Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: yes

Brief summary:
The main objective of this trial is to investigate the safety and tolerability of BI 730357 in Japanese healthy male subjects following oral administration of single rising doses.

Secondary objectives are the explorations of the pharmacokinetic(s) (PK), including dose proportionality as well as investigation of linearity of BI 730357 after single dose administration.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: BI 730357 intervention 2: Placebo
Intervention descriptions: intervention 1: single rising oral dose intervention 2: single rising oral dose

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:
c21031338-02
BI Trial No.
1407-0015
BI Investigational
Medicinal Product
BI 730357
Title
Safety, tolerability, and pharmacokinetics of single rising oral doses of 
BI 730357 in Japanese healthy male subjects  (double-blind, 
randomised, placebo-controlled, parallel group design)
Lay Title
This study is done in healthy Japanese volunteers. It looks at how 
different doses of BI 730357 are taken up in the body and how well 
they are tolerated
Clinical Phase
I
Clinical Trial Leader
Address: 
Phone: 
Fax: 
Principal Investigator:
Phone:
Fax: 
Status
Final Protocol (Revised protocol based on global amendment #1)
Version and Date
Version: 2.0
Date: 13 December 2018
Page 1 of 64
Proprietary confidential information
© 2018 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
09 November 2018
Revision date
13 December 2018
BI trial number
1407-0015
BI Investigational 
Medicinal Product name
BI 730357
Title of trial
Safety, tolerability, and pharmacokinetics of single rising oral doses of BI 730357
in Japanese healthy male subjects  (double-blind, randomised, placebo-controlled, 
parallel group design)
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
This Phase I study is to investigate the safety, tolerability, and pharmacokinetics of 
BI 730357 in order to understand the clinical safety and pharmacokinetic profile in 
healthy male Japanese subjects after single-rising oral doses of BI 730357 within 
the dose range to be evaluated in further clinical studies with BI 730357 in the 
indication of psoriasis and other indications.
Trial objectives
The main objective is to investigate the safety and tolerability of BI 730357 in 
Japanese healthy male subjects following oral administration of single rising doses 
of 50 mg, 100 mg, and 200 mg.
Secondary objectives are the explorations of the PK, including dose proportionality 
as well as investigation of linearity of BI 730357 after single dose administration.
Trial endpoints
Primary endpoint:
to assess safety and tolerability of BI 730357 is the number [N (%)] of subjects with 
drug-related adverse events
Secondary endpoints:
AUC0-∞and Cmax of BI 730357
Trial design
Double-blind, randomised within dose groups, placebo-controlled, parallel-group 
design
Number of subjects 
total entered
24
each treatment
8 per dose group (6 on active drug and 2 on placebo)
Diagnosis
Not applicable


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Main criteria
for inclusion
Healthy male Japanese subjects, age of 20 to 45 years (inclusive), body mass index 
(BMI) of 18.5 to 25.0 kg/m2 (inclusive)
Test product
BI 730357 film-coated tablet (50 mg and 100 mg formulations)
dose
50 mg (dose group [DG] 1), 100 mg (DG 2), and 200 mg (DG 3)
mode of admin.
Oral with approximately 240 mL of water after an overnight fast of at least 10 hours
Comparator product
Matching placebos
dose
Not applicable
mode of admin.
Oral with approximately 240 mL of water after an overnight fast of at least 10 hours
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 laboratory test
Exclusionary laboratory 
tests
PK blood 
8
12-lead ECG
4 hours continuous 3-lead
ECG monitoring9
Vital signs 11
Questioning for AEs and 
concomitant therapy 5
1
-28 to -2
Screening1
x
x
x
x
2
-1
-12:006
21:00
Ambulatory visit,
Admission to trial site
x
x13
x
1
-3:00
06:00
Allocation to treatment
(randomisation)2
x2
x2
x2, 7
x2
x2
0:00
09:00
Drug administration (with 
app. 240 mL water)
▲
x
0:30
09:30
x
x7
│
x
x
1:00
10:00
x
x7
│
x
x
1:30
10:30
x
│
x
x
2:00
11:00
App. 240 mL fluid intake
x
x7
│
x
x
2:30
11:30
x
│
3:00
12:00
x
x7
│
x
x
4:00
13:00
App. 240 mL fluid intake, 
thereafter lunch3
x
x
x7
▼
x
x
5:00
14:00
x
x
6:00
15:00
x
x7
x
x
8:00
17:00
x
x7
x
x
10:00
19:00
Dinner3
x
x
12:00
21:00
x
x7
x
x 
2
24:00
09:00
Breakfast 3
x
x
x
x
x
28:00
13:00
Lunch3
x
34:00
19:00
x
x
x
x
34:30
19:30
Dinner3
x
3
48:00
09:00
Breakfast 3,
discharge from trial site 
x
x
x
x
4
72:00
09:00
Ambulatory visit12
x
x
x
x
5
96:00
09:00
Ambulatory visit12
x
x
x
8
168:00
09:00
Ambulatory visit12
x
x
x
3
9 to 13
End of study (EOS) 
examination4
x
x
x
x
AE: adverse event, app.: approximately, ECG: Electrocardiogram, PK: pharmacokinetic(s)
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures (28 to 2 days before drug administration) include physical examination, check of vital signs, ECG, safety 
laboratory test, exclusionary laboratory tests (including drug screening, infection serology, and alcohol breath test), 
demographics (including determination of body height and weight), relevant medical history, concomitant therapy and 
review of inclusion/exclusion criteria. Screening procedure should complete prior to Visit 2.
2.
The time is approximate; the respective procedure is to be performed and completed within 3 hours prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
EOS examination to be performed within 1-4 days after last PK sampling; includes physical examination, vital signs, 
ECG, safety laboratory, recording of AEs and concomitant therapies.


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5.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above. Concomitant therapy is prohibited in this trial (refer to Section 4.2.2.1) but will be 
recorded if taken.
6.    Safety laboratory, drug screening and alcohol breath test will be performed on admission to be medically evaluation. If
those tests are performed within 2 days prior to admission, they can be omitted.
7.
The ECG recording has to be performed in triplicate at this time point
8.
Sampling times and periods may be adapted based on information obtained during the trial (e.g., preliminary PK data) 
9.    It is monitored for at least 15 min before drug administration (for baseline assessment) and for 4 hours following drug 
administration)
11.  Blood pressure (BP), pulse rate (PR), body temperature, and respiratory rate (RR).
12.  Procedures on Days 4, 5 and 8 to be performed within ±3 hours from planned time
13.  Only drug screening and alcohol test


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................13
Nonclinical pharmacology....................................................................13
1.2.1
Toxicology..............................................................................................13
1.2.2
Nonclinical pharmacokinetics..............................................................15
1.2.3
Prediction of human pharmacokinetics..............................................15
1.2.4
Clinical experience in humans.............................................................16
1.2.5
Residual Effect Period..........................................................................16
1.2.6
Drug product.........................................................................................17
1.2.7
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................17
1.4
BENEFIT - RISK ASSESSMENT ...................................................................18
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 21
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......21
Main objectives......................................................................................21
2.1.1
Primary endpoint..................................................................................21
2.1.2
Secondary endpoints.............................................................................21
2.1.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 23
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................23
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................24
3.3
SELECTION OF TRIAL POPULATION ......................................................24
Main diagnosis for trial entry..............................................................25
3.3.1
Inclusion criteria...................................................................................25
3.3.2
Exclusion criteria ..................................................................................25
3.3.3
Withdrawal of subjects from treatment or assessments ...................26
3.3.4
Discontinuation of trial treatment............................................27
3.3.4.1


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Withdrawal of consent to trial participation ............................27
3.3.4.2
Discontinuation of the trial by the sponsor..............................28
3.3.4.3
Replacement of subjects .......................................................................28
3.3.5
4.
TREATMENTS........................................................................................ 30
4.1
INVESTIGATIONAL TREATMENTS ..........................................................30
Identity of the Investigational Medicinal Products ...........................30
4.1.1
Selection of doses in the trial................................................................30
4.1.2
Method of assigning subjects to treatment groups ............................30
4.1.3
Drug assignment and administration of doses for each subject .......31
4.1.4
Blinding and procedures for unblinding ............................................31
4.1.5
Blinding ...................................................................................31
4.1.5.1
Unblinding and breaking the code...........................................32
4.1.5.2
Packaging, labelling, and re-supply ....................................................32
4.1.6
Storage conditions.................................................................................32
4.1.7
Drug accountability ..............................................................................33
4.1.8
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................33
Other treatments and emergency procedures....................................33
4.2.1
Restrictions............................................................................................34
4.2.2
Restrictions regarding concomitant treatment .........................34
4.2.2.1
Restrictions on diet and life style.............................................34
4.2.2.2
4.3
TREATMENT COMPLIANCE.......................................................................34
5.
ASSESSMENTS....................................................................................... 35
5.1
ASSESSMENT OF EFFICACY.......................................................................35
5.2
ASSESSMENT OF SAFETY............................................................................35
Physical examination ............................................................................35
5.2.1
Vital signs...............................................................................................35
5.2.2
Safety laboratory parameters..............................................................35
5.2.3
Electrocardiogram................................................................................38
5.2.4
12-lead resting ECG.................................................................38
5.2.4.1
4-hours continuous 3-lead ECG monitoring............................40
5.2.4.2
Other safety parameters.......................................................................41
5.2.5
Assessment of adverse events...............................................................41
5.2.6
Definitions of adverse events...................................................41
5.2.6.1
Adverse event ............................................................41
5.2.6.1.1
Serious adverse event ................................................41
5.2.6.1.2
AEs considered ‘Always Serious’.............................42
5.2.6.1.3
Adverse events of special interest .............................42
5.2.6.1.4
Intensity (severity) of AEs.........................................43
5.2.6.1.5
Causal relationship of AEs ........................................43
5.2.6.1.6
Adverse event collection and reporting ...................................44
5.2.6.2


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AE collection.............................................................44
5.2.6.2.1
AE reporting to the sponsor and timelines ................45
5.2.6.2.2
Information required..................................................45
5.2.6.2.3
Pregnancy ..................................................................45
5.2.6.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................45
Assessment of pharmacokinetics .........................................................45
5.3.1
Methods of sample collection...............................................................46
5.3.2
Blood sampling for pharmacokinetic analysis.........................46
5.3.2.1
Urine sampling for pharmacokinetic analysis..........................46
5.3.2.2
Analytical determinations ....................................................................47
5.3.3
Analytical determination of analyte plasma concentration......47
5.3.3.1
Analytical determination of analyte 
 concentration.........47
5.3.3.2
5.4
BIOBANKING ...................................................................................................47
6.
INVESTIGATIONAL PLAN.................................................................. 48
6.1
VISIT SCHEDULE............................................................................................48
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................48
Screening period....................................................................................48
6.2.1
Treatment period ..................................................................................49
6.2.2
End of study period...............................................................................49
6.2.3
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 50
7.1
STATISTICAL DESIGN – MODEL ...............................................................50
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................50
7.3
PLANNED ANALYSES....................................................................................50
Primary endpoint analyses...................................................................51
7.3.1
Secondary endpoint analyses ...............................................................51
7.3.2
Safety analyses.......................................................................................53
7.3.4
7.4
INTERIM ANALYSES .....................................................................................54
7.5
HANDLING OF MISSING DATA ..................................................................54
Safety......................................................................................................54
7.5.1
Plasma/urine drug concentration - time profiles ...............................54
7.5.2
Pharmacokinetics..................................................................................54
7.5.3
7.6
RANDOMISATION ..........................................................................................54
7.7
DETERMINATION OF SAMPLE SIZE ........................................................55
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 56


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8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................56
8.2
DATA QUALITY ASSURANCE .....................................................................57
8.3
RECORDS..........................................................................................................57
Source documents .................................................................................57
8.3.1
Direct access to source data and documents.......................................58
8.3.2
Storage period of records.....................................................................58
8.3.3
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................59
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......59
8.6
TRIAL MILESTONES .....................................................................................59
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................59
9.
REFERENCES......................................................................................... 61
9.1
PUBLISHED REFERENCES...........................................................................61
9.2
UNPUBLISHED REFERENCES.....................................................................61
10. APPENDICES .......................................................................................... 62
11. DESCRIPTION OF GLOBAL AMENDMENT................................... 63
11.1
GLOBAL AMENDMENT 1 .............................................................................63


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ABBREVIATIONS
AE
adverse event
AESI
adverse events of special interest
ALT
alanine transaminase
AST
aspartate transaminase
AUC
area under the concentration
AUC0-∞
area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
β
slope parameter associated with the power model used to evaluate dose 
proportionality
BI
Boehringer Ingelheim
BLQ
below the lower limit of quantification
BMI
body mass index (weight divided by height squared)
BP
blood pressure
CA
competent authority
CI
confidence interval
CNS
central nervous system
Cmax
maximum measured concentration of the analyte in plasma
CRA
clinical research associate
CRF
case report form, paper or electronic (sometimes referred to as ‘eCRF’)
CRO
contract research organisation
CTL
clinical trial leader
CTP
clinical trial protocol
CTR
clinical trial report
DG
dose group
DILI
drug induced liver injury
ECG
electrocardiogram
eDC
electronic data capture
EDTA
ethylenediaminetetraacetic acid
EOS
end of study


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GCP
Good Clinical Practice
HR
heart rate
IB
investigator’s brochure
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
independent ethics committee
ILC
innate lymphoid cell
IPD
important protocol deviation
IRB
institutional review board
IQRMP
integrated quality and risk management plan
ISF
investigator site file
LBD
ligand-binding domain
MedDRA
Medical Dictionary for Regulatory Activities
NK
natural killer
NCE
new chemical entity
NOA
not analysed
NOAEL
no observed adverse effect level
NOP
no peak detectable
NOR
no valid result
NOS
no sample available
PIF
photoirritancy factor
PK
pharmacokinetic(s)
PKS
pharmacokinetic set
PR
pulse rate
PsA
psoriatic arthritis
PsO
psoriasis
QT
time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
reference treatment
REP
residual effect period
RORγt
retinoic acid related orphan receptor γt
RR
respiratory rate


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SAE
serious adverse event
SCR
screening
SOP
standard operating procedure
SRD
single-rising dose
ss
(at) steady state
TMF
trial master file
 
TSAP
trial statistical analysis plan
ULN
upper limit of normal
WoCBP
women of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Retinoic acid related orphan receptor γt (RORγt) is a nuclear hormone receptor/transcription 
factor expressed in Th17 cells and in distinct subsets of lymphoid cells, including natural 
killer (NK) cells, innate lymphoid cells (ILC), and γδT cells. RORγt sits at a key focal point, 
integrating multiple signals, including T cell receptor engagement and cytokines (e.g., IL-1, 
IL-6, IL-23), and driving the expression of multiple genes (e.g., IL-17A, IL-17F, IL-22, IL-
23R). Via sitting at this focal node integrating multiple signals and effecting multiple outputs, 
RORγt has the potential
 
Boehringer Ingelheim (BI) is developing the new chemical entity (NCE),
 
BI 730357, for the treatment of patients 
and other 
 
diseases. BI 730357 binds 
. By integrating multiple activating 
 
signals and via blocking the transcription of multiple key 
effector 
 BI 730357 has the potential to be 
as or more efficacious than 
 agents in the treatment of 
-related disease indications.
1.2
DRUG PROFILE
Nonclinical pharmacology
1.2.1
BI 730357 was profiled in cellular assays in primary human cells central to the pathogenesis 
underlying 
 BI 730357 
provided consistent potency across all stimuli, cell types, and species tested, including  
conditions. BI 730357 provided substantial inhibition of disease-relevant 
biomarker and histology reads in mechanistic 
 models 
 
BI 730357 showed good 
 in that it exhibited 
 and 
only low-level 
 low-level 
 and 
low-level 
 No other 
 were detected.
Toxicology
1.2.2
The toxicity profile of BI 730357 has been assessed in safety pharmacology, genetic toxicity, 
embryo-fetal development and repeat dose toxicity studies up to 26- and 39-weeks
 
 respectively. In general, BI 730357 appears to be well tolerated at clinically-relevant 
plasma exposures in toxicity studies. Effects on the gastrointestinal tract (emesis/vomitus 
and/or soft stool) and/or decreased food consumption associated with adverse decreases in 
body weight were seen
(which achieved 
 the anticipated human therapeutic exposure 
). In the 39-week study, at 
 (equivalent to 
 the anticipated human therapeutic exposure 
 


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, stomach inflammation limited to the cardia and fundus was observed, with evidence 
for reversibility. In the 4- and 13-week studies 
 no stomach inflammation was seen at 
doses 
 however gastrointestinal effects such as emesis/vomitus and 
decreased food consumption and body weight were seen. As similar gastro-intestinal effects 
were seen in the 39-week study 
 the microscopic stomach inflammation 
may be preceded by clinically-notable effects on the gastrointestinal tract. 
The results of the in vitro and in vivo genetic toxicology studies showed that BI 730357 
 
 were free of any genotoxic potential.
The phototoxic potential of BI 730357 was evaluated in in vitro and in vivo studies. 
BI 730357 exhibits an absorption band in the spectral region 
 with a 
maximum absorbance 
 
 
Quantitative tissue distribution of 
 was investigated in male 
pigmented (Long Evans) rats administered a 
 of 
BI 730357. Deposition of 
 was moderate to 
high as was the level 
 in the 
. The approximate half-lives 
 
 and 
 were long, 
, respectively. The half-
lives 
 in 
, including
 
 were significantly 
 than those in plasma 
 and whole blood 
 indicating 
 exposure in these tissues. An in vitro assay for phototoxic 
potential using 
 and measuring 
 as a marker of cellular toxicity 
when simultaneously treated with UV light yielded a mean 
. The 
photoirritancy factor (PIF) 
 as BI 730357 was 
 but 
not 
An in vivo phototoxicity study in rats was conducted in pigmented rats. 
Rats were administered 
 BI 730357 by oral gavage for 
. On 
Drug 
 skin and eyes of the anesthetized animals were exposed to UVR or sham UVR 
exposure. Dose-dependent cutaneous reactions were seen 
 that were indicative 
of a 
 related to the administration of BI 730357 and UVR exposure. 
Based on the 
 in one animal, 
 at 
 could not be ruled out, however, there was no histopathologic correlate for the 
. No cutaneous reactions indicative of phototoxic response were seen 
 
which corresponded to mean 
values of 
 
respectively. No ophthalmic changes indicative of phototoxicity were seen up to 
 
 which corresponded to a mean 
values of 
 
 respectively. Based on a margin of approximately 
 the anticipated 
human therapeutic exposure (based 
) to the no observed adverse effect level
(NOAEL) of 
 skin findings, the phototoxicity potential at therapeutic doses 
in humans may be low. However, trial subjects are advised to apply protection measures,
such as sunscreen, while on BI 730357 therapy.
BI 730357 revealed no evidence of teratogenicity in embryo-fetal development studies in 
 
 In the repeat dose studies up to 26- and 39-weeks in 
 respectively, 
there were no effects on male or female reproductive organs. 
In summary, non-clinical BI 730357 safety data demonstrated an acceptable profile to 
support clinical trials in males and females, including women of child-bearing potential 
(WoCBP). Human exposures up to those achieved at the NOAEL of 
 in the 4-
and 13-week dog studies 
 in males and females 


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combined) are considered safe for dosing up to 13 weeks in clinical trials. For clinical trials 
that exceed 13 weeks duration, human exposures up to those achieved at the NOAEL of 
 in the 39-week dogs study
 in males 
and females combined) are considered safe.
For a more detailed description of the BI 730357 toxicology, please refer to the current 
investigator’s brochure (IB) [c09228382].
Nonclinical pharmacokinetics
1.2.3
The disposition of BI 730357 is characterized in 
 
 oral bioavailability was observed 
across species, which suggests that following oral administration, the bioavailability of 
BI 730357 in humans is likely to be 
 The plasma protein binding of 
BI 730357 was 
 In a quantitative whole body 
autoradiography study in male 
BI 730357-derived 
radioactivity was absorbed and distributed to tissues. There was evidence of central nervous 
system (CNS) exposure to drug-related material. Deposition of radioactivity into melanin-
containing tissues of the ocular bulb was 
When incubated with human 
, BI 730357 undergoes 
 predominately 
via 
 
 This 
 was also observed following 
incubations with rat, dog, and minipig-suspended 
. When BI 730357 was 
incubated with a selective inhibitor of 
in a human 
 model, the 
overall metabolism was inhibited by ~90%, confirming that BI 730357 is mainly metabolized 
 Therefore, if BI 730357 is primarily 
 there is a high risk 
that co-administration with 
 will significantly increase BI 730357 exposure.
The propensities of BI 730357 to inhibit, inactivate, and/or induce CYP isoforms was 
evaluated in vitro. Based on the criteria set in the regulatory authorities’ drug-drug-
interaction guidance documents and considering the current projected efficacious dose and 
exposure, BI 730357 is unlikely to be a clinically-relevant 
 
 nor is it a clinically-relevant 
 However, BI 730357 was determined to be a potentially 
 and was also determined to be an 
 
 The net effect of BI 730357 on a sensitive 
 was 
estimated using a mechanistic static model as recommended in the FDA drug-drug interaction 
guidance. Using this model, BI 730357 is predicted to 
 
by 
. Induction of 
; inhibition of 
 
by BI 730357 at anticipated human therapeutic exposure levels is also predicted to be 
[c09228382].
Prediction of human pharmacokinetics
1.2.4
For detailed information, please refer to Section 1.2.5 and the current IB [c09228382].


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Clinical experience in humans
1.2.5
The Phase Ia, first-in-human, single-rising-dose (SRD) trial 1407.1 was completed.
BI 730357 has been administered to 54 healthy male subjects as a single dose, while 18 
subjects received placebo. An additional 12 subjects were treated with 3 individual doses of 
BI 730357 consecutively. The overall frequency of subjects with treatment-emergent adverse 
event (AE) was higher for subjects who received BI 730357 (7.4%) than for subjects who 
received placebo (5.6%), however no dose-dependency was evident, nor were differences 
observed among treatments in a bioavailability substudy. The most frequent of these was 
headache in 5.6% subjects receiving BI 730357 and in 5.6% in subjects receiving placebo.
The only other drug-related AE was oropharyngeal pain, reported for 1 subject receiving 
BI 730357. AEs generally reflected commonly-occurring events of short duration, were
mostly mild or moderate in severity, and were distributed without discernable trend among 
recipients of placebo and rising dose levels of BI 730357. There were no serious adverse 
events (SAE) reported. Overall, BI 730357 was well tolerated.
Preliminary safety data for recently-completed Phase Ib multiple-rising-dose trial 1407-0002 
indicate that with respect to the kind, incidence and severity of the AEs, there were no 
notable differences among dose groups. No SAEs were reported during the trial. ECG 
recordings, clinical laboratory evaluation, and vital signs showed no clinically-relevant 
changes compared to baseline. Overall, administration of BI 730357 to healthy male subjects 
at doses up to 400 mg for up to 28 days was well tolerated.
In SRD trial 1407.1, exposure to BI 730357 increased in a dose-proportional manner for 
solution between 2 and 8 mg and for tablet up to 50 mg, and thereafter increased in a less-
than-dose-proportional manner, with approximately 1.5-fold increase in exposure with each 
2-fold increase in dose up to 400 mg in the fasted state. Bioavailability of the 25 mg tablet 
fasted was less than that of the 25 mg solution fasted. There was
 greater exposure 
following administration of the 25 mg tablet under fed than fasted conditions, suggesting a 
positive food effect for BI 730357. BI 730357 was also administered at 400 mg and 800 mg 
under fed conditions (following standardized continental and high-fat breakfasts) to further 
evaluate the safety and PK of higher BI 730357 exposures. These results show that exposures 
continue to increase at higher doses with food, suggesting a positive food effect.
In Phase Ib trial 1407-0002, preliminary PK data indicate that exposure appears to increase in 
an approximately dose-proportional manner from 25 mg to 100 mg dose after repeat oral 
dosing of BI 730357 in the fasted state, and in a less-than dose-proportional manner from the 
100 mg to 200 mg dose. 
. 
Accumulation of BI 730357 was approximately 2-fold from single dose to steady state for all 
dose groups.
For a more detailed description of the BI 730357 clinical trial, please refer to the current IB
[c09228382].
Residual Effect Period
1.2.6
The residual effect period (REP) for BI 730357 is not known at this early stage of 
development and therefore conservatively defined as 
. This is the period which covers 


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more than 
 terminal half-lives of the study drug in 1407.1. Please refer the detailed 
data obtained in SRD trial 1407.1 in the current IB [c09228382].
Drug product
1.2.7
BI 730357 is a white to off-white to yellow powder and practically insoluble in 
 
buffer solutions, and it is 
.
For a more detailed description of the BI 730357 profile, please refer to the current IB
[c09228382].
1.3
RATIONALE FOR PERFORMING THE TRIAL
This Phase I study is to investigate the safety, tolerability, and PK of BI 730357, in order to 
understand the clinical safety and pharmacokinetic profile in healthy male Japanese subjects 
after single-rising oral doses of BI 730357 within the dose range to be evaluated in further 
clinical studies with BI 730357 in the indication 
.
Japanese healthy male subjects aged 20 to 45 years will be recruited for this study. This 
population is expected to provide a relatively stable physiological, biochemical, and 
hormonal basis (steady state) for studying drug effects, and to show no disease-related 
variation, and is not expected to use concomitant medication. 
Within each dose group, all actively-treated individuals will receive the same BI 730357 
dose. The next higher dose will only be administered (to the next group) if the treatment in 
the preceding dose groups was safe and showed acceptable tolerability. BI 730357 dose 
levels evaluated in this trial have been previously evaluated in first-in-human trial 1407.1, the 
results of which are provided in Section 1.2.5.
Dose selection
It is intended to investigate the following dose levels of BI 730357 in this trial: 50 mg, 
100 mg, and 200 mg. The background for this dose selection is described in the following 
paragraphs.
A minimum daily dose of about 
 may be required to achieve therapeutic systemic 
exposure to BI 730357. However, higher doses might still be well tolerated while providing a 
larger magnitude of therapeutic effects. Further, testing of doses higher than 
 is also 
reasonable to compensate for any bioavailability and half-life lower than expected. Finally, 
even if the therapeutic dose is determined to be as low as 
, higher than therapeutic 
doses are typically explored Phase I studies to provide a safety margin for following studies 
e.g., drug-drug-interaction studies, studies with patients with impaired excretion function, 
etc., where substantial increases in exposure may be seen.
For this study 200 mg has been selected as the maximum dose, a dose that is expected to be 
high enough to obtain exposure in the therapeutic range, even if the bioavailability was 
significantly lower than the expected 
 (refer to Section 1.2.5). 
Non-clinical BI 730357 safety data demonstrated an acceptable profile to support clinical 
trials in males and females, including women of childbearing potential. Human exposures up 
to those achieved at the NOAEL 
 in the 4- and 13-week 


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 in males and females combined) are considered safe 
for dosing up to 13 weeks in clinical trials. The mean exposures after single dose 
administration 
 for the 200 mg fasting dose group in 
1407-0002 remain below this NOAEL.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the clinical development of a 
new orally available drug, which might improve the therapy in patients 
. Subjects 
participating in this study are exposed to the risks of the study procedures and those related to 
the exposure to the trial medication.
Procedure-related risks
Blood sampling by venipuncture or through an indwelling venous catheter may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn during the trial per subject will not exceed the volume 
of a normal blood donation (400 mL). No health-related risk to healthy subjects is expected 
from this blood withdrawal.
Drug-related risks and safety measures
The nature of the target and the mechanism of action of BI 730357 are well understood from 
preclinical models. The safety, tolerability, and PK exposure following single-dose 
administration of BI 730357 have already been established in first-in-human trial 1407.1, at 
dose levels up to 800 mg, 4-fold higher than the maximum dose level (200 mg) to be 
evaluated in the current trial. Furthermore, since this is not a First-in-Human trial, the risk is 
relatively lower.
The pharmacological effects of BI 730357 are dose dependent and no evidence for prolonged 
or irreversible effects has been observed. Single dose administration of dose levels up to 
800 mg BI 730357 are supported by preclinical safety data.

Extensive safety laboratory testing will be performed with special focus on full blood 
exam (refer to Flow Chart).

A thorough ECG monitoring including 4-hours continuous 3-lead ECG measurement 
for at least 15 min before drug administration (for baseline assessment) and for
4 hours following drug administration to cover the anticipated period of highest drug 
exposure, and additional repeated single 12-lead ECGs over 48 hours (during hospital
stay) following drug administration. Dose escalation would be stopped as soon as at 


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least 2 subjects at one dose level showed relevant QT prolongation (refer to Section 
3.3.4.3 for details).

Prior to each dose escalation, a documented safety review will be performed by the 
principal investigator and the sponsor (clinical trial leader [CTL]). For details, refer to 
Section 3.1.

Subjects will be hospitalized on Day -1 (one day before drug administration) and will 
be discharged on Day 3 only after a formal assessment and confirmation of fitness by 
an investigator or qualified designee. During in-house confinement, subjects will be 
under close medical observation and thoroughly monitored for both, expected and 
unexpected AEs.

Only if the respective dose of BI 730357 was safe and showed acceptable tolerability 
and if no stopping criterion was met (refer to Section 3.3.4.3), the next higher dose 
will be given at least 7 days later (referring to the 1st subject of each dose group).
Since preclinical data indicate that BI 730357 has potential for phototoxicity, subjects will be 
advised to apply protection measures such as sunscreen, and solarium radiation are prohibited 
during this clinical trial until the end of the respective follow-up period.
BI 730357 was determined in vitro to be a substrate, an inactivator, and an inducer of 
, as well as an inducer of 
, thus there is a potential risk of 
clinically relevant drug-drug interactions (DDI) occurring. Whether 
 substrates will 
need to be excluded/monitored in subsequent clinical trials will be determined based on 
results of planned the DDI trials.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety, see also Section 5.2.6.1.4.
As with other
 therapies, impaired 
 is a theoretical target-related
toxicity, potentially resulting in increased risk of 
play an important role in 
 extracellular 
 at mucosal surfaces
 IL-17
 are associated with
 
. Homozygous, but not heterozygous 
 mice have a high incidence 
of T cell lymphoma, thought to originate in the thymus
. While the translatability 
of the 
 phenotype to pharmacological RORγ 
 and to humans is unknown,
this raises the hypothetical concern for clinical T cell lymphoma risk. The exact cause of 
T cell lymphomas in 
 mice is not fully understood, but changes in 
homeostasis in the thymus, such as thymocyte apoptosis and proliferation, are thought to play 
a role. AEs and SAEs consistent with malignancy, and specifically those representing 
lymphoma, are to be carefully monitored and evaluated throughout the BI 730357 clinical 
development program, and monitoring of peripheral blood lymphocyte subsets integrated into 
clinical trials.
In summary, BI 730357 has the potential to become an oral treatment 
 Based upon 
preclinical and clinical data for BI 730357 to date, as well as the implemented safety 
measures described above, healthy subjects will not be exposed to undue risks in relation to 


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the important information expected from this trial as a basis for further clinical development 
of this compound. Healthy volunteers are not expected to have any direct benefit from 
participation in this Phase I clinical trial with BI 730357, as is the usual case in such Phase I 
trials. Considering the medical need of the development of a safer and more effective 
treatment for patients with PsO, the sponsor considers that the benefit outweighs the potential 
risks and justifies exposure of healthy human volunteers.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
2.1.1
The main objective of this trial is to investigate the safety and tolerability of BI 730357 in 
Japanese healthy male subjects following oral administration of single rising doses of 50 mg, 
100 mg, and 200 mg.
Secondary objectives are the explorations of the PK, including dose proportionality as well as 
investigation of linearity of BI 730357 after single dose administration.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
Primary endpoint
2.1.2
Primary endpoint to assess safety and tolerability of BI 730357 is the number [N (%)] of 
subjects with drug-related adverse events.
Secondary endpoints
2.1.3
The following pharmacokinetic parameters will be determined 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)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This SRD trial is designed as double-blind, randomised within dose group, and placebo-
controlled within parallel dose groups.
A total of 24 Japanese healthy male subjects is planned to participate in the trial, according to 
3 sequential groups comprising 8 subjects per dose group. 
Within each dose group, 6 subjects will receive the active drug and 2 will receive placebo. 
Only one dose is tested within each dose group.
The dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups
Dose Group
1
2
3
Dose (mg)
50
100
200
Number of subjects
8
8
8
Subjects receiving placebo
2
2
2
Subjects receiving active drug
6
6
6
The dose groups will be investigated consecutively in ascending order of doses, maintaining a 
time interval of at least 7 days between the last drug administration in the previous dose 
group and the first drug administration of the subsequent dose group. 
The decision to proceed to the next dose group will be based upon the safety and tolerability
data of the preceding dose groups. The next dose group will only be dose if, in the opinion of 
the investigator, no safety concerns arose in the preceding dose group(s) (i.e., no dose-
limiting events occurred) and if none of the pre-specified trial-specific stopping criteria were 
met (refer to Section 3.3.4).
A documented safety review must take place prior to randomization in the next group. 
Furthermore, an unscheduled safety review meeting can be requested anytime for any 
reasonable cause by the principal investigator (or an authorised deputy) or the sponsor of the 
study, e.g., because of any unforeseen AEs, etc. Dose escalation will only be permitted if no 
safety concerns exist in the opinion of the principal investigator (or an authorised deputy) and 
the sponsor. 
The minimum data set for review consists of the following data:

AEs in the current and preceding dose group(s) (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 EGG and 4-hours continuous 3-lead ECG monitoring in the 
current and preceding dose groups.


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
Vital signs in the current and preceding dose groups

Clinical laboratory tests in the current and preceding dose groups

Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the sponsor after in-depth analysis of all available safety data, 
especially SAEs (if any), AEs, and out-of-range laboratory results (if considered clinically 
significant). Safety reviews can be conducted verbally (e.g., teleconference) and/or in writing 
(e.g., encrypted emails, facsimiles correspondences or mails). The CTL is responsible for 
organization and minutes of the reviews. Minutes will be signed off by the principal 
investigator (or an authorised deputy) and filed in the investigator site file (ISF) and trial 
master file (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 SRD trials, the design described in Section 3.1 is viewed as favourable under the 
provision not to expose the subjects involved to undue risks, since the main study objective is 
to investigate safety and tolerability of BI 730357.
With the rising dose design, double-blind conditions regarding the subjects’ treatment (active 
or placebo) are maintained within each dose group. However, the current dose level will be 
known to subjects and investigators. The disadvantage of this trial design is a possible 
observer bias with regard to the dose-depending effects as well as time effects, but it has the 
virtue of minimizing subject risk by sequentially studying ascending doses. As time-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 trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety and tolerability. Each dose group consists of 8 subjects, with 6 on 
active treatment, and 2 on placebo. The placebo control group includes all subjects of all dose 
groups treated with placebo. Six subjects per active treatment group are in general considered 
as sufficient for the exploratory evaluation of pharmacokinetics. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 24 Japanese healthy male subjects will enter the study. Subjects will be 
recruited at the trial site.
Only male subjects will be included into the study.
A log of all subjects enrolled into the trial (i.e., having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.


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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 into the trial if they meet the following criteria:
1.
Healthy male subjects according to the investigator’s assessment, based on a complete
medical history including a physical examination, vital signs (BP, PR, RR, body 
temperature), 12-lead ECG, and clinical laboratory tests
2.
Japanese ethnicity, according to the following criteria:
-
born in Japan, have lived outside of Japan <10 years, and have parents and 
grandparents who are Japanese
3.
Age of 20 to 45 years (inclusive) at screening
4.
BMI of 18.5 to 25.0 kg/m2 (inclusive) at screening
5.
Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
6.
Male subject who agree to minimize the risk of female partners becoming pregnant by 
fulfilling any of the following criteria starting from participation to this trial and until 90 
days after the trial completion:
•
Use of adequate contraception, e.g., any of the following methods plus condom: 
combined oral contraceptives, intrauterine device.
•
Vasectomised (vasectomy at least 1 year prior to enrolment)
•
Surgical sterilised (including hysterectomy) of the subject’s female partner
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) is deviating from 
normal and judged as clinically relevant by the investigator
2.
Repeated measurement of systolic BP outside the range of 90 to 140 mmHg, diastolic BP
outside the range of 50 to 90 mmHg, or PR outside the range of 45 to 90 bpm at 
screening
3.
Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance at screening
4.
Any evidence of a concomitant disease judged as clinically relevant by the investigator
5.
Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6.
Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)


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7.
Diseases of the CNS (including but not limited to any kind of seizures or stroke), and 
other relevant neurological or psychiatric disorders, including but not limited to mood 
disorders and any history of suicidality
8.
History of relevant orthostatic hypotension, fainting spells, or blackouts
9.
Chronic or relevant acute infections including human immunodeficiency virus (HIV), 
viral hepatitis, syphilis and/or tuberculosis
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days or 5 half-lives, whichever is longer, prior to administration 
of trial medication, if that might reasonably influence the results of the trial (including 
potential for QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
13. Previous exposure to BI 730357
14. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
15. Inability to refrain from smoking on specified trial days
16. Alcohol abuse (consumption of more than 30 g per day for males)
17. Drug abuse or positive drug screening
18. Whole blood donation of  more than 200 mL within 30 days or 400 mL within 12 weeks, 
or plasmapheresis and platelet apheresis within 2 weeks prior to administration of trial 
medication, or intended donation during the trial
19. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
20. Inability to comply with dietary regimen of trial site
21. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 mseconds) or any other relevant ECG finding at screening
22. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome) 
23. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a 
condition that would not allow safe participation in the study
For study restrictions, refer to Section 4.2.2.
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 refer to Section 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 


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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 study 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 (refer to 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:
-
The subject wants to discontinue trial treatment, without the need to justify the 
decision
-
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 
-
The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
-
The subject can no longer receive trial treatment for medical reasons (such as 
surgery, AEs, or diseases)
-
An AE or clinically significant laboratory change or abnormality occurs that the 
investigator assesses as warranting not administering trial medication. 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
-
The subject has an elevation of aspartate transaminase (AST) and/or alanine 
transaminase (ALT) ≥3-fold upper limit of normal (ULN) and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample), an elevation of ALT 
and/or AST ≥10-fold ULN, and/or needs to be followed up according to the DILI 
checklist provided in the ISF
In addition to these criteria, the physician 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 follow up as outlined in the Flow Chart and Section 6.2.3.
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 


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for continued follow up after trial treatment discontinuation, please refer to Section 3.3.4.1
above.
Discontinuation of the trial by the sponsor
3.3.4.3
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
any of the following reasons:
-
New toxicological findings or SAEs invalidate the earlier positive benefit-risk-
assessment. More specifically, the trial will be terminated if more than 50% of the 
subjects show drug-related and clinically-relevant AEs of moderate or severe 
intensity, or if at least one drug-related serious AE is reported that is considered to 
be unacceptable
-
The expected enrolment goals overall or at a particular trial site are not met
-
Violation of Good Clinical Practice (GCP), or the clinical trial protocol (CTP), or the 
contract with BI by a trial site or investigator, disturbing the appropriate conduct of 
the trial
-
The sponsor decides to discontinue the further development of the investigational 
product
-
Dose escalation will be stopped as soon as at least 2 subjects at one dose level on 
active drug showed relevant individual QT prolongation, i.e., a QTc increase of 
greater 60 mseconds from baseline in connection with absolute QT or QTc greater 
than 500 mseconds, which has been confirmed by a repeat ECG recording
The investigator/the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
For the following scenario further enrolment randomisation into the trial and treatment of 
already randomised subjects will be interrupted by the sponsor once the sponsor becomes 
aware:

Two SAEs in two different subjects in the same system-organ-class, confirmed by both 
the investigator and sponsor as having a reasonable causal relationship to the trial 
medication administration.

Two ‘severe’ non-serious AEs in two different subjects in the same cohort, independent 
of within or not within the same system-organ-class, confirmed by both the investigator 
and sponsor as having a reasonable causal relationship to the trial medication 
administration.
Replacement of subjects
3.3.5
In case some subjects do not complete the trial, the CTL together with the trial 
pharmacokineticist and the trial statistician are to decide if and how many subjects will be 


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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 products have 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:
Table 4.1.1: 1
Test product
Substance
BI 730357
Pharmaceutical formulation:
Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
50 mg (DG 1) or 100 mg (DG 2, DG 3)
Posology:
1-0-0 (DG 1); 1-0-0 (DG 2); 2-0-0 (DG 3)
Route of administration:
oral
Duration of use:
Day 1 (single dose)
DG: dose group
Table 4.1.1: 2
Reference product
Substance
Placebo matching in size and weight to 50 or 100 mg film-coated tablet
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
1-0-0 (DG 1)
(matching in size and weight to 50 mg film-coated tablet)
1-0-0 (DG 2)
(matching in size and weight to 100 mg film-coated tablet)
2-0-0 (DG 3)
(matching in size and weight to 100 mg film-coated tablet)
Route of administration:
oral
Duration of use:
Day 1 (single dose) 
DG: dose group
Selection of doses in the trial
4.1.2
Three dose groups are to be investigated in this trial. Three dose levels will cover potential 
therapeutic dose ranges. The number of dose levels will also allow for evaluation of dose 
proportionality.
This trial is designed to evaluate the safety, tolerability, and pharmacokinetics of BI 730357 
in Japanese healthy male volunteers. A safe and tolerable dose achieved in previous trials,
including Caucasian SRD trial (1407.1), is used as a reference for the dose selection in this 
trial. 
For safety margins and further details on dose selection, refer to Section 1.2 and 1.3.
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 
according to their temporal availability. Therefore, the allocation of subjects to dose cohorts 
is not influenced by trial personnel, but only by the subjects’ temporal availability. As the 


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study 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. For this purpose, the randomisation list will be provided to the 
trial site in advance. Subjects are then assigned to treatment according to the randomisation list.
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 number of units for 
placebo corresponds to the number of units of the respective dose level.
Table 4.1.4: 1
BI 730357 and placebo treatments, oral administration
Dose
group
Substance
Pharmaceutical 
form
Unit strength
Number of units 
per administration
Total daily 
dose
1
BI 730357
film-coated tablet
50 mg
1 tablet
50 mg
2
BI 730357
film-coated tablet
100 mg
1 tablet
100 mg
3
BI 730357
film-coated tablet
100 mg
2 tablet
200 mg
1
Placebo*
Film-coated tablet
--
identical to active treatment
--
2
Placebo*
Film-coated tablet
--
identical to active treatment
--
3
Placebo*
Film-coated tablet
--
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups
The trial medication will be administered to the subjects, while in a sitting position, as an oral 
dose together with approximately 240 mL of water, under supervision of the investigating 
physician or an authorised designee. The so-called four-eye principle (two-person rule) 
should be applied for administration of trial medication, if correct dosage cannot be ensured 
otherwise.
Subjects will be kept under close medical surveillance until at least 48 hours following drug 
administration. During the first 4 hours after drug administration, they are not allowed to lie 
down (i.e., no declination of the upper body of more than 45 degrees from upright posture), 
except, if required for trial-related measurements (e.g., recording of 12-lead ECG) or for
medical reasons (e.g., AEs). 
For restrictions with regard to diet, refer to Section 4.2.2.2.
Blinding and procedures for unblinding
4.1.5
Blinding
4.1.5.1
The trial is designed double-blind. The treatments administered (active or placebo) will be 
blinded to the subjects and the investigators (outcome assessors) in order to limit the 
occurrence of any bias which the knowledge of treatment may have. According to the rising 
dose design, the current dose level will be known to subjects and investigators.


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At the sponsor’s site, access to the randomisation schedule is restricted to the randomisation 
operators, the Clinical Trial Support group and the Pharmaceutics Department.
The trial pharmacokineticist may receive the randomisation codes prior to official unblinding 
to perform the preliminary PK analysis. He or she will confirm in writing that the codes will 
be treated confidentially.
In addition, regarding the sponsor, all trial data will be handled open label. This means that 
trial functions of the sponsor are unblinded (trial clinical leader, data manager, statistician, 
bioanalyst, pharmacokineticist as well as dedicated CRO personnel). This is acceptable 
because they are neither in contact with subjects nor with site staff.
Within the central ECG lab, the staff involved with interval measurements and morphological 
analyses 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.
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
The investigator or designee will be supplied with a set of sealed envelopes containing the 
medication codes for each subject according to the randomisation scheme. The envelopes will 
be kept unopened at the trial site until the end of data collection. An envelope may only be 
opened in emergency situations when the identity of the trial drug must be known to the 
investigator in order to provide appropriate medical treatment or otherwise assure safety of 
trial participants. If the envelope for a subject is opened, the sponsor must be informed 
immediately. The reason for breaking the code must be documented on the envelope and/or 
appropriate CRF page along with the date and the initials of the person who broke the code.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
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. 
For details of packing and the description of the label, refer to the ISF.
No re-supply is planned.
Storage conditions
4.1.7
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where 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.


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Drug accountability
4.1.8
The investigator/pharmacist who is documented in the trial staff list/investigational drug 
storage manager will receive the investigational drugs delivered by the sponsor when the
following requirements are fulfilled:

Approval of the trial protocol by the institutional review board (IRB),

Availability of a signed and dated clinical trial contract between the sponsor and the 
head of the trial site,

Notification of the regulatory authority, e.g., competent authority (CA)

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated CTP
Only authorised personnel as 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. All unused medication must be returned to sponsor. Receipt, usage and 
return must be documented on the respective forms. Account must be given for any 
discrepancies. 
The investigator/pharmacist who is documented in the trial staff list/investigational drug 
storage manager must maintain records of the product’s delivery to the trial site, the 
inventory at the site, the use by each subject, and the return to the sponsor 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 products and trial subjects. The 
investigator/pharmacist that is documented in the trial staff list/investigational drug storage 
manager will maintain records that document adequately that the subjects were provided the 
doses specified by the CTP, and that reconcile all investigational products received from the 
sponsor. At the time of return to the sponsor or appointed contract research organization
(CRO), the investigator/pharmacist who is documented in the trial staff list/investigational 
drug storage manager must verify that no remaining supplies are in the investigator’s 
possession.
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, in case of AEs in need of 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 medical evaluation 
results have returned to an acceptable level.


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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.
Restrictions on diet and life style
4.2.2.2
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 4 hours after drug intake.
From 1 hour before drug intake until 4 hours post-dose liquid intake is restricted to the fluid 
(approximately 240 mL of water) administered with the drug and an additional approximately
240 mL of water served on Day 1 at 2 hours and 4 hours post-dose (mandatory for all 
subjects).
From 4 hours post-dose until 24 hours post-dose water intake is restricted to 3000 mL. 
During the days of urine collection, total fluid intake should be at least 1500 mL and should 
not exceed 3500 mL.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products including St. John's wort (Hypericum perforatum) are not
permitted starting 7 days before administration of trial medication until after the last PK
sample of each study period is collected.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 24 hours before administration of trial medication until the 
end of plasma pharmacokinetic sampling of the respective visit.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of study examination. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
 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 refer to 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 including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR, RR, and body 
temperature), 12-lead ECG, laboratory tests, and a physical examination. At the end of study 
examination, it will include review of vital signs, 12-lead ECG, laboratory tests, and a 
physical examination.
Vital signs
5.2.2
Systolic and diastolic BP as well as PR will be measured by a BP monitor at the times 
indicated in the Flow Chart, after subjects have rested for at least 10 minutes in a supine 
position. All recordings should be made using the same type of BP recording instrument on 
the same arm if possible.
Further, RR and body temperature will be monitored. Body temperature will be determined at 
the time points indicated in the Flow Chart using electronic thermometers. RR will be 
counted by trained study personal by observing the chest movements over a period of one 
minute (30 second x 2) after the subject has rested in the supine position for 10 minutes. 
Recording of the values will be done at the time points indicated in the Flow Chart.
Safety laboratory parameters
5.2.3
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 hours. Overnight fasting is not required at the discretion of the investigator or 
designee for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF. 
Manual differential white blood cell count will only be performed if there is an abnormality 
in the automatic blood cell count, i.e. if automatic count is not feasible or differential WBC is 
abnormal (i.e., pathological or atypical cells) and clinically relevant in the opinion of the 
investigator.
In case the urinalysis is positive for erythrocytes, leukocytes, nitrite or protein and clinically
relevant in the opinion of the investigator, microscopic examination of the urine sediment


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will be performed. Positive findings of the urine sediment examination will be monitored and
if needed based on the medical judgment of the investigator an urologist may be consulted.
Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
SCR
A1
B2
EOS4
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Automatic WBC 
differential 
(relative)
Neutrophils, eosinophils, 
basophils, monocytes, 
lymphocytes
x
x
x
x
Manual differential WBC 
(if automatic count is not 
feasible or differential WBC 
is abnormal and clinically 
relevant in the opinion of the 
investigator)
Polymorphnuclear neutrophils 
(segs), band neutrophils (stabs), 
eosinophils, basophils, monocytes, 
lymphocytes 
Coagulation
Activated partial thromboplastin 
time (aPTT)
Prothrombin time (Quick’s test 
and INR)
Fibrinogen
x
x
x
x
x
x
x
x
x
x
x
x
Enzymes
Aspartate transaminase 
(AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase 
(GGT/γ-GT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Hormones
Thyroid stimulating hormone 
(TSH)
x
--
--
--
Substrates
Plasma glucose
Creatinine 
Blood Urea Nitrogen (BUN)
Total bilirubin 
Direct bilirubin
Total protein
Albumin 
C-Reactive Protein (CRP) 
Uric acid 
Total cholesterol 
Triglycerides
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
x
x
x
x
x
x
x
x
x
Electrolytes
Sodium
Potassium
Calcium
x
x
x
x
x
x
x
x
x
x
x
x


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Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
Test name 
SCR
A1
B2
EOS
Urinalysis (strip of dipstick) Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
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 sediment3
Only positive findings will be 
reported (for instance, the presence 
of sediment bacteria, casts in 
sediment, squamous epithelial 
cells, erythrocytes, leukocytes)
x
x
--
x
SCR: screening, EOS: end of study
1
A: parameters to be determined at Visit 2 on Day -3 to -1, Day 1, 2, 8 (for time points refer to Flow Chart)
2
B: parameters to be determined at Visit 2, after 4 hours on Day 1 (for time points refer to Flow Chart)
3
Only if erythrocytes, leukocytes nitrite or protein are abnormal in urine and are deemed clinically necessary by the 
investigator
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Infection serology test will be planned during screening only. Drug screening and 
alcohol test will be performed at screening and prior to treatment period.


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates (Morphine)
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis A antibodies (qualitative)
Hepatitis B surface antigen (qualitative) 1
Hepatitis B surface antibody (qualitative) 1
Hepatitis B core antibody (qualitative) 1
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antigen and/or antibody (qualitative)
QuantiFERON TB-Gold or T-SPOT 2
Syphilis test (RPR, TP antibody method)
Alcohol test
Breath alcohol test
1 If hepatitis B surface antigen and/or hepatitis B core antibody is positive, subject will be not allowed participating in this 
study. If hepatitis B surface antibody is positive, hepatitis B surface antigen and hepatitis B core antibody is negative, and
there is evidence that subject gets hepatitis B virus vaccine, subject will be allowed participating in this study.
2 If QuantiFERON® or T-SPOT® is positive; subject will be not allowed participating in this study. Subject with latent 
tuberculosis will be not allowed participating in this study.
To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed 
at screening and prior to each treatment period, 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 Table 5.2.3: 1 and 5.2.3: 2 will be performed by the local 
laboratory at the trial site and/or at an external vendor designated by the site.
Laboratory data will be transmitted electronically from the trial site to BI.
Electrocardiogram
5.2.4
12-lead resting ECG
5.2.4.1
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (MAC 800 ECG machines, GE Healthcare) 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.


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To achieve a stable heart rate (HR) 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 10-second duration after the subjects have rested for at least 
10 minutes in a supine position. ECG recordings will always precede all other study 
procedures scheduled for the same time point (except blood drawing from an intravenous 
cannula which is already in place) to avoid impact of sampling on the ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e., three single ECGs recorded 
within 180 second) as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For time points with triple ECGs, all three single 
ECGs will be repeated. The repeat ECGs are assigned to the respective scheduled time point. 
Additional (unscheduled) ECGs may be collected at the discretion of the investigator for 
safety reasons. These ECGs are assigned to the prior scheduled time point.
Storing
All ECGs will be stored electronically on the Muse Cardiology information System (GE 
Medical Systems, Freiburg, Germany)
Data transfer
For time points specified in the Flow Chart, ECGs will be transferred electronically to the 
central ECG lab (
) for evaluation.
All ECGs (including repeat ECGs due to quality reasons) will be sent to the central ECG lab.
The investigator will judge data adoption and send the information which ECGs were 
adopted to the central ECG lab.
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 (refer to TMF).
Evaluation
a) Central ECG lab
A post-study centralized evaluation of all 12-lead ECGs recorded after Days 1 up to 
72 hours after drug administration will be performed by an independent ECG 
laboratory. This analysis will include the determination of cardiac axis as assessed by 
the ECG machine’s algorithm as well as the intervals RR, PR, QRS and QT measured 
semi-automatically. With the exception of the first triplicate ECG (used as baseline 
before the first drug administration), only the first of the triplicate ECG at a single 
assessment time will be evaluated. The remaining second and third replicate ECG will 
be stored for additional analyses if required, e.g., by authorities at a later time point.


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HR and the QT interval corrected for HR (QTc e.g., QTcF and QTcB) will be 
determined by the sponsor (refer also to trial statistical analysis plan [TSAP] for 
details).
Abnormalities detected during centralized ECG evaluation will not necessarily qualify 
as AE. All 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 blinding arrangements, refer to Section 4.1.5.1. 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 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].
b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (refer to Section 3.3) of a subject and for the 
assessment of cardiac safety during the study, the QTcF 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. 
4-hours continuous 3-lead ECG monitoring
5.2.4.2
Cardiac rhythm (including heart rate) will be monitored by means of 4-hours continuous 3-
lead ECG recording using the Central Monitor DS-8700 (Fukuda, Japan) for at least 15 min 
before drug administration (for baseline assessment) and for 4 hours following drug 
administration). This 4-hours continuous 3-lead ECG monitoring supports the early detection 
of adverse events such as clinically relevant bradycardia, tachycardia, or arrhythmia at the 


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trial site. Beyond this clinical evaluation at the trial site, no further data collection or analyses 
are performed based on 4-hours continuous 3-lead ECG monitoring.
ECG data from 4-hours continuous 3-lead ECG recording will not be transferred to the 
clinical trial database. Abnormal findings during 4-hours continuous 3-lead ECG recording 
will be recorded as AEs if judged clinically relevant by the Investigator.
Other safety parameters
5.2.5
Not applicable
Assessment of adverse events
5.2.6
Definitions of adverse events
5.2.6.1
Adverse event
5.2.6.1.1
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of 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
5.2.6.1.2
A 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 subject 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 subject and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 


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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
The following events will be handled as ‘deemed serious for any other reason’. An AE which 
possibly leads to disability will be reported as an SAE.
AEs considered ‘Always Serious’
5.2.6.1.3
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 Section 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor 
and timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI 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 electronic data capture (eDC)
system, an electronic data capture system which allows the entry of trial data at the trial site.
Adverse events of special interest
5.2.6.1.4
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 refer 
to Section 5.2.6.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST and/or ALT ≥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.


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Intensity (severity) of AEs
5.2.6.1.5
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
5.2.6.1.6
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

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g., pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e., greater effect size if the dose is increased, 
smaller effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g., after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged


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Adverse event collection and reporting
5.2.6.2
AE collection
5.2.6.2.1
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 study: 
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 study:
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.


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AE reporting to the sponsor and timelines
5.2.6.2.2
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
5.2.6.2.3
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.
Pregnancy
5.2.6.2.4
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
5.3.1
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g., preliminary PK data) including addition of samples and 


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visits as long as the total blood volume taken per subject does not exceed 400 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 730357 plasma concentrations, 3 mL of blood will be taken from an 
antecubital or forearm vein into an ethylenediaminetetraacetic acid (EDTA)-anticoagulant 
blood drawing tube at the times indicated in the Flow Chart. Blood will be withdrawn by 
means of either an indwelling venous catheter or by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 minutes at about 
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 plasma. The process 
from blood collection until transfer of plasma aliquots into the freezer should be completed 
within 60 minutes, with interim storage of blood samples and aliquots at in ice water or on 
ice. For each aliquot the time when the sample was placed in the freezer will be documented.
Until transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
about -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 about -20°C or below until 
analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, 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, 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 upon the final study 
report has been signed.
5.3.2.2
 
 
 
 
 
 
 
 
 


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The weight of the empty container will be determined, thereafter suitable volume of 10% 
Tween 20 will be added and the weight of the container at the end of each sampling interval 
will be determined. The urine collection container will be slightly mixed after each urine 
event. Details will be described in the lab manual.
The urine weight/volume for each collection interval will be documented (however, no 
correction for the specific gravity of urine is done, i.e., 1 L is defined to be equal to 1 kg). 
Two 0.5 mL aliquots will be stored in PP tubes for bioanalytical measurement. In case more 
than one collection container is used in an interval, the contents of all containers are to be 
mixed before aliquots are prepared. Mixing should be done by transferring the entire content 
of all collection containers into a single PE/PP or glass container, and stirring the mixed 
fractions for about 1 min (manually or using a stir bar or other stirring device out of PE, PP, 
Teflon or glass).
At minimum, the sample tube labels should list at least the following information: BI trial 
number, subject number, visit, and planned collection time. Further information such as 
matrix and analyte may also be provided. 
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at about 
-20°C or below at the trial site. The second aliquot will be transferred after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory the urine samples 
will be stored at about -20°C or below until analysis. 
After completion of the trial the urine samples may be used for further methodological 
investigations, e.g., for stability testing, assessment of metabolites. However, only data 
related to the analyte and/or its metabolite(s) will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations but not later than 5 years upon the final study report has been signed.
Analytical determinations
5.3.3
Analytical determination of analyte plasma concentration
5.3.3.1
BI 730357 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis. The analysis will be performed at
.
As described in Section 4.1.5, the bioanalyst will be unblinded during sample analysis.
5.3.3.2
 
 
5.4
BIOBANKING
Not applicable.


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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 end of study examination are given 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 hours-period prior to 
the trial drug administration (including blank values for PK).
The tolerance for drug administration will be ± 1 minute on Days 1.
The acceptable deviation on Day 1 from the scheduled time for vital signs and ECG will be -
15 minutes for the first 4 hours after the drug administration and - 30 minutes thereafter. 
After Day 2, vital signs and ECG will be ± 30 minutes from the scheduled time. Blood 
sampling for safety laboratory tests will be ± 30 minutes for the first 24 hours after trial drug 
administration. Urine sampling for safety laboratory tests will be -3 hours on Day 2 (24 hours
after trial drug administration).
Procedures on Days 4, 5 and 8 to be performed within ±3 hours from planned time.
If several activities scheduled at the same time point in the Flow Chart, 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 and urine collection intervals 
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for determination of 
pharmacokinetic parameter.
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 
(blinded) report planning meeting.
Relevant time violations will be identified and their handling discussed no later than at the 
(blinded) report planning meeting (refer to Section 7.4).
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Screening period
6.2.1
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study. 


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For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
Treatment period
6.2.2
Each subject will receive one dose of the respective trial medication (BI 730357 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.
Study participants will be admitted to the trial site in the evening of Day -1 and kept under 
close medical surveillance for at least 48 hours following the 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 his designee. On all other study days, the study will be 
performed in an ambulatory fashion.
For details on time points and procedures for collection of plasma and urine samples for PK 
analysis, refer to Flow Chart. 
The safety measurements performed during the treatment period are specified in Section 5.2
and in the Flow Chart. For details on time points for all other trial procedures, refer to the 
Flow Chart. AEs and concomitant therapy will be assessed continuously from screening until 
the end of study examination.
End of study period
6.2.3
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of study period, refer to Sections 5.2.2 to 5.2.6. 
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of study visit.
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
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.


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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 deviation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 
included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment. Descriptive and model based analyses of PK 
parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol 
deviations (IPD) categories will be specified in the integrated quality and risk 
management plan (IQRMP), IPDs will be identified no later than in the Report Planning 
Meeting, and the IPD categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Sections 2.1 and 2.2 for BI 730357 will be 
calculated according to the relevant standard operating procedure (SOP) of the Sponsor 
(001-MCS-36-472).


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Plasma 
 concentration data and parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol deviation relevant to the evaluation of PK (to be decided no later than in the 
Report Planning Meeting) or due to PK non-evaluability (as revealed during data 
analysis, based on the criteria specified below). Exclusion of a subject`s data will be 
documented in the CTR.
Relevant protocol deviations may be:

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medication
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).
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.
Secondary endpoint analyses
7.3.2
Primary analyses
The secondary endpoints (refer to Section 2.1.3) will be analysed descriptively.


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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.
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 (refer to Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment-emergent AEs). 
Therefore, measurements planned or AEs recorded prior to intake of trial medication will be 
assigned to the screening period, those between trial medication intake and end of REP (refer 
to 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). 
AEs 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 (refer to Section 5.2.6.1) and other significant 
AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.


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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.
7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
Safety
7.5.1
It is not planned to impute missing values for safety parameters.
Plasma/urine drug concentration - time profiles
7.5.2
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472_RD-01).
Drug concentration data identified with no sample available (NOS), no valid result (NOS), 
not analysed (NOA), BLQ, or no peak detectable (NOP) will be displayed as such and not 
replaced by zero at any time point (this rule also applies also to the lag phase, including the 
predose values).
Pharmacokinetics
7.5.3
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472_RD-01).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.6
RANDOMISATION
Subjects will be randomised within each dose group in a 3:1 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 


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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 24 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 SRD studies of the present type and is in general considered as 
sufficient for the exploratory evaluation of single dose safety and pharmacokinetics.


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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 principles laid down in the 
Declaration of Helsinki, in accordance with the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Harmonised Guideline 
for GCP and relevant BI SOPs, the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997), 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 treating physician of the subject.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH-GCP and Japanese GCP.
The BI 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 rule, 
no trial results should be published prior to finalization of the CTR.
The certificate of insurance cover is made available to the investigator and the subjects, and is 
stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB/independent ethics committee (IEC) and 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 investigator or delegate must give a full explanation to trial subjects based on the subject
information form. A language understandable to the subject should be chosen, technical terms 
and expressions avoided, if possible. 
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 his delegate must sign (or place a seal on) and date the informed consent form. 


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If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
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. Refer to Section 4.1.5.2 for 
rules about emergency code breaks. 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 that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make three documented attempts to 
retrieve previous medical records. If this fails, a verbal history from the subject, documented 
in their medical records, would be acceptable.
Before sending or uploading those copies, the investigator must ensure that all subject 
identifiers (e.g., subject’s name, initials, address, phone number, social security number) have 
properly been removed or redacted from any copy of the subjects’ source documents.


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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: gender, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including 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)

Completion of subject’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
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 (CRA), 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 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.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
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 subject data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB/IEC and the regulatory authorities.
8.6
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.
When the trial is completed, the investigator should inform the head of the trial site in writing 
of the completion of the trial, and the head of the trial site should promptly inform the IRB 
and sponsor in writing of the completion.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by BI.
Relevant documentation on the participating (principal) investigators (e.g., their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a CTL, responsible for coordinating all required 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,


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-
ensure appropriate training and information of clinical trial manager (CTM), CRAs, 
and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (operating unit [OPU]) in accordance with applicable 
regulations and BI SOPs, or by a CRO with which the responsibilities and tasks will have 
been agreed and a written contract filed before initiation of the clinical trial.
Safety laboratory tests will be performed by the local laboratory of the trial site or/and at an 
external vendor designated by the site.
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for evaluation. 
The analyses of BI 730357 concentrations in plasma will be performed at the 
 
.
 
On-site monitoring will be performed by BI.
Data Management and Statistical Evaluation will be done by BI or a CRO 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 (as protocol reference, if 
applicable) can be found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
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).
R13-2643
Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, 
Higgins PD, et al. Secukinumab, a human anti-IL-17A monoclonal 
antibody, for moderate to severe Crohn's disease: unexpected results of a 
randomised, double-blind placebo-controlled trial. Gut. 2012; 61 (12): 
1693-1700.
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/Guideline
s/Efficacy/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)
R16-2630
Ueda E, Kurebayashi S, Sakaue M, Backlund M, Koller B, Jetten AM. 
High incidence of T-cell lymphomas in mice deficient in the retinoid-
related orphan receptor RORγ. Cancer Research. 2002;62: 901-909.
R16-3149
Onishi RM, Gaffen SL. IL-17 and its target genes: mechanisms of IL-17 
function in disease. Immunology. 2010; 129: 311-321.
R16-3166
Miossec P. Cliical implications of Th17/IL-17. Diseases that may benefit 
from manipulating the Th17 pathway. Eur J Immunol. 2009; 39: 667-669.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472
Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c09228382
Investigators´s Brochure. BI 730357. Psoriasis (ankylosing spondylitis,
psoriatic arthritis, asthma, inflammatory bowel disease). Current version.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT
11.1
GLOBAL AMENDMENT 1 
Date of amendment
13 December 2018
BI Trial number
1407-0015
BI Investigational Medicinal 
Product(s)
BI 730357
Title of protocol
Safety, tolerability, and pharmacokinetics of single 
rising oral doses of BI 730357 in Japanese healthy 
male subjects  (double-blind, randomised, placebo-
controlled, parallel group design)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Section 3.1
Description of change
Changed section to be referred
Rationale for change
To correct error
Section to be changed
Section 4.1.5.1
Description of change
Added sentences to explain how to handling blind 
status
Rationale for change
To make charily how to handling blind status
Section to be changed
Section 5.2.4.1
Description of change
Deleted duplicate paragraphs
Rationale for change
Because of description mistake
Section to be changed
Section 5.3.3.2
Description of change
Rationale for change
Because of description mistake


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Section to be changed
Section 8.7
Description of change
Changed lab for analyte plasma and urine 
concentration
Rationale for change
Because of description mistake


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21031338
2.0
clinical-trial-protocol-version-02
Safety, tolerability, and pharmacokinetics of single rising oral doses of  BI 730357 in
Japanese healthy male subjects  (double-blind, randomised, placebo-controlled
parallel group design)
Author-Clinical Trial Leader
18 Dec 2018 03:09 CET
Author-Trial Statistician
18 Dec 2018 03:25 CET
Author-Trial Clinical
Pharmacokineticist
18 Dec 2018 03:43 CET
Approval-Therapeutic Area 
18 Dec 2018 09:55 CET
Approval-Team Member Medicine
19 Dec 2018 19:17 CET
Verification-Paper Signature
Completion
25 Dec 2018 16:14 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21031338
2.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
C26572624-02
BI Trial No.:
1407-0015
Title:
Safety, tolerability, and pharmacokinetics of single rising oral 
doses of BI 730357 in Japanese healthy male subjects (double-
blind, randomised, placebo-controlled, parallel group design)
Including Protocol Amendment 1 [c21031338-02]
Investigational
Product:
BI 730357
Responsible trial 
statisticians:
Phone: 
Fax: 
Phone: 
Fax: 
Date of statistical 
analysis plan:
07 MAY 2019 SIGNED 
Version:
Final
Page 1 of 35
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2019 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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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................20
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........22
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................22
7.3
TREATMENT COMPLIANCE........................................................................22
7.4
PRIMARY ENDPOINTS...................................................................................22
7.5
SECONDARY ENDPOINTS.............................................................................22
7.5.1
Key secondary endpoints....................................................................................22
7.5.2
Secondary endpoints...........................................................................................23
7.7
EXTENT OF EXPOSURE.................................................................................24
7.8
SAFETY ANALYSIS..........................................................................................24
7.8.1
Adverse events.....................................................................................................25
7.8.2
Laboratory data ..................................................................................................26
7.8.3
Vital signs.............................................................................................................27
7.8.4
ECG......................................................................................................................27
7.8.5
Others...................................................................................................................29
8.
REFERENCES....................................................................................................30


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10.
HISTORY TABLE..............................................................................................35


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR .........................................................12
Table 6.3: 1
Analysis sets for endpoints/data description ....................................................15
Table 6.7: 1
Time schedule of 12-lead ECG recordings ......................................................18
Table 10: 1
History table .....................................................................................................35


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis Dataset
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BMI
Body mass index
BP 
Blood pressure
CARE
Clinical Analysis and Reporting Environment
CDR
Clinical Data Repository
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic Coefficient of Variation
DB
Dose Proportionality, Between-Subject Design
DBLM
Database Lock Meeting
DILI
Drug induced liver injury
ECG
Electrocardiogram
ECGPCS
ECG Pharmacokinetic Concentration Set
eCRF
Electronic Case Report Form
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
HR
Heart rate
ICH
International Conference On Harmonisation
ISF
Investigators Site File


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Term
Definition / description
iPD
Important Protocol Deviation
IQRMP
Integrated Quality and Risk Management Plan
LLT
Lower Level Term
Max
Maximum
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PK
Pharmacokinetic(s)
PKS
PK parameter analysis set
PR
Pulse rate
PT
Preferred Term
Q1
1st quartile
Q3
3rd quartile
QD
Quaque die, once daily
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RPM
Report Planning Meeting
RR
Respiratory rate
SAS®
Statistical Analysis System
SD
Standard Deviation
SOC
System Organ Class
TMCP
Translational Medicine and Clinical Pharmacology
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, 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, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SAS® (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), 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 described in the TSAP are outlined in the CTP. The following changes 
compared to the protocol will be made:
In the protocol, it is stated that the medical examination at screening will include smoking 
and alcohol history. However, smoking and alcohol history are not captured in the eCRF, and 
thus, will neither be listed nor included in tables.
In contrast to the protocol, the pharmacokinetic parameter analysis set (PKS) will include all 
subjects in the treated set (TS), who provide either at least one secondary PK endpoint 
 
.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Section 2.1.2 of the CTP:
Primary endpoint to assess safety and tolerability of BI 730357 is the number [N (%)] of 
subjects with drug-related adverse events.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 2.1.3 of the CTP: 
The following pharmacokinetic parameters will be determined 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)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
It is planned that in total 24 Japanese healthy male subjects participate in this study, 
according to 3 sequential groups comprising 8 subjects per group. Within each dose group, 6
subjects will receive the active drug and 2 will receive 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 
Dose 
group
Treatment
Short label
1-3
P*
Placebo, tablet, qd
Placebo 
1
A
BI 730357, tablet, 50 mg, qd
BI 50mg 
2
B
BI 730357, tablet, 100 mg, qd
BI 100mg 
3
C
BI 730357, tablet, 2*100 mg, qd
BI 200mg 
*: The placebo 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 0:00h (midnight) on day of informed consent until 
administration time of study drug (BI or Placebo))

On treatment
o
BI/Placebo treatment (separately for each treatment, including residual effect 
period (REP);  i.e. ranging from the time of administration of BI 730357 or 
Placebo until 7 days thereafter or until 0:00h (midnight) on the day after trial 
termination date (whatever occurs first))

Follow-up (separately for each treatment, ranging from end of on treatment phase
until 0:00h (midnight) on the day after trial termination date) – labelled with FU Plc, 
FU 50mg, FU 100mg, and FU 200mg
Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov) of the CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening and Follow-up will not be included in this analysis. 
The following totals will be provided in addition:

a total over all BI treated phases (“BI Total”)

a total over all on treatment phases included in this analysis ("Total on treatment") 
(Section 15.3 only)


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B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov) of the CTR 
displays:

Screening 

On treatment (labelled with the name of the study treatment (short label))

Follow-up
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:

a total over all BI treated phases (“BI Total”)

a total over all study phases ("Total")
Tables of vital signs, ECG and laboratory values will present results by the above mentioned 
on treatment phase.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewer`s guide. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects.
Section 7.3 of the CTP: Important protocol deviations (iPDs) categories will be specified in 
the integrated quality and risk management plan (IQRMP), iPDs will be identified no later 
than in the Report Planning Meeting, and the iPD categories will be updated as needed.
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 and database lock meeting
(RPM/DBLM). 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).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes via an accompanying Excel spreadsheet (3). 
The iPDs will be summarised and listed.


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6.3
SUBJECT SETS ANALYSED

Treated set (TS): 
This subject set includes all subjects who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.
This is the full analysis set population in the sense of ICH-E9 (1). It is used for 
demographics, baseline characteristics, and safety analyses.
The ECG analyses are performed on the TS, except for the exposure-response analyses, 
which are performed on the ECGPCS defined below.
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 deviation relevant to the evaluation of PK (to be decided no later 
than in the Report Planning Meeting) or due to PK non-evaluability (as revealed during data 
analysis, based on the criteria specified below). Exclusion of a subject’s data will be 
documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e., the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medication
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.
parameter analysis set (PKS) includes all subjects from the TS receiving 
BI 730357 who provide either at least one secondary PK endpoint or the further 
pharmacokinetic endpoint AUC0-tz that was not excluded according to the description 
above.
It is used for assessment of dose proportionality and the descriptive analyses of PK 
parameters.


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The descriptive analysis of PK concentrations will be based on the ADS ADPC. The 
descriptive analysis of PK parameters will be based on the ADS ADPP.

ECG Pharmacokinetic Concentration Set (ECGPCS):
This subject set includes all subjects from the TS for whom at least one pair of a valid 
drug plasma concentration of BI 730357 and a corresponding (i.e. time-matched) ECG 
endpoint to be used in the exposure-response analyses was provided. 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 data-base lock.
Table 6.3: 1
Analysis sets for endpoints/data description
Endpoint/data description
Analysis set
TS
PKS
ECGPCS
Primary and further safety endpoints (incl. ECG) 
X
ECG endpoints and plasma concentrations used in 
exposure-response analysis
X
Secondary PK endpoints (and AUC0-tz)
X
Demographic/baseline data
X
Important protocol deviations
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).


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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, a missing value is obtained only in case that
(i)
all on treatment values are missing and
(ii)
the baseline value is less than or equal to 500 msec, or missing.
If condition (i) is fulfilled but the baseline value is greater than 500 msec, this case will be 
categorized as ‘no new onset’. If baseline is missing and the maximum on treatment 
QTc interval is greater than 450 msec (or 500 msec for QT interval, respectively), this is 
classified as a ‘new onset’ in the respective category. If baseline is missing and the maximum 
QTc interval is less than or equal to 450 msec (or 500 msec for QT interval, respectively), 
this will be categorized as ‘no new onset’. If baseline is missing, a QTc/QT interval 
> 500 msec at any time on treatment will be a notable finding.
For placebo subjects, the missing plasma concentration values will be replaced by 0 for the 
exposure-response analyses. 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
The baseline value is defined as the last measurement before administration of BI 730357 or 
Placebo.
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 study 
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 hours-period prior to 
the trial drug administration (including blank values for PK).
The tolerance for drug administration will be ± 1 minute on Days 1.
The acceptable deviation on Day 1 from the scheduled time for vital signs and ECG will be    
-15 minutes for the first 4 hours after the drug administration and - 30 minutes thereafter.
After Day 2, vital signs and ECG will be ± 30 minutes from the scheduled time. Blood
sampling for safety laboratory tests will be ± 30 minutes for the first 24 hours after trial drug


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administration. Urine sampling for safety laboratory tests will be -3 hours on Day 2 (24 
hours after trial drug administration).
Procedures on Days 4, 5 and 8 to be performed within ±3 hours from planned time.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.
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.
There will be a centralised evaluation of the 12-lead ECG recordings at the time points and 
for the ECG recordings specified in the Table 6.7: 1 below:


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Table 6.7: 1
Time schedule of 12-lead ECG recordings
Visit
Day
Planned time [hh:mm]
(relative to drug 
administration)
Study phase
Central evaluation
1
-28 to -2
Screening
NA
2
1
-03:00
Baseline
all 3 single ECGs of the 
triplicate
00:30
On treatment
first single ECG of the 
triplicate
01:00
first single ECG of the 
triplicate
02:00
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
single ECG
34:00
single ECG
3
48:00
single ECG
4
72:00
single ECG
3
9 to 13
End of study 
examination
NA
At Visits 1 and 3 as well as at visit 2, day 2, day 3 and day 4, single ECGs will be recorded.
The baseline value of an ECG variable is defined as the mean of the triplicate ECG 
measurements prior to drug administration.
Section 5.2.4.1 of the CTP: A post-study centralized evaluation of all 12-lead ECGs 
recorded after Days 1 up to 72 hours after drug administration will be performed by an 
independent ECG laboratory. This analysis will include the determination of cardiac axis as 
assessed by the ECG machine’s algorithm as well as the intervals RR, PR, QRS and QT 
measured semi-automatically. With the exception of the first triplicate ECG (used as baseline 
before the first drug administration), only the first of the triplicate ECG at a single 
assessment time will be evaluated. […].


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For the exposure response analyses, pairs of ECG variables and corresponding plasma 
concentrations will be built using the same planned time points, e.g. HR change from 
baseline and the plasma concentration measured at planned time 1:00 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. This critical time deviation depends on the PK properties. When plasma 
concentrations are expected to change only little around a given time point, the acceptable 
time deviation between ECG recording and PK blood sampling may be bigger.


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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 and 7.6) 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 
 
 BI (TCPKr). The individual values of all subjects and 
descriptive statistics will be presented in Appendix 16.1.13.5 and Section 15.6 of the CTR, 
respectively.
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-calculations.
For PK calculation, 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.
The individual values of all subjects will be listed, sorted by treatment group, subject number, 
and visit. 
The listings except PK evaluations 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 non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum


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For analyte concentrations and PK parameters, the following descriptive statistics will 
additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
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. 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 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (7).


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by treatment group and in total. 
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 latest version of the coding system of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA). Medications will be coded 
using the latest version of 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/DBLM.
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 
 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/DBLM and described in the CTR.
7.4
PRIMARY ENDPOINTS
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of 
BI 730357.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been specified in the 
protocol.


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7.5.2
Secondary endpoints


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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.


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7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (9).
The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 
For analysis, multiple AE occurrence data on the electronic case report form (eCRF) will be 
collapsed into an AE provided that all of the following applies:

All AE attributes are identical (lower level term (LLT), intensity, action taken, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest (AESI))

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
two occurrences is given if the second occurrence started within one hour after end of 
the first occurrence)
For further details on summarization of AE data, please refer to [001-MCG-156] (9).
Section 5.2.6.1.4 of the CTP: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥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.
The analysis of adverse events will be based on the concept of treatment emergent AEs. 
Section 1.2.6 of the CTP: The residual effect period (REP) for BI 730357 is not known at 
this early stage of development and therefore conservatively defined as 7 days. 


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Section 7.3.4 of the CTP:
Therefore, measurements planned or AEs recorded prior to intake of trial medication will be 
assigned to the screening period, those between trial medication intake and end of REP […] 
will be assigned to the treatment period. Events occurring after the REP but prior to trial 
termination date will be assigned as ‘follow-up’.
For more details see the TSAP ADS plan.
According to ICH E3 (10), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the investigator or Clinical Trial Leader.
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), as well as by treatment, worst intensity, primary SOC 
and PT. Separate tables will be provided for subjects with other significant AEs according to 
ICH E3 (10), for subjects with serious AEs, for subjects with drug-related AEs, for subjects 
with drug related serious adverse events and for subjects with AESIs.
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.
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/DBLM at the latest).
Descriptive statistics of laboratory data will be calculated by planned time point based on the 
worst value of the subject at that planned time point (or assigned to that planned time point).


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7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (BP, PR, RR and body temperature).
Descriptive statistics will be calculated by planned time point based on the last value of the 
subject at that planned time point (or assigned to that planned time point).
7.8.4
ECG
Continuous safety ECG monitoring (by investigator)
Clinically relevant abnormal findings will be reported as AEs.
No separate listing or analysis of continuous ECG monitoring will be prepared.
12-lead ECG
Abnormal findings, irrespective of whether they originate from central or local evaluation,
will be reported as baseline conditions (at screening) or as AEs (during the trial) if judged 
clinically relevant by the investigator. 
All evaluations 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 changes from 
baseline over time of QTcF, HR, QT, 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 will be provided by 
overlaying time profiles of plasma concentrations and QTcF changes from baseline (QTcF). 
These figures will be generated for each subject (presented in Statistical Appendix of the 
CTR), as well as for means per active treatment (presented in the End-of-Text part of the 
CTR).
The relationship between BI 730357 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 730357 and placebo of QTcF change from baseline and 
its 90% confidence interval at the geometric mean of 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. For 
more details refer to Section 9.3.
For visualization, a scatterplot of the BI 730357 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.
To check model assumptions, the conditional residuals will be plotted and presented in the 
Statistical Appendix of the CTR. 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 9.1 using all time points. A scatterplot of QTcF vs RR including the overall
regression line will be included in the Statistical Appendix of the CTR. The resulting (fixed 


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effect) slope together with two-sided 95% confidence intervals will be included in the 
footnote for this plot.
7.8.5
Others
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e. a condition already existent before intake of study drug) or as AE and will be 
summarised as such. 
No separate listing or analysis of physical examination findings will be prepared.


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8.
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.
BI-KMED-COPS-TMP-0001: "iPD log", current version; KMED
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.
001-MCG-156: “Analysis and Presentation of Adverse Event Data from Clinical Trials”, 
current version; IDEA for CON.
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. Ring A. Statistical models for heart rate correction of the QT interval. Stat Med (2010)
[R10-2920]


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
07-MAY-2019
None
This is the final TSAP without any 
modification