Bioequivalence of the BI 1015550 High Dose Formulation C2 and the BI 1015550 High Dose Formulation C1 (Phase 3 Formulation) Following Oral Administration in Healthy Subjects (an Open-label, Randomised, Single-dose, Two-way Crossover Trial)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

BI-VQD-11906_40-106_AD-13 (8.0)
Clinical Trial Protocol
TITLE PAGE
Document Number:
c43335208-03
EU Trial No.
UTN
2023-509950-67-00
U1111-1301-0834
BI Trial No.
1305-0037
BI Investigational
Medicinal Product
BI 1015550
Title
Bioequivalence of the BI 1015550 high dose Formulation C2 and
the BI 1015550 high dose Formulation C1 (phase 3 formulation)
following oral administration in healthy subjects (an open-label, 
randomised, single-dose, two-way crossover trial)
Lay Title
A study in healthy people to compare how 2 different high dose 
formulations of BI 1015550 are taken up in the body
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
 Investigator
Phone: 
Fax: 
Current Version, Date
Version 3.0, 15 May 2024
Original Protocol Date
09 Feb 2024
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
09 Feb 2024
Revision date
15 May 2024
BI trial number
1305-0037
Title of trial
Bioequivalence of the BI 1015550 high dose Formulation C2 and the BI 
1015550 high dose Formulation C1 (phase 3 formulation) following oral 
administration in healthy subjects (an open-label, randomised, single-dose, two-
way crossover trial)
 Investigator
Trial site
Clinical phase
I
Trial rationale
Proof of bioequivalence of the BI 1015550 Formulation C2 and the BI 1015550 
Formulation C1 (phase 3 formulation) -
 tablet to support bridging of 
other trial results
Trial objective
To establish the bioequivalence of the BI 1015550 Formulation C2 and the 
BI 1015550 Formulation C1 (phase 3 formulation) -
 tablet
Trial endpoints
Primary endpoints: AUC0-tz and Cmax of R-BI 1015550
Secondary endpoints: AUC0-of R-BI 1015550
Trial design
Open-label, randomised, single-dose, two-way crossover trial
Number of subjects 
total entered
64
on each treatment
64
Diagnosis
Not applicable
Main inclusion criteria
Healthy male and female subjects (at least 14 subjects of each sex), age of 18 to 
50 years (inclusive) with a body mass index (BMI) of 18.5 to 29.9 kg/m2
(inclusive)
Test product
BI 1015550 Formulation C2 as 
 - Test, T
dose
mode of 
administration
Oral with 240 mL of water after an overnight fast of at least 10 h
Reference product
BI 1015550 Formulation C1 as
Reference, R
dose
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h

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Duration of treatment
Single dose of each treatment, i.e., two single doses
Statistical methods
The assessment of bioequivalence will be based upon 2-sided 90% confidence 
intervals (CIs) for the ratios of the geometric means (test/reference) for the 
primary and secondary endpoints using an acceptance range of 80.00 to 
125.00%. This method corresponds to the two one-sided t-tests procedure, each 
at a 5% significance level. The statistical model will be an analysis of variance 
(ANOVA) on the logarithmic scale including effects for sequence, subjects 
nested within sequences, period and treatment. CIs will be calculated based on 
the residual error from the ANOVA and quantiles from the t-distribution.
Descriptive statistics will be calculated for all endpoints.

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18:00
Ambulatory visit
x
4
72:00
08:00
Ambulatory visit
x
x
5
96:00
08:00
Ambulatory visit
x
x
6
120:00
08:00
Ambulatory visit
x
x
7
144:00
08:00
Ambulatory visit
x
FU
4
17 to37
End of study (EoS) examination4
B
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening and 
pregnancy test), demographics (including determination of body height and weight, smoking status and alcohol history), 
relevant medical history, concomitant therapy and review of inclusion/ exclusion criteria.
2.
The time is approximate; the procedure is to be performed and completed within the 3h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of study (EoS), the EoS examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies.
5.
Urine drug screening and alcohol breath test as well as urine pregnancy test in all women will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
Letters A and B below define different sets of safety laboratory examinations (for details, refer to Section 5.2.3).
8.
The time is approximate, but no later than 10 hours prior to drug administration.
9.
For details of PK blood sampling, refer to Section 5.3.2.1.

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10. For details of 12-lead ECG, refer to Section 5.2.4.
11. For details of vital signs evaluation, refer to Section 5.2.2. Body weight will be determined at screening and EoS, refer 
to 5.2.1.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS AND DEFINITIONS..................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................13
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................14
1.4
BENEFIT - RISK ASSESSMENT ...................................................................15
1.4.1
Benefits...................................................................................................15
1.4.2
Risks .......................................................................................................15
1.4.3
Discussion...............................................................................................20
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 21
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......21
2.1.1
Main objectives......................................................................................21
2.1.2
Primary endpoints ................................................................................21
2.1.3
Secondary endpoint ..............................................................................21
2.2.2.2
Safety and tolerability..............................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 23
3.1
OVERALL TRIAL DESIGN............................................................................23
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................23
3.3
SELECTION OF TRIAL POPULATION ......................................................23
3.3.1
Main diagnosis for trial entry..............................................................23
3.3.2
Inclusion criteria...................................................................................24
3.3.3
Exclusion criteria ..................................................................................26
3.3.4
Withdrawal of subjects from treatment or assessments ...................27
3.3.4.1
Withdrawal from trial treatment ..............................................28
3.3.4.2
Withdrawal of consent to trial participation ............................29
3.3.4.3
Discontinuation of the trial by the sponsor..............................29

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3.3.5
Replacement of subjects .......................................................................29
4.
TREATMENTS........................................................................................ 31
4.1
INVESTIGATIONAL TREATMENTS ..........................................................31
4.1.2
Selection of doses in the trial................................................................31
4.1.3
Method of assigning subjects to treatment groups ............................31
4.1.4
Drug assignment and administration of doses for each subject .......32
4.1.5
Blinding and procedures for unblinding ............................................32
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
4.2.2.3
Contraception requirements.....................................................36
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................................................................................41
5.2.5
Other safety parameters.......................................................................41
5.2.6
Assessment of adverse events...............................................................41
5.2.6.1
Definitions of adverse events...................................................41
5.2.6.1.1 Adverse event ............................................................41
5.2.6.1.2 Serious adverse event ................................................42
5.2.6.1.3 AEs considered ‘Always Serious’.............................42
5.2.6.1.4 Adverse events of special interest .............................43
5.2.6.1.5 Intensity (severity) of AEs.........................................44
5.2.6.1.6 Causal relationship of AEs ........................................44
5.2.6.2
Adverse event collection and reporting ...................................45
5.2.6.2.1 AE collection.............................................................45
5.2.6.2.2 AE reporting to the sponsor and timelines ................46
5.2.6.2.3 Pregnancy ..................................................................46
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................47
5.3.1
Assessment of pharmacokinetics .........................................................47
5.3.2
Methods of sample collection...............................................................47

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5.5
BIOBANKING ...................................................................................................48
5.6
OTHER ASSESSMENTS .................................................................................48
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................48
6.
INVESTIGATIONAL PLAN.................................................................. 49
6.1
VISIT SCHEDULE............................................................................................49
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................49
6.2.1
Screening period....................................................................................49
6.2.2
Treatment periods.................................................................................50
6.2.3
Follow-up period and trial completion ...............................................50
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 51
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................51
7.2
PLANNED ANALYSES....................................................................................51
7.2.1
General considerations.........................................................................51
7.2.1.1
Analysis sets.............................................................................51
7.2.1.2
Pharmacokinetics.....................................................................52
7.2.2
Primary endpoint analyses...................................................................52
7.2.3
Secondary endpoint analyses ...............................................................54
7.2.5
Safety analyses.......................................................................................54
7.3
HANDLING OF MISSING DATA ..................................................................55
7.3.1
Safety......................................................................................................55
7.3.2
Pharmacokinetics..................................................................................55
7.4
RANDOMISATION ..........................................................................................55
7.5
DETERMINATION OF SAMPLE SIZE ........................................................55
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

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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 .................................60
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......60
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.....................................................................63
10. APPENDICES .......................................................................................... 64
11. DESCRIPTION OF GLOBAL AMENDMENT................................... 68
11.1
GLOBAL AMENDMENT 1 .............................................................................68
11.2
GLOBAL AMENDMENT 2 .............................................................................69

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ABBREVIATIONS AND DEFINITIONS
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury

Bioequivalence margin
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EoS
End of Study
EU Trial No. 
Clinical Trials Information System number

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FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
GMP
Good Manufacturing Practice
HBsAg
hepatitis B surface antigen
HCV Ab
hepatitis C virus antibody
HIV
human immunodeficiency virus
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
iPD
Important protocol deviation
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MACE
Major Adverse Cardiovascular Events
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NOAEL
No observed adverse effect level
PD
Pharmacodynamic(s)
PPF
Progressive Pulmonary Fibrosis
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
OCs
oral contraceptives
QT interval
ECG interval from the start of the QRS complex to the end of the T wave
QTc interval
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening

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SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
T
Test product or treatment
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WOCBP
Woman of child bearing potential
WNOCBP
Woman not of child bearing potential

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1.
INTRODUCTION
BI 1015550 is an oral preferential PDE4B inhibitor being developed by BI for the treatment
of adult patients with Idiopathic Pulmonary Fibrosis (IPF) and Progressive Pulmonary 
Fibrosis (PPF). It is currently investigated in a clinical phase 3 program.
1.1
MEDICAL BACKGROUND
For information about IPF and PPF, refer to the current Investigator’s Brochure (IB) 
[c02094779].
1.2
DRUG PROFILE
For detailed information about the drug profile of BI 1015550, refer to the current 
Investigator’s Brochure (IB) [c02094779].
1.2.2
Clinical safety
BI 1015550 showed acceptable safety and tolerability following single dose administrations 
up to 48 mg and multiple administrations for up to 12 weeks with up to 
 BID.
In healthy volunteer studies, headache, abdominal pain, nausea and diarrhoea, all of mild to 
moderate intensity, were the most commonly reported events. A trend toward weight loss in 
subjects treated with BI 1015550 was observed in study 
 in healthy volunteers. No 
severe, serious, fatal AEs, nor SUSARS have been reported in the healthy volunteer studies.

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In patients with IPF, two clinical studies have been completed with BI 1015550: a Phase 
Ic MRD study in patients without background antifibrotic treatment 
and a proof-of-clinical principle phase 2 study in patients stratified by background antifibrotic 
treatment 
Overall, in Phase Ic and II trials in patients with IPF, BI 1015550 at a dose of 
 bid for 
up to 12 weeks showed acceptable safety and tolerability, in phase 2, also with background 
antifibrotic treatment (nintedanib or pirfenidone). In phase 2, the most common AEs were GI 
events (more specifically diarrhoea), which were reported with a higher frequency under 
BI 1015550 treatment (vs. placebo) and in patients with background antifibrotic treatment.
 vital signs 
(including body weight) or ECG parameters (including QTc) were observed. No changes in 
the C-SSRS and no AEs of suicidal ideation or behaviour were reported during trial 
treatment.
1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 1015550 tablets (Formulation C1) used in the phase 3 safety and efficacy trial contain, 
amongst others, 
 as a standard pharmaceutical excipient in common amounts. 
BI decided to produce a 
 tablet BI 1015550 Formulation C2 as the 
to-be marketed formulation.
This study will be performed in order to bridge data between these two different 
formulations, i.e., between a formulation used in the pivotal clinical studies (BI 1015550 
Formulation C1) and the 
 BI 1015550 Formulation C2 that will be marketed..

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1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance to establish bioequivalence between 
1.4.2
Risks
Subjects are exposed to risks of trial procedures and risks related to the exposure to the trial 
medication. An overview of trial-related risks is given in Table 1.4.2: 1.
Potential side effects of BI 1015550 will be under continuous evaluation during clinical 
development. Vasculitis and foetal loss are considered as important potential risk based only 
on non-clinical findings. The risks shown in the table below are hypothetical in nature; these 
are derived from general safety considerations of immunomodulatory drugs and from 
preclinical and clinical data of compounds with a comparable mode of action. For adverse 
events reported during clinical trials with BI 1015550, refer to Section 1.2.2.

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Table 1.4.2: 1
Overview of trial-related risks for this trial
Possible or known risks of 
clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product: BI 1015550

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Major Adverse
Cardiovascular Events
(MACE) and
tachyarrhythmia
Important potential risk for
marketed PDE4 inhibitor
apremilast.
In preclinical studies with
BI 1015550, no adverse
cardiovascular findings were 
detected - focal myocardial 
degeneration or necrosis in 
monkeys were with no apparent 
vascular changes.
In clinical trials with 
BI 1015550, no relevant findings
were observed.
These risks will be addressed by careful 
safety monitoring and safety measures, 
e.g., close clinical monitoring for AEs;
regular monitoring of vital signs and 
ECG assessments.
Subjects will stay in the Phase I unit 
under close medical surveillance until at
least 24 h after the drug administration 
in each treatment period.

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Psychiatric disorders:
Depression and anxiety
Suicidality
For the marketed PDE4i
depression is listed as side effect 
and they are associated with 
increased risk of depression with 
some patients reporting suicidal 
ideation and attempts and also 
reported cases of completed 
suicide.
Prospective assessment of
suicidal ideation and behaviour
and depression are not required
in single-dose trials in healthy
volunteers.
The risk after 2 single dose
administrations in Phase I (done on site) 
is considered to be low and will be 
addressed by careful close clinical
monitoring for AEs and increased 
awareness by the investigator for signs 
and symptoms of depression and
anxiety as well as for signs and 
symptoms of suicidal ideation and 
behaviour.
Only healthy subjects with no relevant 
medical history including psychiatric
disorders will be enrolled.
Severe infections including, 
serious, opportunistic and
mycobacterium tuberculosis 
infections
Inhibition of the immune
response due to the anti-
inflammatory mode of action of
BI 1015550 potentially increases 
the risk of severe and serious 
infections.
Screening procedures for infections are 
defined for this trial. Subjects with any
relevant chronic or acute infections are 
excluded from the trial.
Close monitoring to detect potential 
infections promptly will minimise the
risk of serious infection.

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Malignancies
Inhibition of the immune
response with an
immunomodulatory drug may
potentially impair immune
defences and thus, theoretically
decrease immune defence
against malignancies.
Subjects with a recent history of 
malignancy within 5 years will be 
excluded from participation in this trial.
In case of occurrence of malignant 
neoplasm other than appropriately 
treated basal cell carcinoma or
squamous cell carcinoma of the skin or 
in situ carcinoma of uterine cervix, the
investigator should discontinue trial 
treatment.
Diagnostics and treatment have to be 
initiated according to local standard of 
care.
The risk after 2 single dose
administrations in Phase I is considered 
low.
Gastrointestinal disorders
(e.g., diarrhoea, nausea,
vomiting, abdominal pain)
Vomiting and diarrhoea are
important dose-limiting side
effects of marketed oral PDE-4
inhibitors.
Increased awareness of symptoms.
Careful monitoring of hydration in 
subjects with diarrhoea recommended.
Symptomatic treatment if required.
Drug-induced liver injury 
(DILI)
Rare but severe event, thus under 
constant surveillance by 
sponsors and regulators.
Timely detection, evaluation, and 
follow-up of laboratory alterations in 
selected liver laboratory parameters to 
ensure subjects´ safety.
Increased awareness and expedited 
reporting (AESI).
Trial procedures
Bruising and, in rare cases, 
phlebitis, or nerve injury, 
potentially resulting in 
paraesthesia, reduced 
sensibility, and/or pain.
General risk by venipuncture for 
blood sampling, acceptable in 
the framework of trial 
participation.
Medical expertise of the trial site.
Local skin irritation and
discomfort.
General risk from ECG stickers,
acceptable in the framework of
trial participation.
Medical expertise of the trial site.
The total volume of blood withdrawn per subject during the entire trial will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.

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1.4.3
Discussion
The nature of the target and the mechanism of action of BI 1015550 is well understood.
BI 1015550 is an oral preferential inhibitor of the PDE4B with broad anti-inflammatory and
antifibrotic activities. 
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. In 
the current trial, adequate safety monitoring including vital signs, ECG, safety laboratory and 
AE monitoring has been implemented. Taking into account these safety measures, as well as 
available preclinical and clinical data, potential risks to healthy subjects are considered to be 
low and outweighed by the benefit of a successful clinical development of BI 1015550 in the 
context of the unmet medical need in IPF and other forms of progressive pulmonary fibrosis.

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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 establish the bioequivalence of the BI 1015550
Formulation C2 (Test, T) and the BI 1015550 Formulation C1 (Reference, R) –
 tablet, 
following a single oral dose administration.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for R-BI 1015550:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for R-BI 1015550:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

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2.2.2.2
Safety and tolerability
Safety and tolerability of 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

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
The trial will be performed as an open-label, randomised, single-dose, two-way crossover 
trial in healthy male and female subjects in order to compare the test treatment (T) to the
reference treatment (R). The treatments consist of 
For details, refer to Section 4.1.
Subjects will be randomly allocated to the 2 treatment sequences (T-R or R-T).
There will be a washout period of at least 10 days between the administration of each 
treatment.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For bioequivalence trials, the crossover design is preferred because of its efficiency: Since 
each subject serves as his/her own control, the comparison between formulations is based on 
an intra-subject comparison, thus removing inter-subject variability from the comparison 
between formulations [R94-1529].
The open-label treatment is not expected to bias results, since the trial endpoints are derived 
from measurement of plasma concentrations of the analyte, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 64 healthy male and female subjects (at least 14 subjects of each sex) will 
enter the trial. They will be recruited from the volunteers' pool of the trial site.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF, irrespective of whether they have been treated with investigational 
drug or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy subjects.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.

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3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male or female subject 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 50 years (inclusive)
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
5. Male subjects who meet any of the following criteria for a highly effective contraception 

Use of condom

Sexually abstinent is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
subject.

Surgically sterilised
6. Female subject who meets any of the following criteria for a highly effective 
contraception 
Highly effective methods of contraception include:

Use of oral hormonal contraception that prevents ovulation, plus condom

Use of combined (estrogen and progestogen-containing) hormonal contraception that 
prevents ovulation (intravaginal or transdermal)

Use of progestogen-only hormonal contraception that inhibits ovulation (only
injectables or implants)

Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

Sexually abstinent is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject.

Bilateral tubal occlusion
7. Women not of non-childbearing potential (WNOCBP) include:
8. Permanently surgically sterilised (including hysterectomy, bilateral oophorectomy and 
bilateral salpingectomy)

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9. Postmenopausal, defined as no menses for 1 year without an alternative medical cause (in 
questionable cases a blood sample with levels of FSH above 40 U/L and estradiol below 
30 ng/L is confirmatory)
10. WNOCBP are not required to use any methods of contraception. Female subjects should 
not participate in egg donation and male subjects should not participate in sperm donation 
from the first study drug administration, 
 

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3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm at screening
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance, in particular, hepatic parameters (ALT, AST, total bilirubin) or renal 
parameters (creatinine) exceeding the ULN at screening
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 assessed as clinically relevant by the investigator
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.
 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Relevant chronic or acute infections within the 30 days prior to first drug administration
10. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ 
carcinoma of uterine cervix
11. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients)
12. Use of drugs within 30 days (or 5 half-lives, whichever is longer) of planned
administration of trial medication that might reasonably influence the results of the trial 
(including drugs that cause QT/QTc interval prolongation)
13. Intake of an investigational drug in another clinical trial within 90 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
14. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
15. Inability to refrain from smoking on specified trial days
16. Alcohol abuse (consumption of more than 12 g per day for females and 24 g per day for
males)
17. Drug abuse or positive drug screening
18. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial

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19. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
20. Inability to comply with the dietary regimen of the trial site
21. A marked prolongation of QT/QTc interval (e.g., QTc intervals that are repeatedly greater 
than 450 ms in males or repeatedly greater than 470 ms in females) or any other relevant 
ECG finding at screening
22. A history of additional risk factors for Torsade de Pointes (e.g., heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
23. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
24. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
25. For female subjects: Lactation, pregnancy, or plans to become pregnant during the trial or 
26. For female subjects: Positive pregnancy test
27. Concomitant intake 
 
and unselective PDE inhibitors (e.g., 
theophylline, roflumilast, apremilast)
28. History or signs 
29. Relevant immunodeficiency
30. History of
 
31. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or 
human immunodeficiency virus (HIV) 1 and 2 antibody results at screening
32. Subjects who do not have suitable veins for multiple venepunctures/cannulation as 
assessed by the investigator or delegate at screening
33. Subjects who are, or are immediate family members of, a study site or sponsor employee
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may withdraw or may be removed from trial treatment or may withdraw consent to 
trial participation as a whole (‘withdrawal of consent’) with very different implications; 
please see Sections 3.3.4.1 and 3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR).

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If a subject is removed from or withdraws from the trial after the first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, trial data will be included in the CRF and will be reported in the CTR.
Following removal or withdrawal, a complete end-of-study examination should be 
performed. If the discontinuation or withdrawal 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
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:
1. The subject wants to withdraw from trial treatment. The subject will be asked to explain 
the reasons but has the right to refuse to answer.
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, the safety of the 
subject cannot be guaranteed as he / she is not willing or able to adhere to the trial 
requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment.
4. The subject can no longer receive trial treatment for medical reasons (e.g., pregnancy, 
surgery, adverse events (AEs), or diseases), in particular, if an AE of severe intensity or a 
serious adverse event (SAE) occurs.
5. The subject fulfils the criteria of a ‘Potential Severe DILI’ (see Section 5.2.6.1.4) and/or 
needs to be followed up according to the DILI checklist provided in the ISF.
6. The subject has relevant individual QT prolongations, i.e., a QTcF increase of greater 
than 60 ms from baseline and/or with absolute QT or QTcF greater than 500 ms, as 
confirmed by a repeat ECG recording.
7. Subjects that experience an unexplained and clinically significant (>10%) weight loss 
during trial treatment.
8. If any of the following AEs is reported, the treatment has to be discontinued:
12. Of note, depending on the current status of the COVID-19 pandemic/endemic, all subjects 
with confirmed SARS CoV-2 infection will be handled in accordance with local guidance 
and SOPs meaning that any confirmed SARS CoV-2 infection during the conduct of the 
trial will lead to discontinuation of the subject (refer to Section 1.4.2).
13. In addition to these criteria, the investigator may discontinue subjects at any time based 
on his or her clinical judgment.

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14. If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. 
The subject is to be followed until she has given birth or until the end of the pregnancy. 
The subject’s data are to be collected until the end of the trial (last visit of last subject) 
and reported in the CTR. For reporting of pregnancy and associated events, refer to 
Section 5.2.6.2.3
15. If new efficacy or safety information becomes available, Boehringer Ingelheim will 
review the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment 
for all subjects or take any other appropriate action to guarantee the safety of the trial 
subjects.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (if reasons 4 and/or 5 are met, the trial should be discontinued 
immediately):
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. The sponsor decides to discontinue the further development of the investigational 
products.
3. Deviation from GCP, or the CTP, or the contract with BI impairing the appropriate 
conduct of the trial
4. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment (see Section 3.3.4.1).
5. Dissolution (in vitro) examinations establish bioequivalence of the two to-be-tested 
formulations and make this trial superfluous.
The investigator/ trial site will be reimbursed for reasonable expenses incurred in case of trial 
termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than 6 subjects do not complete the trial (including subjects non- evaluable for 
PK), subjects may be replaced if considered necessary to reach the objective of the trial.
Subjects who withdraw or are withdrawn from treatment or assessments because of a drug-
related adverse event will not be replaced. The Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. The total number of replacements may not exceed 1/3 of the total number of 

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evaluable subjects anticipated to complete the trial. A replacement subject will be assigned a 
unique trial subject number, and will be assigned to the same treatment sequence as the 
subject he or she replaces.
In case of replacement of subjects, the trial site should ensure that the requirements for 
distribution of sex (at least 14 of each sex) are still met within the overall group of treated 
subjects.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.2
Selection of doses in the trial
The dose selected for this trial is one of the standard clinical doses.
4.1.3
Method of assigning subjects to treatment groups
The randomisation scheme will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). 
Prior to the start of the trial, subjects willing to participate will be recruited according to their 
temporal availability. In the morning of Day 1 (Visit 2), subjects will be allocated to 
treatment sequences prior to the first administration of trial medication according to the 
randomisation scheme.
Once a subject number has been assigned, it cannot be reassigned to any other subject.

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All subjects may receive treatment on the same calendar day. In case this is not feasible (e.g., 
due to logistical or recruitment reasons), the group may be split into several cohorts as 
required. Treatment of all subjects on the same calendar day is acceptable. The randomisation 
procedure is described in Section 7.4.
4.1.4
Drug assignment and administration of doses for each subject
This is a 2-way crossover trial. All subjects will receive the 2 treatments in randomised order. 
The treatments to be evaluated are summarised in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Reference (R)
BI 1015550
Film-coated 
tablet 
(Formulation 
C1 -
 
Test (T)
BI 1015550
Film-coated 
tablet 
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 standing position. Subjects will fast 4 additional 
hours post-drug administration. 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, if correct dosage cannot be ensured otherwise.
Subjects will be kept under close medical surveillance until 24 h 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).
The treatments will be separated by a wash-out phase of at least 10 days.
4.1.5
Blinding and procedures for unblinding
The table below summarizes the masking/blinding level of individual functions, roles and 
responsibilities involved in the trial.

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Table 4.1.5: 1
Blinding level of individual functions
Role/function
Timing of Unblinding / receiving access to the treatment information 
(including rationale)
Subject/Participant
Subjects will be aware of the order of the 2 treatments as soon as the treatment
sequence has been assigned.
Investigator/Site Staff
As requested to prepare trial site prior to first subject entered.
Sponsor trial team 
and data
Unblinded as requested.
Bioanalytical Staff
Persons directly involved in bioanalyses of PK samples will be blinded to trial 
treatments until data ready for final analysis.
Pharmacokineticist/
Pharmacometrician
Unblinded as requested.
Unblinded Pharmacist/ 
Pharmacy staff
Prior to first subject entered.
During the time a role/function is blinded according to the table above, the randomisation 
schemes and medication kit lists (i.e., the treatment information) are kept restricted by the 
global Randomization Team per Sponsor SOP.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with the principles of Good Manufacturing Practice (GMP).
For details of packing and the description of the label, refer to the ISF. The labels will be 
prepared according to Regulation (EU) No 536/2014, Annex 6 omitting certain particulars 
with the following justifications:

The visit number is not relevant for the label because the product will remain at the 
clinical site.

The investigator name was omitted from the label because it is included on the Trial 
Identification Card which will be issued to each trial participant.

The "keep out of reach of children" statement was omitted from the label because the 
product will remain at the clinical site.
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 EU Trial number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms.
This trial is covered by the FDA requirements 21CFR320. Therefore, the packaging and 
labelling must be performed in such a way that the required reserve samples are available for 
storage by the investigational site and that the trial materials can be chosen in a random way 
by the Investigator.

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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 
Clinical Research Associate (as provided in the list of contacts) is to be contacted
immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB/ ethics committee

Availability of a signed and dated clinical trial contract between the sponsor or 
delegate 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 ‘Staff Delegation Log’ may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. These 
records will include dates, quantities, batch/ serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.

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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
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 except for hormonal contraceptives. All 
concomitant or rescue therapies will be recorded (including time of intake on trial days) on 
the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all 
subjects). From lunch until 24 h post-dose, total fluid intake is restricted to 3000 mL.

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Subjects should refrain from eating food containing poppy seeds for 48 h prior to screening 
and for 48 h prior to admission until the end of in-house confinement in each treatment 
period.
Methylxanthine-containing drinks or foods (e.g., coffee, tea, cola, energy drinks, or 
chocolate) are not allowed during in house confinement.
Smoking is not allowed during in-house confinement.
Alcoholic beverages are not allowed from 48 h before administration of trial medication until 
the end of in-house confinement in each treatment period.
No blood or plasma (outside of this study) must be donated from screening until for at least 
90 days following the last dose of study medication.
Excessive physical activity (e.g., competitive sport) should be avoided from 7 days before the 
first administration of trial medication until the end of study examination.
4.2.2.3
Contraception requirements
If female subjects of child-bearing potential are included in the trial, adequate contraception 
is to be maintained throughout the course of the trial (see Section 3.3.2 for the definition of 
adequate measures).
Female subjects should not participate in egg donation and male subjects should not 
participate in sperm donation from dosing, for the duration of the study and for at least 7 days 
after last IMP administration.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).

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

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes
White Blood Cells/Leucocytes
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; Lymphocytes/Leukocytes 
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; Monocytes, 
absol.; Lymphocytes, absol.
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs)/Leukocytes; Neut. Poly (segs), absol.; Neutrophils 
Bands/Leukocytes; Neutrophils Bands, absol.; 
Eosinophils/Leukocytes; Eosinophils, absol.; 
Basophils/ Leukocytes; Basophils, absol.; Monocytes/Leukocytes; 
Monocytes, absol.; Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
Prothrombin time – INR (International Normalization Ratio)
X
X
X
X
X
X
Enzymes
AST [Aspartate aminotransferase] /GOT, SGOT
ALT [Alanine aminotransferase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated]
Lactic Dehydrogenase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
X
--
A: parameters to be determined at Visit 1 (screening examination)
B: parameters to be determined at Visit 2 and 3, on Day -1 and Day 2, and EoS (for time points refer to Flow Chart)

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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic examination 
if erythrocytes, 
leukocytes nitrite or 
protein are abnormal in 
urine)
Only positive findings will be reported (for instance, the presence of 
sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
A: parameters to be determined at Visit 1 (screening examination)
B: parameters to be determined at Visit 2 and 3 on Day -1 and Day 2, and EoS (for time points refer to Flow Chart)
*
Samples are taken, stored appropriately at the site and only analysed if signs and symptoms of vasculitis appear.
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. Pregnancy testing in women will be performed at screening, prior to each treatment 
period. Drug screening will be performed at screening and prior to each treatment period.

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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/Ecstasy
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Hepatitis B DNA PCR (quantitative)1
COVID-19 (nasopharyngeal
swab)4
SARS CoV-2 PCR test or antigen test at screening and prior to admission 
in each treatment period
Pregnancy tests
In serum: beta human chorionic gonadropin (beta HCG) at screening
In urine: beta human chorionic gonadropin (beta HCG)
1 
to be conducted if Hepatitis B core antibody is positive and Hepatitis B surface antigen is negative.
4 
if needed due to the current status of the pandemic/endemic, evaluation will be performed at screening and shortly 
(within 72 h) before admission to trial site as per Flow Chart.
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g., AlcoTrue®
M, 
) will be performed prior to each treatment period, 
and may be repeated at any time during the trial at the discretion of an investigator or 
designee. The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
, with the exception of drug 
screening and pregnancy tests in urine. These tests will be performed at the trial site Surestep 
Multiline test (Ref. No. DOA-1124-031 or DOA-1105-031) and Cleartest® Diagnostik HCG 
test, respectively, or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
The safety laboratory tests’ results will not be entered in the CRF. It is the responsibility of 
the Investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the Investigator are to be reported as adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4).

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5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (e.g., MAC VU360, 
) at the times 
provided in the Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other trial procedures scheduled 
for the same time to avoid compromising ECG quality.
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). Precise electrode placement will be marked with an 
indelible mark on the skin to allow reproducible placement throughout the trial.
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 (if identified at the 
screening visit) if assessed to be clinically relevant by the investigator. Any ECG 
abnormalities will be carefully monitored and, if necessary, the subject will be removed from 
the trial and will receive the appropriate medical treatment.
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons.
5.2.5
Other safety parameters
Not applicable.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

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
Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death

Is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe

Requires inpatient hospitalisation, or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital anomaly/birth defect

Is deemed serious for any other reason, if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.

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5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g., the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters
1.
AST (aspartate aminotransferase) and/ or ALT (alanine aminotransferase) 
elevation ≥3x ULN and TB (total bilirubin) ≥2x ULN measured at the same 
visit, or in samples drawn within 30 days of each other, OR
2.
AST and/ or ALT elevation ≥3x ULN and INR ≥1.5x ULN measured at the 
same visit, or in samples drawn within 30 days of each other, OR
3.
AST and/ or ALT elevation ≥3x ULN with new onset, or worsening of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/ or 
eosinophilia (>5%), OR
4.
AST and/ or ALT elevation ≥5x 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 system. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.

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5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors, e.g., 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)

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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

There is an alternative explanation (e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently.
Subjects will be required to report spontaneously any AEs. In addition, each subject will be 
regularly assessed by the medical staff throughout the clinical trial and whenever the 
investigator deems necessary. As a minimum, subjects will be questioned for AEs (and 
concomitant therapies) at the time points indicated in the Flow Chart. Assessment will be 
made using non-specific questions, e.g., ‘How do you feel?’. Specific questions will be asked 
wherever necessary in order to more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of study
(the End of Study (EoS) visit): 
o
All AEs (serious and non-serious) and all AESIs.
o
The only exception to this rule are AEs (serious and non-serious) and AESIs in 
Phase I trials in healthy volunteers, when subjects discontinue from the trial due to 
screening failures prior to administration of any trial medication. In these cases, 
the subjects’ data must be collected at trial site but will not be entered in the CRF 
and will not be reported in the CTR.

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
After the individual subject’s end of study:
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and trial treatment related SAEs and 
trial treatment related AESIs of which the investigator may become aware of by 
any means of communication, e.g. phone call. Those AEs should be reported on
the BI SAE form (see Section 5.2.6.2.2), but not on the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 
24 hours of becoming aware of the event, the country specific reporting process will be 
provided in the ISF. The same timeline applies if follow-up information becomes available. 
On specific occasions, the Investigator could inform the sponsor upfront via telephone. This 
does not replace the requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after the individual subject’s end of study, 
must be followed up until they have resolved, have been sufficiently characterized (e.g. as 
‘chronic’ or ‘stable’), or no further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported, if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy 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 Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Studies (Part A and Part B).
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 Studies 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.

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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters.
5.3.2
Methods of sample collection

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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.

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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 study examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for vital signs, ECG, and laboratory tests will be ± 30 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled, if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening 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 trial.

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For information regarding laboratory tests (including drug and virus screening, and
pregnancy test in females), ECG, vital signs, and physical examination, refer to Sections 
5.2.1 to 5.2.5.
Screening safety procedures, e.g., blood sampling for safety laboratory, ECGs, vital signs, 
alcohol breath tests and urinalysis can be repeated as clinically indicated upon the discretion 
of the investigator or sub-investigator, if there is a concern regarding a subject’s safety or 
eligibility to participate in the trial.
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Days -1, 1 to 7 in each period). 
On Day -1 of each treatment period, trial participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration. The 
subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness. On all other trial days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis,
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed
continuously from obtaining subject’s written informed consent until the end of study
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoS Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS
Visit for continued safety monitoring.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoS Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
Although there are multiple primary endpoints, an alpha adjustment is not needed because it 
is required that all primary endpoints meet the equivalence criterion as described below 
simultaneously. Therefore, a one-sided alpha of 5% will be used for testing.
The assessment of bioequivalence will be based upon two-sided 90% confidence intervals 
(CIs) for the ratio of the geometric means (test/reference) for the primary and secondary
endpoints using an acceptance range of 80.00 - to 125.00%. This method is equivalent to the 
two-sided t-test procedure, each at the 5% significance level.
The following hypotheses are tested:
Null hypothesis H0 (Inequivalence):
δ
μ
μ
δ
μ
μ
R
T
R
T





or
where 
T

and 
R

are the means of the log-transformed endpoint for the test and reference 
treatments, respectively, and δ is the bioequivalence limit that defines the acceptance range 
on the logarithmic scale.
Alternative hypothesis Ha (Equivalence):
δ
μ
μ
δ
R
T




In this trial, the bioequivalence limit δ is ln(1.25). By back-transforming (exponentiating), 
this translates to an acceptance range of 80.00 to 125.00% for the ratio of the geometric 
means (test/reference) for endpoints on the original scale.
The rejection of the null hypothesis at the = 0.05 level is equivalent to the inclusion of the 
90% confidence interval for 
R
T



in the acceptance range (-δ, δ).
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial drug. The treated set will be used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he/she 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model-based analyses of PK parameters will be based on the PKS.
Descriptions of additional analysis sets may be provided in the TSAP.

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Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be suggested in the iPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the iPD categories will be updated as needed.
7.2.1.2
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for R-BI 1015550 will be 
calculated according to the relevant BI internal procedures. 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Important protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which are flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.2.2
Primary endpoint analyses
Primary analyses
The primary endpoints (refer to Section 2.1.2) will be calculated with Non-Compartmental 
Analysis (NCA).
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-

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transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: sequence, subjects within 
sequences, period and treatment. The effect 'subjects within sequences' will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving 
treatment k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2,
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2,
k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Bioequivalence is considered established if the 90% confidence intervals of the geometric 
means for the primary endpoints are contained in the pre-defined acceptance range, see 
Section 7.1.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, ‘treatment’) 
considered as fixed effects.
In addition to the model based approach all parameters will be analysed descriptively.

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7.2.3
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated using NCA and will be 
assessed statistically using the same methods as described for the primary endpoints.
7.2.5
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 (e.g., ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the time of the measurement or 
on the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements performed or AEs recorded prior to first intake of trial medication will be 
assigned to the screening period, those between first trial medication intake and end of REP 
(see Section 1.2.3) will be assigned to the first treatment period. AEs recorded between 
second trial medication intake and end of REP (see Section 1.2.3) will be assigned to the 
second treatment period. Events occurring after the REP but prior to next intake or end of 
study 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 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, e.g., combined treatments, on-
treatment totals, or periods without treatment effects (e.g., 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 without consideration of 
treatment periods.

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Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be highlighted in the listings. Additionally, differences from baseline will be 
evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
For laboratory data and vital signs, baseline is defined as measurement prior to first drug 
administration.
Relevant ECG findings will be reported as AEs.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures.
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.4
RANDOMISATION
Subjects will be randomised to one of the 2 treatment sequences in a 1:1 ratio. The block size 
will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation scheme will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation scheme will contain additional blocks to allow for subject replacement 
(refer to Section 3.3.5).
7.5
DETERMINATION OF SAMPLE SIZE
The sample size for this trial was determined using assumptions on the intra-individual 
variability of the primary endpoints based on 
[c40013550] investigating 
formulation effect and food effect. For Cmax the intra-individual geometric coefficient of 
variation (gCV) for
 was estimated to be about 23%, while for AUC the gCV 
was about 8%. To account for possible higher variability of the new formulation C2 (i.e.,
treatment T), the expected maximum gCV in the sample size determination below is 30%.

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A sample size of 52 PK evaluable subjects is needed to achieve 90% power to reject both 
one-sided null hypotheses for Cmax each at the 5% level of significance in favour of 
bioequivalence. While a sample size of 12 evaluable subjects would suffice to achieve the 
analogous result for AUC .
Due to the high correlation between the primary endpoints, only Cmax will be considered for 
power calculations. Using a sample size of 52 subjects (26 per sequence group), the power to 
reject both one-sided null hypotheses for one parameter each at the 5% level of significance 
in favour of bioequivalence is displayed in Table 7.5: 1, under various assumptions for the 
T/R gMean ratio. To account for the uncertainty of the gCV, the table displays the power for 
an assumed gCV  of 25% and 30%.
Table 7.5: 1
Power for concluding bioequivalence (acceptance range 80-125%) 
based on a geometric coefficient of variation (gCV) up to 30% and for 
different expected ratios of geometric means (test/reference) in a 2x2 
crossover trial (N=52)
gCV [%]
gMean ratio (T/R) [%]*
92.5
95
100
105
25
90.7
96.9
99.6
97.2
30
80.0
90.2
97.1
90.9
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
From the above table, a sample size of 52 PK evaluable subjects will yield approximately 
90% power to conclude bioequivalence for an assumed gCV of 30% if the ratio is not more 
than 5% different from the ratio of 100% which reflects no difference in exposure. In 
addition, this sample size still provides approximately 80% power in case the ratio is not 
more than 7.5% different from 100% and the gCV is 30%, and more than 90% in case the 
ratio is 7.5% different from 100% and the gCV is 25%.
Accounting for a drop-out rate of approximately 15%, a total of N = 52 + 12 = 64 subjects are 
planned to be entered into the trial.
The calculations were performed as described by Diletti et al. [R94-1445] using the function 
power.TOST() of the R package PowerTOST Version 1.5-4 in R Version 4.1.2.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations. Investigators and site staff must adhere to 
these principles. Deviation from the protocol, the principles of ICH GCP or applicable 
regulations will be treated as ‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a general rule, no trial results should be published prior to finalisation of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject according to ICH-GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional subject-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional subject 
information must be given to each subject or the subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.

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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches.
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
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.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the subject, documented 
in their medical records, would be acceptable.
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.

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

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

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Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last subject
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
In EU/ EEA countries, this trial is sponsored by Boehringer Ingelheim Pharma GmbH & Co. 
KG, Binger Straße 173, 5216 Ingelheim am Rhein, Germany.
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. The investigators will have access to the BI web portal Clinergize to access 
documents provided by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required trial activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local Clinical Trial Managers
(CT Managers), Clinical Research Associates (CRAs), and investigators of 
participating trial sites
The trial medication will be provided by the 
 
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
Analyses of R-BI 1015550 concentrations in plasma will be performed at 
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI, or a contract research
organisation appointed by BI, according to BI SOPs.

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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
R17-2617
Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen 
P, et al. Opportunistic infections and biologic therapies in immune-
mediated inflammatory diseases: consensus recommendations for 
infection reporting during clinical trials and postmarketing surveillance.
Ann Rheum Dis; 2015; 74; 2107-2116. 2017-07-24
R94-1445
Diletti E, Hauschke D, Steinijans VW. Sample size determination for 
bioequivalence assessment by means of confidence intervals. Int J Clin 
Pharmacol Ther Toxicol 1992; 30 (suppl 1): S51-S58.
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
c02094779
Investigator’s Brochure BI 1015550 
c25085412
Clinical Trial Report 
c37065416
Clinical Trial Report 
c39775503
Memo “Assessment of requirement for male contraception”. 09 Jun 2022.
c40013550
Clinical Trial Report 
n00290709
A fertility and early embryonic development to implantation study of BI 
1015550 by oral gavage in male and female rats. CRL study no. 9001829, 
BI no. 21R070.

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10.
APPENDICES
10.1
RANDOMIZATION LIST (MOCK LIST)
Figure 10.1: 1

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Figure 10.1: 1
Randomization list (mock list) (cont.)

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Figure 10.1: 1
Randomization list (mock list) (cont.)

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Figure 10.1: 1
Randomization list (mock list) (cont.)

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11.
DESCRIPTION OF GLOBAL AMENDMENT
11.1
GLOBAL AMENDMENT 1
Date of amendment
11 Apr 2024
EudraCT number
EU number
2023-509950-67-00
BI Trial number
1305-0037
BI Investigational 
Medicinal Product(s)
BI 1015550
Title of protocol
Bioequivalence of the BI 1015550 high dose Formulation 
C2 and the BI 1015550 high dose Formulation C1 (phase 
3 formulation) following oral administration in healthy 
subjects (an open-label, randomised, single-dose, two-
way crossover trial)
Substantial Global Amendment due to urgent safety reasons 
Substantial Global Amendment 
Non-substantial Global Amendment
Section to be changed
1. Flowchart
2. Flowchart
3. Section 1.4.2
4. Inclusion Criteria
5. Table 5.2.3:2
6. Section 6.2.2
7. Section 8.1
Description of change
1. FU Days corrected at Visit 4
2. Wording in Footnote 5 corrected
3. Considerations on male contraception 
requirements adapted
4. Contraception adapted (male subjects must use a 
condom) included
5. Footnote taken out
6. Washout days between treatment periods adapted
7. Sentence regarding legally accepted 
representatives deleted
Rationale for change
1. Changed due to Inconsistency 
2. Changed due to Inconsistency
3. Due to RFI in PART II
4. Due to RFI in PART II
5. Due to RFI PART I
6. Changed due to inconsistency
7. Due to RFI PART I as it does not apply in this 
trial

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11.2
GLOBAL AMENDMENT 2
Date of amendment
15 May 2024
EudraCT number
EU number
2023-509950-67-00
BI Trial number
1305-0037
BI Investigational 
Medicinal Product(s)
BI 1015550
Title of protocol
Bioequivalence of the BI 1015550 high dose Formulation 
C2 and the BI 1015550 high dose Formulation C1 (phase 
3 formulation) following oral administration in healthy 
subjects (an open-label, randomised, single-dose, two-
way crossover trial)
Substantial Global Amendment due to urgent safety reasons 
Substantial Global Amendment 
Non-substantial Global Amendment
Section to be changed
1. 5.2.3 Safety laboratory parameters
Description of change
1. Pregnancy test entered to table 5.2.3: 2 Exclusionary 
laboratory tests
Rationale for change
1.
Entered into correct table 5.2.3: 2 due to 
inconsistency.

 
 
 
 
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clinical-trial-protocol-version-03
Bioequivalence of the BI 1015550 high dose Formulation C2 and the BI 1015550
high dose Formulation C1 (phase 3 formulation) following oral administration in
healthy subjects (an open-label, randomised, single-dose, two-way crossover trial)
Approval-Clinical Project 
15 May 2024 16:02 CEST
Author-Trial Statistician
15 May 2024 16:08 CEST
Author-Clinical Trial Leader
16 May 2024 06:50 CEST
Verification-Paper Signature
Completion
16 May 2024 14:03 CEST

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