Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 64
Healthy volunteers: yes

Brief summary:
The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics (PK) of BI 1595043 in healthy male subjects following oral administration of single rising doses.

Detailed description:

Arms:
arm 1: 1 mg BI 1595043 arm 2: 3 mg BI 1595043 arm 3: 6 mg BI 1595043 arm 4: 12 mg BI 1595043 arm 5: 25 mg BI 1595043 arm 6: 50 mg BI 1595043 arm 7: 90 mg BI 1595043 arm 8: 160 mg BI 1595043 arm 9: Matching Placebo

Interventions: intervention 1: BI 1595043 intervention 2: Placebo
Intervention descriptions: intervention 1: BI 1595043 intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c31692550-05
EudraCT No.
2020-001036-10
BI Trial No.
1445-0001
BI Investigational 
Medicinal Product
BI 1595043
Title
Safety, tolerability and pharmacokinetics of single rising oral 
doses of BI 1595043 (single-blind, partially randomised, placebo-
controlled, parallel (sequential) group design) in healthy male 
subjects
Lay Title
A study in healthy men to test how different doses of BI 1595043 
are tolerated
Clinical Phase
I
Clinical Trial Lead
Phone: 
Fax: 
Principal 
Investigator
Phone: 
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 4))
Version and Date
Version: 5.0
Date: 14 January 2021
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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
11 May 2020
Revision date
14 January 2021
BI trial number
1445-0001
Title of trial
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 1595043 
(single-blind, partially randomised, placebo-controlled, parallel (sequential) group 
design) in healthy male subjects
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
As a transition from non-clinical investigations to clinical development, in this first-
in-man trial, safety, tolerability and pharmacokinetics of BI 1595043 will be 
assessed in healthy male volunteers using single rising oral doses in order to 
provide the basis for a clinical development in the indication of Crohn’s disease.
Trial objectives
To investigate safety, tolerability and pharmacokinetics following single rising 
doses of BI 1595043
Trial endpoints
Primary endpoint: the percentage of subjects with drug-related adverse events after 
single doses of BI 1595043
Secondary endpoints: AUC0-∞ and Cmax of BI 1595043 after single doses
Trial design
Single-blind, partially randomised within dose groups, placebo-controlled, parallel 
(sequential) group design
Number of subjects 
total entered
64*
each treatment
8 per dose group (6 on BI 1595043 and 2 on placebo)
* Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose is not exceeded. Thus, the actual number of subjects entered may 
exceed 64, but is not to exceed 72. The addition of further dose levels exceeding the already 
tested dose levels for the evaluation of safety findings will be subject to a substantial CTP 
amendment requiring approval from IRB/IEC and RA.
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)


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Test product
BI 1595043 solution (2.5 mg/mL)
dose
1 mg, 3 mg, 6 mg, 12 mg, 25 mg, 50 mg, 90 mg, 160 mg q.d.
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h.
Comparator product
Matching placebo as solution (i.e. solvent)
dose
Not applicable
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h.
Duration of treatment
Single dose
Statistical methods
Descriptive statistics will be calculated for all endpoints. 


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FLOW CHART
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory15
PK blood 
10, 11
12-lead ECG
Continuous ECG 
monitoring
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-28 to -1
Screening (SCR)1
A
x
x
2
-3 to -1
-72:00 to 
-24:00
08:00
Ambulatory visit7
B
x
1
-1:30
06:30
Admission to trial site16,17
x5
-1:00
07:30
Allocation to treatment2
x2
x2,13
x2
x2
0:00
08:00
Drug administration
▲
0:30
08:30
x
x9
│
x
x
1:00
09:00
x
x9
│
x
x
1:30
09:30
x
x9
│
x
x
2:00
10:00
240 mL fluid intake
x8
x9
│
x
x
2:30
10:30
x
x9
│
x
x
3:00
11:00
x
x9
│
x
x
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
x9
▼
x
x
6:00
14:00
x
x9
x
x
8:00
16:00
Snack (voluntary)3
x
x9
x
x
10:00
18:00
Dinner3
x
12:00
20:00
x
x9
x
x 
2
24:00
08:00
Breakfast3
B
x
x9
x
x
29:00
13:00
Lunch3
32:00
16:00
Snack (voluntary) 3
34:00
18:00
Dinner3
x
x9
x
x
3
48:00
08:00
Breakfast (voluntary)3,
discharge from trial site
B
x
x9
x
x
4
72:00
08:00
Ambulatory visit
x
x
x
5
96:00
08:00
Ambulatory visit
B
x
x
x
x
6
120:00
08:00
Ambulatory visit
x
x
x
7
144:00
08:00
Ambulatory visit
x
x
x
x
8
168:00
08:00
Ambulatory visit
x
x
x
9
192:00
08:00
Ambulatory visit
x
x
x
3
10 to 15
End of trial (EoTrial) examination4
C
x
x
x
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, ECG, safety laboratory (including drug screening), 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; procedures are 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, ECG, safety laboratory, recording of AEs, and concomitant 
therapies.
5.
Only urine drug screening and alcohol breath test will be done at the time of admission to trial site (refer to Section 
5.2.4).


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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.
Safety laboratory to be taken and to be medically evaluated within 3 days prior to administration of study drug; this 
ambulatory visit can be omitted if the screening examination is performed on Days -3, -2 or -1. 
8.
Only in dose group 4 (12 mg of BI 1595043), one additional blood sample for stability testing will be taken at this time 
(refer to Section 5.3.2.4).
9.
The ECG recording has to be performed in triplicate ECGs at this time.
10. 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.
11. Only in dose group 4 (12 mg of BI 1595043), additional blood sampling will be performed for metabolite identification 
(refer to Section 5.3.2.2).
 
13. At baseline (i.e. Day 1, prior to drug administration) 3 triplicate ECGs are recorded within approximately one hour. The 
recordings should be separated by at least 15 minutes (refer to Section 5.2.5).
14.
 
15. 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.
16. Admission to the trial site is allowed in the evening of Day -1 (refer to Section 6.2.2).
17. SARS-CoV-2 PCR test will be performed shortly (within 72 hours) before admission to trial site.


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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.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................14
1.2.1
Nonclinical pharmacology....................................................................15
Primary pharmacodynamics.....................................................15
1.2.1.1
Safety pharmacology ...............................................................16
1.2.1.2
Pharmacodynamic interactions................................................17
1.2.1.3
1.2.2
Toxicology..............................................................................................17
Single dose toxicity..................................................................17
1.2.2.1
Repeated dose toxicity.............................................................18
1.2.2.2
Genotoxicity.............................................................................20
1.2.2.3
Carcinogenicity........................................................................20
1.2.2.4
Reproductive and developmental toxicity ...............................20
1.2.2.5
Local tolerance.........................................................................20
1.2.2.6
Other toxicity studies ...............................................................20
1.2.2.7
1.2.3
Nonclinical pharmacokinetics..............................................................21
Methods of analysis .................................................................21
1.2.3.1
Absorption................................................................................21
1.2.3.2
Distribution ..............................................................................22
1.2.3.3
Metabolism ..............................................................................22
1.2.3.4
Excretion..................................................................................23
1.2.3.5
Pharmacokinetic drug interactions...........................................23
1.2.3.6
Toxicokinetics..........................................................................23
1.2.3.7
1.2.4
Prediction of human therapeutic dose ................................................24
1.2.5
Clinical experience in humans.............................................................24
1.2.6
Residual Effect Period..........................................................................26
1.2.7
Drug product.........................................................................................26
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................27
1.3.1
Starting dose..........................................................................................27
1.3.2
Maximum dose and dose escalation ....................................................28
1.4
BENEFIT - RISK ASSESSMENT ...................................................................29
1.4.1
Expected benefit for the target indication ..........................................29
1.4.2
Procedure-related risks ........................................................................29


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1.4.3
Drug-related risks and safety measures..............................................29
Mode of action and nature of the target...................................29
1.4.3.1
Relevance of animal models....................................................30
1.4.3.2
Findings in non-clinical safety studies.....................................30
1.4.3.3
Clinical findings.......................................................................32
1.4.3.4
Drug induced liver injury.........................................................32
1.4.3.5
Risk minimization (safety precautions and stopping rules).....32
1.4.3.6
1.4.4
Overall assessment................................................................................33
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 34
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......34
2.1.1
Main objectives......................................................................................34
2.1.2
Primary endpoint..................................................................................34
2.1.3
Secondary endpoint ..............................................................................34
Safety and tolerability..............................................................34
2.2.2.1
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 36
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................36
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................38
3.3
SELECTION OF TRIAL POPULATION ......................................................38
3.3.1
Main diagnosis for trial entry..............................................................39
3.3.2
Inclusion criteria...................................................................................39
3.3.3
Exclusion criteria ..................................................................................39
3.3.4
Withdrawal of subjects from treatment or assessments ...................41
Discontinuation of trial treatment............................................41
3.3.4.1
Withdrawal of consent to trial participation ............................42
3.3.4.2
Discontinuation of the trial by the sponsor..............................42
3.3.4.3
3.3.5
Replacement of subjects .......................................................................42
4.
TREATMENTS........................................................................................ 43
4.1
INVESTIGATIONAL TREATMENTS ..........................................................43
4.1.1
Identity of the Investigational Medicinal Products ...........................43
4.1.2
Selection of doses in the trial................................................................43
4.1.3
Method of assigning subjects to treatment groups ............................43
4.1.4
Drug assignment and administration of doses for each subject .......44
4.1.5
Blinding and procedures for unblinding ............................................45
Blinding ...................................................................................45
4.1.5.1
Unblinding and breaking the code...........................................45
4.1.5.2
4.1.6
Packaging, labelling, and re-supply ....................................................45


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4.1.7
Storage conditions.................................................................................46
4.1.8
Drug accountability ..............................................................................46
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................47
4.2.1
Other treatments and emergency procedures....................................47
4.2.2
Restrictions............................................................................................47
Restrictions regarding concomitant treatment .........................47
4.2.2.1
Restrictions on diet and life style.............................................47
4.2.2.2
4.3
TREATMENT COMPLIANCE.......................................................................48
5.
ASSESSMENTS....................................................................................... 49
5.1
ASSESSMENT OF EFFICACY.......................................................................49
5.2
ASSESSMENT OF SAFETY............................................................................49
5.2.1
Physical examination ............................................................................49
5.2.2
Vital signs...............................................................................................49
5.2.3
Ophthalmological examination............................................................49
5.2.4
Safety laboratory parameters..............................................................49
5.2.5
Electrocardiogram................................................................................52
12-lead resting ECG.................................................................52
5.2.5.1
Continuous ECG monitoring ...................................................54
5.2.5.2
5.2.6
Other safety parameters.......................................................................54
5.2.7
Assessment of adverse events...............................................................54
Definitions of adverse events...................................................54
5.2.7.1
Adverse event ............................................................54
5.2.7.1.1
Serious adverse event ................................................55
5.2.7.1.2
AEs considered ‘Always Serious’.............................55
5.2.7.1.3
Adverse events of special interest .............................56
5.2.7.1.4
Intensity (severity) of AEs.........................................56
5.2.7.1.5
Causal relationship of AEs ........................................56
5.2.7.1.6
Adverse event collection and reporting ...................................57
5.2.7.2
AE collection.............................................................57
5.2.7.2.1
AE reporting to the sponsor and timelines ................58
5.2.7.2.2
Information required..................................................58
5.2.7.2.3
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................58
5.3.1
Assessment of pharmacokinetics .........................................................58
5.3.2
Methods of sample collection...............................................................59
Blood sampling for pharmacokinetic analysis.........................59
5.3.2.1
Blood sampling for metabolism analysis.................................59
5.3.2.2
Additional blood sample for stability-testing ..........................61
5.3.2.4


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5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................62
5.5
BIOBANKING ...................................................................................................63
5.6
OTHER ASSESSMENTS .................................................................................63
5.6.1
Pharmacogenomic evaluation..............................................................63
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................64
6.
INVESTIGATIONAL PLAN.................................................................. 65
6.1
VISIT SCHEDULE............................................................................................65
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................65
6.2.1
Screening period....................................................................................65
6.2.2
Treatment period ..................................................................................65
6.2.3
Follow-up period and trial completion ...............................................66
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 67
7.1
STATISTICAL DESIGN – MODEL ...............................................................67
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................67
7.3
PLANNED ANALYSES....................................................................................67
7.3.1
Primary endpoint analyses...................................................................69
7.3.2
Secondary endpoint analyses ...............................................................69
7.3.4
Safety analyses.......................................................................................70
7.4
INTERIM ANALYSES .....................................................................................72
7.5
HANDLING OF MISSING DATA ..................................................................72
7.5.1
Safety......................................................................................................72
7.5.2
Pharmacokinetics..................................................................................72
7.6
RANDOMISATION ..........................................................................................73
7.7
DETERMINATION OF SAMPLE SIZE ........................................................73
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 74
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................74
8.2
DATA QUALITY ASSURANCE .....................................................................75
8.3
RECORDS..........................................................................................................75
8.3.1
Source documents .................................................................................75
8.3.2
Direct access to source data and documents.......................................76


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8.3.3
Storage period of records.....................................................................76
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................76
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......77
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................77
8.6
TRIAL MILESTONES .....................................................................................77
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................78
9.
REFERENCES......................................................................................... 79
9.1
PUBLISHED REFERENCES...........................................................................79
9.2
UNPUBLISHED REFERENCES.....................................................................80
10. APPENDICES .......................................................................................... 83
10.1
RECONSTITUTION INSTRUCTIONS .........................................................83
10.1.1 Drug supplies overview.........................................................................83
10.1.2 Required equipment and dosing aids - overview ...............................83
10.1.3 Reconstitution procedure.....................................................................84
Reconstitution procedure for the preparation of the active BI 
10.1.3.1
1595043 oral solution 2.5mg/ml..............................................84
Solvent for oral solution for use as placebo solution...............84
10.1.3.2
10.1.4 Illustration of reconstitution procedure..............................................85
10.1.5 In-use stability.......................................................................................86
10.1.6 Mode of application ..............................................................................86
10.1.7 General remarks - important! .............................................................86
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 87
11.1
GLOBAL AMENDMENT 1 .............................................................................87
11.2
GLOBAL AMENDMENT 2 .............................................................................89
11.3
GLOBAL AMENDMENT 3 .............................................................................91
11.4
GLOBAL AMENDMENT 4 .............................................................................92


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine transaminase
AST
Aspartate transaminase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
 
 
 
BA
Bioavailability
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CD
Crohn’s disease
CI
Confidence interval
 
 
 
 
CNS
Central nervous system
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTM
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury
ECG
Electrocardiogram
ECGPCS
ECG pharmacokinetic concentration set
eCRF
Electronic case report form


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eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
 
GCP
Good Clinical Practice
GI
Gastro-intestinal
gMean
Geometric mean
HED
Human Equivalent Dose
HR
Heart rate
IB
Investigator’s brochure
ICF
Informed consent form
IEC
Independent Ethics Committee
IPV
Important protocol violation
IRB
Institutional Review Board
ISF
Investigator site file
IV
Intravenous
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLOQ
Lower limit of quantification
LOAEL
Lowest observed adverse effect level
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MIST
Metabolites in Safety Testing
MRD
Multiple-rising dose
MRSD
Maximum Recommended Starting Dose
NC
Not calculated
NOAEL
No observed adverse effect level
PE
Polyethylene
PfOS
Powder for reconstitution of an oral solution
PK
Pharmacokinetic(s)


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PKS
Pharmacokinetic set
PO
Oral
PP
Polypropylene
PR
Pulse rate
RA
Regulatory authorities
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 product
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SNP
Single nucleotide polymorphism
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
T
Test product or treatment
 
TMDD
Target-mediated drug disposition
TMF
Trial master file
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
Crohn’s disease (CD) is characterized by transmural inflammation with ulcerative lesions
affecting any site within the gastrointestinal tract, with most frequent involvement of terminal
ileum, often combined with inflammation in colon. CD incidence and prevalence have been
rising in all ethnic groups; the recent incidence and prevalence have been reported to range
from 7.9 to 20.2 and from 161 to 319 per 100,000, respectively (R13-2231). CD typically
follows a relapsing and remitting course, and causes substantial acute and long-term
morbidity and increased mortality. Patients often develop local complications (e.g. fistulas,
abscesses, strictures, or perforation), systemic complications (e.g. uveitis, arthritis), or side
effects of treatment, and may require major surgery. Roughly a third of patients fall into each 
of the categories of mild, moderate, and severe disease.
Unmet need in CD is highest in patients with moderate to severe disease. Patients not
responding to conventional therapy of orally administered aminosalicylates (e.g. 5-ASA),
glucocorticoids and immunomodulator agents (azathioprine or 6-MP), are treated with
biologic TNFα inhibitors (TNFi). Induction therapy with a TNFi results in clinical remission
in fewer than 50% of patients, and only about 25% of patients achieve mucosal healing.
Another 30-40% of patients receiving TNFi have only a limited response, or lose their
response over time (maintenance therapy). Additionally, there remain concerns over infection
and lymphoma risks with these agents. Additional biologic options (vedolizumab,
ustekinumab) offer alternative additional treatments options for patients who fail TNFi, but
response rates to these agents do not exceed those associated with TNFi treatment. Medical
treatment options for fistulizing and fibrotic disease remain limited. Thus, a substantial unmet
need remains for agents with greater efficacy than current therapies, either as a standalone
therapy or in combination with existing therapies.
In CD, vanin enzymes are dysregulated and are linked to development of epithelial barrier
injury through their product cysteamine (R18-3167, R17-3322, R17-3323). As described in
Section 5.2, by reducing cysteamine levels, a vanin inhibitor is expected to provide the
epithelial barrier with a broad protective effect against diverse disease-driving stimuli,
leading to direct epithelial barrier repair resulting in mucosal healing. In addition, a vanin
inhibitor is expected to attenuate chronic inflammation underlying the disease. Oral
medicines with a novel mode of action that includes repair of epithelial barrier (leading to
mucosal healing) would be particularly attractive for the current unmet need in CD and will
provide an additional benefit of convenience of oral vs. parenteral treatments. Therefore,
Boehringer Ingelheim is starting a clinical development program for a vanin inhibitor
candidate, BI 1595043.
1.2
DRUG PROFILE


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Nonclinical pharmacology
1.2.1
Primary pharmacodynamics
1.2.1.1
In vitro primary pharmacodynamics
 
 
 
 
 
 
 
 
 
In vivo primary pharmacodynamics
 
 
 
 
 


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Safety pharmacology
1.2.1.2
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). 
 
 
 
 
Respiratory system
 
Central nervous system
 
 
Renal and hepatic system
 
 
Further considerations on safety pharmacology
 
 
 
 
 
 


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Pharmacodynamic interactions
1.2.1.3
No pharmacodynamics interaction studies have been carried out to date.
 
 
 
 
For a more detailed description of the BI 1595043 profile, please refer to the current 
Investigator’s Brochure (IB) (c31270124).
Toxicology
1.2.2
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.
Single dose toxicity
1.2.2.1
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 i
 
 
 
 
 
 


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Repeated dose toxicity
1.2.2.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmology findings:
 
 
 


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Genotoxicity
1.2.2.3
BI 1595043 was not mutagenic 
 
 
 
 
 
).
Carcinogenicity
1.2.2.4
Carcinogenicity studies have not yet been conducted.
Reproductive and developmental toxicity
1.2.2.5
 
 
 
 
 
 
 
 
 
Local tolerance
1.2.2.6
No local tolerance studies have been conducted.
Other toxicity studies
1.2.2.7
 
 


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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).
Nonclinical pharmacokinetics
1.2.3
Methods of analysis
1.2.3.1
To support GLP toxicity studies, GLP LC/MS/MS assay methods were validated for 
quantification of BI 1595043
 
 
.
Absorption
1.2.3.2
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
 


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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.
Distribution
1.2.3.3
Plasma protein binding
 
 
 
Distribution in pigmented rat
Quantitative tissue distribution of total drug-related radioactivity was investigated in male
pigmented (Long-Evans) rats administered a 
.
Metabolism
1.2.3.4
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.


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Excretion
1.2.3.5
 
 
 
 
 
 
 
Pharmacokinetic drug interactions
1.2.3.6
No pharmacokinetic drug interaction studies have been conducted.
Toxicokinetics
1.2.3.7
PK parameters were assessed in GLP-toxicological studies (n00268703, n00270419) and are 
displayed in Table 1.2.3.7: 1:
For a more detailed description of the BI 1595043 profile, please refer to the current IB 
(c31270124).


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Prediction of human therapeutic dose
1.2.4
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 from this clinical trial
(see Table 1.2.5.2).
 
 
 
.
Clinical experience in humans
1.2.5
This is the first-in-human trial with the 
 BI 1595043 consisting of 
7 original dose groups 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. 
To date, BI 1595043 was administered to 42 healthy male subjects within 7 dose groups, and
additional 14 healthy male subjects received matching placebo.
The clinical trial protocol is being amended to add the new maximum dose level of 160 mg of 
BI 1595043 (see Section 1.3.2).
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). 
 
 
 
 
 
 
 
 
 


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Table 1.2.5: 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)
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. After a single oral solution dose, BI 1595043 was
 
 


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Table 1.2.5: 2
gMean (gCV%) values of BI 1595043 PK parameters after single oral 
doses of BI 1595043 – SRD Trial 1445-0001 – Dose Groups 1-7
Residual Effect Period
1.2.6
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 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.
Drug product
1.2.7
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
As a transition from non-clinical investigations to clinical development, in this first-in-human 
trial, safety, tolerability, pharmacokinetics and pharmacodynamics of BI 1595043 will be 
assessed in healthy male volunteers, using single rising oral doses in order to provide the 
basis for the clinical development of BI 1595043, a
, in 
the indication of CD.
Young, healthy male subjects will be recruited for this study. They (1) provide a relatively 
stable physiological, biochemical and hormonal basis for studying drug effects, (2) show no 
disease-related variation and (3) are not taking regular concomitant medications.
Within each dose group, all actively treated individuals will receive the same BI 1595043 
dose. The next higher dose will only be administered to the next group, if the treatment in the 
preceding dose group was safe and showed acceptable tolerability.
 
Starting dose
1.3.1
Maximum Recommended Starting Dose (MRSD) was estimated on the basis of the US FDA 
Guidance for Industry “Estimating the Maximum Recommended Safe Starting Dose in Initial 
Clinical Trials for Therapeutics in Healthy Volunteers” (R06-1037).


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Maximum dose and dose escalation
1.3.2
Based on the cross-species comparison of 
(Section 1.4.3.2), and the results 
of 13-week general toxicology studies (Sections 1.2.2.2 and 1.3.1), dog was chosen as the 
most relevant toxicological species to humans and providing more conservative safety 
margins compared to rat.


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1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance 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.
Expected benefit for the target indication
1.4.1
Procedure-related risks
1.4.2
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising and, in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
1.4.3
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.
Mode of action and nature of the target
1.4.3.1
 
 


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Relevance of animal models
1.4.3.2
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.
Findings in non-clinical safety studies
1.4.3.3
Toxicology data of BI 1595043 support clinical studies in men with daily oral administration 
for up to 91 days. 


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consideration of large safety margin across the planned dose 
range in the study.


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Clinical findings
1.4.3.4
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).
Drug induced liver injury
1.4.3.5
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.
Risk minimization (safety precautions and stopping rules)
1.4.3.6
The following risk minimization measures, including safety precautions and stopping rules, 
will be implemented in this study:

Careful selection of starting dose, as described in Section 1.3.1.

Decreasing escalation factors with increasing doses, as described in Section 1.3.2. 
Dose escalations will only be allowed after documented interim safety reviews (see
Section 3.1).

Preliminary measurement of BI 1595043 pharmacokinetics (Cmax, AUC0-24; see
Section 7.3.2). The expected exposure in the next higher dose group will be estimated 
based on preliminary PK data of preceding dose groups. The next higher dose level 
will only be administered, if estimated mean values of Cmax and AUC0-24 do not 
exceed the maximum acceptable human exposure (see Section 1.3.2).

For safety reasons, division of each dose group of 8 subjects (6 on active treatment, 
2 on placebo) into 3 staggered cohorts. On the first study day of each dose level, 
2 subjects (Cohort 1) will be treated (one with active treatment, the other with 
placebo). On the second study day, the next 2 subjects (Cohort 2) will be treated 
(two with active treatment). On the third study day of each dose level, the remaining 
4 subjects (Cohort 3) will be treated (three with active treatment, one with placebo). 
If BI 1595043 was safe and well tolerated in Cohort 1, the study will continue with 
Cohort 2. If it was safe and well tolerated in the preceding cohorts, the study will 
continue with Cohort 3. Between the first application of BI 1595043 in each cohort, 
there will be a time interval of at least 24 h which is expected to cover the peak 
exposure of the compound. In Cohort 2 and Cohort 3, subjects will be dosed at least 
10 min apart.


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
A monitoring of safety laboratory with specific focus on plasma glucose levels and 
liver enzymes (see Flow Chart).

An ECG monitoring including continuous ECG measurement over 4 hours post dose 
to cover the anticipated period of highest drug exposure and additional repeated 
triplicate 12-lead ECGs up to 48 hours following drug administration. Dose escalation
would be stopped as soon as at least 2 subjects at one dose level showed relevant QT 
prolongation (see Section 3.3.4.3).

Safety monitoring (including e.g. vital signs 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).

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 
 (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.

Application of the next higher dose, only if the respective dose of BI 1595043 is safe, 
shows acceptable tolerability, and no stopping criterion is met (see Section 3.3.4.3). 
At least 7 days will be maintained between the first drug administration to subjects in 
the previous dose group and the first drug administration to subjects in the subsequent 
dose group.

Exclusion of acetaminophen (paracetamol) as concomitant medication.

Due to observed teratogenicity in rat, women will not be enrolled in this study.
Overall assessment
1.4.4
BI 1595043, a 
, has been thus far administered to 42 healthy 
subjects within this study. Despite the novelty of the target, non-clinical safety data in 
relevant animal species, the inhibitory mode of action as well as the risk assessment suggest 
that BI 1595043 is not a high-risk compound and support the application of single doses of BI 
1595043 in this first-in-man trial. 
Based on the risk mitigation strategy, comprising of safety precautions and stopping rules, 
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 Crohn’s disease, 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
Main objectives
2.1.1
The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics
(PK) of BI 1595043 in healthy male subjects following oral administration of single rising 
doses.
Primary endpoint
2.1.2
The primary endpoint for assessment of safety and tolerability of BI 1595043 is the
percentage of subjects with drug-related adverse events.
Secondary endpoint
2.1.3
The following pharmacokinetic parameters will be determined for BI 1595043 if feasible:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
Safety and tolerability
2.2.2.1
Safety and tolerability of BI 1595043 will be assessed based on:

AEs (including clinically relevant findings from the physical examination and 
ophthalmological examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring 

Vital signs (blood pressure, pulse rate)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This single-rising dose trial is designed as single-blind, partially randomised, and placebo-
controlled within parallel (sequential) dose groups.
It is planned to include a total of 64 healthy male subjects in the trial. The subjects will be 
assigned to 8 groups consisting of 8 subjects per group; the groups will be dosed sequentially
(see Table 3.1: 1). The investigator (after consultation with the sponsor) is allowed to alter 
the scheduled dose groups (e.g., add low and/or intermediate dose groups) on the basis of 
experience gained during the study (for instance, based on preliminary PK data), provided the 
planned and approved highest dose is not exceeded. Thus, the actual number of subjects 
entered may be more than 64, but is not to exceed 72. Such changes, which are based on 
preliminary PK data, may be implemented via non-substantial CTP amendments. Changes, 
based on safety findings, will be implemented only via substantial CTP amendments.
Within each dose group, 6 subjects will receive BI 1595043 and 2 will receive placebo. Only 
one dose is tested within each dose group. For safety reasons, each dose group will consist of 
3 cohorts. The trial medication will be administered in the following order: 

Cohort 1 (fixed order): the 1st subject on active treatment and the 2nd subject on 
placebo (in total 2 subjects)

Cohort 2 (fixed order): 2 subjects on active treatment (in total 2 subjects)

Cohort 3 (randomized): 3 subjects on active treatment and 1 subject on placebo (in 
total 4 subjects)
Between first drug administrations in Cohort 1, Cohort 2 and Cohort 3 there will be a time 
interval of at least 24 hours, and Cohort 1 and Cohort 3 will be separated by at least 2 days, 
which based on an anticipated half-life of BI 1595043 of approximately 11.6 hours and 
expected to cover the peak exposure and be sufficient to detect relevant acute effects. If 
BI 1595043 was safe and well tolerated in Cohort 1, the study will continue with Cohort 2. 
The 2 subjects of Cohort 2 will be dosed at least 10 min apart. If BI 1595043 was still safe 
and well tolerated in all subjects of Cohort 1 and Cohort 2, the study will proceed with the 
4 subjects of Cohort 3, who will be dosed at least 10 min apart. At each dose level Cohort 3 
may be started only after at least 2 subjects have been treated with BI 1595043 in the 
preceding Cohort 1 and Cohort 2.
The dose groups to be evaluated are outlined in Table 3.1: 1 below.


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Table 3.1: 1
Dose groups
Dose Group
1
2
3
4
5
6
7
8
Dose (mg)
1
3
6
12
25
50
90
160
Number of subjects
8
8
8
8
8
8
8
8
Subjects receiving placebo
2
2
2
2
2
2
2
2
Subjects receiving BI 1595043
6
6
6
6
6
6
6
6
The groups will be dosed consecutively in ascending order, and a time interval of at least 
7 days will be maintained between the last drug administration to subjects in the previous 
dose group and the first drug administration to subjects in the subsequent dose group. The 
decision to treat the next dose group will be based upon safety, tolerability and
pharmacokinetic data of all the preceding dose groups. The next dose group will only be 
treated if, in the opinion of the investigator, no safety concerns have arisen in the preceding 
dose groups (i.e. no dose-limiting events occurred), and if none of the pre-specified trial-
specific stopping criteria have been met (refer to Section 3.3.4.1).
A documented Safety Review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime by the Principal Investigator (or 
an authorised deputy) or the sponsor of the study (for instance, due to the occurrence of any 
unforeseen adverse events). 
Although no formal Safety Review meeting will take place within a given dose group, safety 
will be continuously monitored during this trial, and an individual will only be dosed in the 
absence of any safety concern (i.e. no dose-limiting events occurred) and if none of the pre-
specified trial-specific stopping criteria have been met (refer to Section 3.3.4.1).
At minimum, data from 4 subjects on active drug need to be available for escalation to a 
higher dose. For the minimum dataset with regards to preliminary PK data, see Section 7.4.
The minimum data set for review consists of the following:

AEs in the current and preceding dose groups up to at least 48 h post dosing, 
including clinically relevant findings from ancillary safety testing listed below (Note: 
AEs may be ongoing at the time of Safety Reviews and AE information may be 
subject to change prior to Database Lock)

Results from 12-lead ECG and continuous ECG monitoring in the current and 
preceding dose groups up to at least 48 h post dosing

Vital signs in the current and preceding dose groups up to at least 48 h post dosing

Clinical laboratory tests in the current and preceding dose groups up to at least 48 h 
post dosing

Preliminary PK data for the selected time as per Section 7.4. For escalation from dose 
group 1 to dose group 2, preliminary PK data are not required.

Check of criteria for stopping subject treatment as per Section 3.3.4.1


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The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the Clinical Trial Lead (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs, and out-of-range 
laboratory results (if considered clinically significant). In addition and depending on the 
results and findings, suitable experts from the sponsor or external institutions may be 
consulted on as needed basis. In these cases expert recommendations will be documented in 
the minutes of the Safety Review and considered for the decision making. Dose escalation 
will only be permitted if no safety concerns exist neither in the opinion of the Principal 
Investigator (or an authorised deputy) nor the Clinical Trial Lead (or an authorised deputy). 
Safety Reviews can be conducted face-to-face or by video/telephone conference. The Clinical 
Trial Lead (or an authorised deputy) is responsible for the organisation and minutes of the 
reviews. Minutes will be signed off by the Principal Investigator (or an authorised deputy) 
and Clinical Trial Lead (or an authorised deputy), and will be filed in the ISF and TMF.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For single-rising dose trials, the sequential rising dose design described in Section 3.1 is 
viewed favourably under the provision not to expose the subjects involved to undue risks.
Single-blind conditions regarding the subject’s treatment (active or placebo) are maintained 
within each dose group. However, subjects and investigators will be aware of the dose of 
drug administered. The disadvantage of the trial design is a possible observer bias with regard 
to the dose-dependent effects; in addition, the sequential dosing of groups could potentially 
result in time-related effects. However, as such effects are expected to be small relative to the 
differences between the doses in the broad range investigated, unbiased comparisons between 
treatments can still be expected.
It is standard in single or multiple rising dose trials involving healthy volunteers to include a 
placebo group to control for safety and tolerability of the trial medication. Each dose group 
consists of 8 subjects, with 6 on active treatment, and 2 on placebo. For data analysis 
purposes, the placebo control group will include all subjects of all dose groups treated with 
placebo. Six subjects per active treatment group are generally considered to be sufficient for 
the exploratory evaluation of pharmacokinetics.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 64 healthy male will enter the study. The actual number of subjects entered 
may exceed the total of 64, if additional intermediate doses are tested (see Section 3.1). 
Subjects will be recruited from the volunteers' pool of the trial site. 
Only male subjects will be included in the trial because no data on reproductive toxicology 
are available at this time.


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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.
Main diagnosis for trial entry 
3.3.1
The study will be performed in healthy subjects.
Inclusion criteria
3.3.2
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests
2. Age of 18 to 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, e.g. 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 (e.g. condom)
Unprotected sexual intercourse with a pregnant female partner and sperm donation is not 
allowed throughout the study and until 30 days after trial completion.
Exclusion criteria
3.3.3
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


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4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
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.


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Withdrawal of subjects from treatment or assessments
3.3.4
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.
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 1.2.6), 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.
Discontinuation of trial treatment
3.3.4.1
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
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.


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Withdrawal of consent to trial participation
3.3.4.2
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above
Discontinuation of the trial by the sponsor
3.3.4.3
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk assessment. Dose escalation will be terminated if more 
than 50% of the subjects at one dose level show drug-related and clinically relevant 
adverse events of moderate or severe intensity, or if at least one drug-related serious 
adverse event is reported.
3. 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
5. Dose escalation will be stopped if at least 2 subjects on active treatment at one dose level 
have relevant individual QT prolongations, i.e. a QTc increase of greater than 60 ms from 
baseline in connection with absolute QT or QTc greater than 500 ms, as confirmed by a 
repeat ECG recording
6. Dose escalation will be stopped, if the Cmax or AUC0-24 of at least 1 subject of one dose 
group increases above the following exposure thresholds or if the estimated gMean 
exposure is expected to exceed a Cmax of 
 or an AUC0-24 of 
. 
Estimation will be done based on preliminary PK results of preceding dose groups (see 
Section 7.4)
7. Occurrence of severe non-serious adverse events considered as drug-related by the 
investigator in 2 subjects of the same dose group (8 subjects).
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
Replacement of subjects
3.3.5
If some subjects do not complete the trial, the Clinical Trial Lead 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.
Identity of the Investigational Medicinal Products
4.1.1
The characteristics of the test product are given below:
Substance:
BI 1595043
Pharmaceutical formulation: Powder for oral solution
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
2.5 mg/mL
Posology:
1-0-0 (0.4 mL = 1 mg, 1.2 mL = 3 mg, 2.4 mL = 6 mg, 
4.8 mL = 12 mg, 10 mL = 25 mg, 20 mL = 50 mg, 
36 mL = 90 mg, 64 mL = 160 mg)
Route of administration:
oral
Duration of use:
Single dose 
The characteristics of the reference product (placebo) are given below:
Substance:
Not applicable, solvent only (Tartaric acid 5 mg/mL)
Pharmaceutical formulation: Solvent only
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Not applicable
Posology:
1-0-0 (0.4 mL, 1.2 mL, 2.4 mL, 4.8 mL, 10 mL, 
20 mL, 36 mL, 64 mL)
Route of administration:
oral
Duration of use:
Single dose 
Selection of doses in the trial
4.1.2
The doses selected for this trial cover the subtherapeutic as well as the estimated therapeutic 
range and include a safety margin (see Section 1.2).
Method of assigning subjects to treatment groups
4.1.3
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups 
(3 cohorts per dose group) according to their temporal availability. As soon as enough 


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subjects are allocated to 1 of the 21 dose cohorts, the following subjects will be allocated to 
one of the other dose cohorts. Therefore, the allocation of subjects to dose cohorts is not 
influenced by trial personnel, but only by the subjects’ temporal availability. Because the trial 
includes healthy subjects from a homogenous population, relevant imbalances between the 
dose groups are not expected.
Subjects will be assigned to treatments (active treatment or placebo) prior to the first 
administration of trial medication. In Cohorts 3 of each dose group, subjects will be randomly 
assigned to treatments, while treatments in Cohort 1 and Cohort 2 will be assigned in a fixed 
order for safety reasons, as described in Section 3.1.
For the purpose of random assignment, the randomisation list will be provided to the trial site 
in advance. Numbers of the randomization list will be allocated to subjects by the method 
‘first come - first served’ at the time of registration. Subjects are then assigned to treatment 
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.
Drug assignment and administration of doses for each subject
4.1.4
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The dose volume for 
placebo corresponds to the dose volume of the corresponding dose level.
Table 4.1.4: 1
BI 1595043 and placebo treatments, oral administration
Dose
group
Substance
Pharmaceutical 
form
Unit strength
Dose volume 
per administration
Total daily
dose
1
BI 1595043
oral solution
2.5 mg/mL
0.4 mL q.d.
1 mg
2
BI 1595043
oral solution
2.5 mg/mL
1.2 mL q.d.
3 mg
3
BI 1595043
oral solution
2.5 mg/mL
2.4 mL q.d.
6 mg
4
BI 1595043
oral solution
2.5 mg/mL
4.8 mL q.d.
12 mg
5
BI 1595043
oral solution
2.5 mg/mL
10 mL q.d.
25 mg
6
BI 1595043
oral solution
2.5 mg/mL
20 mL q.d.
50 mg
7
BI 1595043
oral solution
2.5 mg/mL
36 mL q.d.
90 mg
8
BI 1595043
oral solution
2.5 mg/mL
64 mL q.d.
160 mg
1-8
Placebo*
oral solution
(solvent only)
--
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups 
The oral solutions for dosing (active treatment and placebo) will be prepared by pharmacists 
or qualified pharmacy staff members or qualified medical study personnel at the trial site 
under the responsibility of the investigator according to the instructions provided in 
Appendix 10.1.
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. The investigator (or 


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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 preparation of trial medication and its
administration to subjects.
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.
Blinding and procedures for unblinding
4.1.5
Blinding
4.1.5.1
The trial is designed single-blind. The treatments administered (active or placebo) will be 
blinded to subjects, but will be known to the investigators (outcome assessors). Only the 
current dose level will be known to the subjects due to the rising dose design.
A single–blind design is considered acceptable because the potential bias in this type of study 
seems to be low and according to study procedures it is assured that the investigator's 
knowledge of the next treatment does not influence the decision to enter a subject. 
All trial data will be handled open label. This means that trial functions of the sponsor are 
unblinded (including clinical trial lead, data manager, statistician, bioanalyst, 
pharmacokineticist, pharmacometrician, drug metabolism scientist as well as dedicated 
personnel of the trial site).
Within the central ECG lab, the staff involved with interval measurements will be blinded 
with respect to the treatment and also with regard to the recording date and time as well as 
planned time points of the ECGs. The interval measurements for a given subject will be 
performed in a random and blinded sequence by a single technician. No more than two 
different blinded readers will evaluate the ECGs of the study.
If a preliminary analysis of ECG data is required during the trial, a part of the staff of the 
central ECG lab (different from the ECG evaluation team) may be unblinded. This part of the 
staff will receive the necessary information, which will be stored with no access to the ECG 
evaluation team.
Access to the randomisation schedule will be controlled and documented by a signed 
confidentiality statement, which will be stored in the TMF.
Unblinding and breaking the code
4.1.5.2
As this trial will be conducted single-blind, subjects’ treatment assignments will be known to 
investigators. Therefore, no emergency envelopes will be provided.
Packaging, labelling, and re-supply
4.1.6
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. 


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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. 
Examples of the labels will be available in the ISF.
Storage conditions
4.1.7
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.
Drug accountability
4.1.8
The investigator or designee will receive the investigational drugs from the sponsor when the 
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor 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 trial medication will be disposed of locally by the trial site upon written 
authorisation of the Clinical Trial Lead. Receipt, usage, and disposal of trial medication must 
be documented on the appropriate forms. Account must be given for any discrepancies.


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
Other treatments and emergency procedures
4.2.1
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
Restrictions
4.2.2
Restrictions regarding concomitant treatment
4.2.2.1
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.
Restrictions on diet and life style
4.2.2.2
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water served on Day 1 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 is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 10 h before the administration of trial medication 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. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.


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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 
and/or urinary excretion of trial medication will provide additional confirmation of 
compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable. No efficacy endpoints will be evaluated in this trial.
5.2
ASSESSMENT OF SAFETY
Physical examination
5.2.1
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), 12-lead ECG, laboratory tests, ophthalmological examination, 
and a physical examination. At the end of trial examination, it will include review of vital 
signs, 12-lead ECG, laboratory tests, ophthalmological examination, and a physical 
examination including determination of weight.
Vital signs
5.2.2
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) 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.
Ophthalmological examination
5.2.3
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.
Safety laboratory parameters
5.2.4
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.
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).


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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
Hormones
Thyroid Stimulating Hormone 
Free T3 - Triiodothyronine
Free T4 – Thyroxine
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
X
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 2 on Days -3 to -1, 2, 3 and 5 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 3 (end of trial examination)


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Table 5.2.4: 1
Routine laboratory tests (cont).
Functional lab group
BI test name [comment/abbreviation]
A
B
C
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 2 on Days -3 to -1, 2, 3 and 5 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 3 (end of trial examination)
The tests listed in Table 5.2.4: 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.
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 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
COVID-191
SARS CoV-2 PCR test
1 evaluation will be performed shortly (within 72 hours) before admission to trial site as per Flow Chart


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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.
Electrocardiogram
5.2.5
12-lead resting ECG
5.2.5.1
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (e.g.
device, 
 at the time 
points given 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 recording 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.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart. For baseline, 3 triplicate-ECGs will be 
recorded, the recordings should be separated by at least 15 minutes.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database.
Storing
All ECGs will be stored electronically at the site.


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Data transfer
For time points of triplicate ECGs specified in the Flow Chart, ECGs will be transferred 
electronically to the central ECG lab (
) for evaluation.
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded. 
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).
Evaluation
a) Central ECG lab (only triplicate ECGs)
Central ECG lab evaluation will be performed only for the first of three replicate 
ECGs per time point specified in the Flow Chart. The remaining second and third 
replicate ECGs will be stored for additional analyses if required, e.g. by authorities at 
a later time point. 
This will include the determination of cardiac QRS-axis as assessed by the ECG 
machine´s algorithm, as well as the intervals RR, PR, QRS and QT measured semi-
automatically. 
Heart rate (HR) and the QT interval corrected for HR (QTc e.g.QTcF and QTcB) will 
be determined by the Sponsor (see TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the 
same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be 
used, or if that lead is not measurable, then lead I will be used. The lead actually used 
will be reported in the CTR.
For automatic interval measurements no lead will be provided. After quality control, 
the fiducial point markings will be reviewed by the cardiologist assigned to the study.
For blinding arrangements see Section 4.1.5. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular subject should be evaluated by 
a single reader. For quality assurance and control of the measurements, all ECGs of a 
subject will be subsequently reviewed by the ECG technician supervisor or his/her 
designee to assess the overall variance of the measured intervals and, to detect 
accidental switching of leads and/or false subject assignments of the ECGs. After 
quality control, the fiducial point markings will be reviewed by the cardiologist 
assigned to the study.
Evaluation of ECGs will comply with the ICH E14 guidance document and 
supplements (R07-4722, R16-0366) as well as the FDA requirements for annotated 
digital ECGs (R09-4830).


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b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of 
cardiac safety during the study, the QT and QTcB values generated by the 
computerised ECG system or their manual corrections by the investigators will be 
used. In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data 
transfer) for cardiologic assessment by the central lab. In this case, these centrally 
measured results would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 
clinically relevant by the investigator. Any ECG abnormalities will be monitored carefully 
and, if necessary, the subject will be removed from the trial and will receive the appropriate 
medical treatment.
Continuous ECG monitoring
5.2.5.2
Cardiac rhythm (including heart rate) will be monitored by means of continuous 5-lead ECG 
recording using the monitor (e.g. 
) for at least 15 min 
before drug administration (for baseline assessment) and for 4 h following drug 
administration). This continuous ECG monitoring supports the early detection of adverse 
events such as clinically relevant bradycardia, tachycardia, or arrhythmia at the trial site. 
Beyond this clinical evaluation at the trial site, no further data collection or analyses are 
performed based on continuous ECG monitoring.
ECG data from continuous ECG recording will not be transferred to the clinical trial 
database. Abnormal findings during continuous ECG recording will be recorded as AEs if 
judged clinically relevant by the Investigator.
Other safety parameters
5.2.6
Not applicable.
Assessment of adverse events
5.2.7
Definitions of adverse events
5.2.7.1
Adverse event
5.2.7.1.1
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):


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
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
5.2.7.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

Requires inpatient hospitalisation

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital anomaly/birth defect

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.7.1.3
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 5.2.7.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.


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Adverse events of special interest
5.2.7.1.4
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 5.2.7.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
Intensity (severity) of AEs
5.2.7.1.5
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
5.2.7.1.6
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


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
Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
Adverse event collection and reporting
5.2.7.2
AE collection
5.2.7.2.1
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: 


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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 new AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF
AE reporting to the sponsor and timelines
5.2.7.2.2
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
5.2.7.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no 
further information can be obtained.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
5.3.1
Plasma samples will be collected for the purpose of pharmacokinetic analysis. Only in dose 
group 4 (12 mg of BI 1595043), additional blood samples will be collected for stability 
testing and metabolism analysis.
 
. The time points of the samples collection are indicated in the Flow 
Chart.
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.


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PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. as a result of preliminary PK data), including addition of 
samples and visits, as long as the total blood volume taken per subject does not exceed 
500 mL. Such changes would be implemented via non-substantial CTP Amendments.
Methods of sample collection
5.3.2
Blood sampling for pharmacokinetic analysis
5.3.2.1
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 60 min, with 
interim storage of blood samples and aliquots in ice water or on ice. 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. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g., for stability testing or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations, but not later than 5 years after the CTR is 
archived.
Blood sampling for metabolism analysis
5.3.2.2
Additional K2-EDTA plasma samples for the identification of drug metabolites will be 
investigated in dose group 4 (12 mg of BI 1595043). Based on the knowledge gained during 
the trial conduct, e.g. from preliminary PK results, the dose group may be modified to a 
different one. The change will be implemented via a non-substantial CTP amendment.
The blood samples will be drawn at the same time points as PK samples (see Flow Chart). At 
each of these times, 2.7 mL blood will be needed for metabolite analysis. The blood samples 
will be processed in the same way as the PK samples (see Section 5.3.2.1).
Two plasma aliquots will be obtained and stored in polypropylene (PP) tubes. The first
aliquot (labelled as MIST-1 samples), should contain at least 0.5 mL plasma. The remaining


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plasma will be the second aliquot (labelled as MIST-2 samples). The process from blood
collection to the transfer of plasma aliquots into the freezer should be completed within
90 min, with interim storage of blood samples on crushed ice between blood collection and
centrifugation. Until transfer on dry ice to the metabolism laboratory, the aliquots will be
stored at the trial site. Samples will be positioned upright and will be frozen at approximately
-70°C. The second aliquot will be shipped to the metabolism laboratory after the metabolism
scientist has acknowledged safe arrival of the first aliquot. At the metabolism laboratory, the
plasma samples will be stored at approximately -70°C until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number,
subject number, day, planned sampling time and ‘MIST-1’ or ‘MIST-2’. Further information
such a matrix and analyte may also be provided.
Plasma samples dedicated to metabolism investigation are transferred to:
Phone: 
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
drug metabolism will be reported separately and will not be included in the CTR. The study 
samples will be discarded after completion of the experiments but not later than 5 years after 
the CTR has been archived. 


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Additional blood sample for stability-testing
5.3.2.4
In order to assess the stability of the analyte in whole blood, one additional blood sample will 
be obtained from all subjects of dose group 4 (12 mg of BI 1595043). Based on the 
knowledge gained during the trial conduct, e.g. from preliminary PK results, the chosen 
timing or dose group may be changed to a different one. The change will be implemented via 
a non-substantial CTP amendment.
Approximately 2.4 mL blood will be drawn from an antecubital or forearm vein into two 
1.2 mL K2-EDTA-blood drawing tubes at the time indicated in the Flow Chart (immediately 
after the drawing of a regular blood PK sample, which means that no additional venous 
puncture will be necessary).
From each K2-EDTA tube, one aliquot will be generated:

One aliquot (‘stability reference’) will be centrifuged within 10 min after collection. 
Centrifugation will last for approximately 10 min (at approximately 2000 g to 4000 g 
and 4 to 8 °C), plasma will be separated and transferred into a freezer

The second aliquot (‘stability test’) will be stored for about 4 h at room temperature 
and ambient light conditions (storage time must be documented) and will then be 
centrifuged and stored as for the first aliquot. 
At a minimum, the aliquots should be labelled with BI trial number, administered drug, 
subject number, planned sampling time, and whether the sample is the ‘stability reference’ or 
‘stability test’ sample.
Until transfer to the analytical laboratory, both aliquots will be stored at approximately
-20 °C or below at the trial site. Both aliquots will be provided to the responsible bioanalyst 
together with the information about sample handling (i.e., storage time of stability test sample
at room temperature). After receipt, the aliquots will be stored at the bioanalytical laboratory 
at approximately -20°C or below until analysis.
The results of the analysis of these samples will not be reported in the CTR but will be used 
for bioanalytical assay validation and therefore included in the corresponding method 
validation report. The remaining sample volume will be discarded at latest upon completion
of the method validation report.


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Pharmacokinetic - pharmacodynamic relationship
5.3.4
An analysis of the relationship between pharmacokinetic and pharmacodynamic parameters 
may be investigated in an exploratory manner, see Section 7.3.5.


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5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Pharmacogenomic evaluation
5.6.1
Pharmacogenomic evaluations are not considered necessary for assessment of response to 
BI 1595043 and will not be conducted.


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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 (including blank values for PK 
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 
, as 
well as PD 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
Screening period
6.2.1
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 Section 5.2.
Treatment period
6.2.2
Each subject will receive one dose of trial medication (BI 1595043 or placebo) at Visit 2.
Trial medication will be taken orally by each subject under direct supervision of the 
investigator or 
 designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.


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Study participants will be admitted to the trial site in the morning of Day 1 (or in the evening 
of Day -1) 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 by the investigator or 
 designee. On all other 
study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma 
 samples for PK 
analysis, refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.3
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.
Follow-up period and trial completion
6.2.3
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 objectives of this trial will be assessed by calculating descriptive statistics for 
safety as well as for PK parameters, which will be compared between the treatment groups.
Further analyses of these endpoints comprise the power model for assessment of dose 
proportionality.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in this study.
Any confidence intervals computed are to be interpreted in the perspective of the exploratory 
character of the study; i.e., confidence intervals are considered as interval estimates for 
effects.
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 treatment assignment will be 
determined based on the first treatment the subjects received. 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 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.

ECG pharmacokinetic concentration set (ECGPCS):This subject set includes all 
subjects from the TS who provide at least one pair of a valid drug plasma 
concentration and a corresponding (i.e. time-matched) ECG endpoint to be used in the 
exposure-response analyses. For placebo subjects, the plasma concentration is set to 
zero and hence always considered as valid. The decision whether a time deviation 
between PK blood sampling and ECG recording is acceptable (and thus whether the 
pair of values will be used) is to be made no later than at the Report Planning Meeting
before data base lock. The ECGPCS will be used for the exposure-response analyses.


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Adherence to the protocol will be assessed by the trial team. Important protocol violation 
(IPV) categories will be specified in the TSAP, IPVs will be identified no later than in the 
Report Planning Meeting, and the IPV categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1.3 and Section 2.2.2.2 for drug 
BI 1595043 will be calculated by means of non-compartmental analysis. Non-compartmental 
PK parameters will be calculated based on actual sampling times using a validated 
pharmacokinetic software (
 Descriptive statistics will be used to 
evaluate plasma concentration data and PK parameters. The derivation of PK parameters will 
be 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 violation 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 violations 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),

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.
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 as in the bioanalytical report (that is 
to the same number of decimal places provided in the bioanalytical report).


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If a pre-dose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a pre-dose concentration is above BLQ, but less than or equal to 5% 
of the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case to case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis.

If a concentration is only excluded from half-life determination, it will be used for all 
other calculations (e.g. descriptive statistics) and for graphical presentation.

If a concentration value is excluded from all calculations, it will not be presented
graphically or used for the calculation of descriptive statistics and parameter 
determination. However the excluded concentration itself will be listed in the clinical 
trial report associated with an appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual
parameter estimates of a certain parameter are available. If the actual sampling time will not
be recorded or will be missing for a certain time point, the planned time will generally be
used for this time point instead. Pharmacokinetic parameters which cannot be determined will
be identified by "not calculated" (NC).
 
 
 
Primary endpoint analyses
7.3.1
The primary endpoint as specified in Section 2.1.2 will be derived according to BI standards. 
The analysis will be based on the treated set (TS) and will be descriptive in nature. See
Section 7.3.4 for further details.
Secondary endpoint analyses
7.3.2
Primary analyses
The secondary endpoints (refer to Section 2.1.3) will be analysed descriptively. Analyses will 
be performed for the parent drug and for metabolites.


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Further exploratory analyses
Dose proportionality will be explored via graphical checks and, if applicable, via the power 
model stated below. The analysis will be performed for the pharmacokinetic endpoints 
AUC0-∞and Cmax specified in Section 2.1.3.
The power model describes the functional relationship between the dose level and PK 
endpoint on the log scale via
 =  log (xkm) = μ +    ∙ log (Dk) +  ekm ,
where 
ykm
logarithm of response (PK parameter) measured on subject m receiving dose k,
xkm
response (PK parameter) measured on subject m receiving dose k,
μ
the overall mean,
β
slope parameter of linear regression line,
D
level of dose k, k=1,…,8,
ekm
the random error associated with the mth subject who was administered dose k 
(e~(0, ) iid).
The slope parameter β together with its two-sided 90% confidence interval will be estimated. 
Additionally, the r-fold change  together with its 90% CI will be derived.
As some small doses at the beginning and/or some doses at the upper end might not 
contribute to the linear relationship between dose and PK, dose proportionality over the entire 
dose range investigated might not be shown. In that case an attempt will be made to identify a 
subrange of at least 3 consecutive doses where dose proportionality can be concluded.
Safety analyses
7.3.4
Safety will be assessed as defined by the endpoints listed in Section 2.1.2 and 2.2.2 based on 
the treated set (TS). Safety analyses will be descriptive in nature and will be based on BI 
standards. 


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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. The placebo group in the safety evaluation 
will consist of all subjects treated with placebo, regardless of the dose group in which they 
were treated. The test treatment groups will be compared to the placebo group in a descriptive 
way. Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.
Measurements (such as ECGs, vital signs, or laboratory parameters) or AEs will be assigned 
to treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment-emergent AEs). 
Therefore, measurements planned or AEs recorded prior to intake of trial medication will be 
assigned to the screening period, those between the 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 trial termination date will be assigned to ’follow-up’. These assignments 
including the corresponding time intervals will be defined in detail in the TSAP. Note that 
AEs occurring after the last per protocol contact but entered before database lock will be 
reported to Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (called analysing treatments) may be defined in the 
TSAP in order to provide summary statistics for other than above periods, such as combined 
treatments, on-treatment totals, or periods without treatment effects (such as screening and 
post-study 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 possibly clinically significant values will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline. 
The ECG variables QT, HR, QTcF, QTcB, PR, QRS, and RR obtained from the centralised 
evaluation of 12-lead ECG recordings will be the basis for the derivation of quantitative and 
categorical ECG endpoints. These endpoints and their analyses will be described in the 
TSAP.


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7.4
INTERIM ANALYSES
No interim analysis is planned.
A preliminary analysis of PK parameters (AUC0-24 and Cmax of BI 1595043) provided as 
individual values and geometric means of all available data from at least 4 subjects on active 
treatment per current dose level, supported by all the available data from subjects of 
preceding dose levels, will be performed before proceeding to the next higher  dose level. For 
escalation from dose group 1 to dose group 2, and after the last dose group, preliminary PK 
data are not required, see Section 3.
In contrast to the final PK calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows. Therefore, minor deviations may occur between preliminary and final results. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification information. The 
preliminary results will be distributed to the investigator and the trial team.
Depending on the results of available preliminary PK analyses and the tolerability and safety 
of the compound, changes to the dosing schedule (e.g., additional intermediate doses),) and 
additional PK/PD preliminary analysis may be performed if requested by the Clinical Trial 
Lead, the investigator, or Trial Clinical Pharmacokineticist. Preliminary PK results will not 
be reported in the CTR. No formal preliminary PK report will be written.
No inferential statistical interim analysis is planned. However, after completion of each dose 
group the investigator (or his or her deputy) is allowed to postpone further dose progression 
until a preliminary analysis of the data has been performed.
7.5
HANDLING OF MISSING DATA
Safety
7.5.1
It is not planned to impute missing values for safety parameters.
Pharmacokinetics
7.5.2
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.


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7.6
RANDOMISATION
Each dose group will be divided into three cohorts. The subjects of the first 2 cohorts (2 
subjects per cohort) will not be randomized to maintain a treatment sequence of 
active-placebo (Cohort 1) and active-active (Cohort 2) due to safety reasons. In the third 
cohort of each dose level (4 subjects) the subjects will be assigned to active or placebo 
treatment using a 3:1 allocation ratio (test treatment to placebo).
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 include a total of 64 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 8 subjects per dose group (6 on active treatment, and 2 on 
placebo) is commonly used in single-rising dose studies of the present type and is in general 
considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics.
Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded. Thus, the actual number of subjects entered 
may exceed 64, but will not exceed 72 subjects entered.


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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. As treatment assignments will 
be known to investigators, rules about emergency code breaks are not applicable (see Section 
4.1.5.2). For drug accountability, refer to Section 4.1.8.
Source documents
8.3.1
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)


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
Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Direct access to source data and documents
8.3.2
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.
Storage period of records
8.3.3
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.


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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. 
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.
Collection, storage and future use of biological samples and corresponding 
8.5.1
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

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 
 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 
data
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.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 


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A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted the 
, 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 Lead, 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 manager (CTM), 
Clinical Research Associates, and investigators of participating trial sites
The trial medication will be provided by the 
 
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
).
Analyses of BI 1595043 concentrations in plasma 
 will be performed at 
 
. 
Analyses of BI 1595043 metabolites concentrations in plasma will be performed at the 
Department of
 
 
 will be performed at the Department of
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for evaluation.
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
R06-1037
Guidance for industry: estimating the maximum safe starting dose in initial 
clinical trials for therapeutics in adult healthy volunteers. U.S. Department 
of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER); 2005.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) (2005).
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R13-2231
Baumgart DC, Sandborn WJ. Crohn's disease. Lancet 2012;380:1590-1605.
R16-0366
E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs: questions & 
answers (R3) (current version dated 10 December 2015).
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2016) ; 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015).


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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.
 
 
R18-2868
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.
 
 
 
 
 
R18-3167
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). website hma.eu/fi 
leadmin/dateien/Human_Medicines/01 About_HMA/Working 
Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance Version 
1.1.pdf (access date: 16 October 2020) ; Clinical Trial Facilitation Group 
(CTFG), Head of Medicine Agencies (HMA); 2020.
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
Preliminary snapshot analysis, 1445-0001. 17Dec2020.
c34816263
Preliminary data analysis ECG, 1445-0001. 14Dec2020.
 


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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.
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.
 
 
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 mouse 
fibroblasts. 24Feb2020.
n00273365
Quantitative whole-body autoradiography in male pigmented rats after 
single oral administration of [14C]BI 1595043. 05Nov2019.


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n00274794
BI 1595043 Nonclinical expert statement. Report in progress.
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 quantitation 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.
n00278622
 A GLP Embryo-fetal Development Study of BI 
1595043 by Oral Gavage in Rats 20R005. Report in progress.
n00278281
A GLP Embryo-fetal Development Study of BI 1595043 by Oral Gavage in 
Rabbits Barbeau S 20R006 02 Dec 2020


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10.
APPENDICES
10.1
RECONSTITUTION INSTRUCTIONS
Drug supplies overview
10.1.1
a) BI 1595043 Powder for Oral Solution 200 mg (target solution concentration 
BI 1595043: 2.5 mg/mL), provided in 100 mL amber glass bottles with plastic screw 
cap
b) Solvent for Oral Solution 80 mL (Tartaric acid 5mg/ml) provided in 100 mL amber 
glass bottle with plastic screw cap
Required equipment and dosing aids - overview
10.1.2
a) Mechanical (orbital) shaker for bottles (e.g. 
 Typ KL2)
b) Dosing dispensers/syringes and bottle adapters
For the withdrawal of respective volume aliquots from the final Oral Solution to be 
administered, amber 
 ExactaMed Syringes should be used in a size 
as close as possible to the required dose volume. For this purpose, a range of syringe 
sizes from 1 mL up to 60 mL should be stocked in the trial site.
In order to ease the withdrawal of the oral solution from the glass bottles with the 
amber 
 ExactaMed syringes, 
 bottle adapters and 
dispenser tip caps  should be used and stocked in the trial site, preferably 
 Adapta Cap Bottle Adapters (E-28 mm) or 
 Press-
In Bottle Adapters (PIBATM)
Possible 
 Med Oral amber dispensers

ExactaMed amber oral dispenser 1 mL 

ExactaMed amber oral dispenser 3 mL 

ExactaMed amber oral dispenser 5 mL 

ExactaMed amber oral dispenser 10 mL 

ExactaMed amber oral dispenser 20 mL 

ExactaMed amber oral dispenser 50 mL 
Only CE certified syringes are to be used!


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Reconstitution procedure
10.1.3
2 bottle concept, see also Appendix 10.1.4.
Reconstitution procedure for the preparation of the active BI 1595043 oral 
10.1.3.1
solution 2.5mg/ml
Necessary materials
a) BI 1595043 Powder for Oral Solution 200 mg (target solution concentration 
BI 1595043: 2.5 mg/mL), provided in 100 mL amber glass bottles with plastic screw 
cap.
b) Solvent for Oral Solution 80 mL (Tartaric acid 5 mg/ml) provided in 100 mL amber 
glass bottles with plastic screw cap.
Reconstitution procedure
Step 1: 
Open the bottle containing the Solvent for Oral Solution 80 mL (Tartaric acid 
5 mg/ml)
Step 2: 
Transfer the content of the Solvent for Oral Solution 80 mL (Tartaric acid 
5 mg/ml) completely and carefully into the bottle containing the BI 1595043 
Powder for Oral Solution 200 mg
Step 3:
Close the bottle with the plastic screw cap and shake the bottle manually until 
the BI 1595043 powder is wetted. Mount the bottle in a horizontal recumbent 
position on a mechanical shaker (e.g. 
 Typ KL2) 
Step 4:
Let the bottle shake orbitally for 30 min. at 350 rpm in its horizontal 
recumbent position.
Step 5:
Visually control that the powder is completely dissolved (clear to almost clear 
solution). 
The final BI 1595043 Oral Solution concentration is 2.5 mg/mL.
The allowable dose range is from 0.5 mg - 175 mg
Solvent for oral solution for use as placebo solution
10.1.3.2
Necessary materials
a) Solvent for Oral Solution 80 mL (Tartaric acid 5mg/ml) provided in 100 mL amber 
glass bottles with plastic screw cap.
The Placebo Solution is the Solvent for Oral solution 80 ml (Tartaric acid 5 mg/ml).


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Illustration of reconstitution procedure
10.1.4
The following scheme on the principle followed for the present PfOS formulation, 2-bottle
concept, should serve as an additional illustration to clarify, how the reconstitution procedure
for the preparation of the active oral solution has to be performed.
Active oral solution reconstitution procedure
2-bottle concept: SfOS + PfOS (API)
Component
g/bottle
Function
Tartaric
acid
0,4000
Solubilizer
Water
79,6480
Solvent
80,0480
Component
g/bottle
Function
Active 
ingredient
Transfer  the complete SfOS
SfOS
Solvent for Oral Solution
Final solution for
administration
2.5 mg/mL
PfOS
API powder in bottle
Powder for Oral Solution
BI 1595043
0,200
The following picture shows the bottles needed to prepare the active PfOS formulation to 
clarify the procedure in additional.


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In-use stability
10.1.5
The in-use stability of both placebo and the reconstituted solution is 24 h after its preparation, 
incl. storage in 
 dispensers until administration.
Mode of application
10.1.6
Withdraw the required volume aliquot to obtain the required doses. In case the complete 
content of a bottle is used, content is administered directly out of the bottle.
Use amber 
 ExactaMed syringes for dose withdrawal/administration, and 
subsequently if necessary amber glass bottles for administration of aliquots.
Use 
 ExactaMed syringes at a volume size as close as possible to the 
volume to be withdrawn.
Please note that it is the responsibility of the CTL to assure that appropriate supplies are used 
for administration of a dose, based on guidance in the clinical trial protocol, and dosing is 
limited to the allowed dosing range for a specific dose formulation as stated in this 
Reconstitution Instruction.
General remarks - important!
10.1.7
Because of lacking analytical coverage beyond the instructed preparation procedure of the 
different dose formulations no further (external) dilutions of the reconstituted solutions are 
allowed!
The present reconstitution instruction does not contain any advice how to withdraw a specific 
dose from the reconstituted solutions. The specific dose volumes to be withdrawn from the 
described dose formulations in order to obtain a required dose will be calculated and 
documented by 
 in the Clinical Trial Protocol (CTP) and subsequent documents (e.g. 
work sheets)!


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1 
Date of amendment
12 June 2020
EudraCT number
EU number
2020-001036-10
BI Trial number
1445-0001
BI Investigational Medicinal 
Product(s)
BI 1595043
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1595043 (single-blind, 
partially randomised, placebo-controlled, parallel 
(sequential) group design) 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. Flow Chart (pages 4 - 5)
2. Table 5.2.3: 1 Routine laboratory tests
3. Table 5.2.3: 2 Exclusionary laboratory tests
4. Section 5.2.3
5. Section 5.2.4.1
Description of change
1. A) Footnote 17 has been added to the Flow 
Chart,
B) Clarification to footnote 5 has been made,
C) Discrepancy between footnote 12 and the 
Flow chart has been corrected;
2. Glutamate Dehydrogenase (GLDH) was 
removed from the routine laboratory tests;
3. SARS-CoV-2 virus PCR test has been added to 
the exclusionary laboratory tests, and footnote 1 
explaining the time points;
4. A) Clarification to a breath alcohol test at 
admission has been added,
B) Details of SARS-CoV-2 virus PCR test have 
been provided;
5. Clarification to storing and evaluation of ECGs 
at the central ECG lab has been added.


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Rationale for change
1, 3, 4. Due to the recent COVID-19 outbreak, and 
given infected individuals may be clinically 
asymptomatic, SARS-CoV-2 virus PCR tests are 
being implemented shortly before admission to 
the research site. Implementation of these tests 
should safeguard the subject’s safety, and 
exclude infected volunteers from study 
participation.
2. Due to a feasibility feedback from the local 
safety laboratory at 
 Glutamate 
Dehydrogenase is removed from the list of 
required routine tests.
5. Due to a clarification received from the central 
ECG lab, the details of storing and evaluation of 
ECGs are updated.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
16 July 2020
EudraCT number
EU number
2020-001036-10
BI Trial number
1445-0001
BI Investigational Medicinal 
Product(s)
BI 1595043
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1595043 (single-blind, 
partially randomised, placebo-controlled, parallel 
(sequential) group design) 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. Flow Chart (page 4)
2. Section 1.2.2.2
3. Section 1.4.3.3
4. Section 1.4.3.5
5. Section 2.2.2.1
6. Section 3.3.3
7. Section 5.2.1
8. Section 5.2.3
9. Section 5.2.5.1
Description of change
1. Clarification to footnotes 1 and 4 has been 
made: ophthalmological examination has been 
added to Screening and EoTrial Visit;
2. Ophthalmology findings in the 13-w toxicology 
study in rats have been described in details;
3. Clinical relevance of the ophthalmology 
findings in rats have been described;
4. Ophthalmological monitoring has been 
implemented as a risk minimization measure;
5. Clarification to further safety and tolerability 
endpoints has been made: clinically relevant 
findings from the ophthalmological examination 
will be reported as AEs;
6. Exclusion criterion 24 has been added: subjects 
with ocular disorders will be excluded;


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Trial Protocol
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7. List of medical examinations at Screening and 
EoTrial Visit has been updated with the 
ophthalmological examination;
8. Details of the ophthalmological examination 
have been described;
9. Clarification to storing and evaluation of ECGs 
at the central ECG lab has been added.
Rationale for change
1. – 8. Changes are based on the regulatory feedback 
of FAMHP / EC after review of the study protocol as 
part of the approval procedure;
9. Further clarification to storing and evaluation of 
ECGs received from the central ECG lab.


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11.3
GLOBAL AMENDMENT 3
Date of amendment
06 November 2020
EudraCT number
EU number
2020-001036-10
BI Trial number
1445-0001
BI Investigational Medicinal 
Product(s)
BI 1595043
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1595043 (single-blind, 
partially randomised, placebo-controlled, parallel 
(sequential) group design) 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 4.1.5.1
Description of change
Clarification to evaluation of ECG by the central 
ECG lab has been added, in case a preliminary 
analysis of ECG data is required during the trial.
Rationale for change
Changes are based on the clarification of the 
blinding procedures at the central ECG lab.


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11.4
GLOBAL AMENDMENT 4
Date of amendment
14 January 2021
EudraCT number
EU number
2020-001036-10
BI Trial number
1445-0001
BI Investigational Medicinal 
Product(s)
BI 1595043
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 1595043 (single-blind, 
partially randomised, placebo-controlled, parallel 
(sequential) group design) 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. CTP Synopsis and other sections as applicable
2. Section 1.2.2.5
3. Section 1.2.4
4. Section 1.2.5
5. Section 1.2.6
6. Section 1.3.2
7. Section 1.4.3
Description of change
1. Dose group 8 (160 mg of BI 1595043) has been 
added, and the number of study subjects has been 
updated from 56 to 64 throughout the CTP text.
2. Details of pre-clinical embryo-fetal development 
toxicity studies have been added.
3. Prediction of human therapeutic dose has been 
updated.
4. Clinical experience with BI 1595043 has been 
described.
5. Evaluation of REP has been provided.
6. The maximum dose level to be tested in the study
has been updated.
7. New pre-clinical and clinical data have been
included into considerations on drug related risks 
and safety measures.


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Rationale for change
The clinical trial protocol is being amended to add 
the new maximum dose level of 160 mg of 
BI 1595043 based on the available clinical data 
(Section 1.2.5) and the updated prediction of the 
human therapeutic dose (Section 1.2.4). Also, 
embryo-fetal development toxicity studies have been 
completed as described in Section 1.2.2.5.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c31692550
5.0
clinical-trial-protocol-version-05
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 1595043
(single-blind, partially randomised, placebo-controlled, parallel (sequential) group
design) in healthy male subjects
Author-Trial Statistician
14 Jan 2021 13:48 CET
Approval-Clinical Pharmacokinetics
14 Jan 2021 15:11 CET
Approval-Team Member Medicine
14 Jan 2021 15:19 CET
Author-Clinical Trial Leader
15 Jan 2021 19:02 CET
Verification-Paper Signature
Completion
18 Jan 2021 08:23 CET
Approval-
 Medicine
18 Jan 2021 18:45 CET


Boehringer Ingelheim 
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Document Number: 
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SAP_001.pdf: 
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TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c34330267-01
BI Trial No.:
1445-0001
Title:
Safety, tolerability and pharmacokinetics of single rising oral 
doses of BI 1595043 (single-blind, partially randomised, placebo 
controlled, parallel (sequential) group design) in healthy male 
subjects
Including Protocol Amendments 1 to 4 [c31692550-05]
Investigational
Product(s):
BI 1595043
Responsible trial 
statistician(s):
Phone:
Fax:   
Date of statistical 
analysis plan:
16 APR 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.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................7
5.
ENDPOINTS(S).....................................................................................................7
5.1
PRIMARY ENDPOINT(S)...................................................................................7
5.2
SECONDARY ENDPOINT(S).............................................................................7
5.2.1
Key secondary endpoint(s) ...................................................................................7
5.2.2
Secondary endpoint(s)...........................................................................................7
6.
GENERAL ANALYSIS DEFINITIONS...........................................................10
6.1
TREATMENT(S) ................................................................................................10
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................11
6.3
SUBJECT SETS ANALYSED ...........................................................................11
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 ......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........18
7.2
CONCOMITANT DISEASES AND MEDICATION......................................19
7.3
TREATMENT COMPLIANCE ........................................................................19
7.4
PRIMARY ENDPOINT(S).................................................................................19
7.4.1
Primary analysis of the primary endpoint(s)....................................................19
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoint(s) ............................................................................................19
7.5
SECONDARY ENDPOINT(S)...........................................................................20
7.5.1
Key secondary endpoint(s) .................................................................................20
7.5.2
(Other) Secondary endpoint(s)...........................................................................20
7.7
EXTENT OF EXPOSURE .................................................................................22
7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse Events ....................................................................................................22
7.8.2
Laboratory data...................................................................................................23
7.8.3
Vital signs.............................................................................................................24
7.8.4
ECG ......................................................................................................................24
7.8.5
Others ...................................................................................................................26
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION .............27
9. 
REFERENCES ....................................................................................................28


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11.
HISTORY TABLE..............................................................................................33


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR .........................................................10
Table 6.3: 1
Analysis sets for endpoints/data description ....................................................13
Table 6.7: 1
Time schedule of 12-lead ECG recordings for central evaluation ...................16
Table 11: 1
History table .....................................................................................................33


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BLQ
Below Limit of Quantification
BMI
Body mass index
BP
Blood pressure
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CV
Arithmetic Coefficient of Variation
DILI
Drug induced liver injury
ECGPCS
ECG Pharmacokinetic Concentration Set
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
HR
Heart rate
LLOQ
Lower limit of quantification
LLT
Lower Level Term
Max
Maximum
Min
Minimum
N
Number non missing observations
P10
10th percentile
P90
90th percentile
PKS
PK parameter analysis set
PR
Pulse rate
Q1
1st quartile
Q3
3rd quartile
RAGe
Report Appendix Generator system


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Term
Definition / description
REP
Residual Effect Period
SD
Standard Deviation
 
TS
Treated Set
ULN
Upper Limit of Normal
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, randomisation.
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 SAS® (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 will be performed as planned in the CTP and are described in more detail in this 
TSAP. 
5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
Section 2.1.2 of the CTP: The primary endpoint for assessment of safety and tolerability of 
BI 1595043 is the percentage of subjects with drug-related adverse events.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoint(s)
Section 2.1.3 of the CTP: 
The following pharmacokinetic parameters will be determined for BI 1595043 if feasible:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
Safety and tolerability:
Section 2.2.2.1 of the CTP: Safety and tolerability of BI 1595043 will be assessed based on:

AEs (including clinically relevant findings from the physical examination and 
ophthalmological examination)


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Details on ECG measurements and endpoints:
12-lead ECG endpoints
For the definition of baseline and a summary of time points scheduled for ECG recording and 
central evaluation please refer to Section 6.7.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
It was planned that 64 healthy male subjects will enter the study (8 per dose group, 6 on active 
and 2 on placebo).
For details of dosage and formulation see Table 6.1:1 below.
Table 6.1: 1
Labels for treatments for use in the CTR 
Treatment
Short label
P
Placebo, oral solution, po, qd*
Placebo
A
BI 1595043, 0.4 ml solution, po, qd 
BI 1mg 
B
BI 1595043, 1.2 ml solution, po, qd
BI 3mg 
C
BI 1595043, 2.4 ml solution, po, qd
BI 6mg 
D
BI 1595043, 4.8 ml solution, po, qd
BI 12mg 
E
BI 1595043, 10 ml solution, po, qd
BI 25mg 
F
BI 1595043, 20 ml solution, po, qd
BI 50mg 
G
BI 1595043, 36 ml solution, po, qd
BI 90mg 
K
BI 1595043, 64 ml solution, po, qd
BI 160mg
*: The placebo control group in the safety evaluation will consist of all placebo treated 
subjects, regardless of the dose group in which they were treated.
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from 0:00 h on day of informed consent until administration time 
of study drug)

On treatment
Separately for each treatment, ranging from the time of first administration of BI / 
Placebo until 0:00h on the day after trial termination date
All AEs until end of trial examination will be considered on treatment.
Displays of AEs will be presented separately for the treatments described in Table 6.1: 1
above. 


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The following AE displays will be provided in the report:
Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT) of the CTR 
displays:
In these displays, the on treatment phase will be analysed by dose group (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:

a total over all on treatment phases included in this analysis ("Total on treatment”; in 
16.1.13.1.8)

a total over all BI treated phases ("BI Total on treatment")
AEs during screening will be listed in Section 16.2, but not tabulated.
Tables of vital signs, laboratory values, and ECG values will present results by the above 
mentioned screening and on treatment phase.
More details on the technical implementation of these analyses are provided in the Technical 
TSAP ADS (analysis data set) plan and 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).
Handling of iPDs in analysis is included in the DV domain specifications and stored within 
the TMF in EDMS. 
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the decision log (3). 
Protocol deviations will be summarised and listed.
6.3
SUBJECT SETS ANALYSED

Treated set (TS):
The treated set includes all subjects who were randomised and treated with at least one 


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dose of study drug. The treatment assignment will be determined based on the first 
treatment the subjects received.
This is the full analysis set population in the sense of ICH-E9 (1). It is used for safety 
analysis. The ECG analyses are performed on the TS, except for the exposure-response 
analyses, which are performed on the ECGPCS defined below.

PK parameter analysis set (PKS):
This set includes all subjects in the treated set (TS) who provide at least one PK endpoint 
that was not excluded due to a protocol deviation relevant to the evaluation of PK or due 
to PK non-evaluability. Thus, a subject will be included in the PKS, even if he 
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.
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.
Section 7.3 of the CTP: 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 violation 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 violations 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),

Missing samples/concentration data at important phases of PK disposition curve. (…)
If a pre-dose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a pre-dose concentration is above BLQ, but less than or equal to 5% 
of the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.


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
ECG Pharmacokinetic Concentration Set (ECGPCS):
This subject set includes all subjects from the TS who provide at least one pair of a valid 
drug plasma concentration of BI 1595043 and a corresponding (i.e. time-matched) ECG 
endpoint to be used in the exposure-response analyses. For placebo subjects, the plasma 
concentration is set to zero and hence always considered as valid. 
The decision whether a time deviation between PK blood sampling and ECG recording is 
acceptable (and thus whether the pair of values will be used) is to be made no later than at 
the RPM before database lock.
Table 6.3: 1
Analysis sets for endpoints/data description
Analysis set
Endpoint/data description
TS
PKS
ECGPCS
Primary endpoint / Safety assessments  (incl. ECG) 
X
Secondary and further PK endpoints 
X
ECG endpoints and plasma concentrations used in exposure-
response analysis
X
Demographic/baseline data
X
Important Protocol Deviations
X
Disposition
X


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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 exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-36-
472_RD-01) (5).
If single cardiac cycles of an ECG (out of the generally four) are missing, the arithmetic mean 
for this single ECG will be computed with the reduced (1, 2 or 3) number of cardiac cycles.
If replicate ECG recordings are missing, the arithmetic means per time point will be computed 
with the reduced number (1 or 2) of recordings.
For the classification of the on-treatment QTc/QT intervals into “no new onset” / “new onset” 
categories, the handling of missing values is described in Appendix Section 10.3.
For placebo subjects the missing plasma concentration values will be replaced by 0 for the 
exposure response analysis. For subjects on active drug, missing plasma concentration values 
with ‘BLQ’ in the comment field will be replaced by ½ LLOQ.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For the analysis of vital signs the baseline value is defined as the last measurement before trial 
drug administration.
For laboratory analysis the baseline is defined as the last measurement before trial drug 
administration.
Unscheduled measurements of laboratory data or vital signs 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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Section 6.1 of the CTP: Exact times of measurements outside the permitted time windows 
will be documented. The acceptable time windows for screening and end of trial examination 
are given in the CTP 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 (including blank values for PK 
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, ± 30 min thereafter, Starting 
from 48 h post-dose a deviation from the scheduled time for vital signs, ECG and laboratory 
test of ± 120 min is acceptable.
Adherence to time windows will be checked via the consistency check listings at the RPM.
There will be a centralised evaluation of the 12-lead ECG recordings at the time points and 
for the ECG recordings specified in Table 6.7: 1 below:


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Table 6.7: 1
Time schedule of 12-lead ECG recordings for central evaluation
Visit
Day
Planned time [hh:mm]
(relative to drug 
administration)
Study 
phase
Central evaluation
1
-28 to -1
Screening
Not applicable
2
1
-01:00
-00:45
-00:30
Baseline
first single ECG of each of the 3 
triplicates
00:30
On 
treatment
first single ECG of the triplicate
01:00
first single ECG of the triplicate
01:30
first single ECG of the triplicate
02:00
first single ECG of the triplicate
02:30
first single ECG of the triplicate
03:00
first single ECG of the triplicate
04:00
first single ECG of the triplicate
06:00
first single ECG of the triplicate
08:00
first single ECG of the triplicate
12:00
first single ECG of the triplicate
2
24:00
first single ECG of the triplicate
34:00
first single ECG of the triplicate
3
48:00
first single ECG of the triplicate
5
96:00
Not applicable
7
144:00
Not applicable
3
10 to 15
Not applicable
Three triplicate ECGs will be recorded as the baseline before the first drug administration, but 
only the first ECG of each of the 3 triplicates will be transferred to the database. At all other 
time points, 1 triplicate ECG will be recorded, but only the first single ECG of the triplicate 
will be transferred to the database. The baseline value of an ECG variable is defined as the 
mean of the transferred baseline ECG measurements prior to drug administration.
For the exposure response analyses, pairs of ECG variables and corresponding plasma 
concentrations will be built using the same planned time points, e.g., the HR change from 
baseline and the plasma concentration measured at planned time 2:00 will build one pair. 
Whether a time deviation between PK blood sampling time and corresponding ECG recording 
is too big and the pair has to be excluded from the analysis will be decided no later than at the 
RPM.


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7.
PLANNED ANALYSIS
The placebo group in the safety evaluation will consist of all placebo treated subjects, 
regardless of the dose group in which they were treated.
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 7.5.2) 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 parameters and concentrations will be performed by the 
department of 
 at 
 and will be presented 
in Section 15.6 of the CTR.
Descriptive data analysis of PD parameters and concentrations will be performed by the 
department of 
 at 
 and will be presented 
in Section 15.7 of the CTR.
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of Clinical Trials and Project Summaries” [001-MCG-159] (6) with the 
exception of those generated for PK and PD calculations.
The individual values of all subjects will be listed, sorted by treatment group, subject number, 
and visit. The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number of 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


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Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated 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 (%) for each 
treatment group/sequence. Percentages will be rounded to one decimal place and will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not. The category 'missing' will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
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 or 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 “Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies” [001-MCS-36-472_RD-01] (5) and “Description of Analytical 
Transfer Files and PK/PD Data Files” [001-MCS-36-472_RD-03] (7).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables 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
Section 4.3 of the CTP: 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 and/or urinary excretion of trial medication will provide 
additional confirmation of compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 1595043.
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint(s)
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 1595043.


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoint(s)
Pharmacokinetics
Descriptive statistics of plasma concentrations and PK endpoints will be done by department 
at 
 and will be presented in Section 15.6 of 
the CTR.
Assessment of dose proportionality
Dose proportionality of the PK endpoints AUC0-∞and Cmax of BI 1595043 in plasma as a 
further analysis will be explored using the power model that describes the functional 
relationship between dose and PK endpoints. The basic model consists of a regression model 
applied to log-transformed data (log-transformation refers to using the natural logarithm). The 
corresponding ANCOVA (Analysis of Covariance) model includes the logarithm of the dose 
as a covariate.


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Section 7.3.2 of the CTP:  The power model describes the functional relationship between 
the dose level and PK endpoint on the log scale via
ykm = log (xkm) = μ + β · log (Dk) + ekm ,
where
ykm
logarithm of response (PK parameter) measured on subject m receiving dose 
k,
xkm
response (PK parameter) measured on subject m receiving dose k,
μ 
the overall mean,
β 
slope parameter of linear regression line,
Dk
level of dose k, k=1,…,8,
ekm
the random error associated with the mth subject who was administered dose k
(ekm~N(0, σ2) iid).
The slope parameter β together with its two-sided 90% confidence interval will be estimated. 
Additionally, the r-fold change rβ-1 together with its 90% CI will be derived.
As some small doses at the beginning and/or some doses at the upper end might not 
contribute to the linear relationship between dose and PK, dose proportionality over the 
entire dose range investigated might not be shown. In that case an attempt will be made to 
identify a subrange of at least 3 consecutive doses where dose proportionality can be 
concluded.
A regression plot will be performed, where the logarithm of dose is depicted versus logarithm 
of PK endpoint, including the estimated regression line from the power model and reference 
line of perfect proportionality (β=1).


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
If not stated otherwise, the safety results will be sorted by treatment group.
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.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
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.
For details on summarization of AE data, please refer to (9).
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:
- 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


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- Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
According to ICH E3 (10), 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 AEs (including AESIs) will be presented. 
The frequency of subjects with AEs will be summarized 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. Furthermore, tables will be provided for AEs of at least 
moderate severity and AEs leading to treatment discontinuation.
The SOC 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.
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 
[001-MCG-157] (11).
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 possible 
clinically significant will be flagged in the data listings. 
It is the investigator's responsibility to decide whether a lab value is clinically significant 
abnormal or not (at the RPM at the latest).


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7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate). Descriptive statistics will be calculated by planned time 
point based on the last value of the patient at that planned time point (or assigned to that 
planned time point).
7.8.4
ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during the 
trial) if judged clinically relevant by the investigator.  
Continuous safety ECG monitoring (by investigator)
Clinically relevant abnormal findings will be reported as adverse events.
No separate listing or analysis of continuous ECG monitoring will be prepared.
12-lead ECG 
The descriptive evaluation of ECG data will be based on the TS, except the exposure-response 
analyses, which are based on the ECGPCS set.
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR only listings will be provided. Occurrences of notable findings will be flagged.
Comments regarding the ECGs will be listed.
Categorical endpoints
For the categorical endpoints, frequency tables will be provided.
For all subjects with any notable finding in ECG intervals, a separate listing will be created as 
end-of-text display (based on the same display template as in Appendix 16.2), and the 
corresponding time profiles will be shown.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the absolute 
values and changes from baseline over time of QTcF, QT, HR, PR and QRS. The time 
profiles of mean and SD for the changes from baseline on treatment will be displayed 
graphically by treatment.
For QTcF and HR changes from baseline, the relationship to the corresponding plasma 
concentrations will be evaluated using a random coefficient model. For subjects in the 


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ECGPCS, all time points with available ECG endpoints and valid time-matched drug plasma 
concentrations will be included. For the handling of missing values, see Section 6.6.
The response variable will be the change from baseline in QTcF (QTcF). The placebo 
subjects will be included in the analysis, setting their plasma concentrations to zero.
As a first step, it is investigated if there is a potential delayed or accelerated (e.g. due to 
metabolites) effect of the drug on QTcF. A general visual impression is provided by 
overlaying time profiles of plasma concentrations and QTcF changes from baseline (QTcF). 
These figures will be generated for each subject (presented in the Statistical Appendix of the 
CTR), as well as for means per active treatment group (presented in the End-of-Text part of 
the CTR).
The relationship between BI 1595043 plasma concentrations and QTcF changes from baseline 
will be investigated in an exploratory manner using a random coefficient model to estimate 
the difference in means between BI 1595043 and placebo of QTcF change from baseline and 
its 90% confidence interval at the geometric mean of the Cmax for each dose. Additionally, the 
estimated overall slope with its 90% confidence interval will be provided. The used random 
coefficient model is based on a white paper from Garnett et al. (12) with QTcF as response 
variable, centered baseline QTc and plasma concentration as continuous covariates, treatment 
and time as fixed categorical effects, and a random intercept and slope for each subject. 
Restricted maximum likelihood estimation will be performed, and the Kenward-Roger 
method will be applied to adjust stadanrd errors and estimate denominator degrees of 
freedom. For more details refer to Section 10.4.
For visualization, a scatterplot of the BI 1595043 plasma concentration against the following 
individual QTcF values will be provided: For each subject on active treatment and each time 
point, subtract the mean value of all individual observed ΔQTcF values from the placebo 
group for this time point from the individual observed ΔQTcF value for this subject and time 
point. This results in estimates for “individual ΔΔQTcF” values, which should only be used 
for plotting purposes. The corresponding regression line and its pointwise confidence bands 
as well as and the geometric mean of Cmax for each dose will additionally be displayed in the 
plot.
The goodness of fit of the above model will be checked. The visual checks will include the 
inspection of concentration-QTcF quantile plots (see Garnett et al. (12)) and residual plots. In 
case of non-linearity or if there is evidence for a delayed effect, further models will be 
explored in order to better characterise the PK-ECG relationship (e.g. effect compartment 
models, non-linear models, etc.).
All of the above described graphical and statistical analyses will be also performed for HR in 
place of QTcF.
Appropriateness of heart rate correction methods of QT interval
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval (values log-transformed using the natural 
logarithm) will be estimated by applying the random coefficient model described in 
Section 10.2 using all time points. A scatterplot of QTcF vs RR including the overall 


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regression lines will be included in the Statistical Appendix of the CTR. The resulting (fixed 
effect) slope together with two-sided 95% confidence intervals will be included in the 
footnote for this plot.
7.8.5
Others
Physical / ophthalmological 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 / ophthalmological 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, BIRDS
3.
001-MCS-50-415_RD-03: "Clinical Trial Analysis Decision Log", current version; 
IDEA for CON.
4.
001-MCG-156_RD-01: "Handling of Missing and Incomplete AE Dates", current 
version; IDEA for CON.
5.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic 
Analyses of Clinical Studies”, current version; IDEA for CON.
6.
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current version; 
IDEA for CON.
7.
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.
8.
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
9.
BI-KMED-BDS-HTG-0066: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials”, current version; KMED.
10. 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
11. 001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.
12. Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper 
on concentration-QTc modeling. J Pharmacokin Pharmacodyn 2017 [R18-0143]
13. BI Statistical Position Paper - Statistical Methods for PK - Reference Document 3: 
Regulatory recommendations for BA/BE trials and implementation instructions in 
clinical trial documents, version 1.0 (2017).


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-YYYY)
Author
Sections 
changed
Brief description of change
1
16-APR-2021
This is the final TSAP without any 
modification