Clinical trial NCT03588390
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2018-07-31; Completion date: 2018-11-14
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to investigate the safety and tolerability of BI 1323495 in healthy male subjects following oral administration of single rising doses.

Secondary objectives are the exploration of the pharmacokinetics (PK) including dose proportionality and pharmacodynamics (PD) of BI 1323495 after single dosing and the assessment of the PK/PD relationship.

Detailed description:

Arms: arm 1: Participants were orally administered single dose of BI 1323495 dose group 1 or matching placebo film-coated tablet with 240 mL of water after an overnight fast of at least 10 h. arm 2: Participants were orally administered single dose of BI 1323495 dose group 2 or matching placebo film-coated tablet with 240 mL of water after an overnight fast of at least 10 h. arm 3: Participants were orally administered single dose of BI 1323495 dose group 3 or matching placebo film-coated tablet with 240 mL of water after an overnight fast of at least 10 h. arm 4: Participants were orally administered single dose of BI 1323495 dose group 4 or matching placebo film-coated tablet with 240 mL of water after an overnight fast of at least 10 h. arm 5: Participants were orally administered single dose of BI 1323495 dose group 5 or matching placebo film-coated tablet with 240 mL of water after an overnight fast of at least 10 h. arm 6: Participants were orally administered single dose of BI 1323495 dose group 6 or matching placebo film-coated tablet with 240 mL of water after an overnight fast of at least 10 h. arm 7: Participants were orally administered single dose of BI 1323495 dose group 7 or matching placebo film-coated tablet with 240 mL of water after an overnight fast of at least 10 h. arm 8: Participants were orally administered single dose of BI 1323495 dose group 8 or matching placebo film-coated tablet with 240 mL of water after an overnight fast of at least 10 h.
Interventions: intervention 1: BI 1323495 intervention 2: BI 1323495 intervention 3: BI 1323495 intervention 4: Placebo intervention 5: Placebo intervention 6: Placebo
Intervention descriptions: intervention 1: Low strength tablet intervention 2: Middle strength tablet intervention 3: High strength tablet intervention 4: Placebo to low strength tablet intervention 5: Placebo to middle strength tablet intervention 6: Placebo to high strength tablet

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c21116620-03
EudraCT No.:
BI Trial No.:
2017-004899-62
1405-0001
BI Investigational
Product:
BI 1323495
Title:
Safety, tolerability, pharmacokinetics, and pharmacodynamics of 
single rising oral doses of BI 1323495 in healthy male subjects
(single-blind, partially randomised, placebo-controlled parallel group 
design)
Lay Title:
This study in healthy men tests how different doses of BI 1323495 are 
taken up in the body and how well they are tolerated.
Clinical Phase:
I
Trial Clinical Monitor:
Phone: 
Fax: 
Principal Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date:
Version: 3.0
Date: 28 August 2018
Page 1 of 77
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1323495
Protocol date:
Trial number:
Revision date:
28 August 2018
24 April 2018
1405-0001
Title of trial:
Safety, tolerability, pharmacokinetics, and pharmacodynamics of single rising oral 
doses of BI 1323495 in healthy male subjects (single-blind, partially randomised, 
placebo-controlled parallel group design)
Principal Investigator:
Trial site:
 
Clinical phase:
I
Objectives:
To investigate safety, tolerability, pharmacokinetics, and pharmacodynamics 
following single rising oral doses of BI 1323495
Methodology:
Single-blind, partially randomised within dose groups, placebo-controlled, parallel-
group
No. of subjects: 
total entered:
64* 
each treatment:
8 per dose group (6 on active drug and 2 on placebo)
* Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned and 
approved highest dose will not be exceeded and none of the stopping criteria apply. Thus, the 
actual number of subjects entered may exceed 64, but will not exceed 80 subjects.
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 45 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test products:
BI 1323495 film-coated tablets (dose strengths 
 mg)
dose:
 mg as single dose
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h
Comparator products: Matching placebo tablets
dose:
Not applicable
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment: one single dose


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1323495
Protocol date:
Trial number:
Revision date:
28 August 2018
24 April 2018
1405-0001
Criteria for
pharmacokinetics:
Secondary endpoints: AUC
and C
Criteria for 
pharmacodynamics:
 
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 1323495 is the number [N 
(%)] of subjects with drug-related adverse events.
Further criteria of interest: AEs including clinically relevant findings from the 
physical examination, safety laboratory tests, 12-lead electrocardiogram (ECG), 
continuous ECG monitoring, vital signs (blood pressure [BP], pulse rate [PR]).
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
Dose proportionality of BI 1323495 will be explored using a regression model. A 
95% confidence interval (CI) for the slope will be computed.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 12
1.2
DRUG PROFILE...............................................................................................13
1.2.2
Toxicology..............................................................................................14
1.2.5
Clinical experience in humans.............................................................18
1.2.6
Drug product.........................................................................................19
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 20
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................20
2.1.1
Starting dose..........................................................................................20
2.1.2
Maximum dose and dose escalation ....................................................21
2.1.3
Conclusion .............................................................................................22
2.2
TRIAL OBJECTIVES.......................................................................................22
2.3
BENEFIT - RISK ASSESSMENT ...................................................................23
2.3.1
Procedure-related risks ........................................................................23
2.3.2
Drug-related risks.................................................................................23
2.3.2.5
Drug-induced liver injury ........................................................25
2.3.3
Safety measures.....................................................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 28
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................28
3.1.1
Administrative structure of the trial...................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................30
3.3
SELECTION OF TRIAL POPULATION ......................................................31
3.3.1
Main diagnosis for study entry............................................................31


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3.3.2
Inclusion criteria...................................................................................31
3.3.3
Exclusion criteria ..................................................................................31
3.3.4
Removal of subjects from therapy or assessments.............................33
3.3.4.1
Removal of individual subjects................................................33
3.3.4.2
Discontinuation of the trial by the sponsor..............................33
3.3.5
Replacement of subjects .......................................................................34
4.
TREATMENTS........................................................................................ 35
4.1
TREATMENTS TO BE ADMINISTERED....................................................35
4.1.1
Identity of BI investigational and comparator products...................35
4.1.2
Method of assigning subjects to treatment groups ............................36
4.1.3
Selection of doses in the trial................................................................37
4.1.4
Drug assignment and administration of doses for each subject .......37
4.1.5
Blinding and procedures for unblinding ............................................38
4.1.5.1
Blinding....................................................................................38
4.1.5.2
Procedures for emergency unblinding .....................................38
4.1.6
Packaging, labelling, and re-supply ....................................................38
4.1.7
Storage conditions.................................................................................39
4.1.8
Drug accountability ..............................................................................39
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................40
4.2.1
Other treatments and emergency procedures....................................40
4.2.2
Restrictions............................................................................................40
4.2.2.1
Restrictions regarding concomitant treatment .........................40
4.2.2.2
Restrictions on diet and life style.............................................40
4.3
TREATMENT COMPLIANCE.......................................................................41
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 42
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................42
5.1.1
Endpoints of efficacy.............................................................................42
5.1.2
Assessment of efficacy...........................................................................42
5.2
SAFETY..............................................................................................................42
5.2.1
Endpoints of safety................................................................................42
5.2.2
Assessment of adverse events...............................................................42
5.2.2.1
Definitions of adverse events...................................................42
5.2.2.2
Adverse event collection and reporting ...................................45
5.2.3
Assessment of safety laboratory parameters......................................46
5.2.4
Electrocardiogram................................................................................50
5.2.4.1
12-lead resting ECG.................................................................50
5.2.4.2
Continuous ECG monitoring ...................................................52
5.2.5
Assessment of other safety parameters...............................................52
5.2.5.1
Vital signs ................................................................................52
5.2.5.2
Medical examinations..............................................................52


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5.4
APPROPRIATENESS OF MEASUREMENTS.............................................53
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................53
5.5.1
Pharmacokinetic endpoints..................................................................53
5.5.1.1
Secondary endpoints................................................................53
5.5.2
Methods of sample collection...............................................................54
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................54
5.5.3
Analytical determinations ....................................................................57
5.7
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....58
6.
INVESTIGATIONAL PLAN.................................................................. 59
6.1
VISIT SCHEDULE............................................................................................59
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................59
6.2.1
Screening period....................................................................................59
6.2.2
Treatment period ..................................................................................59
6.2.3
End of trial period.................................................................................60
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 61
7.1
STATISTICAL DESIGN – MODEL ...............................................................61
7.1.1
Objectives...............................................................................................61
7.1.2
Endpoints...............................................................................................61
7.1.3
Model......................................................................................................61
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................61
7.3
PLANNED ANALYSES....................................................................................61
7.3.1
Primary analyses...................................................................................62
7.3.2
Secondary analyses ...............................................................................62
7.3.3
Safety analyses.......................................................................................63
7.3.4
Preliminary PK analyses......................................................................64
7.3.5
Pharmacokinetic analyses ....................................................................65
7.3.6
Biomarker analysis ...............................................................................66
7.4
HANDLING OF MISSING DATA ..................................................................66
7.4.1
Safety......................................................................................................66
7.4.2
Plasma
 drug concentration - time profiles ...............................66


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7.4.3
Pharmacokinetic parameters...............................................................66
7.5
RANDOMISATION ..........................................................................................66
7.6
DETERMINATION OF SAMPLE SIZE ........................................................67
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 68
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................68
8.2
DATA QUALITY ASSURANCE .....................................................................68
8.3
RECORDS..........................................................................................................69
8.3.1
Source documents .................................................................................69
8.3.2
Direct access to source data and documents.......................................69
8.3.3
Storage period of records.....................................................................69
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................70
8.5
STATEMENT OF CONFIDENTIALITY.......................................................70
8.6
COMPLETION OF TRIAL..............................................................................70
9.
REFERENCES......................................................................................... 71
9.1
PUBLISHED REFERENCES...........................................................................71
9.2
UNPUBLISHED REFERENCES.....................................................................73
10. APPENDICES .......................................................................................... 74
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 75


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
ANCOVA
Analysis of covariance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 hours after administration
 
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL
Clearance
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
Cmin
Minimum measured concentration of the analyte in plasma
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury
ECG
Electrocardiogram
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
 
gMean
Geometric mean
HPC
Human Pharmacology Centre


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HR
Heart rate
IB
Investigator’s brochure
IC50
Half-maximal inhibitory concentration
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MedDRA
Medical Dictionary for Regulatory Activities
MRSD
Maximum recommended starting dose
MRTpo
Mean residence time of the analyte in the body after oral administration
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
ss
(at) steady state
TMF
Trial master file
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
tz
Time of last measurable concentration of the analyte in plasma
TDMAP
Trial Data Management and Analysis Plan
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vss
Volume of distribution at steady state
Vz/F
Apparent volume of distribution during the terminal phase after
extravascular administration


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1.
INTRODUCTION
 
 
 In this study, BI 1323495 will be given to humans for the first time. Safety, 
tolerability, pharmacokinetics, and pharmacodynamics of single rising doses of BI 1323495
will be investigated.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2
DRUG PROFILE
 
 
 
 
 
 
 
 
 
 


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For details on nonclinical pharmacology refer to the current version of the Investigator’s 
Brochure (IB, c21238478-01).
1.2.2
Toxicology
 
Details on toxicology results are provided in the current 
version of the IB (c21238478-01).
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2.5
Clinical experience in humans
To date, no experience with BI 1323495 is available in human.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2.6
Drug product
 
Further details are given in the Investigator’s Brochure
(c21238478-01).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
As a transition from preclinical investigations to clinical development in this first-in-man 
trial, safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 1323495 will be 
assessed in healthy male volunteers using single rising oral doses in order to provide the basis 
for a potential ongoing clinical development of BI 1323495 
 
Healthy male subjects aged 18 - 45 years will be recruited for this study. They provide a 
relatively stable physiological, biochemical, and hormonal basis (steady state) for studying 
drug effects, they show no disease-related variation, and they are not taking concomitant 
medication. 
Within each dose group, all actively treated individuals will receive the same BI 1323495
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.
It is intended to investigate the following dose levels of BI 1323495 in this trial: 
 mg.
The background for this dose selection is described in the following paragraphs.
2.1.1
Starting dose
It is best practice to use different methods for dose selection and to take a starting dose at the
lower end of the dose range if different methods give different estimates (err on the side of
caution).
Applying the respective calculation as given in the US FDA Guidance for Industry 
'Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers' (R06-1037), and assuming a no adverse effect level (NOAEL) of 
 a maximum recommended starting dose (MRSD) as high as 
could be 
selected based on the 4 week toxicology data 
 A detailed description of the derivation 
of the MRSD can be found in the IB (c21238478-01).
The therapeutic human dose of BI 1323495 is predicted to be 
(see Section 
1.2.4). The starting dose should be sub-therapeutic; therefore it should be lower than the 
expected therapeutic dose. Application of a factor of 10 to the predicted therapeutic human 
dose results in a maximum recommended safe starting dose of approximately 
 in 
humans. 
A single dose of 
is predicted to achieve exposures of 
 
which is well below expected therapeutic exposures of 
 
providing even sufficient margin to therapeutic exposures should the 
bioavailability be higher than the predicted 
 (see Section 1.2.4).
 


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Finally, another commonly used NOAEL-based approach, following ICH guidance M3 (R2), 
is to use a fraction of the NOAEL, e.g. 1/50 or 1/100 (R09-1400). Based on the 
NOAEL 
of 
 body weight and assuming a body weight of 50 kg the starting dose would be in 
the range of 
Taken together, different approaches give a starting dose in the range of 
is finally considered as an appropriate and safe starting dose based on:

Published experience from clinical trials with administration of 
 
and achieving higher levels of target engagement over longer periods of time not 
revealing any mode of action-related adverse effects (Section 1.2.5);

the toxicological profile of BI 1323495 in relevant animal models (Section 1.2.2);

the effect 
 being reversible;

only single doses being applied;

lower peak exposures being expected in 
Therefore at expected exposures achieved with this dose, 
 is not expected to 
trigger any relevant or unacceptable biological activity (Section 1.2.5).
2.1.2
Maximum dose and dose escalation
As stated above, a minimum daily dose of about 
 may be required to achieve 
therapeutic systemic exposure of BI 1323495. Nevertheless, it is planned to explore higher 
doses / exposures in this trial for several reasons. Subsequent clinical trials in patients might 
show that required therapeutic doses and exposures are significantly higher than predicted. 
Also, higher doses / exposures might be required for more severe disease states, for induction 
vs. maintenance treatment, and for other indications. So while higher doses and exposures
might still be well tolerated they provide a larger magnitude of therapeutic effects. Further, 
testing of doses higher than 
 is also reasonable to compensate for any bioavailability 
and half-life being lower/shorter than expected. If, for example, bioavailability was 
significantly less than the predicted 
 (see Section 1.2.4), the therapeutic dose could 
eventually turn out to be several fold higher than currently predicted. And even if the 
therapeutic dose turns out to be as low as 
 higher than therapeutic doses / exposures 
are typically explored in the well-controlled clinical environment of first-in-man trials to 
provide a safety margin for following trials, e.g. drug-drug-interaction trials, trials with 
patients with impaired excretion function, etc., where substantial increases in exposure may 
be seen.
The maximum human exposure to BI 1323495 in this trial will be limited to 
 nM for 
Cmax and 
 nM*h for AUC0-24.
This provides a safety margin with a factor of at least 24 (Cmax) and 21 (AUC) to the 
exposures achieved after 4-week administration of 
/kg in the most sensitive species, 


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These findings are not expected after a single administration of BI 1323495 at doses 
achieving exposure levels well below exposures 
 
With respect to the NOAEL 
 in the 4-week toxicity study 
 
 the maximum human exposure defined above 
provides safety factors of 16 and 10, respectively. The given safety margins refer to the lower 
exposures 
With respect to the NOAEL in 
 in the 4-week toxicity study  
 this maximum 
human exposure provides safety margins of approximately 28 and 34, respectively.
On the other hand, the defined acceptable maximum exposure for this trial provides a margin 
of factor 
 (Cmax) and  (AUC) above the expected therapeutic exposure 
 
 to explore the therapeutic potential of the compound. 
For the present trial, a maximum dose of 
has been selected, but this dose will only be 
administered if, based on interim PK measurements (see Section 7.3.4), individual Cmax or 
AUC0-24 values at a lower dose or predicted geometric mean values of Cmax or mean AUC0-24
do not exceed exposure limits defined above. Otherwise dose escalation will be stopped at 
lower doses. Based on the preclinical safety profile of BI 1323495, these exposure limits are 
anticipated to be safe and well tolerated.
The escalation schedule has been chosen in a way that a shallow escalation will be applied for 
the higher dose levels with a factor not greater than 1.5. This dose escalation is considered to 
be adequate and safe, particularly when the selected exposure safety margins are taken into 
consideration.
2.1.3
Conclusion
The safe starting dose in this study is determined to be 
 This dose is not expected to 
trigger any relevant or unacceptable biological activities.
An exposure threshold is defined 
The following dose escalation scheme is planned: 
as single oral dose. Dose escalation will be guided by interim PK measurements (see Section 
7.3.4) and projected exposure levels.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and tolerability of BI 1323495 in 
healthy male subjects following oral administration of single rising doses.
Secondary objectives are the exploration of the pharmacokinetics (PK) including dose 
proportionality and pharmacodynamics (PD) of BI 1323495 after single dosing and the 
assessment of the PK/PD relationship. 


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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.
2.3
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 development of a new
orally available drug, which might improve the therapy in patients with 
The subjects are exposed to the risks of the study procedures and the risks 
related to the exposure to the trial medication.
2.3.1
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling 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 same risks apply to venipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
2.3.2
Drug-related risks
Factors of risk may derive from particular knowledge or the lack thereof, regarding (1) the 
mode of action, (2) the nature of the target, (3) the relevance of animal models and/or (4) 
findings in non-clinical safety studies.
 
 
 
 
 


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2.3.2.5
Drug-induced liver injury
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety, see also Section 5.2.2.1, adverse events of special interest.
2.3.3
Safety measures

Dose selection was based on a sound preclinical package including 4 week toxicological 
studies (see Section 1.2.3) and non-clinical pharmacology data (Section 1.2.1).
Careful selection of starting dose as described in Section 2.1. 
Dose escalation will be shallow with an increase of not more than 1.5 fold at the higher 
dose groups.


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
Measurement of BI 1323495 plasma concentrations and preliminary determination of PK 
parameters (Cmax, AUC0-24, see Section 7.3.4). For precautionary reasons, drug plasma 
concentrations in this healthy volunteer trial should not exceed a Cmax of 
 or an
AUC0-24 of 
and will be considered as a preliminary threshold (see Section 
2.1). Further dose progression would only be allowed after a safety interim analysis and 
filing and approval of a substantial CTP amendment.

For safety reasons, each dose group of 8 subjects (6 on active, 2 on placebo) will be 
divided into three cohorts. In the 1st cohort only 2 subjects will be treated: one subject
will receive active treatment, the other subject will receive placebo. If BI 1323495
treatment is safe and well tolerated in this first cohort, the following 2 subjects on active 
will be treated in the 2nd cohort with drug administration occurring not earlier than 24
hours after the first subject of the dose level received active treatment. The remaining 4 
subjects (either active or placebo) are the third cohort and will be treated no sooner than 
48 hours following the 1st cohort. Within each cohort, a time interval of at least 10 min 
will be maintained between administrations of study drug.
This design ensures that between first and second active dose of each dose level there is a 
time interval of at least 24 hours, which is expected to be sufficient to detect relevant first 
acute effects of BI 1323495.

Only if the respective dose of BI 1323495 was safe and showed acceptable tolerability 
and if no stopping criterion was met (see Section 3.3.4.2), the next higher dose will be 
given at least 6 days later (referring to the 1st subject of each dose group).
A documented Safety Review must take place prior to each dose escalation (see Section 
3.1).

An extensive safety laboratory will be performed (see Section 5.2.3).

A thorough ECG monitoring including continuous ECG measurement over 4 hours post-
dose and repeated 12-lead ECGs during the observation period following drug 
administration. Dose escalation would be stopped as soon as at least 2 subjects at one 
dose level showed relevant QT prolongation (see Section 3.3.4.2 for details).

The subjects will stay at the trial site (BI Human Pharmacology Centre) for at least 34
hours after study drug administration. Based on an anticipated half-life of BI 1323495 of 
approximately 
 this is expected to cover the period of highest risk / peak effect.

During in-house confinement the subjects will be under medical observation and 
thoroughly monitored for both expected and unexpected adverse events.
In summary, although not tested in humans to date, BI 1323495 has the potential to become 
an oral treatment for patients with 
. Based upon preclinical data for BI 1323495 and 
clinical information from competitor compounds as well as the implemented safety measures
described above, healthy subjects will not be exposed to undue risks in relation to 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 first-in-man clinical trial with BI 1323495. Considering the medical need 
of the development of an effective treatment for patients with 
 the Sponsor considers 


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that the benefit outweighs the potential risks and justifies exposure of healthy human 
volunteers.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This single-rising dose trial is designed as single-blind, partially randomised, and placebo-
controlled within parallel dose groups.
A total of 64 healthy male subjects is planned to participate in the trial, according to 8 
sequential groups comprising 8 subjects per group. However, additional subjects may be 
entered to allow testing of additional doses on the basis of experience gained during the trial 
conduct (e.g., preliminary PK data), provided the planned and approved highest dose will not 
be exceeded. Thus, the actual number of subjects entered may exceed 64, but will not exceed 
80 subjects entered. Such changes may be implemented via non-substantial CTP 
Amendments provided additional doses are used for the further evaluation of 
pharmacokinetics or pharmacodynamics in the absence of new safety signals. The addition of 
dose groups to further evaluate safety findings may be implemented only after notification of 
a substantial amendment.
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. Each dose group will consist of 3 cohorts 
which will be treated subsequently for safety reasons.
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
4
5
6
7
8
Dose 
Number of subjects
8
8
8
8
8
8
8
8
Subjects receiving placebo
2
2
2
2
2
2
2
2
Subjects receiving active drug
6
6
6
6
6
6
6
6
The dose groups will be investigated consecutively in ascending order of doses, maintaining a 
time interval of at least 6 days between the first 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, tolerability, and pharmacokinetic data of
the preceding dose groups. The next dose will only be given if, in the opinion of the 
investigator, no safety concerns arose in the preceding dose group (i.e., no dose-limiting 
events occurred) and if none of the pre-specified trial-specific stopping criteria were met 
(refer to Section 3.3.4.2).
A documented Safety Review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested any time for any reasonable cause by the 
Principal Investigator (or an authorised deputy) or the sponsor of the study, e.g. because of 
any unforeseen adverse events, etc. Dose escalation will only be permitted if no safety 


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concerns exist in the opinion of the Principal Investigator (or an authorised deputy) and the 
trial clinical monitor (or an authorised deputy).
Although no formal Safety Review meeting will take place within a given dose group, safety 
will be continuously monitored during this trial, and an individual will only be dosed in the 
absence of any safety concern (i.e., no dose-limiting events occurred) and if none of the pre-
specified trial-specific stopping criteria have been met (refer to Section 3.3.4.2).
The minimum data set for review consists of the following data:

AEs in the current* and preceding dose groups including clinically relevant findings 
from ancillary safety testing listed below up to at least 48 h post-dosing.
Note: AEs may be ongoing at the time of Safety Reviews and AE information may be 
subject to change prior to Database Lock.
 

Vital signs in the current* and preceding dose groups up to at least 48 h post-dosing

Clinical laboratory tests in the current* and preceding dose groups up to at least 24 
hours post-dose

Preliminary PK data for selected time points as per Section 7.3.4

Check of criteria for stopping subject treatment as per Section 3.3.4.1
*”Current dose group” means: all subjects of that dose group with at least 4 subjects being on active treatment.
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the trial clinical monitor (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs, and out-of-range 
laboratory results (if considered clinically significant). Safety Reviews can be conducted 
face-to-face or by video/telephone conference. The trial clinical monitor 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 ISF and TMF.
The investigator is allowed to alter the scheduled dose levels (e.g. add low and/or
intermediate dose levels) on the basis of experience gained during the study, provided the 
planned and approved highest dose is not exceeded. In this case, the total number of subjects 
in this trial might increase. The investigator and/or the sponsor should stop dose escalation in 
case the safety evaluation leads to concerns that would not allow higher dosing.
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.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,


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-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany.
The trial will be conducted at the 
 
, under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
 
 
 
 
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research 
organisation appointed by BI and according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For single-rising dose trials, the design described in Section 3.1 is viewed 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 1323495.
With the rising dose design, single-blind conditions regarding the subject’s 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.


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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. 6 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 64 healthy male subjects will enter the study. The actual number of subjects 
entered may exceed the total of 64 if additional intermediate doses will be tested (see Section 
3.1). Subjects will be recruited from the volunteers' pool of the trial site.
Only male subjects will be included into the study because hitherto no data on reproductive 
toxicology are available.
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.
3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 45 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator


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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)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. 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. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 30 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. A marked baseline prolongation of QT/QTc interval such as QTc intervals that are 
repeatedly greater than 450 ms or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
22. 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 
23. Male subjects with female partner of childbearing potential who are unwilling to use male 
contraception (condom or sexual abstinence) from the first administration of trial 
medication until 30 days after last administration of trial medication
24. Current or history of relevant kidney, urinary tract diseases or abnormalities (e.g. 
nephrolithiasis, hydronephrosis, acute or chronic nephritis, renal injury, renal failure)
25. Estimated glomerular filtration rate according to CKD-EPI formula < 90 mL/min at 
screening (R12-1392)
26. Within 10 days prior to administration of trial medication, use of any drug that could 
reasonably inhibit platelet aggregation or coagulation (e.g., acetylsalicylic acid)


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27. Liver enzyme (ALT, AST, GGT) values above upper limit of normal at the screening 
examination
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events (AEs), or diseases)
4. The subject shows 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) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. Dose escalation will be terminated if more than 50% of the 
subjects at one dose level show drug-related and clinically relevant adverse events of 
moderate or severe intensity.


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No further subjects will be dosed without thorough re-evaluation of the benefit-risk ratio, 
if severe non-serious adverse events considered as drug-related by the investigator are 
reported in 2 subjects of the same dose group or if at least one drug-related serious 
adverse event is reported.
2. The expected enrolment goals overall are not met
3. Violation of GCP, or the CTP by a trial site or investigator, disturbing the appropriate 
conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
5. Dose escalation will be stopped as soon as at least 2 subjects at one dose level on active 
drug showed relevant individual QT prolongation, i.e. absolute QT or QTc greater than 
500 which has been confirmed by a repeat ECG recording or QTc increase of greater 60
ms from baseline in connection with absolute QT or QTc greater than 500 ms, which has 
been confirmed by a repeat ECG recording.
6. Dose escalation will be stopped if the Cmax or AUC0-24 of at least 1 subject of one dose 
group increases above the following exposure thresholds or if the estimated systemic 
exposure (group gMean values) of the next dose level is expected to exceed a Cmax of 
nM or an AUC0-24 of 
 nM*h. In this case, one or two dose levels lower than 
the planned next dose level may be given, as long as the expected systemic exposure 
(group gMean values) of each dose is not expected to exceed the aforementioned
thresholds.
3.3.5
Replacement of subjects
In case some subjects do not complete the trial or there is not a sufficient number of subjects 
on active within one dose group (see Section 3.1), the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. A replacement subject will be assigned a unique study subject number, and will 
be assigned to the same treatment as the subject he replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational products have been manufactured by BI Pharma GmbH & Co. KG. 
4.1.1
Identity of BI investigational and comparator products
The characteristics of the test products are given below:
 Tablet
Substance:
BI 1323495
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
1-0-0 (DG 1), 3-0-0 (DG 2), 6-0-0 (DG 3)
Route of administration:
p.o.
Duration of use:
Single dose
 Tablet
Substance:
BI 1323495
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
2-0-0 (DG 4), 4-0-0 (DG 5), 6-0-0 (DG 6)
Route of administration:
p.o.
Duration of use:
Single dose
 Tablet
Substance:
BI 1323495
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
3-0-0 (DG 7), 4-0-0 (DG 8)
Route of administration:
p.o.
Duration of use:
Single dose


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The characteristics of the reference products (placebo) are given below:
Placebo to 
 Tablet
Substance:
Placebo matching in size and weight to 
mg tablet
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
1-0-0 (DG 1), 3-0-0 (DG 2), 6-0-0 (DG 3)
Route of administration:
p.o.
Duration of use:
Single dose
Placebo to 
 Tablet
Substance:
Placebo matching in size and weight to 
mg tablet
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
2-0-0 (DG 4), 4-0-0 (DG 5), 6-0-0 (DG 6)
Route of administration:
p.o.
Duration of use:
Single dose
Placebo to 
 Tablet
Substance:
Placebo matching in size and weight to 
mg tablet
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
3-0-0 (DG 7), 4-0-0 (DG 8)
Route of administration:
p.o.
Duration of use:
Single dose
In addition to the above listed test and reference products, 
 BI 1323495 film-coated 
tablets and matching placebo tablets will be provided if need be to test doses that cannot be 
covered by 
 tablets.
4.1.2
Method of assigning subjects to treatment groups
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 cohorts 
according to their temporal availability. As soon as enough subjects have been allocated to a 
dose cohort, the following subjects will be allocated to one of the other dose cohorts. 
Therefore, the allocation of subjects to dose cohorts is not influenced by trial personnel, but 
only by the subjects’ temporal availability. As the study includes healthy subjects from a 
homogenous population, relevant imbalances between the dose groups are not expected. 


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The randomisation list with study subject numbers and allocated treatments will be provided 
to the trial site in advance. The allocation of subjects to study subject numbers will be 
performed prior to the first administration of trial medication. For this purpose, the subjects 
will be allocated to a study subject number by drawing lots. Once a subject number has been 
assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
The doses selected for this trial cover the sub-therapeutic as well as the estimated therapeutic 
range and include a safety margin (see Section 1.2 and 2.1).
4.1.4
Drug assignment and administration of doses for each subject
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 1323495 and placebo treatments, oral administration
Dose
Substance
Pharmaceutical 
form
Unit strength
Number of units  
per administration
Total dose
1
BI 1323495
Film-coated 
tablet
1 tablet as single dose
2
BI 1323495
Film-coated 
tablet
3 tablets as single dose
3
BI 1323495
Film-coated 
tablet
6 tablets as single dose
4
BI 1323495
Film-coated 
tablet
2 tablets as single dose
5
BI 1323495
Film-coated 
tablet
4 tablets as single dose
6
BI 1323495
Film-coated 
tablet
6 tablets as single dose
7
BI 1323495
Film-coated 
tablet
3 tablets as single dose
8
BI 1323495
Film-coated 
tablet
4 tablets as single dose
1-8
Placebo*
Film-coated 
tablet
--
identical to respective active 
treatment
--
* Subjects receiving placebo are equally distributed across dose groups 
The trial medication will be administered to the subjects, while in a standing or sitting 
position, as an oral dose together with about 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 and – if applicable – its 
preparation (e.g. reconstitution), if correct dosage cannot be ensured otherwise. 


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Administration will be performed following an overnight fast, which is to start no later than 
10 h before the scheduled dosing. 
Subjects will be kept under close medical surveillance until 24 h following drug 
administration. During the first 4 h 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 for 
medical examination), or to sleep. For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The treatments administered (active or placebo) will be single-blind (that is, subjects will not 
know whether they receive active treatment or placebo). However, the current dose level will 
be known to the subjects. 
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site. The trial bioanalyst and pharmacokineticist may receive the randomisation 
codes prior to official unblinding to perform the interim / preliminary PK analysis. He or she 
will treat the codes confidentially.
In addition, the drug metabolism scientist may receive the randomization codes prior to 
official unblinding to perform metabolites in safety testing analysis (MIST). He or she will 
confirm in writing that the codes will be treated confidentially.
Within the central ECG lab, the staff involved with interval measurements will be blinded 
with respect to the treatment and also with regard to the recording date and time as well as 
planned time points of the ECGs. The interval measurements for a given subject will be 
performed in a random and blinded sequence by a single technician.
If an interim safety analysis of ECG data is required, a part of the staff of the central ECG lab 
may be unblinded. This part of the staff will be strictly separated from the blinded staff 
members who are involved with ECG interval measurements and assessments of ECGs.
The database of this trial will be handled open-label, because no bias with regard to data 
cleaning or safety measures is expected. This is considered acceptable because the potential 
for bias seems to be low and does not outweigh practical considerations.
4.1.5.2
Procedures for emergency unblinding
As this trial will be conducted single-blinded, the treatment information will be known to the 
investigator. Therefore, no emergency envelopes will be provided.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication, which are labelled
with trial identification. The required information according to the German Drug Law as well 


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as Annex 13/EU GMP Guideline will be provided on the containers. Smaller boxes within the 
clinical trial supply containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Subject or medication number

Batch number
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area 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 immediately contacted.
4.1.8
Drug accountability
The investigator will receive the investigational drugs delivered by the sponsor when the 
following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel 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 will be disposed locally by the trial site upon 
written authorisation by the clinical monitor. Receipt, usage and disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each subject, and the disposal of unused products. 


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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 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 disposal, the investigator must verify that no remaining supplies 
are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of adverse events 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.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
 should 
be avoided during the entire study. If necessary, short term use of ibuprofen or paracetamol is 
acceptable.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
beverages 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 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water served at 2 h and 4 h post-dose (mandatory 
for all subjects). From lunch until 24h post-dose, total fluid intake is restricted to 2.75 litres.
 
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 the administration of trial medication until after the last PK 
sample is collected.
Smoking is not allowed during in-house confinement at the trial site.


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Methylxanthine-containing beverages or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed during the in-house confinement at the trial site.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
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 see Section 3.3.4.1). 


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 1323495 is the number [N (%)] of 
subjects with drug-related adverse events.
Further criteria of interest:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring 

Vital signs (blood pressure, pulse rate)
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable): 

Worsening of the underlying disease or of other pre-existing conditions  

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator. 
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the CRF only.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death, 

is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,

requires inpatient hospitalisation,

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, 

is a congenital anomaly/birth defect, 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse. 
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.2.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see Section 5.2.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 


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


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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. 
5.2.2.2
Adverse event collection and reporting
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware 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 sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs that 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 relevant to these events, a follow-up SAE form has to 
be provided.. For follow-up information, the same rules and timelines apply as for the initial 
information.
Information required
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no 
further information can be obtained.
Pregnancy
Once a 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 a male trial participant immediately (within 
24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s unique 
entry point. This requires 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.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood 
 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 h. 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. 


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Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or if erythrocytes, 
leukocytes, nitrite or protein are abnormal in the urinalysis, respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
D1
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes [RBC]
Reticulocytes, absol.
Reticulocytes/Erythrocyte
White Blood Cells/Leucocytes [WBC]
Platelet Count/Thrombocytes (quant)
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/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
x
x
x
x
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
x
x
x
x
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands;  Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, 
absol.; Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
x
x
x
x
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
x
x
x
x
x
x
x
x
-
-
-
-
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase [AP]
Gamma-Glutamyl Transferase [GGT]
Glutamate Dehydrogenase [GLDH]
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [CK-MB], if CK is elevated 
Lactic Dehydrogenase [LDH]
Lipase
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
Glucose Plasma (fluorid citrate) 
Creatinine
GFR/ CKD-EPI 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
C-Reactive Protein (Quant)  
Uric Acid 
Urea
Cholesterol, total 
Triglyceride
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
-
x
x
x
x
-
x
x
-
x
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Electrolytes
Sodium
Potassium
Chloride
Calcium
x
x
x
x
x
x
x
x
x
x
x
x
-
-
-
-
1
A, B, C, and D are different sets of laboratory values. The Flow Chart defines at what time point which 
set is to be investigated


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Table 5.2.3: 1
Routine laboratory tests (cont)
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
D1
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x2
x2
x2
x2
x2
x2
x2
x2
x2
-
-
-
-
-
-
-
-
-
Urine sediment 
(microscopic 
examination)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
x
x
x2
-
Spot urine
Urine Albumin (quant)
Urine Alpha-1 Microglobulin (quant)
Urine Creatinine
Urine Immunoglobulin G (quant)
x
x
x
x
x
x
x
x
x2
x2
x2
x2
-
-
-
-
1
A, B, C, and D are different sets of laboratory values. The Flow Chart defines at what time point which 
set is to be investigated
2
Urinalysis will not be done at time point 4h (Day 1/Visit 2)
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. Infectious serology tests will be performed during screening only. Drug screening will 
be performed at screening and prior to drug administration on Day 1.
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 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qual)
Hepatitis B core antibody (qual)
Hepatitis C antibodies (qual)
HIV-1 and HIV-2 antibody (qual)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed prior to treatment, 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.


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The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
 with the exception of 
the drug screening tests. These tests will be performed at the trial site using M-10/14-PDT
test (or comparable test kit).
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) 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 inhouse 
confinement.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment so that all subjects are at 
complete rest.
All ECGs will be recorded for 10 sec duration after subjects have rested for at least 5 min in a 
supine position. ECG recording should precede all other study procedures scheduled for the 
same time to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database.
Storing
All ECGs will be stored electronically 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 ECG recordings including repeat ECGs will be sent to the central ECG lab which will 
select the ECGs with the best quality at each time point.


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Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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. 
5.2.4.2
Continuous ECG monitoring
Cardiac rhythm (including heart rate) will be monitored by means of continuous 3-lead ECG 
recording using the CARESCAPE Monitor B450 (GE Healthcare, Freiburg, Germany) for at 
least 15 min before drug administration (for baseline assessment) and for 4 h following drug 
administration). This continuous ECG monitoring supports the early detection of adverse
events such as clinically relevant bradycardia, tachycardia, or arrhythmia at the trial site. 
Beyond this clinical evaluation at the trial site, no further data collection or analyses are 
performed based on continuous ECG monitoring.
ECG data from continuous ECG recording will not be transferred to the clinical trial 
database. Abnormal findings during continuous ECG recording will be recorded as AEs if 
judged clinically relevant by the Investigator.
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100, GE Medical Systems, Freiburg, Germany) at the times indicated in the 
Flow Chart, after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of blood pressure recording instrument on the same arm 
if possible.
5.2.5.2
Medical examinations
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), 12-lead ECG
(including rhythm strip of at least 15 minutes), laboratory tests, and a physical examination. 
At the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, and a physical examination.
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic and 
pharmacodynamic parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 
might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of an orally administered drug, 
and are widely used in clinical trials. The pharmacokinetic parameters and measurements 
outlined in Section 5.5 are generally used assessments of drug exposure. The biomarkers and 
measurements outlined in Section 5.6 are of exploratory nature only.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded.
Exact time points of plasma sampling will be derived from the study management system 
ClinBase™ and documented in the CRFs by the medical personnel or sent as electronic files
to the trial data manager. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
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 
visits as long as the total blood volume taken per subject does not exceed 500 mL. Such 
changes would be implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters will be determined if feasible:
5.5.1.1
Secondary endpoints

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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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 1323495 plasma concentrations, 2.7 mL of blood will be taken from 
an antecubital or forearm vein into an K2-EDTA (dipotassium ethylenediaminetetraacetic 
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venipuncture with a 
metal needle.
 
 
 
 
 
 
 
 
 


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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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.5.3
Analytical determinations
BI 1323495 concentrations in plasma 
will be determined by validated LC-MS/MS
(liquid chromatography tandem mass spectrometry) assays. All details of the analytical 
methods will be available prior to the start of sample analysis. The analyses will be 
performed at
 
As described in Section 4.1.5, the bioanalyst will be unblinded during sample analysis.
 
 
 
 
 
 
 
 
 
 
 


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5.7
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
The relationship of BI 1323495 plasma concentrations and biomarker results will be 
investigated in an exploratory manner 
 Other correlations will be explored 
as 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 trial 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 h-period prior to the 
trial drug administration (including blank values for PK and biomarkers).
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 15 min for the first 4 h after trial drug administration and ± 30 min thereafter.
Starting from 48 h post administration a deviation from the scheduled time for vital signs,
ECG and laboratory tests (including PK) of ±120 min is acceptable.
If several activities are 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 
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 Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
Pharmacogenomic genotyping will be performed in those volunteers whose genotypes are not 
known (for details see Section 5.3). 
6.2.2
Treatment period
Each subject will receive one dose of the respective trial medication (BI 1323495 or placebo) 
at Visit 2. 


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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 morning of Day 1 and kept under 
close medical surveillance for at least 34 h following drug administration. The subjects will 
then be allowed to leave the trial site after formal assessment and confirmation of their fitness 
by the investigator or 
 designee. From Day 3 onwards, the study will be performed in an 
ambulatory fashion.
For details on time points and procedures for collection of blood
 samples for PK 
analysis, refer to Flow Chart and Section 5.5.2. 
For details on time points and procedures for collection of blood samples for PD analysis, 
refer to Flow Chart and Section 5.6.2. 
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol 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 trial examination.
6.2.3
End of trial period 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who withdraw before the end of the planned treatment period should undergo the 
end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained. 
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
7.1.1
Objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 1323495
by using descriptive statistics for all endpoints comparing active dose groups to placebo. 
The secondary objective is the exploration of the pharmacokinetics (PK) and 
pharmacodynamics (PD) of BI 1323495. 
7.1.2
Endpoints
Safety and tolerability will be determined on the basis of the primary endpoint and the 
additional criteria specified in Section 5.2.1. PK and PD endpoints are specified in Sections 
5.5.1 and 5.6.1, respectively.
7.1.3
Model
Endpoints will be analysed by descriptive statistics. Inferential statistics is not planned (as 
explained in Section 7.2).
Secondary endpoints, as defined in Section 5.5.1.1, will be subjected to analysis of dose 
proportionality by use of the power model.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of the different dose groups of BI 1323495 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
Confidence intervals will be computed and will have 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
All individual data will be listed.
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness, and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.


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7.3.1
Primary analyses
Analysis of safety and tolerability is described in Section 7.3.3.
7.3.2
Secondary analyses
The secondary parameters (refer to Section 5.5.1) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472). Analyses will be 
performed for parent drug.
Plasma 
 concentration data and parameters of a subject will be included in the
statistical PK analyses if they are not flagged for exclusion due to a protocol violation 
relevant to the evaluation of PK (to be decided no later than in the Report Planning Meeting)
or due to PK non-evaluability (as revealed during data analysis, based on the criteria 
specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be:

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma 
 concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example:

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (median tmax is to be determined excluding the subjects 
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve.
The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one PK parameter that was not excluded according to the description above.
 
 


 
 


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Based on the estimate for slope parameter (β), a 2-sided 95% CI for the slope will be 
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of a 
linear relationship between the log-transformed pharmacokinetic endpoint and the log-
transformed dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed.
To support the analyses of dose proportionality, graphical representations of the data might 
be created. These might include (but are not limited to) individual time-courses of plasma 
concentrations and the (geometric) mean plasma concentration time profiles.
7.3.3
Safety analyses
Safety will be assessed for the endpoints and parameters of interest listed in Section 5.2.1. All 
treated subjects (that is, all subjects who received at least one dose of study drug), will be 
included in the safety analysis. For additional analyses sets used in the ECG evaluation see 
TSAP for further details. Safety analyses will be descriptive in nature and will be based on BI 
standards. No hypothesis testing is planned.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active 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.
The analyses will be done by ‘treatment at onset’.
The REP for BI 1323495, the time interval when measurable drug levels or PD effects are 
still likely to be present after administration, is not known for this first-in-human trial.
Therefore, all AEs with an onset between start of treatment and the end of trial examination
(last per protocol contact) will be considered on treatment.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs). 


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Therefore, measurements planned or AEs recorded prior to intake of trial medication will be 
assigned to 'screening' and those between trial medication intake until the end of trial visit 
will be assigned to the treatment period. These assignments including the corresponding time 
intervals will be defined in detail in the TSAP. Please note that AEs occurring after the last 
per protocol contact but entered before database lock will be reported to drug safety only and 
will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening and post-study intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.2.1), and 
other significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
 
 
 
7.3.4
Preliminary PK analyses
A preliminary analysis of PK parameters (AUC0-24 and Cmax of BI 1323495) provided as 
individual values and geometric means will be performed for

DG 1 before proceeding to DG 3

DG 1-2 before proceeding to DG 4

DG 1-4 before proceeding to DG 5

DG 1-5 before proceeding to DG 6

DG 1-6 before proceeding to DG 7

DG 1-7 before proceeding to DG 8
Note: Data from the first cohorts of the above mentioned dose levels will be sufficient as long 
as the data from at least 2 subjects on active were available.
 


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In contrast to the final PK/PD calculations, the preliminary analysis will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows or not. Therefore, minor deviations of preliminary and final results may occur. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification. The preliminary 
results will be distributed to the Investigator and the trial team. 
Depending on the results of available preliminary PK/PD analyses, the tolerability and safety 
of the compound, and changes of dosing schedule (e.g. additional intermediate doses) 
additional PK/PD preliminary analysis may be performed based on the request of the Trial 
Clinical Monitor, the investigator, or Trial Clinical Pharmacokineticist. No formal 
preliminary PK report will be written.
No inferential statistical interim analysis is planned. However, after each dose group the 
investigator (or 
 deputy) is allowed to postpone further dose progression until a 
preliminary analysis of the data already obtained has been performed.
The pharmacokinetic parameters AUC0-24 and Cmax for BI 1323495 will be calculated 
according to the BI SOP
 
The non-compartmental analysis 
will be performed using the validated software program 
 A 
quality check of the interim data will be performed. 
 
 
 
 
Available 
information on dose linearity from preceding dose groups will be considered when estimating 
Cmax and AUC values to be expected for the next higher dose to be administered.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for BI 1323495 will be calculated 
according to the BI SOP 
 
Subjects who are not included in the PKS (refer to Section 7.3.1) will be reported with their 
individual plasma
 concentrations and individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for plasma
 concentrations, 
pharmacokinetic parameters or other statistical assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).


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7.3.6
Biomarker analysis
The biomarker parameters listed in Section 5.6 will be evaluated according to the BI SOP 
Graphical representations versus time and descriptive statistics will be provided for above 
mentioned biomarkers as well as for raw data thereof. If applicable, a statistical model will be 
applied to the biomarker data. Biomarker assessments might be used to establish a PK/PD 
relationship. Further details will be provided in the TSAP.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma
drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), or BLQ (below the lower limit of quantification) will be displayed as 
such and not replaced by zero at any time point (this rule also applies to the lag phase,
including the pre-dose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
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 will 
be set to zero. All other BLQ 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.
7.5
RANDOMISATION
Each dose group will be divided into three cohorts. The subjects of the first and second 
cohorts will not be randomised to maintain a treatment sequence of active-placebo-active-
active due to safety reasons. In the third cohort of each dose level the subjects will be 
assigned to active or placebo treatment using a 3:1 allocation ratio.
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, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.


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The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 64 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 8 subjects per dose group (6 on active treatment, and 2 on 
placebo) is commonly used in single-rising dose studies of the present type and is in general 
considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics (R95-0013).
Additional subjects may be entered to allow testing of additional doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned 
and approved highest dose will not be exceeded and none of the stopping criteria apply. Thus, 
the actual number of subjects entered may exceed 64, but will not exceed 80 subjects entered.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
As a general rule, no trial results should be published prior to finalisation of the CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, 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.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.


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8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
 
 
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
Data directly entered 
 
(that is, without prior written or electronic record) are 
considered to be source data. The place where data is entered first will be defined in a trial 
specific Source Data Agreement. The data in 
are available for inspection at any 
time.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
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
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated 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, i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P02-06423 
 
 
P12-00627
 
 
 
 
 
P12-07103
 
 
P13-08996
P15-08723
 
 
P17-01597
 
 
 
 
R06-1037
Guidance for industry: estimating the maximum safe starting dose in 
initial clinical trials for therapeutics in adult healthy volunteers. U.S. 
Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER); 2005.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 
Rockville: U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER), 
Center for Biologics Evaluation and Research (CBER); 2005.
R09-1400
European Medicines Agency (EMEA). ICH topic M3 (R2) non-clinical 
safety studies for the conduct of human clinical trials and marketing 
authorization for pharmaceuticals: step 4: note for guidance on non-
clinical safety studies for the conduct of human clinical trials and 
marketing authorization for pharmaceuticals (June 2009, 
CPMP/ICH/286/95). http://www.emea.europa.eu; 2009


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R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 
2005). 2005
R12-1392
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
Kusek JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI). A new equation to 
estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604-612.
R16-0366
E14 Implementation Working Group. ICH E14 guideline: the clinical 
evaluation of QT/QTc interval prolongation and proarrhythmic potential 
for non-antiarrhythmic drugs: questions & answers (R3) (current version 
dated 10 December 2015). 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/
Efficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2015); 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use; 2015.
R16-1084
 
R16-1085
 
 
R16-1086
 
R16-2237 
 
 
R16-2239
R17-2928
 
 
R17-2929
 
R17-3101
 


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R18-0132
 
 
 
R18-0467
 
 
 
 
R18-0468
R18-0515
 
R18-1291
 
 
R95-0013
Broom C. Design of first-administration studies in healthy man. In: 
O'Grady J, Linet OI, editors. Early Phase Drug Evaluation in Man. 
London: Macmillan Press; 1990. p. 206-213.
9.2
UNPUBLISHED REFERENCES
 
c21238478-01
Investigator’s Brochure BI 1323495. 
. 05 Apr 2018.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
4 July 2018
EudraCT number
2017-004899-62
BI Trial number
1405-0001
BI Investigational Product(s)
BI 1323495
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of single rising oral doses of 
BI 1323495 in healthy male subjects (single-
blind, partially 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
1)
Synopsis
2)
Flow Chart
3)
2.1 Rationale for performing the trial
4)
2.1.2 Maximum dose and dose escalation
5)
2.3.3 Safety measures
6)
3.1 Overall trial design and plan
7)
3.3.3 Exclusion criteria
8)
3.3.4.2 Discontinuation of the trial by the sponsor
9)
5.2.3 Assessment of safety laboratory parameters
10)
5.6.1 Biochemical and cellular biomarkers
11)
6.2.2 Treatment period
12)
7.3.4 Preliminary PK analyses
13)
7.3.6 Determination of sample size


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Number of global amendment
1
Description of change
1)+
6)+
13)
Clarification under which circumstances 
additional subjects / dose groups may be entered
2)
 
 
 
3)
“X” deleted in heading
4)
Individual exposure limits defined
5)
Individual exposure limits defined; inhouse 
observation period extended
7)
Amended eGFR value (exclusion criterion 25) 
and limits for liver enzyme values (new ex-
criterion 27)
8)
Stopping criteria with respect to adverse events 
and exposure limits revised
9)
Added parameter Set D in Table 5.2.3: 1 and 
specified that fasting is not required for 
timepoints when Set D is to be taken
10)
 
11)
Text adapted to extended inhouse oberservation 
period
12)
Specified methods and software used for 
preliminary PK analyses
Rationale for change
1)
Request by Competent Authority/risk mitigation
2)
Flow chart amended according to changes 
introduced
3)
Typo corrected
4)
Request by Competent Authority/risk mitigation
5)
Request by Competent Authority/risk mitigation
6)
Request by Competent Authority/risk mitigation
7)
Request by Competent Authority/risk mitigation
8)
Request by Competent Authority/risk mitigation
9)+
10)
 
11)
Amended according to changes introduced
12)
Request by Competent Authority
13)
Request by Competent Authority/risk mitigation


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Number of global amendment
2
Date of CTP revision
28 August 2018
EudraCT number
2017-004899-62
BI Trial number
1405-0001
BI Investigational Product(s)
BI 1323495
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of single rising oral doses of 
BI 1323495 in healthy male subjects (single-
blind, partially 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
Flow Chart
Description of change
New time points for PK blood sampling
introduced:
 
 
 
 
 
 
 
 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21116620
3.0
clinical-trial-protocol-revision-2
Safety, tolerability, pharmacokinetics, and pharmacodynamics of single rising oral
doses of BI 1323495 in healthy male subjects (single-blind, partially randomised,
placebo-controlled parallel group design)
Author-Trial Clinical Monitor
29 Aug 2018 10:10 CEST
Approval-Team Member Medicine
29 Aug 2018 10:42 CEST
Approval-Therapeutic Area
29 Aug 2018 11:01 CEST
Author-Trial Clinical
Pharmacokineticist
29 Aug 2018 12:10 CEST
Verification-Paper Signature
Completion
29 Aug 2018 14:17 CEST
Author-Trial Statistician
03 Sep 2018 09:27 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c21116620
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c26461609-01
BI Trial No.:
1405-0001
Title:
Safety, tolerability, pharmacokinetics, and pharmacodynamics of
single rising oral doses of BI 1323495 in healthy male subjects
(single-blind, partially randomised, placebo-controlled parallel 
group design)
Including Protocol Amendment 1 and 2 [c21116620-03]
Investigational
Product:
BI 1323495
Responsible trial 
statisticians:
Phone:
Fax: 
Phone: 
Fax: 
Date of statistical 
analysis plan:
10 JAN 2019 SIGNED 
Version:
Final
Page 1 of 36
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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 ENDPOINTS.....................................................................................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...........................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................17
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.............................................................................23
7.5.1
Key secondary endpoints....................................................................................23
7.5.2
Secondary endpoints...........................................................................................23
7.7
EXTENT OF EXPOSURE.................................................................................26
7.8
SAFETY ANALYSIS..........................................................................................26
7.8.1
Adverse events.....................................................................................................26
7.8.2
Laboratory data ..................................................................................................28
7.8.3
Vital signs.............................................................................................................28
7.8.4
ECG......................................................................................................................28
7.8.5
Others...................................................................................................................30
8.
REFERENCES....................................................................................................31


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10.
HISTORY TABLE..............................................................................................36


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR .........................................................12
Table 6.2: 1
Important protocol deviations ..........................................................................14
Table 6.3: 1
Analysis sets for endpoints/data description ....................................................16
Table 10: 1
History table .....................................................................................................36


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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
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BMI
Body mass index
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form
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
EudraCT
European Union Drug Regulating Authorities Clinical Trials
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
ICH
International Conference On Harmonisation
ISF
Investigators Site File
iPD
Important Protocol Deviation
LLT
Lower Level Term


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Term
Definition / description
Max
Maximum
MedDRA
Medical Dictionary For Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
PK parameter analysis set
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
SAS®
Statistical Analysis System
SD
Standard Deviation
SOC
System Organ Class
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary
XPKISTAT
Library of SAS® Macros for PK analysis


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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 will be stored in a trial database within the RAVE EDC system.
Pharmacokinetic (PK) parameters will be calculated using 
 
 
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 as planned in the CTP will be performed and are described in more detail in this 
TSAP. The following changes compared to the protocol will be made:
 
 
 
 
 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 5.2.1 of the CTP:
Primary endpoint to assess safety and tolerability of BI 1323495 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 5.5.1.1 of the CTP: 

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 64 healthy male subjects will participate in this study, according to 8
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
1-8
P*
Placebo, tablet, qd
Placebo
1
A
BI 1323495, 
tablet, po, qd
BI 
2
B
BI 1323495, 
tablet, po, qd
BI 
 
3
C
BI 1323495, 
 tablet, po, qd
BI 
 
4
D
BI 1323495, 
 tablet, po, qd
BI 
 
5
E
BI 1323495, 
 tablet, po, qd
BI 
6
F
BI 1323495, 
 tablet, po, qd
BI 
7
G
BI 1323495, 
 tablet, po, qd
BI 
8
H
BI 1323495, 
 tablet, po, qd
BI 
*: 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, ranging from the time of 
administration of BI / Placebo until 0:00h (midnight) on the day after trial 
completion date)
Please note that all AEs reported between start of trial drug administration and the last per-
protocol contact will be considered on treatment (i.e. no follow-up period is considered in this 
trial).


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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 and EudraCT) of the CTR 
displays:
In these displays, the on-treatment phase will be analysed (labelled with the name of the 
study treatment (short label)). Screening will not be included in this analysis. 
The following 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)
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of 
the CTR displays:

Screening 

On treatment (labelled with the name of the study treatment (short label))
In Section 16.1.13.1.8 AE tables, the following 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 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 Data Reviewers guide. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects.
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting 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).


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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 following table 
contains the categories which are considered to be iPDs in this trial. If the data show other 
iPDs, this table will be supplemented accordingly by the time of the RPM/DBLM at the 
latest.
Important protocol deviations will be summarised and listed.
Table 6.2: 1
Important protocol deviations
Category/Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C2
Randomisation not followed
C3
Non-compliance
C4
Incorrect intake of trial medication
D
Concomitant medication
D1
Concomitant medication with the potential to affect the assessment of the 
trial medication
E
Missing data *
E1
None
F
Incorrect timing1
F1
Certain deviations from time schedule used to measure secondary data
G
Other trial specific important deviations
G1
Incorrect intake of meal before administration of treatment
G2
Protocol deviations affecting safety and rights
1 Time deviations will only be flagged as iPD, when leading to exclusion of the entire subject from an analysis set
* Missing visits, evaluations, and tests will be considered missing data, not protocol deviations


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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, as well as for the description 
of biomarkers.
 

PK parameter analysis set (PKS):
The PK parameter analysis set (PKS) includes all subjects from the TS receiving 
BI 1323495 who provide at least one secondary PK parameter that was not excluded 
according to the description below.
It is used for assessment of dose proportionality.
Section 7.3.2 of the CTP: Plasma 
 concentration data and parameters of a subject 
will be included in the statistical 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 RPM) 
or due to PK non-evaluability (as revealed during data analysis, based on the criteria 
specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be:

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma 
 concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example:

The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (median tmax is to be determined excluding the subjects 
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve.
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.


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Table 6.3: 1
Analysis sets for endpoints/data description
Endpoint/data description
TS
PKS
Primary and further safety endpoints 
 
X
Description of biomarkers
X
 
Secondary PK endpoints
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 7.4.
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)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5).


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before administration of BI 1323495 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 trial examination 
are given in the CTP Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration (including blank values for PK and biomarkers).
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.
 


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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.
Descriptive data analysis of PD parameters will be performed by 
 
 and will be presented in Sections 15.7 of the CTR.
Inferential statistical analyses of PK and PD endpoints (refer to Section 7.5.2) will also be 
performed by 
 and will be presented in Section 15.5, and 15.7
of the CTR and in Appendices 16.1.13.3 and 16.1.13.6.
Descriptive data analysis of PK parameters and concentrations will be performed by the 
department Translational Medicine and Clin. Pharmacology at BI and will be presented in 
Section 15.6 and 15.7 of the CTR.
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of Clinical Trials and Project Summaries” [001-MCG-159] (6) with the 
exception of those generated for PK-calculations.
The individual values of all subjects will be listed, sorted by treatment group, subject number, 
and visit. 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation


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For PK parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment group. 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.


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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).
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 (cf. TSAP Section 6.2) 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 1323495.


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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.
7.5.2
Secondary endpoints
Section 7.3.2 of the CTP: 
Assessment of dose proportionality
Dose proportionality will be assessed using the pharmacokinetic endpoints as specified in
Section 5.2.2
 
 
Based on the estimate for slope parameter (β), a 2-sided 90% CI for the slope will be
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of 
a linear relationship between the log-transformed pharmacokinetic endpoint and the log-
transformed dose will be checked.


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If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed.
This analysis will be accomplished by using the XPKISTAT macro (design DB), based on 
the PKS.
Graphical displays:
A regression plot will be performed, where the logarithm of dose is depicted versus logarithm 
of PK endpoint, including the estimated regression line from the power model and reference 
line of perfect proportionality (β=1).


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
If not stated otherwise, the safety results will be sorted by treatment group.
The safety data for treated subjects who failed to complete the study (dropouts or
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
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 CRF 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)

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).


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Section 5.2.2.1 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 adverse 
events. 
Section 7.3.3 of the CTP: The REP for BI 1323495, the time interval when measurable drug 
levels or PD effects are still likely to be present after administration, is not known for this 
first-in-human trial. Therefore, all AEs with an onset between start of treatment and the end 
of trial examination (last per protocol contact) will be considered on treatment. 
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 Clinical Monitor/Investigator at the RPM at the latest.
An overall summary of AEs (including AESIs) will be presented.
The frequency of subjects with AEs will be summarized by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with 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.


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For disclosure of adverse events on EudraCT additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on 
BI standards [001-MCG-157] (11). Tables and listings will be based on standardized values 
only.
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).
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate).
7.8.4
ECG
Continuous safety ECG monitoring (by investigator)
Clinically relevant abnormal findings will be reported as adverse events.
No separate listing or analysis of continuous ECG monitoring will be prepared.
12-lead ECG
Abnormal findings 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.


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


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8.
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.
 
13. BI Statistical Position Paper - Statistical Methods for PK - Reference Document 3: 
Regulatory recommendations for BA/BE trials and implementation instructions in 
clinical trial documents, version 1.0 (2017).
 


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
10-JAN-19
,
None
This is the final TSAP without any 
modification