Clinical trial NCT04789291
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2021-05-18; Completion date: 2021-08-07
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main objective of this trial is to investigate the relative bioavailability of BI 1595043 under fed state (Test, T) and under fasted state (Reference, R).

Detailed description:

Arms: arm 1: Two period crossover separated by a wash-out of at least 8 days:

Period 1: Healthy subjects received a single dose of 30 milligram (mg) BI 1595043 as film coated tablets (1x 5mg tablet and 1x 25mg tablet) following an overnight fast of at least 10 hours.

Period 2: Healthy subjects received a single dose of 30 milligram (mg) BI 1595043 as film coated tablets (1x 5mg tablet and 1x 25mg tablet) following an following a high fat/high calorie breakfast. arm 2: Two period crossover separated by a wash-out of at least 8 days:

Period 1: Healthy subjects received a single dose of 30 milligram (mg) BI 1595043 as film coated tablets (1x 5mg tablet and 1x 25mg tablet) following an following a high fat/high calorie breakfast.

Period 2: Healthy subjects received a single dose of 30 milligram (mg) BI 1595043 as film coated tablets (1x 5mg tablet and 1x 25mg tablet) following an overnight fast of at least 10 hours.
Interventions: intervention 1: BI 1595043
Intervention descriptions: intervention 1: Single dose of 30 milligram (mg) BI 1595043 as film coated tablets (1x 5mg tablet and 1x 25mg tablet).

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
ABCD
Clinical Trial Protocol
TITLE PAGE
Document Number:
c34388550-04
EudraCT No.
2020-004924-40
BI Trial No.
1445-0011
BI Investigational
Medicinal Product
BI 1595043
Title
A randomised, open-label, single-dose, two-way cross-over 
relative bioavailability comparison of BI 1595043 as tablets with 
and without food in healthy male subjects
Lay Title
A study in healthy men to test how BI 1595043 is taken up in the 
body when given with or without food
Clinical Phase
I
Clinical Trial Lead
Phone: 
Fax: 
Principal 
Investigator
Phone: 
Fax:
Status
Final Protocol (Revised Protocol (based on global amendment 3))
Version and Date
Version: 4.0
Date: 30 June 2021
Page 1 of 75
Proprietary confidential information
© 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
16 February 2021
Revision date
30 June 2021
BI trial number
1445-0011
Title of trial
A randomised, open-label, single-dose, two-way cross-over relative bioavailability 
comparison of BI 1595043 as tablets with and without food in healthy male subjects
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
The trial is conducted to gain information about the effect of food on the relative 
bioavailability of the BI 1595043 tablet formulation to support upcoming clinical 
studies in terms of improved trial designs and optimized formulations.
Trial objective
To investigate the influence of food on the relative bioavailability of the tablet 
formulation of BI 1595043
Trial design
Open-label, randomised, two-way cross-over design
Trial endpoints
Primary endpoints: AUC0-tz and Cmax of BI 1595043
Secondary endpoint: AUC0-∞of BI 1595043
Number of subjects 
total entered
14
each treatment
14
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 50 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product (T)
BI 1595043 as tablets (25 mg and 5 mg)
dose
30 mg
mode of admin.
Oral with 240 mL of water after a high fat/high calorie breakfast
Reference product (R)
BI 1595043 as tablets (25 mg and 5 mg)
dose
30 mg
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h


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Duration of treatment
One day (single dose) for each treatment, separated by a washout period of at least 
8 days
Statistical methods
Relative bioavailability will be estimated by the ratios of the geometric means 
(test / reference) 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 
nested within sequences, period and treatment. CIs will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution.
Descriptive statistics will be calculated for all endpoints.


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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 laboratory 7
PK blood 9,14
12-lead ECG 10
Vital signs (BP, PR) 13
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening1
A
x
x11
1/2 (two identical periods separated by a washout of at least 8 days between drug administrations)
2/3
-3 to -18
-72:00
08:00
Ambulatory visit8
B
x11
x
-1
-14:00
18:00
Admission to trial site12
x5
1
-02:00
06:00
Allocation to treatment (visit 2 only)2
x2
x²
x2,11
x2
-00:30
07:30
High fat, high calorie breakfast (only in 
treatment T2)
00:00
08:00
Drug administration
00:15
08:15
x
00:30
08:30
x
00:45
08:45
x
01:00
09:00
x
x
x
x
01:15
09:15
x
01:30
09:30
x
02:00
10:00
240 mL fluid intake3
x
x
x
02:30
10:30
x
03:00
11:00
x
04:00
12:00
240 mL fluid intake, thereafter lunch3
x
x
x
06:00
14:00
x
08:00
16:00
Snack (voluntary)3
x
x
x
10:00
18:00
Dinner3
12:00
20:00
x
x
x
2
24:00
08:00
Breakfast3
B
x
x
x11
x
29:00
13:00
Lunch
32:00
16:00
Snack (voluntary)
34:00
18:00
Dinner3
x
x
3
48:00
08:00
Confirmation of fitness and discharge 
from trial site, breakfast3
x
x11
x
4
72:00
08:00
Ambulatory visit
x
x11
x
5
96:00
08:00
Ambulatory visit
B
x
x11
x
6
120:00
08:00
Ambulatory visit
x
x11
x
7
144:00
08:00
Ambulatory visit
x
x11
x
8
168:00
08:00
Ambulatory visit
x
x11
x
EoT
4
9 - 14
End of trial (EoTrial) examination4
C
x
x11
x


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1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, ophthalmological examination (exclusion of ocular disorders), check of vital 
signs, assessment of body temperature, ECG, safety laboratory (including drug screening and infectious serology), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. 
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
Allocation to treatment may be performed at any time following enrolment but must be completed prior to first 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 trial visit the EoTrial examination includes physical examination, ophthalmological examination 
(exclusion of ocular disorders), body weight, vital signs, assessment of body temperature, ECG, safety laboratory, 
recording of AEs, and concomitant therapies.
5.
Only urine drug screening and alcohol breath test will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7. 
For details of safety laboratory testing at Visit 1 (A), Visit 2 (B) and Visit 3 (C) refer to Section 5.2.4 and 
Table 5.2.4: 1.
8.
Only for Visit 2: Safety laboratory to be taken and to be medically evaluated within 3 days prior to first single dose
administration of study drug; this ambulatory visit can be omitted if the screening examination is performed on Days -3, 
-2 or -1. 
9.  Sampling times and periods may be adapted based on information obtained during the trial (e.g., due to preliminary PK 
data) including addition of samples and visits as long as the total blood volume removed does not exceed 500 mL per 
subject.
10. For details of 12-lead ECG, refer to Section 5.2.5.
11. Including assessment of body temperature.
12. PCR test for SARS-COV-2/ COVID-19 will be performed shortly (within 72 hours) before admission to trial site in 
each treatment period.
13. For details of vital signs evaluation, refer to Section 5.2.2.
14. For details of PK blood sampling for BI 1595043, refer to Section 5.3.2.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................13
1.2.1
Nonclinical pharmacology....................................................................14
1.2.1.1
Primary pharmacodynamics.....................................................14
1.2.1.2
Safety pharmacology ...............................................................15
1.2.1.3
Pharmacodynamic interactions................................................16
1.2.2
Toxicology..............................................................................................16
1.2.2.1
Single dose toxicity..................................................................16
1.2.2.2
Repeated dose toxicity.............................................................17
1.2.2.3
Genotoxicity.............................................................................19
1.2.2.4
Carcinogenicity........................................................................19
1.2.2.5
Reproductive and developmental toxicity ...............................19
1.2.2.6
Local tolerance.........................................................................19
1.2.2.7
Other toxicity studies ...............................................................19
1.2.3
Nonclinical pharmacokinetics..............................................................20
1.2.3.1
Methods of analysis .................................................................20
1.2.3.2
Absorption................................................................................20
1.2.3.3
Distribution ..............................................................................21
1.2.3.4
Metabolism ..............................................................................21
1.2.3.5
Excretion..................................................................................22
1.2.3.6
Pharmacokinetic drug interactions...........................................22
1.2.3.7
Toxicokinetics..........................................................................22
1.2.4
Prediction of human therapeutic dose ................................................23
1.2.5
Clinical experience in humans.............................................................23
1.2.5.1
Safety
...................................................................................23
1.2.5.2
Pharmacokinetics.....................................................................24
1.2.6
Residual Effect Period..........................................................................25
1.2.7
Drug product.........................................................................................25
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................26
1.4
BENEFIT - RISK ASSESSMENT ...................................................................26
1.4.1
Expected benefit for the target indication ..........................................26
1.4.2
Procedure-related risks ........................................................................26
1.4.3
Drug-related risks and safety measures..............................................27
1.4.3.1
Mode of action and nature of the target...................................27


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1.4.3.2
Relevance of animal models....................................................27
1.4.3.3
Findings in non-clinical safety studies.....................................28
1.4.3.4
Clinical findings.......................................................................29
1.4.3.5
Drug induced liver injury.........................................................29
1.4.3.6
Risk minimization (safety precautions and stopping rules).....29
1.4.4
Overall assessment................................................................................30
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 31
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......31
2.1.1
Main objectives......................................................................................31
2.1.2
Primary endpoints ................................................................................31
2.1.3
Secondary endpoint ..............................................................................31
2.2.2.2
Safety and tolerability..............................................................32
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 33
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................33
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................33
3.3
SELECTION OF TRIAL POPULATION ......................................................33
3.3.1
Main diagnosis for trial entry..............................................................33
3.3.2
Inclusion criteria...................................................................................33
3.3.3
Exclusion criteria ..................................................................................34
3.3.4
Withdrawal of subjects from treatment or assessments ...................35
3.3.4.1
Discontinuation of trial treatment............................................36
3.3.4.2
Withdrawal of consent to trial participation ............................36
3.3.4.3
Discontinuation of the trial by the sponsor..............................37
3.3.5
Replacement of subjects .......................................................................37
4.
TREATMENTS........................................................................................ 38
4.1
INVESTIGATIONAL TREATMENTS ..........................................................38
4.1.1
Identity of the Investigational Medicinal Products ...........................38
4.1.2
Selection of doses in the trial................................................................38
4.1.3
Method of assigning subjects to treatment sequences .......................39
4.1.4
Drug assignment and administration of doses for each subject .......39
4.1.5
Blinding and procedures for unblinding ............................................40
4.1.6
Packaging, labelling, and re-supply ....................................................40
4.1.7
Storage conditions.................................................................................41
4.1.8
Drug accountability ..............................................................................41
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................41
4.2.1
Other treatments and emergency procedures....................................41


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4.2.2
Restrictions............................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment .........................42
4.2.2.2
Restrictions on diet and life style.............................................42
4.3
TREATMENT COMPLIANCE.......................................................................42
5.
ASSESSMENTS....................................................................................... 43
5.1
ASSESSMENT OF EFFICACY.......................................................................43
5.2
ASSESSMENT OF SAFETY............................................................................43
5.2.1
Physical examination ............................................................................43
5.2.2
Vital signs...............................................................................................43
5.2.3
Ophthalmological examination............................................................43
5.2.4
Safety laboratory parameters..............................................................43
5.2.5
Electrocardiogram................................................................................46
5.2.6
Other safety parameters.......................................................................47
5.2.7
Assessment of adverse events...............................................................47
5.2.7.1
Definitions of adverse events...................................................47
Adverse event ............................................................47
Serious adverse event ................................................47
AEs considered ‘Always Serious’.............................48
Adverse events of special interest .............................48
Intensity (severity) of AEs.........................................49
Causal relationship of AEs ........................................49
5.2.7.2
Adverse event collection and reporting ...................................50
AE collection.............................................................50
AE reporting to the sponsor and timelines ................51
Information required..................................................51
Pregnancy ..................................................................51
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................51
5.3.1
Assessment of pharmacokinetics .........................................................51
5.3.2
Methods of sample collection...............................................................52
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................52
5.4
ASSESSMENT OF BIOMARKER(S) .............................................................53
5.5
BIOBANKING ...................................................................................................53
5.6
OTHER ASSESSMENTS .................................................................................53
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................53
6.
INVESTIGATIONAL PLAN.................................................................. 54
6.1
VISIT SCHEDULE............................................................................................54
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................54
6.2.1
Screening period....................................................................................54


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6.2.2
Treatment periods.................................................................................54
6.2.3
Follow-up period and trial completion ...............................................55
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 56
7.1
STATISTICAL DESIGN – MODEL ...............................................................56
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................56
7.3
PLANNED ANALYSES....................................................................................56
7.3.1
Primary endpoint analyses...................................................................57
7.3.2
Secondary endpoint analyses ...............................................................58
7.3.4
Safety analyses.......................................................................................59
7.4
INTERIM ANALYSES .....................................................................................60
7.5
HANDLING OF MISSING DATA ..................................................................60
7.5.1
Safety......................................................................................................60
7.5.2
Pharmacokinetics..................................................................................60
7.6
RANDOMISATION ..........................................................................................60
7.7
DETERMINATION OF SAMPLE SIZE ........................................................60
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 62
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................62
8.2
DATA QUALITY ASSURANCE .....................................................................63
8.3
RECORDS..........................................................................................................63
8.3.1
Source documents .................................................................................63
8.3.2
Direct access to source data and documents.......................................64
8.3.3
Storage period of records.....................................................................64
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................64
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......64
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................65
8.6
TRIAL MILESTONES .....................................................................................65
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................66
9.
REFERENCES......................................................................................... 67
9.1
PUBLISHED REFERENCES...........................................................................67
9.2
UNPUBLISHED REFERENCES.....................................................................68
10. APPENDICES .......................................................................................... 71
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 72
11.1
GLOBAL AMENDMENT 1 .............................................................................72


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11.2
GLOBAL AMENDMENT 2 .............................................................................74
11.3
GLOBAL AMENDMENT 3 .............................................................................75


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
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
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials DataBAse
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file


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LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLOQ
Lower limit of quantification
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRT,ex
Mean residence time of the analyte in the body, extravascular
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
XTC
Ecstasy 


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
1.2
DRUG PROFILE
Vanin-1 and -2 (Vascular Non-Inflammatory molecules 1 and 2) are extracellular enzymes
expressed on epithelial cells, macrophages, monocytes, T-cells and neutrophils, shed in
significant amounts into the extracellular milieu, and found in most extracellular
compartments across tissues.


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Inflammatory mediators and bacterial endotoxins drive expression of vanin-1 and 2 enzymes,
whose common function is to convert pantetheine into pantothenic acid and cysteamine. It is
through production of cysteamine that vanin enzymes directly impact extracellular metabolic
homeostasis of tissues by depleting cystine in tissues through reducing it to cysteine. Cystine
depletion is understood to alter the intracellular redox balance of tissues, resulting in
increased oxidative stress, endoplasmic reticular stress, and disruption and eventual
destruction of tissue. In addition, cystine depletion is postulated to result in increased
extracellular cysteine levels, enhancing adaptive immune response, increasing CD4+ T-cell
production of pro-inflammatory cytokines IFNγ, IL-4, IL-5 and IL-13.
Therefore, it is expected that inhibition of vanin enzyme function will directly restore tissue
metabolite homeostasis and redox balance leading to tissue repair, while curbing chronic
inflammation, which could prove beneficial in diseases characterized by tissue lesions and
ulceration as well as the presence of chronic inflammation.
For consistency of nomenclature, vanin-1 and vanin-2 isoforms, unless referenced otherwise, 
will be referred to as vanin.
1.2.1
Nonclinical pharmacology
1.2.1.1
Primary pharmacodynamics
In vitro primary pharmacodynamics
In a human recombinant vanin-1 enzyme activity assay (n00273892), measuring pantothenic 
acid product formation, formed in a 1:1 ratio with cysteamine through cleavage of pantethine, 
BI 1595043 inhibited vanin-1 with an IC50 of 0.17 nM. In human whole blood, containing 
both vanin-1 and vanin-2 (n00273893), BI 1595043 inhibited vanin activity with a mean IC50
value of 1.9 nM. In a human ex vivo colon tissue assay, using non-inflammatory bowel 
disease human colon explants (n00273895), BI 1595043 inhibited vanin activity and lowered 
release of cytokeratin-18 (CK-18). CK-18 is a marker of epithelial injury, elevation of which 
is a hallmark of diseases of the epithelial barrier (R18-2868). Reduction of CK-18 was 
interpreted as a signal of epithelial healing. The effect of BI 1595043 on T-lymphocyte 
activity, measured by cytokine production (IFN gamma, IL-4 IL-13, IL-5) , was tested in 
human CD3/CD28 stimulated T-cells (n00273897). Cytokine production was significantly 
reduced in a majority of donors, which was interpreted as a sign of decreased inflammation.
In vivo primary pharmacodynamics
In a model of dextran sodium sulfate (DSS) mediated intestinal injury in C57Bl/6 mice 
(n00273898), BI 1595043 demonstrated target engagement, as measured by decreased levels 
of the vanin product, pantothenic acid, in both central plasma compartments and target colon 
tissue, as well as increased levels of the vanin substrate, pantetheine, in the plasma. Mice 
treated with BI 1595043 showed reduced epithelial damage assessed by histology score, but 
formation of inflammatory infiltrate was not significantly altered with BI 1595043. 
BI 1595043 did not reduce intestinal permeability (assessed by detection of sucralose uptake 
through the colon). While other vanin inhibitors similar to BI 1595043, tested in separate 


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studies (n00259753), showed reduction of inflammation and improved barrier integrity, in 
BI 1595043’s case a trend was observed that fell short of statistical significance.
1.2.1.2
Safety pharmacology
General and safety pharmacology studies have been conducted with BI 1595043 to assess 
possible effects on cardiovascular, CNS, respiratory, renal and hepatic function.
Cardiovascular system
BI 1595043 was tested for blocking hERG-mediated potassium current in HEK293 cells 
(n00270147). BI 1595043 inhibited the current with the IC50 of 157.88 μM or 233-times the 
estimated human therapeutic Cmax. Effect of BI 1595043 on cardiovascular function was 
assessed in conscious male telemetry-instrumented Beagle dogs at oral doses of 3, 10 or 
200 mg/kg (n00271655). At doses of 3 and 10 mg/kg, no BI 1595043-related abnormalities 
were observed. At 200 mg/kg of BI 1595043, decrease in blood pressure with accompanying
increase in heart rate were observed.
Respiratory system
BI 1595043 effects on the respiratory function was assessed at single oral doses of 10, 50 or 
300 mg/kg in rat (n00270318). At doses of 10 and 50 mg/kg, BI 1595043 had no effect on 
the respiratory system. Rats administered 300 mg/kg had mildly lower tidal volume from 
1 through 3 h post-dose and slightly lower minute volume from 1 through 2 h post-dose.
Central nervous system
BI 1595043 effects on neurological function were assessed in rat at single oral doses of 10, 
50 or 300 mg/kg (n00270317). With the exception of transiently lower body temperature at
300 mg/kg, no effects of BI 1595043 were observed up to 24 hours post-dose.
Renal and hepatic system
The effect of BI 1595043 on urine- and serum-derived parameters was evaluated in rat after a 
single oral dose of 1, 3 or 10 mg/kg (n00275784). BI 1595043 had no relevant effect on 
urinary excretion or serum-based parameters following the oral doses of 1 and 3 mg/kg for 
most parameters assessed. Following the 10 mg/kg dose, BI 1595043 caused only slight 
effects on renal function or renal injury markers during 4 h post-dose.
Further considerations on safety pharmacology
In a vanin-1 knock-out/NOD diabetic mouse model, vanin deficiency aggravated islet cell 
death and diabetes, whereas treatment with super-physiological levels of cysteamine reduced 
pancreatic islet cell death and thus might play a role in islet cell protection (R17-3327). Other 
findings suggest that elevated expression of vanin-1 in pancreatic ductal adenocarcinoma 
cells aggravated loss of pancreatic islet function and was associated with the onset of 
pancreatic cancer-associated new-onset diabetes (R18-2866). However, further studies, 
assessing the metabolic impact of vanin-1 deficiency, absence of vanin-1 either in knock-out 


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mice or by pharmacological inhibition, did not impact glycemic control (R18-2867). 
Pharmacological inhibition of vanin-1 in diabetic rats for 8 days using RR6, a small molecule 
vanin-1 inhibitor, was well tolerated and showed no significant effects on hepatic steatosis in 
diabetic rats (R18-2867). These diverse data suggest that BI 1595043 might impact islet cell 
survival and glycemic control although the findings of different studies are contradictory. 
Thus far conducted safety pharmacology, genetic toxicology and general toxicology studies 
did not indicate any toxicity of BI 1595043 related to glycemic control.
A human missense single nucleotide polymorphism (SNP) (rs2272996) in the gene encoding 
vanin-1 is associated with decreased blood pressure, with the SNP causing faster degradation 
of vanin-1 and significant reduction of vanin-1 plasma levels (R18-2692).
1.2.1.3
Pharmacodynamic interactions
No pharmacodynamics interaction studies have been carried out to date.
Conflicting literature exists regarding effect of vanin inhibition on acetaminophen 
(paracetamol) toxicity. An earlier study (R18-2954) suggested that vanin-1 deficiency (in 
knock-out mice) might protect mice against acetaminophen-induced liver toxicity. In another 
(R17-3326), acetaminophen-induced liver toxicity was exacerbated in vanin-1 knock-out 
mice compared to wild type littermates.
For a more detailed description of the BI 1595043 profile, please refer to the current 
Investigator’s Brochure (IB) (c31270124).
1.2.2
Toxicology
The nonclinical safety program investigating the in vivo toxicological profile of BI 1595043 
comprised repeat-dose studies up to 13 weeks of once daily oral treatment in rats and dogs 
and a complete battery of in vitro and in vivo studies assessing the genotoxic and phototoxic 
potential of the compound. Rats and Beagle dogs were employed as suitable animal species 
for general toxicology investigations (see Section 1.4.3.2).
A comprehensive detailed description of the BI 1595043 profile is provided in the current IB 
(c31270124). Main findings are summarized in the following sections.
1.2.2.1
Single dose toxicity
Single-dose toxicity studies were not conducted but acute toxicity information was obtained 
from short-duration toxicity studies, in which high doses of BI 1595043 were administered. 
BI 1595043-related effects were observed in rats at ≥300 mg/kg and in dogs at 200 mg/kg 
after single dose administration. 
In an in vivo genotoxicity assay in rats (n00271724), clinical signs of piloerection, crusty eye 
and hunched posture were observed after administration of 500 mg/kg/day (250 mg/kg BID, 
2 h apart). Decreased motor activity, slight labored breathing, piloerection, and hunched 
posture were noted after administration of 1000 mg/kg/day (500 mg/kg BID, 2 h apart) for 
one day. At 2000 mg/kg/day (1000 mg/kg BID, 2 h apart) in addition to the clinical signs 
observed at the lower doses, squinty eyes were noted. BI 1595043 induced a reduction in 


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body weight gain at 1000 mg/kg/day. Three of six animals administered 2000 mg/kg/day 
were found dead on day 2 (n00271724).
Details of BI 1595043-related effects observed following single doses in a rat CNS study 
(transiently lower body temperature at 300 mg/kg) (n00270317), a rat respiratory study 
(transiently lower tidal and minute volumes at 300 mg/kg) (n00270318) and a dog 
cardiovascular function study (decrease in blood pressure with increase in heart rate) 
(n00271655) are detailed in Section 1.2.1.2. In the dog cardiovascular function study 
(n00271655), at 200 mg/kg, post-dose vomitus was observed in 5 out of 10 animals.
1.2.2.2
Repeated dose toxicity
In a 13-week GLP study in Wistar Han rats, BI 1595043 was administered for 13 weeks at 
oral doses of 10, 50 and 300 mg/kg/day, followed by a 10-week recovery period 
(n00268703). No mortality was observed. No BI 1595043-related effects on clinical signs or 
urinalysis were observed at any dose level.
At doses of ≥10 mg/kg/day, non-adverse body weight gain increase was observed in males 
and females.
At doses of ≥50 mg/kg/day, non-adverse effects were observed: increased thyroid gland 
weight in male and female without microscopic correlate; decreased AST in male and female.
At doses of 300 mg/kg/day, non-adverse effects were observed: body weight gain reduced in 
males and females; increased kidney weight in males and females without microscopic 
correlate; increased liver weight in males and females correlating to hepatocellular 
hypertrophy (diminished but not absent at the end of recovery); increased mean white blood 
cell counts and absolute lymphocytes counts in males and females (of lower magnitude at the 
end of recovery, suggesting reversibility of the effect); increased total T cell, T helper cell, 
T cytotoxic cell and B cell numbers in males (generally within range of control males at the 
end of recovery, suggesting reversibility of the effect); increased ALT in males and females, 
likely correlated with the incidence of hepatocellular hypertrophy and increase in 
hepatocellular microsomal enzyme activity.
Also, at doses of 300 mg/kg/day, adverse testicular changes (abnormal spermatogenesis, 
minimal spermatid retention) and adverse minimal-to-mild debris within duct lumen of the 
epididymides were observed in males, not present at the end of the recovery phase. The 
findings were considered adverse because they may indicate disruption of the normal 
spermatogenic cycle that could result in effects on fertility (R18-2864).
Ophthalmology findings:
During pretest-evaluation, no abnormalities were identified by indirect ophthalmoscopy. At the 
end of BI 1595043 dosing, unilateral or bilateral visualization of cataract was noted, a descriptive 
term used synonymous with a change in lens opacity, in rats in the 50 mg/kg/day group (1/20 rats
with unilateral cataract) and 300 mg/kg/day group (8/20 male [7 bilateral and 1 unilateral] and 
7/20 female rats [all bilateral]). No abnormalities were observed in control animals. At the end of 
recovery, this finding was observed in a total of 0/10 male and 4/10 female rats from the control 
group and 9/10 males (all bilateral) and 8/10 females (all bilateral) from 300 mg/kg/day group.
However, upon thorough histologic examination, there was no microscopic evidence of cataract 


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formation correlating to any of these ophthalmoscopic observations in any rats. Due to a lack of 
histologic correlate, this finding is considered non-adverse.
Under the conditions of this study the NOAEL at steady state was considered to be 
50 mg/kg/day, which corresponded to a Cmax of 39,900 nM and AUC0-24 of 188,000 nM•h in 
males and Cmax of 50,500 nM and AUC0-24 of 240,000 nM•h in females. As compared to the 
estimated human exposure at the predicted therapeutic dose, exposures at the NOAEL are 
about 58- and 75- fold higher for Cmax in male and female respectively; and 54- and 69-fold 
higher for AUC in male and female respectively.
In a 13-week GLP study in Beagle dogs with a 10-week recovery period (n00270419), 
BI 1595043 was administered for at least 13 weeks in low- and mid-dose groups at oral doses 
of 3 and 10 mg/kg/day. High dose group dogs were given 200 mg/kg/day on days 1 and 2, 
which was reduced to 100 mg/kg/day on day 3 due to adverse vomitus/emesis. The female 
high dose dogs received 100 mg/kg/day from day 3 to the end of the dosing phase. Due to 
poor tolerability, male dogs in the high dose group receiving 100 mg/kg/day were not dosed 
between days 21 and 34; dosing resumed on day 35 at 30 mg/kg/day for the remainder of the 
dosing phase.
BI 1595043-related moribundity occurred in one male dog at the 100 mg/kg/day dose level
and resulted in humane euthanasia on day 16. Decrease in body weight corresponded to 
decreased food consumption, instances of liquid feces, vomitus, salivation, shivering or 
trembling and dehydration were observed. On day 16, results of blood tests showed increased 
absolute lymphocytes, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, and 
gamma-glutamyl transferase. At necropsy, the macroscopic observation of depressed foci in 
the liver corresponded microscopically to moderate panlobular hepatocellular degeneration 
with slight bile duct hyperplasia and moderate mononuclear parenchymal infiltrate. The 
macroscopic observation of abnormal coloration of the lung correlated microscopically to 
severe acute alveolar inflammation; and laryngeal ulcer. Decreased cellularity in the axillary 
lymph node and moderate decreased cellularity in the thymus.
There were no BI 1595043-related effects on ophthalmology, physical examinations,
urinalysis or immunophenotyping observed at any dose level.
At doses of 3 mg/kg/day and 10 mg/kg/day, no abnormalities were observed.
At doses of 30 mg/kg/day, reversible adverse effects on the liver was seen in males consisted 
of hepatocellular degeneration and loss of parenchyma (not evident in recovery animals).
At doses of ≥100 mg/kg/day, reversible non-adverse effects were observed: increases in mean 
heart rate in females; changes in hematology parameters (increased in red blood cell 
parameters (mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution 
width), increased absolute neutrophils, decreased mean platelet volume) in females; increases 
in partial thromboplastin time and activated partial thromboplastin time in a single male dog; 
increase in mean triglycerides in males and females; increased creatinine in females.
Also, at doses of ≥100 mg/kg/day, administration of BI 1595043 resulted in adverse 
reactions: vomitus/emesis at 200 mg/kg/day which required dose reduction (to 
100 mg/kg/day in females and 30 mg/kg/day in males); shivering or trembling in males 
at 200 mg/kg/day (decreased in frequency with a reduction in dose to 100 mg/kg/day); 
decreases in body weight and food consumption in males and females (comparable to control 


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at the end of recovery); reversible increases in ALT, AST and alkaline phosphatase in males 
and females; increases in total bilirubin, direct bilirubin and gamma-glutamyl transferase in a 
single male correlated microscopically to slight periportal hepatocellular degeneration.
Under the conditions of this study the NOAEL at steady state was considered to be 
10 mg/kg/day, which corresponded to a Cmax of 8,550 nM and AUC0-24 of 81,700 nM•h in 
males and Cmax of 10,700 nM and AUC0-24 of 81,400 nM•h in females. As compared to the
estimated human exposure at the predicted therapeutic dose, exposures at the NOAEL are 
about 13- and 16- fold higher for Cmax in male and female respectively, and about 23- fold 
higher for AUC in both sexes.
1.2.2.3
Genotoxicity
BI 1595043 was not mutagenic in the bacterial reverse gene mutation (Ames) test 
(n00271737) up to the dose limit of 5000 μg/ plate, and in the in vitro micronucleus assay 
(n00271739) up to the dose limit of 1 mM. In the in vivo rat bone marrow micronucleus 
assay (n00271724), BI 1595043 was concluded to be negative up to dose levels of 
1000 mg/kg/day. Evaluation at the highest dose level of 2000 mg/kg/day was not 
conducted due to the overt clinical signs and mortality (see Section 1.2.2.1).
1.2.2.4
Carcinogenicity
Carcinogenicity studies have not yet been conducted.
1.2.2.5
Reproductive and developmental toxicity
Definitive embryo-fetal development toxicity studies have been completed in rat and rabbit 
(n00278622, n00278281). Maternal and embryo-fetal toxicity were not observed in these 
studies (rat NOAEL AUC 125,000 nM•h and Cmax 25,500 nM, rabbit NOAEL AUC 323,000 
nM•h and Cmax 97,400 nM). Teratogenicity (digit malformations) was observed in rat 
(LOAEL AUC 6,900  nM•h and Cmax 2,270 nM) (n00278622). Teratogenicity was not 
observed in rabbit (NOAEL AUC 323,000 nM•h and Cmax 97,400 nM) (n00278281).
In the 13-week rat study (n00268703), there were adverse microscopic effects on the testis 
and epididymis at 300 mg/kg/day of BI 1595043 in males (see Section 1.2.2.2). No adverse 
effects on the reproductive tract were seen at 50 mg/kg/day in males, and at doses up to 
300 mg/kg/day in female rats. No effects on the reproductive tract were seen in the 13-week 
dog study (n00270419).
1.2.2.6
Local tolerance
No local tolerance studies have been conducted.
1.2.2.7
Other toxicity studies
BI 1595043 exhibits an absorption band in the spectral region of 290-700 nm with 
absorbance peaks at 290 and 310 nm (molar extinction coefficient of 12505 L mol-1 cm-1 in 
PBS) (n00267953). In an in vitro assay using BALB/c 3T3 mouse fibroblasts (n00272671), 
BI 1595043 did not demonstrate phototoxic potential up to concentrations of 100 μg/mL. 


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Overall, it is considered that BI 1595043 is unlikely to cause phototoxicity at clinically 
relevant doses.
For a more detailed description of the BI 1595043 profile, please refer to the current IB 
(c31270124).
1.2.3
Nonclinical pharmacokinetics
1.2.3.1
Methods of analysis
To support GLP toxicity studies, GLP LC/MS/MS assay methods were validated for 
quantification of BI 1595043 in rat plasma (lower limit of quantitation (LLOQ): 5.00 nM) 
(n00270399), dog plasma (LLOQ: 15.0 nM) (n00270319), and rabbit plasma (LLOQ: 
5.00 nM) (n00275663).
1.2.3.2
Absorption
The pharmacokinetics (PK) of BI 1595043 following single intravenous (IV) or oral (PO)
doses were investigated in male Wistar Han rats, male beagle dogs, and female minipigs
(n00274794).
The PK parameters in animals (n00274794) are summarized in Table 1.2.3.2: 1. The 
disposition of BI 1595043 is characterized in rats, dogs and minipigs by low-to-moderate 
clearance (CL) and a moderate volume of distribution (Vss). The half-life (t1/2) was short in 
rats, short-to moderate in dogs, and moderate-to-long in minipigs. The bioavailability (BA) 
in rats and dogs was high, while the BA in minipigs was moderate.
Table 1.2.3.2: 1
Mean PK parameters in rats, dogs and minipigs for BI 1595043
PK Parameter
Male Han Wistar Rat
(n=3 mean ± SD)
Male Beagle Dog
(n=3, mean ±SD)
Female Minipig
(n=3, mean ± SD)
Route of 
Administration
IV
PO
IV
PO
IV
PO
Dose (mg/kg)
11
12
0.4
4
0.4
4
CL 
(mL/min/kg)
18.6 ± 4.6
--
6.6 ± 0.4
--
10.8 ± 4.2
--
Vss (L/kg)
2.32 ± 0.49
--
1.70 ± 0.14
--
2.43 ± 0.12
--
t1/2 (h)
3.0 ± 0.66
3.11 ± 0.75
4.30 ± 0.72
8.68  ± 1.60
12.1 ± 0.83
8.63 ± 1.30
tmax (h)
median (range)
--
2
(2-2)
--
0.83
(0.5-1)
--
3
(2-4)
Cmax (nM)
--
7,850 ± 2,920
--
5,097 ± 365
--
293 ± 119
AUC0-inf
(nM•h)
2,370 ±670
22,100 ± 7,290
2,550 ± 140
27,570 ± 4,110
1,750 ± 770 4,740 ± 1,380
Ae renal
(% dose)
±
17.7 ± 5.2
19.6 ± 4.1
11.8 ± 1.0
6.7 ± 2.1
1.0 ± 0.49
Renal CL 
(mL/min/kg)
±
3.5
1.3 ± 0.27
0.73 ± 0.15
0.77 ± 0.45
0.35 ± 0.06
BA (%) 2
--
72.5 3
--
119
--
21.9
1.
Three IV dose levels (0.01, 0.1, 1 mg/kg) were tested in the rat. The results of the highest dose tested are represented in 
this table.


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2.
BA values are model based and incorporate non-linear binding to target.
3.
Rat BA was calculated based on modeling of all available rat PK data.
1.2.3.3
Distribution
Plasma protein binding
The binding of [14C]-BI 1595043 to plasma proteins was assessed in rat, dog and human 
plasma in vitro by equilibrium dialysis (n00275691). Binding in rat and human plasma is 
concentration-dependent due to saturable binding to target in plasma, ranging from 60.5-
45.8% bound in rat plasma at concentrations from 0.001 to 100 μM, and 78.5% - 49.5% 
bound in human plasma at concentrations from 0.001 to 1 μM. Concentration-dependent 
binding was not observed in dog plasma (46.2% - 43.4% bound at all concentrations tested).
Distribution in pigmented rat
Quantitative tissue distribution of total drug-related radioactivity was investigated in male
pigmented (Long-Evans) rats administered a single 10 mg/kg oral dose of [14C]-BI 1595043
(n00273365). 
As measured by autoradiography, tissue:plasma ratios were variable, ranging from 0.045 to 
15 at 1 h post dose. At 24 h post dose, tissue:plasma ratios ranged from not detectable to 650, 
with the highest levels of radioactivity found in the liver, renal cortex, skin, cutis, eyeball, 
and melanin-containing tissues (MCT) of the ocular bulb. At 168 h post dose radioactivity 
was not measurable in any tissue. Radioactivity was detectable in the CNS only at 1 h post 
dose at levels of up to 8.1% in relation to the levels in whole blood. These results suggest low 
penetration of [14C]-BI 1595043 into the CNS.
The approximate half-lives (β-phase) of radioactivity in total eyeball and MCT of the ocular
bulb, based on limited data (2 data points) from 24 to 168 h, were 42 and 45 h, respectively.
The approximate half-life of radioactivity in plasma was determined to be 3.3 h. These data 
indicate high affinity and long-term (yet reversible) exposure of radioactivity to ocular 
tissues. In the skin and cutis, approximate half-lives calculated from 1 to 24 h were 12 and 
15 h, respectively. These data indicate moderate affinity and medium-term exposure of 
radioactivity to the integumentary system.
1.2.3.4
Metabolism
Data from hepatocyte incubations, conducted in both human and preclinical species (rat, dog,
minipig), in addition to in vivo data from preclinical species, were used to predict human
hepatic clearance. From this in vitro - in vivo correlation, hepatic clearance in human was
estimated to be 1.7 mL/min/kg. Based on this estimate, hepatic clearance is considered to be
the major route of elimination in humans. Additionally, renal clearance was estimated to be
0.4 mL/min/kg based on data scaled from non-rodent species (n00274794).


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1.2.3.5
Excretion
In Wistar Han rats, excretion of radioactivity was assessed after a PO dose (10 mg/kg) or an
IV dose (2 mg/kg) of [14C]-BI 1595043 (n00275520). Little to no difference in excretion
patterns were noted between PO and IV dosing, indicating good absorption.
Following the PO dose and collection of urine up to 96 h, 30.8% and 51.1% of the 
administered radioactivity was recovered from male and female rats, respectively, while the 
recovery of total radioactivity in feces was 62.8% and 43.7% in male and female rats, 
respectively. These data indicate slight differences in excretion patterns between male and 
female rats, with female rats showing slightly more urinary excretion than male rats, and 
male rats showing slightly more fecal excretion than female rats.
The excretion of radioactivity after IV and PO dosing was rapid, with >90% of dosed 
radioactivity recovered within 24 h for both male and female rats.
In bile duct cannulated rats administered an IV dose of [14C]-BI 1595043 the biliary excretion 
within 6 h was 28.0%. This time course in bile suggests that biliary excretion is not 
completed within this time interval.
1.2.3.6
Pharmacokinetic drug interactions
No pharmacokinetic drug interaction studies have been conducted.
1.2.3.7
Toxicokinetics
PK parameters were assessed in GLP-toxicological studies (n00268703, n00270419) and are 
displayed in Table 1.2.3.7: 1:
Table 1.2.3.7: 1 
PK parameters in GLP toxicological studies following oral 
administration of BI 1595043
Study Type
(Study or
Report No.)
Dose
(mg/kg
/day)
Cmax (nM)1
AUC0-241
(nM•hr)
Cmax Multiple2
AUC 
Multiple2
M
F
M
F
M
F
M
F
10
7,050
11,700
15,600
28,500
10
17
4
8
13 Week Rat
50
39,900
50,500
188,000
240,000
59
74
54
69
(n00268703)
300
167,000 188,000 1,910,000 2,080,000
246
277
547
595
3
2,570
2,190
25,600
18,800
4
3
7
5
13 Week Dog
10
8,550
10,700
81,700
81,400
13
16
23
23
(n00270419)
30
35,700
NA
352,000
NA
53
NA
101
NA
100
NA
127,000
NA
1,580,000
NA
187
NA
452
Human
30 mg/day
678
3,494
1.
Data shown are end of study exposures
2.
Multiples calculated based on estimated human therapeutic exposure
Exposures corresponding to NOAEL dose are listed in bold.
For a more detailed description of the BI 1595043 profile, please refer to the current IB 
(c31270124).


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1.2.4
Prediction of human therapeutic dose
A two compartment population PK model with first-order oral absorption and a TMDD 
process was constructed using PK data from the completed dose groups of the first in human 
single rising dose (SRD) study 1445-0001 (see Section 1.2.5.2). This model was linked to the 
original PK/PD model to derive the human therapeutic dose that is expected to lead to a 75% 
reduction in cysteamine exposure over a 24 h period (AUC24, cysteamine). The linked PK/PD 
model was developed using in vitro and in vivo data from preclinical species, human in vitro
data regarding the binding properties of BI 1595043 to vanin, and a correlation between 
target engagement in mouse and ex vivo analysis using human intestinal tissue (n00274794). 
From the linked PK/PD model, it is expected that clinical efficacy will be maintained at a 
BI 1595043 dose of 30 mg q.d. At this dose, Cmax,ss and AUC24,ss are predicted to be 678 nM 
and 3,494 nM•h, respectively.
1.2.5
Clinical experience in humans
The first in human study SRD study 1445-0001 is ongoing at the time of current 1445-0011
clinical trial protocol preparation. The SRD study consists of 7 original dose groups of 8 
subjects each that have been completed. These include dose levels 1 mg, 3 mg, 6 mg, 12 mg, 
25 mg, 50 mg, and 90 mg of BI 1595043, administered as oral solution, with 6 subjects in 
each dose group assigned to active treatment and 2 subjects assigned to placebo. The SRD 
clinical trial protocol is being amended to add one additional dose level of 160 mg of 
BI 1595043 at the time of preparation of 1445-0011 clinical trial protocol.
At this point in the clinical trial, BI 1595043 has been administered to 42 healthy male 
subjects as oral single doses of oral solution within 7 dose groups. Additionally, 14 healthy 
male subjects have received matching placebo.
1.2.5.1
Safety
The safety evaluation in Trial 1445-0001 includes physical examination, ophthalmological 
examination, vital signs, 12-lead ECG, laboratory tests and adverse event (AE) assessment. In 
the completed dose groups, i.e. up to an oral single dose of 90 mg, BI 1595043 was well
tolerated with a low frequency of AEs of mild intensity (see Table 1.2.5.1: 1). The most 
frequent AE was headache reported in 17.1% (n=3) subjects on BI 1595043 and 14.3% (n=2) 
subjects on placebo. During planned ophthalmological examination, a mild retinal 
haemorrhage was observed at the End-of-Trial visit in one subject who received 12 mg of BI 
1595043 without any symptoms. At the follow up ophthalmological investigation, the AE 
was resolved without consequences, and the AE was considered as not drug related. There 
were no AEs considered to be dose limiting, in particular no AEs of severe intensity and no
SAEs. Vital signs evaluation and safety laboratory testing did not reveal relevant findings 
[c34604736]. Thorough descriptive ECG analyses did not reveal a marked prolongation of 
the QT/QTc interval. There were no QTc increases to >500 ms or changes from baseline of 
>60 ms [c34816263].


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Table 1.2.5.1: 1
Frequency [N (%)] of patients with AEs by treatment, primary system 
organ class and preferred term – SRD Trial 1445-0001 – Dose Groups 
1-7 (1-90 mg BI 1595043 or placebo)
System organ class/
Preferred term
Placebo
N (%)
1 mg 
N (%)
3 mg 
N (%)
6 mg
N (%)
12 mg
N (%)
25 mg 
N (%)
50 mg
N (%)
90 mg
N (%)
BI Total
N (%)
Total
N (%)
Number of subjects
14 (100) 6 (100)
6 (100)
6 (100)
6 (100)
6 (100)
6 (100) 6 (100) 42 (100) 56 (100)
Total with adverse events
6 (42.9)
0 (0)
1 (16.7)
1 (16.7)
2 (33.3)
3 (50)
4 (66.7)
0 (0) 11 (26.2) 17 (30.4)
Nervous system disorders
3 (21.4)
0 (0)
0 (0)
0 (0)
0 (0)
1 (16.7)
3 (50)
0 (0)
4 (9.5)
7 (12.5)
Headache
2 (14.3)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
3 (50)
0 (0)
3 (7.1)
5 (8.9)
Dizziness
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (16.7)
0 (0)
1 (2.4)
1 (1.8)
Somnolence
1 (7.1)
0 (0)
0 (0)
0 (0)
0 (0)
1 (16.7)
0 (0)
0 (0)
1 (2.4)
2 (3.6)
Eye disorders
0 (0)
0 (0)
0 (0)
0 (0)
1 (16.7)
0 (0)
0 (0)
0 (0)
1 (2.4)
1 (1.8)
Retinal haemorrhage
0 (0)
0 (0)
0 (0)
0 (0)
1 (16.7)
0 (0)
0 (0)
0 (0)
1 (2.4)
1 (1.8)
Gastrointestinal disorders
2 (14.3)
0 (0)
1 (16.7)
1 (16.7)
1 (16.7)
0 (0)
0 (0)
0 (0)
3 (7.1)
5 (8.9)
Diarrhoea
0 (0)
0 (0)
1 (16.7)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (2.4)
1 (1.8)
Flatulence
0 (0)
0 (0)
0 (0)
0 (0)
1 (16.7)
0 (0)
0 (0)
0 (0)
1 (2.4)
1 (1.8)
Nausea
0 (0)
0 (0)
0 (0)
1 (16.7)
0 (0)
0 (0)
0 (0)
0 (0)
1 (2.4)
1 (1.8)
Angular cheilitis
1 (7.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (1.8)
Dyspepsia
1 (7.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (1.8)
Gastrointestinal pain
1 (7.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (1.8)
General disorders and 
administration site 
conditions
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (16.7)
1 (16.7)
0 (0)
2 (4.8)
2 (3.6)
Fatigue
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (16.7)
1 (16.7)
0 (0)
2 (4.8)
2 (3.6)
Infections and infestations
1 (7.1)
0 (0)
0 (0)
0 (0)
0 (0)
1 (16.7)
0 (0)
0 (0)
1 (2.4)
2 (3.6)
Conjunctivitis
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (16.7)
0 (0)
0 (0)
1 (2.4)
1 (1.8)
Rhinitis
1 (7.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (1.8)
1.2.5.2
Pharmacokinetics
A preliminary PK data analysis for BI 1595043 in Trial 1445-0001 has been performed using 
planned sampling times instead of actual sampling times. As actual sampling time should 
deviate from planned time only slightly, the principal PK conclusions are not expected to be 
subject of clinically relevant change. 
The single-dose PK parameters of BI 1595043 from dose groups 1 to 7 (1 to 90 mg) are 
summarized in Table 1.2.5.2: 2. After a single oral solution dose, BI 1595043 was rapidly 
absorbed with median tmax values of 0.75-1 h. Cmax increased in a close to dose proportional 
manner. AUC0-24 increased in a less than dose-linear manner between 1 and 6 mg, and at 
doses above 6 mg, AUC0-24 increased approximately dose proportionally. Geometric mean 
terminal t1/2 ranged from 16 to 29 h.
In Trial 1445-0001, 160 mg has been selected as maximum dose, predicted to result in a Cmax
of 3,550 nM and AUC0-24 of 17,620 nM•h in humans based on the interim population PK
model.


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Table 1.2.5.2: 2
gMean (gCV%) values of BI 1595043 PK parameters after single oral 
doses of BI 1595043 – SRD Trial 1445-0001 – Dose Groups 1-7
Parameter
Dose (mg)
1
3
6
12
25
50
90†
AUC0-24
(h∙nmol/L)
207 (16.6)
453 (7.20)
747 (11.2)
1450 (16.4)
2810 (16.8)
5150 (19.5)
11400 
(8.76)
AUC0-tz 
(h∙nmol/L)
258 (27.8)
537(14.3)
921 (18.8)
1790 (19.2)
3140 (20.1)
5460 (20.2)
NC
Cmax (nmol/L)
23.6 (16.6)
78.4 (10.9)
119 (21.2)
286 (20.5)
516 (26.2)
1100 (27.1)
2500 (20.0)
tmax (h)*
1.0 (0.5-1.0)
1.0 (0.5-1.0)
1.0 (0.5-1.5)
0.75 (0.5-
1.0)
1.0 (1.0-1.0)
0.75 (0.5-
1.0)
0.75 (0.5-
1.0)
t½ (h)
16.8 (28.2)
15.6 (35.2)
21.3 (59.6)
26.8 (33.9)
29.3 (25.9)
20.6 (43.6)
NC
CL/F 
(mL/min)
143 (27.0)
220 (15.0)
263 (19.7)
274 (19.2)
327 (19.5)
382 (20.3)
NC
Vz/F (L)
209 (9.61)
298 (20.6)
486 (40.8)
637 (29.9)
830 (34.2)
683 (26.3)
NC
* median (min-max)
† 90 mg dose, concentration data are available only to 24 h post-dose. All quantifiable concentrations at all time points are 
available for all other doses.
NC – Not Calculated, too few data points available
1.2.6
Residual Effect Period
The residual effect period (REP) for BI 1595043, when measurable drug levels or PD effects 
are still likely to be present after the last administration, is about 6 days (estimated based on 5 
times terminal t1/2 of dose group 5 of up to 29.3 h). Conservatively, all AEs reported until the 
end of trial examination will be considered on treatment.
1.2.7
Drug product
Please refer to Section 4.1.
For a more detailed description of the BI 1595043 profile, please refer to the current IB 
(c31270124).


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1.3
RATIONALE FOR PERFORMING THE TRIAL
The trial is conducted to gain information about the effect of food on the relative 
bioavailability of the BI 1595043 tablet formulation. The data obtained in this study will 
support the optimization of trial design in upcoming clinical studies, and may be crucial 
information for formulation development.
Dose selection of 30 mg of BI 1595043 is based on the assumption to include a potential 
therapeutic dose (see Section 1.2.4).
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance to for the development of BI 1595043, 
which represents a novel approach for the treatment of patients with Crohn’s disease. 
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
1.4.1
Expected benefit for the target indication
BI 1595043, a first-in-class vanin inhibitor, will be developed in CD. There is a substantial 
unmet medical need for agents with greater efficacy than current therapies, like 
aminosalicylates (e.g. 5-ASA), glucocorticoids, immunomodulator agents (azathioprine or 
6-MP), biologic TNFα inhibitors (TNFi), or other biologic options (vedolizumab, 
ustekinumab). Concerns over infection- and lymphoma risks attached to some of these 
treatments remain. Treatment options for fistulizing and fibrotic disease are limited.
In CD, direct barrier injury is believed to be (at least partially) channeled through vanin 
enzymes and their product, cysteamine. By reducing cysteamine levels, a vanin inhibitor is 
expected to lead to direct epithelial barrier repair, resulting in mucosal healing, and to 
attenuate the chronic inflammation that is underlying the disease. Oral medicines with a novel 
mode of action that includes repair of epithelial barrier would address the unmet medical 
need in CD.
1.4.2
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising and, in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.


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1.4.3
Drug-related risks and safety measures
Factors of risk may derive from particular knowledge or the lack thereof, regarding (1) the
mode of action, (2) the nature of the target, (3) the relevance of animal models and/or (4) 
findings in non-clinical safety studies.
1.4.3.1
Mode of action and nature of the target
Vanin-1 and -2 are extracellular enzymes expressed in humans on epithelial (lung, kidney, 
and intestinal tract), liver-, and immunological cells. It is shed in significant amounts into the 
extracellular milieu, and is found in most tissues. It’s function is to convert pantetheine into 
pantothenic acid and cysteamine. Through the production of cysteamine, vanin is directly 
impacting extracellular metabolic homeostasis of different tissues by chemically reducing and 
depleting cysteine, resulting in increased oxidative stress, endoplasmic reticular stress, and 
disruption and eventual destruction of tissue. Therefore, it is expected that vanin inhibition 
will directly restore tissue metabolite homeostasis and redox balance leading to tissue repair 
in CD-patients.
As described in Section 1.2.1, the human missense SNP (rs2272996) in the gene, encoding 
vanin-1, is associated with decreased blood pressure (R18-2692). Considering this data as 
well as the findings from the dog telemetry study, blood pressure and heart rate will be 
closely monitored after BI 1595043 administration.
In toxicology studies with BI 1595043, there were no adverse histological pancreas findings 
or a lack of glycemic control. However, considering the conflicting literature, described in 
Section 1.2.1 about pancreatic islet cell survival, fasting blood glucose levels will be closely 
monitored as a precautious measure.
Since there might be a relationship between vanin inhibition and acetaminophen 
(paracetamol) induced liver toxicity, in this study, acetaminophen will be strictly prohibited 
as concomitant medication.
1.4.3.2
Relevance of animal models
Vanin-1 is expressed in preclinical species including mouse, rat, and dog. Rat and Beagle dog 
were chosen as the rodent and non-rodent toxicology species due to the conserved amino acid 
sequence for vanin-1 (>78% compared to human) and previously demonstrated 
pharmacological activity of vanin inhibitors in these species (n00261263, n00261387). 
However, as rodents lack vanin-2, there is a considerable discrepancy between species. In 
dogs, vanin-1 mRNA levels are high in the lung, liver, spleen and kidney. Comparative 
expression in tissues is generally lower in the rat, although tissue distribution is comparable. 
While dogs possess a vanin-2 gene, its expression in dog tissues is not characterized. Target 
risk assessments generated for vanin-1 and vanin-2 did not reveal any unique on target 
concerns for vanin-2 when compared to vanin-1. However, any unique effects mediated by 
vanin-2 may not be evaluated in rodent studies, but dog toxicity studies would inform on 
potential vanin-2 effects. Potency of BI 1595043 in dog whole blood was comparable to 
human; while in mouse whole blood, BI 1595043 displayed twenty-five-fold lower potency.


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In conclusion, rat and dog were considered suitable species for nonclinical safety profiling of 
BI 1595043, with dog as the most sensitive species. Confidence in the suitability of rat and 
dog as toxicology species was increased by favorable oral pharmacokinetics characteristics 
(see Section 1.2.3), demonstration of pharmacological activity of BI 1595043 in the rat and 
dog dose range finding studies (n00266340, n00266444), and similar metabolite profiles in 
human and rat/dog.
1.4.3.3
Findings in non-clinical safety studies
Toxicology data of BI 1595043 support clinical studies in men with daily oral administration 
for up to 91 days. 
In the rat 13-week study (n00268703), signs of reproductive toxicity were seen in male rats at 
300 mg/kg/day (adverse microscopic effects on the testis and epididymis), not considered 
relevant in humans at planned clinical doses due to large safety margins. Under the 
conditions of this study the NOAEL at steady state was considered to be 50 mg/kg/day, 
which corresponded to a Cmax of 39,900 nM and AUC0-24 of 188,000 nM•h in males and Cmax
of 50,500 nM and AUC0-24 of 240,000 nM•h in females. With regard to the non-adverse 
ophthalmology findings (visualization of cataract, descriptively synonymous with a change in 
lens opacity), no microscopic evidence of correlating cataract formation was observed upon 
thorough histologic examination in any rat. Likewise, no ophthalmology findings were 
observed in 1-week repeat-dose toxicity study in rats (n00266340) and in the 2-week and 13-
week studies in dogs (most sensitive toxicological species) (n00266444, n00270419), which 
suggests an unlikely clinical relevance for human subjects receiving two isolated doses in the
planned dose range.
In the dog 13-week study (n00270419), once daily oral administration of BI 1595043 resulted 
in moribundity at 100 mg/kg/day in one male dog. Based on reversible adverse effects on the 
liver in male dogs at 30 mg/kg/day, liver enzymes parameters will be closely monitored after 
BI 1595043 administration. Under the conditions of this study the NOAEL at steady state 
was considered to be 10 mg/kg/day, which corresponded to a Cmax of 8,550 nM and AUC0-24 
of 81,700 nM•h in males and Cmax of 10,700 nM and AUC0-24 of 81,400 nM•h in females.
BI 1595043 has a low risk for QT prolongation based on results of the dog telemetry study 
(n00271655). The observed decreases in blood pressure with accompanying increases in heart 
rate in dogs may be related to the pharmacological inhibition of vanin (R18-2692). Based on 
these findings, blood pressure and heart rate will be closely monitored after BI 1595043 
administration.
Embryo-fetal development toxicity studies have been completed in rat and rabbit 
(n00278622, n00278281). Maternal and embryo-fetal toxicity were not observed in these 
studies (rat NOAEL AUC 125,000 nM•h and Cmax 25,500 nM, rabbit NOAEL AUC 323,000 
nM•h and Cmax 97,400 nM). Teratogenicity (digit malformations) was observed in rat 
(LOAEL AUC 6,900  nM•h and Cmax 2,270 nM) (n00278622). There is a very low risk of 
relevant systemic exposure through exposure to seminal fluid in women of child-bearing 
potential (WOCBP) partners of male subjects dosed with BI 1595043. Given the results of 
the embryo-fetal development study in rats, BI 1595043 currently falls into a category of 
possible human teratogenicity [R20-3402] for which additional birth barrier contraception 
(condom) is not strictly required. However, considering the limited clinical data available for 


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BI 1595043, study subjects will be conservatively required to follow the birth control 
measures as specified in inclusion criterion No. 5. In addition, unprotected sexual intercourse 
with a pregnant female partner and sperm donation is not allowed throughout the study and 
until 30 days after trial completion.
The risk of genotoxicity and phototoxicity is low. Carcinogenicity and local tolerance has not 
yet been examined. Reproductive studies have not yet been completed.
Overall, it should be highlighted that all toxicological findings occurred at exposures far 
beyond the estimated therapeutic exposure (Cmax of 678 nM and AUC0-24 of 3,494 nM•h at 30 
mg of BI 1595043) supporting consideration of large safety margin across the planned dose 
range in the study.
1.4.3.4
Clinical findings
To date, BI 1595043 was administered to 42 healthy male subjects as single doses up to 
90 mg in this FIH study. Overall, BI 1595043 was well tolerated with a low frequency of AEs 
of mild intensity. There were no AEs considered to be dose limiting and no SAEs (see 
Section 1.2.5).
1.4.3.5
Drug induced liver injury
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.7.1.4, adverse events of special interest.
1.4.3.6
Risk minimization (safety precautions and stopping rules)
The following risk minimization measures, including safety precautions and stopping rules, 
will be implemented in this study:

Careful selection of the study dose, as described in Section 4.1.2.

If dosing of several subjects is scheduled on a same day, subjects will be dosed at 
least 5 min apart.

Application of the second single dose of BI 1595043 to each subject, only if the first 
single dose of BI 1595043 is safe, shows acceptable tolerability, and no stopping 
criterion is met (see Sections 3.3.4.1 and 3.3.4.3). At least 8 days will be maintained 
between the two drug administrations to each subject.

A monitoring of safety laboratory with specific focus on plasma glucose levels and 
liver enzymes (see Flow Chart).

Safety monitoring (including e.g. vital signs, 12-lead ECGs and adverse events) with 
a special focus on blood pressure and heart rate measurements.

Ophthalmological examination at Screening and EoTrial Visit (see Section 5.2.3).


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
Hospitalization of subjects at the trial site for at least 48 hours after study drug 
administration at each dose level. Based on the longest gMean terminal t1/2 in dose 
group 5 of up to 29.3 h (based on preliminary PK data) for BI 1595043 in this study,
this is expected to cover the period of highest risk/ peak effect. During in house-
confinement, subjects will be under medical observation and thoroughly monitored 
for both expected and unexpected adverse events.

Exclusion of acetaminophen (paracetamol) as concomitant medication.

Due to observed teratogenicity in rat, women will not be enrolled in this study.
1.4.4
Overall assessment
BI 1595043, a first-in-class vanin inhibitor, has been thus far administered to 42 healthy 
subjects in the preceding FIH SRD study. This is the third trial with BI 1595043 and the first 
with administration under fed condition. Despite the novelty of the target, non-clinical safety 
data in relevant animal species, preliminary clinical data obtained in 1445-0001 SRD study, 
the inhibitory mode of action as well as the comprehensive risk assessment suggest that BI 
1595043 is not a high-risk compound and support the application of BI 1595043 under fed 
condition in this trial.
Based on the risk mitigation strategy, healthy subjects should not be exposed to undue risks 
by the intake of BI 1595043. Healthy volunteers are not expected to have any direct benefit 
from participation in this trial, as is usually the case in Phase I studies. Considering the high 
medical need for novel, effective and safe treatment for CD, it is believed that the benefit of 
this trial outweighs the potential risks and justifies exposure of healthy volunteers to BI 
1595043.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the relative bioavailability of 30 mg of 
BI 1595043 under fed state (Test, T) compared with 30 mg of BI 1595043 under fasted state 
(Reference, R) following oral administration.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 1595043:

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 BI 1595043:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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2.2.2.2
Safety and tolerability
Safety and tolerability of BI 1595043 will be assessed based on:  

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, open-label, two-way cross-over trial in healthy 
male subjects in order to compare test treatment T (fed) and reference treatment R (fasted). 
The treatments will be one single dose of 30 mg of BI 1595043 administered as tablets in the 
fasting state (R) and one single dose of 30 mg of BI 1595043 administered as tablets in the 
fed state (T). The 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 8 days between the treatments.
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(S)
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between treatments is based on 
an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529].
Blinding is not possible because the treatments are distinguishable. The open-label treatment
is not expected to bias the results, since the PK 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 14 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site.
Only male subjects will be included in the trial (refer to Section 1.4.3.3).
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:


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1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR, body 
temperature), 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 prior to admission to the study, in accordance 
with GCP and local legislation
5. Male subjects who meet any of the following criteria from at least 30 days before the first 
administration of trial medication until 30 days after trial completion:
-
Use of adequate contraception, i.e. use of condom (male subjects) plus any of 
the following methods (female partners): intrauterine device, hormonal contraception 
(e.g. implants, injectables, combined oral or vaginal contraceptives) that started at 
least 2 months prior to first drug administration to the male subject, or barrier method 
(e.g. diaphragm with spermicide), or surgically sterilised (including bilateral tubal 
occlusion, hysterectomy or bilateral oophorectomy), or postmenopausal, defined as at 
least 1 year of spontaneous amenorrhea
-
Sexually abstinent
-
Vasectomised (vasectomy at least 1 year prior to enrolment) in combination 
with a barrier method (i.e. condom)
Unprotected sexual intercourse (i.e. without use of condom) with a pregnant female 
partner and sperm donation is not allowed throughout the study and until 30 days after 
trial completion.
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections


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10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval 
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more 30 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study
In addition, the following trial-specific exclusion criteria apply:
23. History of acute pancreatitis
24. History of relevant ophthalmological disorders (with exception of myopia and hyperopia) 
or detection of ocular disorders in slit lamp examination at screening.
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. 


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At the time of discontinuation, a complete end of trial examination will be performed, if 
possible, and the information will be recorded in the CRF. If the discontinuation occurs 
before the end of the REP (see Section 1.2.3), the discontinued subject should if possible be 
questioned for AEs and concomitant therapies at or after the end of the REP in order to 
ensure collection of AEs and concomitant therapies throughout the REP, if not contrary to 
any consent withdrawal of the subject.
Due to teratogenicity observed in embryo-fetal development study in rat and the theoretically 
possible risk that relevant systemic concentrations being achieved in women of child-bearing 
potential (WOCBP) from exposure to seminal fluid of subject receiving BI 1595043, 
adequate contraception as outlined in Section 3.3.2 is a prerequisite for participation in the 
study.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. An AE or clinically significant laboratory change or abnormality occurs that the 
investigator assesses as warranting discontinuation of treatment. This may include cases 
of sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP >180/100 
mmHg), clinically relevant changes in ECG requiring intervention, or unexplained 
hepatic enzyme elevations at any time during the trial
6. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
7. The subject has a serious adverse event or a severe non-serious adverse reaction 
considered at least possibly related to the IMP administration.
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.
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 


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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 (item No. 2 describes mandatory discontinuation criteria):
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events (SAE), or any safety information
invalidating the earlier positive benefit-risk-assessment. More specifically, the trial will 
be terminated if 2 or more subjects experience an adverse event of moderate or greater 
intensity within the same system organ class (SOC), unless they have been demonstrated 
to be unrelated to study drug; or if any subject experiences a SAE, unless the SAE has 
been demonstrated to be unrelated to study drug.
3. Violation of GCP, or the CTP, or the contract with BI impairing the appropriate conduct 
of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item No. 3 applies).
3.3.5
Replacement of subjects
If more than 2 subjects do not complete the trial, the Clinical Trial Leader together with the 
Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects 
will be replaced. A replacement subject will be assigned a unique trial subject number and 
will be assigned to the same treatment as the subject he replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product has been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
BI 1595043
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
2 single doses separated by a washout period of at least 8 days 
Substance:
BI 1595043
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg
Posology:
1-0-0
Route of administration:
oral
Duration of use:
2 single doses separated by a washout period of at least 8 days
4.1.2
Selection of doses in the trial
BI 1595043 dose selected in this trial is at the current predicted therapeutic dose of 30 mg
(see Section 1.2.4).
BI 1595043 is a BCS class I compound with high permeability and high solubility. In SRD 
study (1445-0001), BI 1595043 was administered as oral solution and was rapidly absorbed 
with tmax of 0.75 or 1 hour, which is in line with BCS class I properties. In pre-clinical testing, 
tablet formulation had fast disintegration (1-3 min). Thus, no substantial difference in 
bioavailability is expected between oral solution and tablet formulation. Based on BCS class I 
properties, BI 1595043 exposures are expected to be minimally affected by food.
The selected dose of 30 mg is 3-fold lower than the maximum tested dose to date (90 mg) in 
the ongoing SRD study. At the dose of 30 mg, Cmax is predicted to be 678 nM and AUC0-24 –
3,494 nM•h; these are about 3.7-fold and 3.3-fold lower, respectively, than the observed 
exposure after a single dose of 90 mg (Cmax of 2,500 nM and AUC0-24 of 11,400 nM•h).
Overall, based on physical, chemical and PK properties, the exposure of 30 mg of 
BI 1595043 as tablet formulation under fed condition will unlikely exceed the observed 
exposure of 90 mg administered as oral solution in fasted state.


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4.1.3
Method of assigning subjects to treatment sequences
Prior to the screening visit, subjects will be contacted in writing and informed about the
planned visit dates. Subjects willing to participate will be recruited to the trial.
The randomisation list will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). For this purpose, numbers of the randomisation 
list will be allocated to the subjects by the method ‘first come - first served’ at the time of 
registration. Therefore, the allocation of subjects to treatment sequences is not influenced by 
trial personnel, but only by subjects’ temporal availability. Subjects are then assigned to a 
treatment sequence according to the randomisation list.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.6.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a two-way cross-over study. All subjects will receive the 2 treatments in 
randomised order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total  dose
R (Reference)
BI 1595043
film-coated 
tablet
5 and 25 mg
1 tablet 5 mg and 1 tablet 25 mg 
under fasted condition (single dose)
30 mg
T (Test)
BI 1595043
film-coated 
tablet
5 and 25 mg
1 tablet 5 mg and 1 tablet 25 mg 
under fed condition (single dose)
30 mg
In treatment R (in the fasted state), 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. 
In treatment T (in the fed state), a high-fat, high-calorie meal will be served 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 ‘Food-Effect Bioavailability and Fed 
Bioequivalence Studies’ [R03-2269]. 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


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Ingredients
kcal
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. 
In each treatment period, the investigator (or authorised designee) will administer the trial
medication as an oral dose together with about 240 mL of water to subjects who are in a 
sitting or 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, and – if applicable – its preparation (dispensing of BI 1595043), if correct dosage 
cannot be ensured otherwise.
Subjects will be kept under close medical surveillance until 48 h after drug administration. 
During the first 2 h after drug administration, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture except for 
medical examination) or to sleep.
The treatments will be separated by a wash-out phase of at least 8 days.
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
All trial data will be handled open label. This means that trial functions of the sponsor are
unblinded (e.g. clinical trial lead, data manager, statistician, bioanalyst, pharmacokineticist,
pharmacometrician, drug metabolism scientist as well as dedicated personnel of the trial site).
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms.
No re-supply is planned.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (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
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 


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kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
Acetaminophen (paracetamol) is prohibited as concomitant mediation in this study. If 
necessary, short-term use of ibuprofen or acetylsalicylic acid is acceptable.
Drugs with a known hepatotoxicity profile should be avoided during the entire study.
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).
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample of each study period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 10 h before until the end of the in-house period at the trial 
site.Smoking is not allowed during in-house confinement while admitted to the trial site.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Subjects with pregnant or non-pregnant WOCBP partners should use male contraception (i.e. 
condom) to avoid exposure of an existing embryo/fetus. Additional contraception 
requirements detailed in Inclusion Criterion No. 5 must be considered.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable. No efficacy endpoints will be evaluated in this trial.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported),
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR, body temperature), 12-lead ECG, laboratory tests, and a 
physical examination. At the end of trial examination, it will include review of vital signs, 12-
lead ECG, laboratory tests, and a physical examination including determination of weight.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100, 
) at the times indicated in the Flow Chart, 
after subjects have rested for at least 5 min in a supine position. All recordings should be 
made using the same type of blood pressure recording instrument on the same arm, if 
possible.
Body temperature will be measured orally or under the armpit (axillary method) or in the ear 
(tympanic method) at each ambulatory visit, at admission to the trial site, and each day in the 
morning during in-house stay (refer to Flow Chart).
5.2.3
Ophthalmological examination
A slit lamp examination (e.g. 
 RSL 110) will be conducted by an 
ophthalmologist at Screening and EoTrial examination to exclude findings suspicious for 
signs of cataract and/or other ocular disorders.
Data from ophthalmological examination will not be transferred to the CRF/database, only 
abnormal findings will be recorded as AEs if judged clinically relevant by the Investigator.
5.2.4
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
The parameters that will be determined are listed in Tables 5.2.4: 1 and 5.2.4: 2. Reference 
ranges will be provided in the ISF, Section 10. 


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Manual differential white blood cell count will be performed if there is an abnormality 
detected with the automatic blood cell count. Urine microscopic examinations will be 
performed in addition to urinalysis (Stix) in order to correctly evaluate possible abnormalities 
detected at the urinalysis (Stix).
Table 5.2.4: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count (Erythrocytes), absol. 
Reticulocytes, absol.
White Blood Cells (Leucocytes), absol. 
Platelet Count (Thrombocytes), absol.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/ Leukocytes; Eosinophils/ Leukocytes; 
Basophils/ Leukocytes; Monocytes/ Leukocytes; 
Lymphocytes/ Leukocytes
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands;  Neutrophils Bands, absol.; Eosinophils/ Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; Lymphocytes/ 
Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
Albumin (Protein Electrophoresis) 
Alpha-1-Globulin (Protein Electrophoresis)
Alpha-2-Globulin (Protein Electrophoresis)
Beta-Globulin (Protein Electrophoresis)
Gamma-Globulin (Protein Electrophoresis)
C-Reactive Protein (Quant)  
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
--
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X


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Table 5.2.4.: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Hormones
Thyroid Stimulating Hormone 
Free T3 - Triiodothyronine
Free T4 – Thyroxine
X
X
X
--
--
--
--
--
--
Electrolytes
Sodium
Potassium
Calcium
X
X
X
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 1 on Day -3 to -1; and on Day 2 and Day 5 in each treatment period (i.e. 
at Visits 2 and 3) (for time points refer to Flow Chart)
C: parameters to be determined at Visit 4 (end of trial examination)
The tests listed in Table 5.2.4: 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. Drug screening will be performed at screening and after admission to the trial site. 
Infectious serology will be performed at screening only.


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Table 5.2.4: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
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)
COVID-191
SARS CoV-2 PCR test
1 evaluation will be performed shortly (within 72 hours) before admission to trial site in each treatment period as 
per Flow Chart
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
6510 and Alcotest® 5510, 
) will be performed at admission to the trial site,
and may be repeated at any time during the study at the discretion of an investigator or 
designee. The results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.4: 1 and 5.2.4: 2 will be performed at 
 
, with the exception of 
drug screening. These tests will be performed at the trial site using e.g.Triage® TOX Drug 
Screen, 
 or Combur9 Test®, or comparable test systems. SARS-CoV-2 virus PCR test 
will be performed either by 
 or the trial site.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.5
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, 
 
) at the times provided in the Flow Chart. 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 study. 
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time (except for blood drawing from an intravenous cannula that is already in 
place) to avoid compromising ECG quality.


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All ECGs will be stored electronically at the site. 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.6
Other safety parameters
Not applicable.
5.2.7
Assessment of adverse events
5.2.7.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation  

Requires prolongation of existing hospitalisation


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
Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in Section 5.2.7.1.9 and Section 5.2.7.1.10, subsections ‘AE Collection’ and ‘AE
reporting to sponsor and timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from
other compounds in the same class. AESIs need to be reported to the sponsor’s
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see
Section 5.2.7.1.10.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 


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


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
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.7.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.


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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 via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
Pregnancy
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood 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. 


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Date and clock times of drug administration and pharmacokinetic sampling will be recorded 
in the CRFs. The actual sampling times will be 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 BI 1595043 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into an K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venepuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma, the 
second aliquot will contain the remaining 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. The second aliquot will be transferred to the analytical laboratory after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory, the plasma 
samples will be stored at approximately -20°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, day, and 
planned sampling time. Further information such as matrix and analyte may also be provided. 
Plasma samples will be transferred to 
.
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g., assessment of metabolites). However, only data related to the analyte 
and/or its metabolite(s) will be generated by these additional investigations. The study 
samples will be discarded after completion of the additional investigations, but not later than 
5 years after the CTR is archived.


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5.4
ASSESSMENT OF BIOMARKER(S) 
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used assessments of drug exposure.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests 
will be ± 15 min for the first 4 h after trial drug administration and ± 30 min thereafter. 
Starting from 48 h post-dose a deviation from the scheduled time for vital signs, ECG and 
laboratory tests of ±120 min is acceptable.
If several activities are scheduled at the same time point in the Flow Chart, blood sampling, 
vital signs, and 12-lead ECG should be the first and meal the last activity. 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 individual plasma concentration sampling times refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods. At least 8 days will separate 
drug administrations in the first and second treatment periods.
On Day 1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 48 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 study days, subjects will be treated in an ambulatory fashion.


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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 5.3
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the relative bioavailability of 30 mg of 
BI 1595043 in the fed state (Test, T) compared with 30 mg of BI 1595043 in the fasting state 
(Reference, R) following oral administration on the basis of the primary and secondary 
pharmacokinetic endpoints, as listed in Section 2.1.2 and 2.1.3. The trial is designed to allow 
intra-subject comparisons and will be evaluated statistically by use of a linear model for 
logarithmically transformed PK endpoints. 
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of BI 1595043 in the fed state compared with BI 1595043 in the 
fasted state will be estimated by the ratios of the geometric means (test/reference), and their 
corresponding 2-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-test procedure, each at the 5% significance level. Since the 
main focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for safety 
analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol violation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he/she 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(iPD) categories will be suggested in the iPD specification file, iPDs will be identified no 
later than in the Report Planning Meeting, and the iPD categories will be updated as needed.


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Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for BI 1595043 will be calculated 
according to the relevant SOP of the Sponsor (001-MCS-36-472). 
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.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma 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),

The subject experiences emesis at any time during the labelled dosing interval.

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.3.1
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: 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:


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yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment  
k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2,
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2,
k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means).
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
7.3.2
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will be assessed statistically using the same 
methods as described for the primary endpoints.


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7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between first trial medication intake and end of 
REP (see Section 1.2.6) will be assigned to the treatment period. Events occurring after the 
REP but prior to next intake or end of trial termination date will be assigned to ’follow-up’. 
In case of two or more treatments, the follow-up will be summarized according to the 
previous treatment. These assignments including the corresponding time intervals will be 
defined in detail in the TSAP. Note that AEs occurring after the last per protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.7.1), and
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.


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Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
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 list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 14 subjects in the trial, 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.
Based on the previous SRD trial (see Section 1.2.5.2), the intra-individual coefficient of 
variation (gCV) for BI 1595043 is assumed to be roughly 23%.
For various assumptions around the gCV of 23%, Table 7.7: 1 provides an overview of the 
achievable precision for estimating the ratio of geometric means (test/reference). For 


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illustrative purposes, the expected 90% confidence intervals are displayed for a value of 
100% for the ratio T/R of geometric means.
Table 7.7: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratio of geometric 
means (T/R) for different gCVs and sample sizes N in a 2x2 
crossover trial
gCV [%]
N
Precision**
Ratio [%]*
Lower CL 
[%]
Upper CL 
[%]
20
10
1.258
100
79.51
125.77
12
1.219
82.01
121.93
14
1.193
83.81
119.31
16
1.174
85.18
117.40
23
10
1.301
100
76.88
130.07
12
1.255
79.67
125.52
14
1.224
81.67
122.44
16
1.202
83.20
120.19
27
10
1.360
100
73.56
135.95
12
1.304
76.68
130.42
14
1.267
78.94
126.69
16
1.240
80.67
123.97
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
**Defined as ratio of upper CL and relative BA estimate.
The expected 90% confidence interval limits in the table were derived by
CI limit,  = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 4.0.2.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a general rule, no trial results should be published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the  subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the responsible 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.


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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number,
and social security number) have properly been removed or redacted to ensure subject
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication


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


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


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The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at
, under the supervision of the Principal Investigator.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of clinical trial managers (CTM), Clinical 
Research Associates, and investigators of participating trial sites
The trial medication (BI 1595043) will be provided by the 
 
.
Safety laboratory tests will be performed by the local laboratory of the trial site (
)
Analyses of BI 1595043 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 according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2002:1-
9.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R13-2231
Baumgart DC, Sandborn WJ. Crohn's disease. Lancet 2012;380:1590-1605.
R17-3322
Berruyer C, Pouyet L, Millet V, Martin FM, LeGoffic A, Canonici A, et al. 
Vanin-1 licenses inflammatory mediator production by gut epithelial cells 
and controls colitis by antagonizing peroxisome proliferator-activated 
receptor gamma activity. J Exp Med 2006;203(13):2817-2827.
R17-3323
Martin F, Penet MF, Malergue F, Lepidi H, Dessein A, Galland F, et al. 
Vanin-1-/- mice show decreased NSAID- and Schistosoma-induced 
intestinal inflammation associated with higher glutathione stores. J Clin 
Invest 2004;113(4):591-597.
R17-3326
Ferreira DW, Goedken MJ, Rommelaere S, Chasson L, Galland F, Naquet 
P, et al. Enhanced hepatotoxicity by acetaminophen in vanin-1 knockout 
mice is associated with deficient proliferative and immune responses. 
Biochim Biophys Acta Mol Basis Dis 2016;1862(4):662-669.
R17-3327
Roisin-Bouffay C, Castellano R, Valero R, Chasson L, Galland F, Naquet 
P. Mouse vanin-1 is cytoprotective for islet beta cells and regulates the
development of type 1 diabetes. Diabetologia 2008;51(7):1192-1201.
R18-2692
Wang YJ, Tayo BO, Bandyopadhyay A, Wang H, Feng T, Franceschini N, 
et al. The association of the vanin-1 N131S variant with blood pressure is 
mediated by endoplasmic reticulum-associated degradation and loss of 
function. Plos Genet 2014;10(9):e1004641
R18-2864
Creasy DM. Evaluation of testicular toxicity in safety evaluation studies: 
the appropriate use of spermatogenic staging. Toxicol Pathol 
1997;25(2):119-131.
R18-2866
Kang M, Qin W, Buya M, Dong X, Zheng W, Lu W, et al. VNN1, a 
potential biomarker for pancreatic cancer-associated new-onset diabetes, 
aggravates paraneoplastic islet dysfunction by increasing oxidative stress. 
Cancer Lett 2016;373:241-250.
R18-2867
Diepen JA van, Jansen PA, Ballak DB, Hijmans A, Rutjes FPJT, Tack CJ, 
et al. Genetic and pharmacological inhibvition of vanin-1 activity in animal 
models of type 2 diabetes. Sci Rep 2016;6:21906


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R18-2868
Aida Y, Abe H, Tomita Y, Nagano T, Seki N, Sugita T, et al. Serum 
cytokeratin 18 fragment level as a noninvasive biomarker for non-alcoholic 
fatty liver disease. Int J Clin Exp Med 2014;7(11):4191-4198.
R18-2954
Matthews HC, Concas D, Kudo H, Anstee Q, Thomas H, Cox R, et al. Cell 
surface pantetheinase, vanin-1, increases oxidative damage in 
acetaminophen induced liver injury via a reduction in glutathione. Int Liver 
Cong 2010, 45th Ann Mtg of the European Association for the Study of the 
Liver (EASL), Vienna, 14 - 18 Apr 2010. J Hepatol 2010;52(Suppl 
1):S311-S312.
R18-3167
Gensollen T, Bourges C, Rihet P, Rostan A, Millet V, Noguchi T, et al. 
Functional polymorphisms in the regulatory regions of the VNN1 gene are 
associated with susceptibility to inflammatory bowel diseases. Inflamm 
Bowel Dis 2013;19(11):2315-2325.
R20-3402
Recommendations related to contraception and pregnancy testing in clinical 
trials (version 1.1, CTFG 21/09/2020). 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contracepti
on_guidance_Version_1.1.pdf (access date: 16 October 2020) ; Clinical 
Trial Facilitation Group (CTFG), Head of Medicine Agencies (HMA); 
2020.
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
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c31270124
Investigator's Brochure BI 1595043 Crohn's Disease. Current version.
c34604736
 8-05-output-preliminary-snapshot-with-QC-17Dec2020. 
1445-0001.
c34816263
Preliminary-data-analysis-ecg. Imported. 1445-0001. 08Jan2020.
n00259753
Pharmacodynamics of BI764122 in the dextran sulfate sodium model of
colon injury in mice. 19Oct2018.
n00261263
BI 764122: Four-week oral (gavage) toxicity and toxicokinetics study in the
dog followed by a four-week recovery period. 20May2019.
n00261387
BI 764122: Four-week oral (gavage) toxicity and toxicokinetics study in the 
rat followed by a four-week recovery period. 05Apr2019.
n00266340
BI 1595043: One week oral (gavage) exploratory study in the rat. 
19Sep2019.
n00266444
BI 1595043: An oral (gavage) dose escalation study in the dog. 
02Aug2019.


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n00267953
Determination of the molar extinction coefficient of BI 1595043 XX. 
02Apr2019.
n00268703
BI 1595043: Thirteen-week oral (gavage) toxicity and toxicokinetics study 
in the rat followed by a ten-week recovery period. Report in progress.
n00270147
BI 1595043: Effect on hERG inactivating tail currents recorded from stably 
transfected HEK 293 cells. 29Jan2020.
n00270317
BI 1595043: Central nervous system safety pharmacology evaluation
following oral gavage administration to male and female rats. 03Mar2020.
n00270318
BI 1595043: Respiratory safety pharmacology evaluation using head-out 
plethysmography following oral gavage administration to male rats. 
03Mar2020.
n00270319
Validation of an LC/MS/MS method for the quantitation of BI 1595043 in 
EDTA dog plasma. 20Dec2019.
n00270399
Validation of an LC/MS/MS Method for the quantitation of BI 1595043 in 
EDTA rat plasma. 06Feb2020.
n00270419
BI 1595043: Thirteen-week oral (gavage) toxicity and toxicokinetics study 
in the dog followed by a ten-week recovery period. Report in progress.
n00271655
BI 1595043: Cardiovascular safety pharmacology evaluation by oral gavage 
to male telemetry-instrumented conscious dogs. 13Mar2020.
n00271724
BI 1595043: In vivo mammalian erythrocyte micronucleus assay in rats. 
05Mar2020.
n00271737
BI 1595043: Bacterial reverse mutation with an independent repeat assay.
Report in progress.
n00271739
BI 1595043: In vitro mammalian cell micronucleus assay in human 
peripheral blood lymphocytes (HPBL) cells. 09Mar2020.
n00272671
BI 1595043: neutral red uptake phototoxicity assay in BALB/c 3T3 
mousefibroblasts. 24Feb2020.
n00273365
Quantitative whole-body autoradiography in male pigmented rats after 
single oral administration of [14C]BI 1595043. 05Nov2019.
n00273892
Inhibition of recombinant human vanin-1 enzymatic activity. 25Feb2020.
n00273893
Vanin inhibition in human whole blood. 03Mar2020.
n00273895
Human colon explant assay-release of CK-18 and cysteamine production.
06Jan2020.
n00273897
Impact of Vanins’ Inhibition on Human CD4+ T Cells Effector Functions.
Report in progress.
n00273898
Pharmacodynamics of BI 1595043 in the dextran sulfate sodium model of
colon injury in mice. 07Apr2020.
n00274794
BI 1595043 Nonclinical expert statement. Report in progress.


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n00275520
Excretion of radioactivity in urine, feces and bile after oral and intravenous
administration of [14C]BI 1595043 to rats. 07Feb2020.
n00275663
Validation of an LC/MS/MS Method for the quantiation of BI 1595043 in 
EDTA rabbit plasma. Report in progress. 
n00275691
Species comparison of in vitro binding of [14C]BI 1595043 to rat, dog and 
human plasma proteins. Report in progress.
n00275784
Effects of BI 1595043 (1, 3 and 10 mg/kg p.o.) on urine- and serum-derived
parameters in conscious rats. 19Feb2020.
n00278281
A GLP Embryo-fetal Development Study of BI 1595043 by Oral Gavage in 
Rabbits. 02Dec2020.
n00278622
A GLP Embryo-fetal Development Study of BI 1595043 by Oral Gavage in 
Rats. 


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
11 March 2021
EudraCT number
EU number
2020-004924-40
BI Trial number
1445-0011
BI Investigational Medicinal 
Product(s)
BI 1595043
Title of protocol
A randomised, open-label, single-dose, two-way 
cross-over relative bioavailability comparison of BI 
1595043 as tablets with and without food in healthy 
male subjects
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Section 1.4.3.3
2. Section 1.4.3.6
3. Section 3.3.2
4. Section 4.1.2
5. Section 4.2.2.2
6. Section 5.2.2
Description of change
1. Clinical relevance of the toxicology 
ophthalmology findings clarified to reflect two 
planned doses.
2. The data duplicating Section 4.1.2 removed.
3. Use of male contraception (i.e. condom) 
explicitly defined in study Inclusion Criterion No. 5
4. Section expanded to describe relevance of 
possible food effect and possible difference in 
bioavailability between oral solution and tablets.
5. Use of male contraception (i.e. condom) 
explicitly defined in the study restrictions for 
subjects with pregnant or non-pregnant WOCBP 
partners.6. Oral measurement of body temperature 
added.


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Rationale for change
Changes are based on the regulatory feedback
from FAMHP after review of the study protocol as
part of the approval procedure.
With this amendment minor inconsistencies in the 
study protocol have been corrected.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
08 April 2021
EudraCT number
EU number
2020-004924-40
BI Trial number
1445-0011
BI Investigational Medicinal 
Product(s)
BI 1595043
Title of protocol
A randomised, open-label, single-dose, two-way 
cross-over relative bioavailability comparison of BI 
1595043 as tablets with and without food in healthy 
male subjects
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Section 3.3.4.3
Description of change
Item No. 2 of Discontinuation of the trial by the 
sponsor updated
Rationale for change
The change is based on FDA feedback after review 
of the trial protocol as part of the IND opening trial 
approval procedure.


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11.3
GLOBAL AMENDMENT 3
Date of amendment
30 June 2021
EudraCT number
EU number
2020-004924-40
BI Trial number
1445-0011
BI Investigational Medicinal 
Product(s)
BI 1595043
Title of protocol
A randomised, open-label, single-dose, two-way 
cross-over relative bioavailability comparison of BI 
1595043 as tablets with and without food in healthy 
male subjects
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Title Page
Clinical Trial Protocol Synopsis
Description of change
The Principal Investigator was changed to 
.
Rationale for change
The study has been handovered to the new Principal 
Investigator 
.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34388550
4.0
clinical-trial-protocol-version-04
A randomised, open-label, single-dose, two-way cross-over relative bioavailability
comparison of BI 1595043 as tablets with and without food in healthy male subjects
Author-Clinical Trial Leader
01 Jul 2021 09:50 CEST
Author-Trial Statistician
01 Jul 2021 09:52 CEST
Verification-Paper Signature
Completion
01 Jul 2021 10:36 CEST
Approval-Team Member Medicine
01 Jul 2021 13:37 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c34388550
4.0

SAP_001.pdf: 
001-MCS-50-415_RD-01 (3.0) / Saved on: 18 Jan 2021
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c36157604-01
BI Trial No.:
1445-0011
Title:
A randomised, open-label, single-dose, two-way cross-over 
relative bioavailability comparison of BI 1595043 as tablets with 
and without food in healthy male subjects
(Revised Protocol including Amendments 1, 2 [c34388550-03])
Investigational
Product:
BI 1595043
Responsible trial 
statistician(s):
Phone:
Fax:
Date of statistical 
analysis plan:
30 AUG 2021 SIGNED
Version:
1
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reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................8
5.
ENDPOINTS..........................................................................................................9
5.1
PRIMARY ENDPOINTS .....................................................................................9
5.2
SECONDARY ENDPOINTS ...............................................................................9
5.2.1
Key secondary endpoints ......................................................................................9
5.2.2
Secondary endpoint...............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED ...........................................................................13
6.5
POOLING OF CENTRES..................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................14
7.
PLANNED ANALYSIS ......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........17
7.2
CONCOMITANT DISEASES AND MEDICATION......................................18
7.3
TREATMENT COMPLIANCE ........................................................................18
7.4
PRIMARY ENDPOINTS ...................................................................................18
7.4.1
Primary analysis of the primary endpoints ......................................................18
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoints...............................................................................................19
7.5
SECONDARY ENDPOINTS .............................................................................20
7.5.1
Key secondary endpoints ....................................................................................20
7.5.2
(Other) Secondary endpoints .............................................................................20
7.7
EXTENT OF EXPOSURE .................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................20
7.8.1
Adverse Events ....................................................................................................21
7.8.2
Laboratory data...................................................................................................22
7.8.3
Vital signs.............................................................................................................22
7.8.4
ECG ......................................................................................................................22
7.8.5
Others ...................................................................................................................23
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............24
9. 
REFERENCES ....................................................................................................25


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11.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................11
Table 6.3: 1
Subject sets analysed ........................................................................................14
Table 11: 1
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Aspartate transaminase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BMI
Body mass index
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CSD
Company Standard Displays
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
gCV
Geometric coefficient of variation
gMean
Geometric mean
LLT
Lower level term
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PKS
PK parameter analysis set
Q1
1st quartile
Q3
3rd quartile
R
Reference treatment
RAGe
Report Appendix Generator system


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Term
Definition / description
RPM
Report Planning Meeting
SD
Standard deviation
SOC
System organ class
T
Test treatment
TS
Treated set
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This Trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomization.
Study data (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher, 
).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP:
The following pharmacokinetic parameters will be determined for BI 1595043:

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)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoint
Section 2.1.3 of the CTP:
The following pharmacokinetic parameter will be determined for BI 1595043:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
Safety and tolerability endpoints
Section 2.2.2.2 of the CTP:
Safety and tolerability of BI 1595043 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 temperature)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment groups, 
selection of doses, refer to CTP Section 4.
The study will be performed as a randomised, open-label, two-way cross-over trial. The 
treatments will be one single dose of 30 mg of BI 1595043 administered as tablets in the
fasting state (R) and one single dose of 30 mg of BI 1595043 administered as tablets in the
fed state (T). In total, it was planned to assign 14 healthy male subjects to the 2 treatment 
sequences RT or TR. 
There will be a washout period of at least 8 days between the treatments.
For details of dosage and formulation see Table 6.1: 1 below:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
R
BI 1595043, 1*5mg + 1*25 mg film coated tablets, qd, fasted
BI 30mg fast
T
BI 1595043, 1*5mg + 1*25 mg film coated tablets, qd, fed
BI 30mg fed
Section 1.2.6 of CTP:
The residual effect period (REP) for BI 1595043, when measurable drug levels or PD effects
are still likely to be present after the last administration, is about 6 days (estimated based on 
5 times terminal t1/2 of dose group 5 of up to 29.3 h). Conservatively, all AEs reported until 
the end of trial examination will be considered on treatment.
The following study phases will be defined for the analysis of adverse events (AEs):

Screening
o
Ranging from 0:00h on day of informed consent until administration time of 
study medication in treatment period 1.

On treatment (labelled “BI 30mg fast”, “BI 30mg fed”)
o
Ranging from the administration time of BI 1595043 until next administration 
time or until 0:00 h on day after trial termination date (whatever occurs first)
Section 7.3.4 of the CTP: Note that AEs occurring after the last per protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.


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The following AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) of the 
CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the 
study treatment (short label)). Screening will not be included in this analysis. 
The following total will be provided in addition (Section 15.3 only):
a total over all on treatment phases included in this analysis ("Total")
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of 
the CTR displays:
Screening 
On treatment (labelled with the name of the study treatment (short label))
In Section 16.1.13.1.8 AE tables, the following total will be provided in addition:
a total over all study phases ("Total")
In Appendix 16.2 (Listings) of the CTR displays, screening will be included and no totals will 
be provided.
For detailed information on the handling of the treatments, refer to Technical TSAP ADS plan 
and Analysis Data Reviewers guide.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, all 
manual deviations identified at the sites by the CRAs and deviations too complex to program 
will be reviewed by the trial team to decide which are considered important. For definition of 
important protocol deviations (iPD), and for the process of identification of these, refer to the 
Boehringer Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" 
(2).
Section 7.3 of the CTP: Important protocol deviation (iPD) categories will be suggested in 
the iPD specification file, iPDs will be identified no later than in the Report Planning 
Meeting, and the iPD categories will be updated as needed.
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the iPD specification file and the decision log. The iPD specification file (e.g. the DV domain 
specifications) will be stored within the TMF in EDMS.


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The iPDs will be summarized and listed in the CTR.
6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for safety 
analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol violation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if 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.
[…]
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.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma 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),

The subject experiences emesis at any time during the labelled dosing interval.

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.


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The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Analyses of PK endpoints 
X
Safety parameters 
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
X
Exposure
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exceptions where imputation might be necessary for safety evaluation are AE dates.
Missing or incomplete AE dates are imputed according to BI standards (see BI-KMED-BDS-
HTG-0035) (3).
Missing data and outliers of PK data are handled BI standards (see BI-KMED-TMCP-MAN-
0012 (4) and BI-KMED-TMCP-MAN-0014 (5).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before study drug administration in 
each treatment period. For laboratory data, baseline for both periods is the last measurement 
before study drug administration in the first period (-72:00).


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Section 6.1 of the CTP: 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.
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests
will be ± 15 min for the first 4 h after trial drug administration and ± 30 min thereafter.
Starting from 48 h post-dose a deviation from the scheduled time for vital signs, ECG and
laboratory tests of ±120 min is acceptable.
Adherence to time windows will be checked via the consistency check listings at the RPM.
Unscheduled measurements of laboratory data and vital signs data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement.


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Section 7.4 and Section 7.5.2) will
also be performed by 
and will be presented in Section 15.5 of 
the CTR and in Appendix 16.1.13.3.
Descriptive data analysis of PK endpoints and concentrations will be performed by the 
at 
 and will be 
presented in Section 15.6 of the CTR.
The format of the listings and tables will follow the BI standards (see BI-KMED-BDS-HTG-
0045 (6)) with the exception of those generated for PK-calculations following BI standards 
for PK/PD analysis (7).
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number and visit. The listings will be included in Appendix 16.2 of the CTR.
For End-Of-Text (EoT) tables, the set of summary statistics is:
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
The data format for descriptive statistics of concentrations will be identical to the data format 
of the respective concentrations. The descriptive statistics of PK parameters will be calculated 


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using the individual values with the number of decimal places as provided by the evaluation 
program. Then the individual values as well as the descriptive statistics will be reported with 
three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all subjects in the respective subject
set whether they have non-missing values or not). 
The precision for percentages should be one decimal point, unless the denominator is smaller 
than 100 (in all treatment columns), in which case percentages are given in integer numbers.
The category missing will be displayed only if there are actually missing values.
Exclusion of PK parameters
The ADS “ADPP” (PK parameters) contains column variables APEXC and APEXCO 
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for 
exclusion, that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS “ADPC” (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC and ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in BI-KMED-TMCP-MAN-0014 “Noncompartmental 
Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” (5) and BI-KMED-
TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD Data Files” (8).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by treatment sequence and in total.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM (see Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
For BI 1595043, the effect of food on the relative bioavailability will be investigated on the 
basis of the primary PK endpoints AUC0-tz and Cmax (see Section 5.1)
7.4.1
Primary analysis of the primary endpoints
Section 7.3.1 of the CTP:
The statistical model used for the analysis of the primary 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 
= µ + ζi + sim + πj + τk + eijkm, where
yijkm
= logarithm of response measured on subject m in sequence i receiving 
treatment k in period j,
µ
= the overall mean,
ζi
= the ith sequence effect, i = 1, 2
sim
= the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., ni


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πj
= the jth period effect, j = 1, 2
τk
= 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 sim ~ N(0, 
) i.i.d., eijkm ~ N(0, 
 ) i.i.d. and sim, eijkm are independent random
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see CTP 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.
The implementation for this analysis will be accomplished by using the CSD macros based on 
PKS. The following SAS code can be used:
PROC MIXED DATA=indata METHOD=REML; 
CLASS subject treatment sequence period; 
MODEL logpk = treatment sequence period / DDFM=KR; 
RANDOM subject(sequence); 
LSMEANS treatment / PDIFF CL ALPHA=0.1; 
RUN;
   
   
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoints
Section 7.3.1 of the CTP: 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.
The following SAS code can be used to fit the model:
PROC GLM DATA=indata; 
CLASS subject treatment sequence period; 
MODEL logpk = treatment subject(sequence) sequence period; 
LSMEANS treatment / PDIFF CL ALPHA=0.1; 
ESTIMATE 'T-R' treatment 1 -1; 
RUN;


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoints
Section 7.3.2 of the CTP:
The secondary endpoints (refer to Section 5.2.2) will be calculated according to the BI SOP
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/
Pharmacodynamics’ (BI-KMED-TMCP-MAN-0014 (5)) and will be assessed statistically 
using the same methods as described for the primary endpoints.
Safety and tolerability endpoints
Refer to Section 7.8 for a description of the analysis of safety and tolerability.
7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and
time of each drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. 
The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.


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7.8.1
Adverse Events
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of subjects with AEs and NOT on the number of AEs. BI 
standards as presented in “Analysis and Presentation of Adverse Event Data from Clinical 
Trials – Display Template” [BI-KMED-BDS-HTG-0041] (9) and [BI-KMED-BDS-HTG-
0066] (10) will be applied.
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to ‘screening’ or ‘on-treatment’ phases as defined in Section 6.1. AEs 
will be analysed based on actual treatments, as defined in Table 6.1: 1.
According to the clinical study protocol, adverse events of special interest (AESI) will be 
analysed:
Section 5.2.7.1.4 of the CTP: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
According to ICH E3 (11), in addition to deaths and serious adverse events, ‘other significant’ 
AEs need to be listed in the clinical trial report. These will be any non-serious adverse event 
that led to an action taken with study drug (e.g. discontinuation or dose reduced or 
interrupted).
An overall summary of adverse events will be presented. 
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with 
serious AEs, for subjects with drug-related AEs, for subjects with drug-related serious adverse 
events and for subjects with AESIs. In addition, the frequency of subjects with AEs will be 
summarised by treatment, worst intensity, primary SOC and PT.
The SOCs and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.


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For disclosure of adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
[BI-KMED-BDS-HTG-0042] (12). 
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possibly 
clinically significant will be flagged in the data listings.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significantly 
abnormal or not (at the RPM at the latest). 
Descriptive statistics of laboratory data including change from baseline will be calculated by 
planned time point based on the worst value of the subject at that planned time point (or 
assigned to that planned time point).
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure, pulse rate and body temperature). In the listing the difference from 
baseline will also be displayed.
For vital signs, descriptive statistics will be calculated by planned time point based on the last 
value of the subject at that planned time point (or assigned to that planned time point).
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as AEs (when they 
occurred during treatment), and will be analysed as such.
No separate ECG listing will be provided.


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7.8.5
Others
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition
(i.e., a condition already existent before intake of study drug) or as AE and will be
summarised as such. 
No separate listing or analysis of physical examination findings will be prepared.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be loaded into the trial database after completion of enrolment, 
i.e. the randomization has been completed.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, IDEA for CON.
3.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version; KMED.
4.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
5.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; KMED.
6.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project
Summaries”, current version; KMED.
7.
BI-KMED-TMCP-OTH-0003: “Graphs and Tables for Clinical Pharmacokinetics and 
Pharmacodynamic Noncompartmental Analyses”, current version, KMED.
8.
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; KMED.
9.
BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
10. BI-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from clinical 
trials”, current version, KMED.
11. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version.
12. BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1 
30-AUG-21
None
This is the final TSAP