The Effect of Food on the Pharmacokinetics of BI 1015550 (Formulation C2) Following Single Oral Dose Administration in Healthy Subjects (an Open-label, Randomised, Single-dose, Two-period, Two-sequence Crossover Design)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

BI-VQD-11906_40-106_AD-13 (8.0)
Clinical Trial Protocol
TITLE PAGE
Document Number:
c43335244-03
EU Trial No.
UTN: 
2023-509889-38-00
U1111-1301-0891
BI Trial No.
1305-0039
BI Investigational
Medicinal Product
BI 1015550
Title
The effect of food on the pharmacokinetics of BI 1015550 
(Formulation C2) following single oral dose administration in 
healthy subjects (an open-label, randomised, single-dose, two-
period, two-sequence crossover design)
Lay Title
A study in healthy people to test how BI 1015550 is taken up in 
the body when given with or without food
Clinical Phase
I
Clinical Trial Leader
Phone: +
Fax: +
 Investigator
Phone: +
Current Version, Date
Version 3.0, 16 May 2024
Original Protocol Date
13 Feb 2024
Page 1 of 64
Proprietary confidential information
© 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 2 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
13 February 2024
Revision date
16 May 2024
BI trial number
1305-0039
Title of trial
The effect of food on the pharmacokinetics of BI 1015550 (Formulation C2)
following single oral dose administration in healthy subjects (an open-label, 
randomised, single-dose, two-period, two-sequence crossover design)
 Investigator
Trial site
Clinical phase
I
Trial rationale
This trial is intended to investigate the effect of food on the pharmacokinetics of the 
BI 1015550 Formulation C2 as the to-be marketed formulation which is different 
from the phase 3 formulation
Trial objectives
The main objective is to investigate the effect of food on the pharmacokinetics of 
the 18 mg tablet of BI 1015550.
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-period, two-sequence crossover design
Number of subjects 
total entered
18
on each treatment
18
Diagnosis
Not applicable
Main inclusion criteria
Healthy male or female subjects (at least 6 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)
Reference treatment
BI 1015550 Formulation C2 as film-coated 18 mg tablet – Reference, R
dose
18 mg (one tablet)
mode of admin.
One 18 mg tablet orally with 240 mL of water after an overnight fast of at least 10 h

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 3 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
Test treatment
BI 1015550 Formulation C2 as film-coated 18 mg tablet – Test, T
dose
18 mg (one tablet)
mode of 
administration
One 18 mg tablet orally with 240 mL of water after a high-fat, high-calorie 
breakfast
Duration of treatment
Each of the two treatments is administered once
Statistical methods
For the main objective, the relative bioavailability will be estimated by the ratio of 
the geometric means (T/R) for the primary and secondary endpoints. Additionally, 
their two-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-test procedure, each at a 5% significance level. 
Since the main focus is on estimation and not testing, a formal hypothesis test and 
associated acceptance range is not specified. The statistical model will be an 
analysis of variance (ANOVA) on the logarithmic scale including effects for 
sequence, subjects within sequences, period and treatment. CIs will be calculated 
based on the residual error from the ANOVA. Descriptive statistics will be 
calculated for all endpoints.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 4 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
FLOW CHART
Period
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory7
PK blood9
12-lead ECG10
Vital signs (BP, PR)8
Questioning for AEs and 
concomitant therapy 6
SCR
1
-28 to -1
Screening (SCR)1
A
x
x
1/2 (two identical periods separated by a wash-out of at least 10 days
2/3
-1
-24:00
08:00
Admission to trial site
B
x5
x
x
x
1
-1:00
07:00
Allocation to treatment2 (visit 2 only)
x2
x2
x2
x2
-0:30
07:30
High fat, high calorie breakfast (Treatment 
T, only)
0:00
08:00
Drug administration
0:15
08:15
x
0:30
08:30
x
0:45
08:45
x
1:00
09:00
x
x
1:15
09:15
x
1:30
09:30
x
1:45
09:45
x
2:00
10:00
240 mL fluid intake
x
x
2:30
10:30
x
3:00
11:00
x
3:30
11:30
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3
x
11:00
19:00
Dinner3
12:00
20:00
x
x
2
24:00
08:00
B
x
x
x
x
34:00
18:00
x
3
48:00
08:00
Breakfast (voluntary),
discharge from trial site
x
x
58:00
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 to 2811
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
including pregnancy test, recording of AEs and concomitant therapies.
5.
Only 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 define different sets of safety laboratory examinations (for details, refer to Section 5.2.3).

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 5 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
8
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.
9.
For details of PK blood sampling, refer to Section 5.3.2.1.
10. For details of 12-lead ECG, refer to Section 5.2.4.
11. From Day 7 to Day 14 after the last drug administration

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 6 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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
1.2.1
Clincal pharmacokinetics.....................................................................13
1.2.2
Clinical safety ........................................................................................13
1.2.3
Residual Effect Period..........................................................................14
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...............................................................................................19
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 20
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......20
2.1.1
Main objectives......................................................................................20
2.1.2
Primary endpoints ................................................................................20
2.1.3
Secondary endpoint ..............................................................................20
2.2.2.2
Safety and tolerability..............................................................21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 22
3.1
OVERALL TRIAL DESIGN............................................................................22
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................22
3.3
SELECTION OF TRIAL POPULATION ......................................................22
3.3.1
Main diagnosis for trial entry..............................................................22
3.3.2
Inclusion criteria...................................................................................23
3.3.3
Exclusion criteria ..................................................................................24
3.3.4
Withdrawal of subjects from treatment or assessments ...................25
3.3.4.1
Withdrawal from trial treatment ..............................................26
3.3.4.2
Withdrawal of consent to trial participation ............................27
3.3.4.3
Discontinuation of the trial by the sponsor..............................27

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 7 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
3.3.5
Replacement of subjects .......................................................................27
4.
TREATMENTS........................................................................................ 29
4.1
INVESTIGATIONAL TREATMENTS ..........................................................29
4.1.1
Identity of the Investigational Medicinal Products ...........................29
4.1.2
Selection of doses in the trial................................................................29
4.1.3
Method of assigning subjects to treatment groups ............................29
4.1.4
Drug assignment and administration of doses for each subject .......29
4.1.5
Blinding and procedures for unblinding ............................................31
4.1.6
Packaging, labelling, and re-supply ....................................................31
4.1.7
Storage conditions.................................................................................32
4.1.8
Drug accountability ..............................................................................32
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................33
4.2.1
Other treatments and emergency procedures....................................33
4.2.2
Restrictions............................................................................................33
4.2.2.1
Restrictions regarding concomitant treatment .........................33
4.2.2.2
Restrictions on diet and life style.............................................33
4.2.2.3
Contraception requirements.....................................................34
4.3
TREATMENT COMPLIANCE.......................................................................34
5.
ASSESSMENTS....................................................................................... 35
5.1
ASSESSMENT OF EFFICACY.......................................................................35
5.2
ASSESSMENT OF SAFETY............................................................................35
5.2.1
Physical examination ............................................................................35
5.2.2
Vital signs...............................................................................................35
5.2.3
Safety laboratory parameters..............................................................35
5.2.4
Electrocardiogram................................................................................39
5.2.5
Other safety parameters.......................................................................39
5.2.6
Assessment of adverse events...............................................................39
5.2.6.1
Definitions of adverse events...................................................39
5.2.6.1.1 Adverse event ............................................................39
5.2.6.1.2 Serious adverse event ................................................40
5.2.6.1.3 AEs considered ‘Always Serious’.............................40
5.2.6.1.4 Adverse events of special interest .............................41
5.2.6.1.5 Intensity (severity) of AEs.........................................42
5.2.6.1.6 Causal relationship of AEs ........................................42
5.2.6.2
Adverse event collection and reporting ...................................43
5.2.6.2.1 AE collection.............................................................43
5.2.6.2.2 AE reporting to the sponsor and timelines ................44
5.2.6.2.3 Pregnancy ..................................................................44
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................45
5.3.1
Assessment of pharmacokinetics .........................................................45
5.3.2
Methods of sample collection...............................................................45

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 8 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................45
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................46
5.4
ASSESSMENT OF BIOMARKERS................................................................46
5.4.1
Drug-Drug Interaction Biomarkers ....................................................46
5.4.2
Pharmacodynamic biomarkers............................................................46
5.4.3
Pharmacogenomic biomarkers............................................................46
5.5
BIOBANKING ...................................................................................................46
5.6
OTHER ASSESSMENTS .................................................................................46
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................46
6.
INVESTIGATIONAL PLAN.................................................................. 47
6.1
VISIT SCHEDULE............................................................................................47
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................47
6.2.1
Screening period....................................................................................47
6.2.2
Treatment periods.................................................................................48
6.2.3
Follow-up period and trial completion ...............................................48
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 49
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................49
7.2
PLANNED ANALYSES....................................................................................49
7.2.1
General considerations.........................................................................49
7.2.1.1
Analysis sets.............................................................................49
7.2.1.2
Pharmacokinetics.....................................................................49
7.2.2
Primary endpoint analyses...................................................................50
7.2.3
Secondary endpoint analyses ...............................................................51
7.2.5
Safety analyses.......................................................................................51
7.2.6
Interim analyses ....................................................................................52
7.3
HANDLING OF MISSING DATA ..................................................................53
7.3.1
Safety......................................................................................................53
7.3.2
Pharmacokinetics..................................................................................53
7.4
RANDOMISATION ..........................................................................................53
7.5
DETERMINATION OF SAMPLE SIZE ........................................................53
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 55
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................55
8.2
DATA QUALITY ASSURANCE .....................................................................56
8.3
RECORDS..........................................................................................................56

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 9 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
8.3.1
Source documents .................................................................................56
8.3.2
Direct access to source data and documents.......................................57
8.3.3
Storage period of records.....................................................................57
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................58
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......58
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................58
8.6
TRIAL MILESTONES .....................................................................................58
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................59
9.
REFERENCES......................................................................................... 61
9.1
PUBLISHED REFERENCES...........................................................................61
9.2
UNPUBLISHED REFERENCES.....................................................................61
10. APPENDICES .......................................................................................... 62
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 63
11.1
GLOBAL AMENDMENT 1 .............................................................................63
11.2
GLOBAL AMENDMENT 2 .............................................................................64

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 10 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
ABBREVIATIONS AND DEFINITIONS
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
C2
Formulation C2 is TiO2-free formulation
CA
Competent authority
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
Cmax
Maximum measured concentration of the analyte in plasma
COVID-19
SARS-CoV-2 induced disease
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
Cytochrome P
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EFD
Embryo-Fetal Development
EoS
End of Study
FDA
Food and Drug Administration
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 11 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
IB
Investigator’s brochure
IEC
Independent Ethics Committee
iPD
Important protocol deviation
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NOAEL
No observed adverse effect level
NCA
Non-Compartmental Analysis
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PPF
Progressive Pulmonary Fibrosis
PR
Pulse rate
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
Rmax
Maximum rate of urinary excretion
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SCR
Screening
SMQ
Standardized MedDRA Queries
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

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 12 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
WOCBP
Woman of child bearing potential
WNOCBP
Woman not of child bearing potential

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 13 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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].
1.2.1
Clincal pharmacokinetics
BI 1015550 has a chiral sulfur within the sulfoxide group. The administered BI 1015550 
product in the clinical trials is in essentially chirally pure (R)-BI1015550 form (>99.5% 
chiral purity). 
 
 R-BI 1015550 was 
clearly identified as the predominant circulating enantiomer and (S)-enantiomer was 
determined to be a minor metabolite of (R)-enantiomer.
The previous pharmacokinetic (PK) characterization has utilized non-chiral assay that 
measured mixture of R-BI 1015550 and S-BI 1015550 as total BI 1015550. After oral 
administration, BI 1015550 is rapidly absorbed with peak plasma concentrations occurring at 
a median tmax of 1-4 h post-dose. 
 
After single and multiple oral doses, BI 1015550 exposure (Cmax and AUC0-∞) appeared to 
increase dose proportionally. 
 
. Accumulation ratio based on Cmax and AUC were 1.66 and 
1.87, respectively. Administration of BI 1015550 Formulation C1 (used in phase 3 trial) 
together with food did not change the exposure to BI 1015550 to a clinically relevant extent.
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 18 mg 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 1305-0011 [c22991937] in healthy 

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 14 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
volunteers. No severe, serious, fatal AEs, nor SUSARS have been reported in the healthy 
volunteer studies.
In patients with IPF, two clinical studies have been completed with BI 1015550: a Phase Ic 
MRD study in patients without background antifibrotic treatment (1305-0012, c25085412) 
and a proof-of-clinical principle phase 2 study in patients stratified by background antifibrotic 
treatment (1305-0013, c37065416).
Overall, in Phase Ic and II trials in patients with IPF, BI 1015550 at a dose of 18 mg 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.
In the phase 2 trial which investigated treatment with BI 1015550 18 mg bid for 12 weeks in 
patients with IPF, diarrhoea was the most common AE leading to discontinuation of 
treatment (3 out of 97 treated patients [3.1%]) and all AEs leading to discontinuation were 
reported in the BI 1015550 group. The frequency of SAEs in patients was numerically higher 
in placebo-treated patients, which was driven by placebo-treated patients without antifibrotic 
background treatment. Two patients with IPF treated with BI 1015550 had fatal AEs: one 
case of COVID-19 pneumonia and one case of suspected condition aggravated/suspected 
vasculitis; in both cases, risk factors were present. One AESI was reported (the fatal AE of 
suspected vasculitis), and evaluation by an external, independent DMC could neither confirm 
the diagnosis of vasculitis, nor a causal relationship with BI 1015550. There were no AESIs 
of hepatic injury. No relevant patterns, clusters or imbalances were observed for any of the 
other safety topics of interest, including depression, anxiety, malignancies, insomnia, major 
adverse cardiac events, or tachyarrhythmia. No clinically relevant changes in 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.
1.2.3
Residual Effect Period
. This is the period after the last 
dose during which measurable drug levels and/or pharmacodynamic effects are still likely to 
be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 1015550 tablets used in the phase 3 safety and efficacy trials (Formulation C1) contain, 
amongst others, titanium dioxide as a standard pharmaceutical excipient in common amounts. 
BI decided to produce a titanium dioxide-free tablet BI 1015550 Formulation C2 as the 
formulation to-be marketed.
This study will be performed to test the effect of food on the pharmacokinetics of the 
BI 1015550 Formulation C2 which is different than the formulation used in the phase 3 
(Formulation C1).

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 15 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of the BI 1015550 
Formulation C2.
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.
Table 1.4.2: 1
Overview of trial-related risks for this trial
Possible or known risks 
of clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product: BI 1015550
Vasculitis
Vasculopathy is an 
established preclinical 
toxicity finding of PDE4 
inhibitors.
Vasculitis has been shown in 
rats and minipigs following 
oral administration of BI 
1015550 but not in monkeys 
treated for up to 39 weeks.
Vasculitis is listed as an 
important potential risk for 
the marketed PDE4 inhibitor 
apremilast.
In marketed PDE4 inhibitors, 
vasculitis has not been 
identified as an adverse drug 
reaction in humans.
Close clinical monitoring for AEs of 
vasculitis.
Treatment will be interrupted in 
case of any suspected vasculitis 
adverse event.
Weight decrease in 
underweight patients 
(BMI < 18.5 kg/m2)
For the marketed PDE4i 
apremilast and roflumilast 
weight loss in underweight 
participants is an identified 
important risk.
Inclusion of subjects with BMI 
> 18.5 only is a routine inclusion 
criterion in Phase I.
Subjects who reach a BMI 
< 18.5kg/m2, and subsequently 
experience unexplained and 

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 16 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
clinically significant weight loss 
(>10%) will be discontinued from 
trial treatment.
Weight will be monitored 
throughout the study. With 2 single 
dose administrations of BI 1015550, 
the risk is considered to be very low.
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
Investigational Medicinal Product: BI 1015550
Reproductive toxicity: 
foetal loss, decreased 
fertility
No teratogenicity was seen in 
preclinical studies and 
exposure with BI 1015550 via 
the semen is expected to be 
very low.
In rats, male and female 
fertility was potentially 
reduced. Long-term toxicity 
studies with BI 1015550 in rat 
and monkey showed no 
microscopic evidence of 
changes in female 
reproductive organs or male 
spermatogenesis.
For another PDE4 inhibitor 
with comparable preclinical 
findings (class-effect), 
clinical data showed no effect 
on male fertility and sperm in 
humans.
Foetal loss was increased in 
female rats treated with BI 
1015550.
Women of childbearing potential 
(WOCBP) need to use a highly 
effective method of contraception 
from 30 days before first intake of 
trial drug
 
 
WOCBP 
taking oral contraceptives (OCs) 
also have to ensure the use of one 
barrier method during sexual 
intercourse with their partner, e.g., 
condom to account for the risk of 
potentially reduced efficacy of the 
OCs in the event of severe vomiting 
and diarrhea.
Thorough counselling about 
appropriate contraceptive measures.
Repeated pregnancy testing.
Discontinuation of trial treatment in 
case of pregnancy.
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.
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 

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 17 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
In clinical trials with 
BI 1015550, no relevant 
findings were observed.
administration in each treatment 
period.
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
Investigational Medicinal Product: BI 1015550
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.
In IPF patients treated with 
18 mg BI 1015550 bid up to 
12 weeks, no on treatment 
events of suicidal ideation or 
behaviour and no events of 
depression or anxiety were 
reported.
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.
Serious infections were 
balanced between placebo 
and BI 1015550 in phase 2
trial.
Nasopharyngitis was more 
frequently reported under 
treatment with BI 1015550 in 
Phase Ic/II but not in Phase I 
trials and the numbers were 
very small.
Screening procedures for infections 
are defined for this trial. Subjects 
with any relevant chronic or acute 
infections are excluded from the 
trial.
Treatment of infections should be 
initiated promptly according to 
standards of care.
Treatment interruption in case of 
severe acute infection until the 
subject has recovered based on the 
investigator’s medical judgement.
Close monitoring to detect potential 
infections promptly will minimise 
the risk of serious infection.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 18 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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
Investigational Medicinal Product: BI 1015550
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.
In phase 2 study of BI 
1015550, diarrhoea was the 
most frequently reported AE.
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 
Medical expertise of the trial site.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 19 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
framework of trial 
participation.
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.
Considerations on male contraception requirements
The exposure through seminal fluid to sexual partners of males receiving BI 1015550 is 
expected to be minimal. At a plasma BI 1015550 Cmax
 following an 18 mg BID 
dose, the worst-case seminal fluid level is anticipated to be 460 nM. Assuming a seminal 
fluid volume of 5 mL, a worst-case 100% absorption from the vagina, and a plasma volume 
of 3.5L, the resulting plasma concentration in the woman would be 0.66 nM. This 
concentration is approximately 3,500-fold below the most conservative maximum plasma 
level of 2,300 nM at the NOAEL in rats in a fertility and early embryonic development study 
[n00290709], and in EFD studies in rats and rabbits. This large safety margin, the absence of 
dysmorphogenesis in two species, and a lack of genotoxicity suggest that barrier methods of 
contraception should not be required for a male administered BI 1015550 [c39775503].
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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 20 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective is to investigate the effect of food on the pharmacokinetics of the 18 mg 
tablet BI 1015550 Formulation C2.
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)

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 21 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 22 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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 period, 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 will be as follows:

One 18 mg BI 1015550 Formulation C2 film-coated tablet administered to subjects in 
the fasting state (R).

One 18 mg BI 1015550 Formulation C2 film-coated tablet administered to subjects in 
the fed state (T).
Subjects will be randomly allocated to the 2 treatment sequences (T- -R or R-T). For details,
refer to Section 4.1.
There will be a washout period of at least 10 days between the administrations 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 relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his/her own control, the comparison between treatments is based 
on an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529].
The open-label treatment is not expected to bias results, since the trial endpoints are derived 
from measurement of plasma concentrations of the analyte, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 18 healthy male and female subjects (at least 6 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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 23 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male or female subjects according to the assessment of the investigator, as based 
on a complete medical history including a physical examination, vital signs (BP, PR), 12-
lead ECG, and clinical laboratory tests
2. Age of 18 to 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. Female subject meets any of the following criteria for a highly effective contraception 
from at least 30 days before the first administration of trial medication until 7 days after 
last administration
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
6. Women of not of childbearing potential (WNOCBP) include:
⁃
Permanently surgically sterilised (including hysterectomy, bilateral oophorectomy 
and bilateral salpingectomy)
⁃
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)
7. 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, for the duration of the study and for at least 7 
days after the last study drug administration

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 24 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders including but not 
limited to depression and suicidal behaviour
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Relevant chronic or acute infections within the 30 days prior 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

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 25 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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 
within 7 days after trial completion
26. For female subjects: Positive pregnancy test
27. Concomitant intake of strong CYP3A inhibitors (e.g., amprenavir, indinavir, nelfinavir, 
ritonavir, itraconazole or ketoconazole) and unselective PDE inhibitors (e.g., 
theophylline, roflumilast, apremilast)
28. History or signs of vasculitis
29. Relevant immunodeficiency
30. History of residential exposure to tuberculosis, or a positive QuantiFERON® test within 
4 weeks prior to or at the time of screening
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).

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 26 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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:
⁃
Severe or serious infections, opportunistic or mycobacterium tuberculosis infections
⁃
Malignancies
⁃
Vasculitis
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).

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 27 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
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.
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 reason 4 is 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).
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, that is, additional subjects may be randomized, if considered 
necessary to reach the objective of the trial. Subjects who withdraw or are withdrawn from 
treatment or assessments because of a drug-related adverse event will not be replaced. The 
Clinical Trial Leader together with the Trial Pharmacokineticist and the Trial Statistician are 
to decide, if and how many subjects will be replaced. A replacement subject will be assigned 
a unique trial subject number, and will be assigned to the same treatment sequence as the 
subject he or she replaces.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 28 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
In case of replacement of subjects, the trial site should ensure that the requirements for 
distribution of sex (at least 6 of each sex) are still met within the overall group of treated 
subjects.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 29 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
BI 1015550
Pharmaceutical formulation: Film-coated tablets (Formulation C2)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
18 mg
Posology:
1-0-0
Mode of administration:
Oral
4.1.2
Selection of doses in the trial
The doses selected for this trial are 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.
Prior to the start of the trial, subjects willing to participate will be recruited to cohorts 
according to their temporal availability. In the morning of Day 1 (Visit 2), subjects will be 
allocated to treatment sequences prior to the first administration of trial medication according 
to the randomisation scheme.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 30 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit 
strength
Dosage/ fasting state
Total dose
Reference (R)
BI 1015550
Film-coated 
tablet 
(Formulation 
C2 - TiO2 free)
18 mg
1 tablet (18 mg) -fasting
18 mg
Test (T)
BI 1015550
Film-coated 
tablet 
(Formulation 
C2 - TiO2 free)
18 mg
1 tablet (18 mg) - fed
18 mg
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. 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.
In the fed treatment period (T), the subjects will start to consume a high-fat, high-calorie 
meal 30 min before drug administration. The subjects must completely consume the meal 
prior to drug intake. The composition of the standard high-fat, high-calorie meal is detailed in 
Table 4.1.4: 2; this meal is in compliance with the FDA guidance ‘Assessing the effects of 
food on drugs in INDs and NDAs (June 2022)’’ [R23-0862]. For restrictions with regard to 
diet, see Section 4.2.2.2.
Table 4.1.4: 2
Composition of the high-fat, high-calorie meal
Ingredients
kcal
2 chicken eggs (whole content) for scrambled eggs
192
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum1
984
1
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal 
as carbohydrate, and 500 to 600 kcal as fat. 
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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 31 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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. 
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. 

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 32 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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.
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 'Trial Staff List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. These 
records will include dates, quantities, batch/ serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 33 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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.
Vasculitis
In case of events suspicious for vasculitis, trial treatment will be discontinued. A thorough 
work-up has to be initiated including at least but not limited to
⁃
appropriate imaging, including angiography
⁃
biopsy, if possible
⁃
appropriate laboratory screening, including measurements of vasculitis markers at the 
local lab, see Section 5.2.3. In addition, an analysis of the previously collected and 
stored samples will need to be requested and considered.
⁃
thorough documentation of all reported symptoms
Referral to a vasculitis expert is recommended. If required, vasculitis treatment should be 
initiated according to standard of care.
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 milk served with 
breakfast (see Table 4.1.4: 2), 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.
Grapefruits, Seville oranges (sour or bitter oranges) and their juices are not permitted from 
7 days before the first administration of trial medication until after the last PK sample in the 
trial is collected.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 34 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
Dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 30 days before the first administration of trial medication until after the last 
PK sample in the trial is collected.
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.
There is no evidence of phototoxicity. So, no restrictions related to sun exposure are required.
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).

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 35 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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., 
Philips IntelliVne MP70/X2, 
 at the times indicated 
in the Flow Chart, after subjects have rested for at least 5 min in a supine position. All 
recordings should be made using the same type of blood pressure recording instrument on the 
same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For 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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 36 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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)

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 37 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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)
Vasculitis markers*
MPO-ANCA
PR3-ANCA
IL-6
Antiglomerular basement membrane (GBM) antibodies
Rheumatoid factor
Antinuclear antibodies
Complement C3, C4, CH 50, anti-C1q antibodies.
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. Except for pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, prior to 
each treatment period, and as part of the end of study examination. Drug screening will be 
performed at screening and prior to each treatment period.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 38 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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
QuantiFERON®-TB Gold Test (IGRA)
COVID-19 (nasopharyngeal
swab)2
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 gonadotropin (beta-HCG) at screening
and EoS
In urine: Beta human chorionic gonadotropin (beta-HCG)
1 to be conducted if Hepatitis B core antibody is positive and Hepatitis B surface antigen is negative.
2 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., Dräger 
Alcotest®,
 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 using 
SURESTEP Urine Drug Test and
hCG URINE TestPack™ Plus with OBC, 
respectively, or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
It is the responsibility of the Investigator to evaluate the laboratory reports. Clinically 
relevant abnormal findings as judged by the Investigator are to be reported as adverse events 
(please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4).

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 39 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (e.g., CardioSoft EKG System,
 at the times provided in the Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other 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 

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 40 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)

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.
Adverse event report for diarrhea events:
In case of events of diarrhoea the following definitions should be followed:

Diarrhoea is defined ≥3 loose/liquid stools per day (WHO definition)

If <3 stools please report as ‘frequent bowel movements’
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’.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 41 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.

Vasculitis events
In this CTP, vasculitis is defined as any event term included in the MedDRA SMQ 
Vasculitis (broad). This includes clinical and pathological features related to primary 
or secondary vasculitis syndromes and involving any type, size, and location of blood 
vessels.
The investigator should monitor for any signs and symptoms of vasculitis at all times 
and specifically as part of the AE questioning.
In case of (suspected) events of vasculitis, further work-up and management as 
outlined in Section 4.2.1 has to be followed, including biopsy, appropriate 
imaging/angiography, laboratory measures (e.g. ESR, additional lab sample for 
immunological and further inflammation markers).

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 42 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)

Serious infections, opportunistic or mycobacterium tuberculosis infections
These include Pneumocystis jirovecii, BK virus disease including 
polyomavirusassociated nephropathy (PVAN), Cytomegalovirus (CMV), post-
transplant lymphoproliferative disorder (Epstein–Barr virus [EBV]), progressive 
multifocal leucoencephalopathy, bartonellosis (disseminated only), blastomycosis, 
toxoplasmosis, coccidioidomycosis, histoplasmosis, aspergillosis (invasive only), 
candidiasis (invasive or pharyngeal), cryptococcosis, other invasive fungi 
(mucormycosis (zygomycosis, rhizopus, mucor, lichtheimia), 
Scedosporium/Pseudallescheria boydii, fusarium), legionellosis, Listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous 
mycobacterium, salmonellosis (invasive only), HBV reactivation, herpes simplex 
(invasive only), herpes zoster, strongyloides (hyperinfection syndrome and 
disseminated forms only), paracoccidioides, Penicillium marneffei, Sporothrix 
schenckii, cryptosporidium species (chronic only), microsporidiosis, leishmaniasis 
(visceral only), Trypanosoma cruzi infection (Chagas’ disease) (disseminated only), 
campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis (invasive due 
to vibrio vulnificus), HCV progression [R17-2617].
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)

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 43 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 44 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)

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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 45 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of R-BI 1015550 concentrations in plasma, at least 2.7 mL of blood will be 
drawn from an antecubital or forearm vein into an K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle. The first 0.5 mL withdrawn by an indwelling cannula 
will be discarded.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot (‘A1’) should contain at least 0.5 mL of 
plasma. The process from blood collection until transfer of plasma aliquots into the freezer 
should be completed in less than 90 min, with interim storage of blood samples and aliquots 
at room temperature. The time each aliquot was placed in the freezer will be documented.
Until transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. Any remaining plasma will be the second 
aliquot (‘A2’) and will be transferred to the analytical laboratory after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory, the plasma 
samples will be stored at approximately -20°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time and aliquot (‘A1’ or ‘A2’).
After analysis, the plasma samples may be used for further methodological investigations 
(e.g., for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/ methodology. However, only data related to the analyte and/ 
or its metabolite(s) including anti-drug antibodies (if applicable) will be generated by these 
additional investigations. The trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 46 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
5.4
ASSESSMENT OF BIOMARKERS
Not applicable.
5.4.1
Drug-Drug Interaction Biomarkers
Not applicable.
5.4.2
Pharmacodynamic biomarkers
Not applicable.
5.4.3
Pharmacogenomic biomarkers
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used assessments of drug exposure.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 47 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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.
The acceptable deviations from the nominal blood sampling times are as follows:

The pre-dose samples will be taken ≤3h before dosing.

0 to 2 h post-dose samples will be taken within ± 2 min of the planned post-dose 
sampling time.

2.5 to 4 h post-dose samples will be taken within ± 5 min of the planned post-dose 
sampling time.

6 to 12 h post-dose samples will be taken within ± 10 min of the planned post-dose 
sampling time.

24 h or later post-dose samples will be taken within ± 60 min of the planned post-dose 
sampling time.
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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 48 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.5.
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). 
At least 10 days will separate drug administrations between each treatment.
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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 49 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
For the primary and secondary endpoints, the effect of food on pharmacokinetics of an 18 mg 
tablet BI 1015550 will be estimated by the ratios of the geometric means (Test/ Reference),
and their corresponding 2-sided 90% confidence intervals (CIs) will be provided. This 
method corresponds to the two one-sided t-test procedure, each at the 5% significance level.
Since the main focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified.
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial drug. The treated set will be used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary 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.
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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 50 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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

Use of restricted medications
Plasma and 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, 
(i.e., 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-
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

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 51 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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.
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 calculated and analysed 
descriptively.
7.2.3
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated with 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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 52 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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
actual period.
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.
7.2.6
Interim analyses
No interim analysis is planned.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 53 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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
It is planned to enter a total of 18 subjects in the trial with the aim of ≥ 12 evaluable subjects, 
because this sample size is considered sufficient to achieve the aims of this exploratory trial. 
With this sample size, the following precision in estimating the ratio of geometric means 
(Test/ Reference) can be expected with 95% probability. Precision is defined as the ratio of 
upper CI limit to the relative BA estimate. Note that the precision is independent of the actual 
ratio of geometric means.
The sample size for this trial was determined using assumptions on the intra-individual 
variability of the primary endpoints based on the previous trial 1305-0028 [c37740081]
investigating formulation effect and food effect. The intra-individual geometric coefficient of 
variation (gCV) for R-BI 1015550 was estimated to be about 23% for Cmax and 8% for AUC.
For various assumptions around the gCV of 25% , Table 7.5: 1 provides an overview of the 
achievable precision for estimating the ratio of geometric means (T/ R). For illustrative 
purposes, the expected 90% confidence intervals are displayed for different values of the 
ratios T/R of geometric means.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 54 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
Table 7.5: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/ R) for different gCVs in a 2x2 crossover trial (N=18)
N
gCV 
[%]
Precision 
upper CL** 
/ relative BA 
estimate
90% CI [%] of respective ratio*
95
100
105
12
20
1.22
(77.91; 115.83)
(82.01; 121.93)
(86.12; 128.03)
12
25
1.28
(74.25; 121.56)
(78.15; 127.95)
(82.06; 134.35)
12
30
1.34
(70.81; 127.46)
(74.54; 134.16)
(78.26; 140.87)
18
20
1.16
(81.95; 110.13)
(86.26; 115.92)
(90.58; 121.72)
18
25
1.2
(79.06; 114.16)
(83.22; 120.17)
(87.38; 126.17)
18
30
1.25
(76.31; 118.26)
(80.33; 124.49)
(84.35; 130.71)
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
**Confidence interval limit
The calculation was performed as described by Julious [R11-5230] using R Version 4.2.2.
The expected 90% confidence interval limits in the table were derived by
CI limit,  = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 55 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations. Investigators and site staff must adhere to 
these principles. Deviation from the protocol, the principles of ICH GCP or applicable 
regulations will be treated as ‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to finalisation of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 56 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 57 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 58 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 59 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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 Mangers
(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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 60 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 61 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
9.
REFERENCES
9.1
PUBLISHED REFERENCES
R23-0862
Food and Drug Administration. Guidance for industry: assessing the 
effects of food on drugs in INDs and NDAs – clinical pharmacology 
considerations (June 2022, clinical pharmacology). 2022
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
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.
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
c02094779
 Investigator's Brochure BI 
1015550 for 1305.P3, current version.
c22991937
Safety, tolerability and pharmacokinetics of single and multiple rising oral 
doses of BI 1015550 in healthy subjects. 1305-0011.
c25085412
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of 
BI 1015550 in patients with idiopathic pulmonary fibrosis (IPF) on no 
background anti-fibrotic therapy. 1305-0012.
c37065416
A randomised, double-blind, placebo-controlled parallel group study in IPF 
patients over 12 weeks evaluating efficacy, safety and tolerability of BI 
1015550 taken orally. 1305-0013.
c37740081
Relative bioavailability comparison of BI 1015550 as the intended 
commercial formulation (iCF) versus trial formulation 2 and iCF with and 
without food following oral administration in healthy subjects (an open-
label, randomised, single-dose, three-way crossover trial). 1305-0028.
c39775503
 Assessment of requirement for male contraception. Memo. 09 
June 2022.
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.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 62 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
10.
APPENDICES
Not applicable.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 63 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
25 Apr 2024
EU Trial number
2023-509889-38-00
BI Trial number
1305-0039
BI Investigational Medicinal 
Product
BI 1015550
Title of protocol
The effect of food on the pharmacokinetics of BI 
1015550 (Formulation C2) following single oral 
dose administration in healthy subjects (an open-
label, randomised, single-dose, two-period, two-
sequence crossover design)
Substantial Global Amendment due to urgent safety reasons 
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
Flowchart
Description of change
Visit number 5 changed to visit number 4.
Deletion of pharmacogenomics sampling in the 
footnote number 1.
Rationale for change
Correction of a formatting oversight.
No pharmacogenomics sampling is planned.
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Inserting Numbering
Rationale for change
Format CS numbering was missing (only 
administrative changes).
Section to be changed
5.2.3: 1 Routine laboratory test
Description of change
Table Haematology: deleted 4 excessive 
checkboxes.
Rationale for change
Correction of a formatting oversight.
Section to be changed
5.2.3: 1 Routine laboratory tests (cont.)
Description of change
Table Vasculitis markers: additional checkboxes 
added in the respective table.
Rationale for change
Correction of a formatting oversight.

Boehringer Ingelheim
16 May 2024
BI Trial No.: 1305-0039
c43335244-03
Trial Protocol
Page 64 of 64
Proprietary confidential information © 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
BI-VQD-11906_40-106_AD-13 (8.0)
11.2
GLOBAL AMENDMENT 2
Date of amendment
16 May 2024
EU Trial number
2023-509889-38-00
BI Trial number
1305-0039
BI Investigational Medicinal 
Product
BI 1015550
Title of protocol
The effect of food on the pharmacokinetics of BI 
1015550 (Formulation C2) following single oral 
dose administration in healthy subjects (an open-
label, randomised, single-dose, two-period, two-
sequence crossover design)
Substantial Global Amendment due to urgent safety reasons 
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
5.2.3: 1 Routine laboratory tests
Description of change
Pregnancy test entered to table 5.2.3: 2 
Exclusionary laboratory tests.
Rationale for change
Entered into correct table 5.2.3. due to 
inconsistency.
Section to be changed
5.2.3: 1 Routine laboratory tests (cont.)
Description of change
Table Vasculitis markers: ‘Anti-C1q antibodies 
(immune complex-associated small-vessel 
vasculitis)’ was deleted.
Rationale for change
Correction due to inconsistency.
Section to be changed
Flowchart
Description of change
Foodnote number 4. “Pregnancy test” added, 
foodnote number 7. word “below” deleted
Rationale for change
Correction due to inconsistency

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c43335244
3.0
clinical-trial-protocol-version-03
The effect of food on the pharmacokinetics of BI 1015550 (Formulation C2)
following single oral dose administration in healthy subjects (an open-label,
randomised, single-dose, two-period, two-sequence crossover design)
Approval-Clinical Trial Leader
16 May 2024 16:03 CEST
Approval-Clinical Program
16 May 2024 16:17 CEST
Author-Trial Statistician
17 May 2024 08:05 CEST
Verification-Paper Signature
Completion
17 May 2024 09:20 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c43335244
3.0