021 16:55 CET
Approval-Therapeutic Area
29 Jan 2021 12:49 CET

Boehringer Ingelheim 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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