Clinical trial NCT04107805
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2019-11-04; Completion date: 2021-03-26
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this trial is to investigate the safety and tolerability of BI 1323495 in healthy subjects following bid oral administration of multiple rising doses, each over an 11 day treatment period.

Secondary objectives are the exploration of the pharmacokinetics (PK) including dose proportionality (only for Part 1) as well as attainment of steady state. This includes exploration of a therapeutic exposure range, a range not adequately achieved in the single-rising dose trial 1405-0001.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None arm 9: None
Interventions: intervention 1: BI 1323495 intervention 2: Placebo intervention 3: Midazolam
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet intervention 3: Oral administration

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (15.0) / Saved on: 30 Nov 2017
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c21861538-08
EudraCT No.
2018-004238-13
BI Trial No.
1405-0002
BI Investigational
Medicinal Product
BI 1323495
Title
Safety, tolerability, pharmacokinetics, and pharmacodynamics of 
multiple rising oral doses of BI 1323495 versus placebo in 
healthy subjects, including an investigation of drug-drug 
interaction with microdose midazolam (double-blind, 
randomised, placebo-controlled [within dose groups] trial)
Lay Title
A study in healthy men and women to test how well different 
doses of BI 1323495 are tolerated
Clinical Phase
Ib
Clinical Trial Leader
Phone: 
Fax:
Principal 
Investigator
Phone: 
Status
Final Protocol (Revised Protocol (based on global amendment 
7))
Version and Date
Version: 8.0
Date: 10 Dec 2020
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Proprietary confidential information.
2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
06 Aug 2019
Revision date
10 Dec 2020
BI trial number
1405-0002
Title of trial
Safety, tolerability, pharmacokinetics, and pharmacodynamics of 
multiple rising oral doses of BI 1323495 versus placebo in healthy 
subjects, including an investigation of drug-drug interaction with 
microdose midazolam (double-blind, randomised, placebo-controlled 
[within dose groups] trial)
Principal Investigator
Phone: 
Trial site
Clinical phase
Ib
Trial rationale
Based on results from a single-rising dose trial in healthy volunteers, 
the trial is intended to show the safety and tolerability of multiple 
doses of BI 1323495 and 
 
 The results will provide 
the basis for a potential ongoing clinical development of BI 1323495
in the indications
 
Trial objectives
To investigate safety, tolerability, pharmacokinetics, and 
pharmacodynamics of (increasing) multiple bid or qd oral doses of 
BI 1323495 versus placebo in healthy subjects.
Trial endpoints
Primary endpoint:

To assess safety and tolerability of BI 1323495
o
Number of subjects with treatment-emergent drug-related 
adverse events.
Secondary endpoints:

Pharmacokinetics
o
After the first dose: AUC0-12, AUC0-24 (only for qd dosing) and
Cmax of BI 1323495
o
After the last dose: AUCτ,ss and Cmax,ss of BI 1323495


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Trial design
Randomised, placebo-controlled, multiple rising dose, double blind 
within dose groups, 2-part trial with 8 dose groups
Total number of 
subjects randomised 
88* healthy subjects
Number of subjects 
on each treatment
Part I (Extensive Metabolizer Part): 
12 subjects per each of 6 dose groups (9 on active drug and 3 on 
placebo)
Part II (Poor Metabolizer Part):
8 subjects per each of 2 dose groups(6 on active drug and 2 on placebo)
Diagnosis
Not applicable
Main in- and 
exclusion criteria

Healthy male and female subjects, age of 18 to 70 years, body mass 
index (BMI) of 18.5 to 29.9 kg/m2

Part I: UGT2B17 extensive-metabolizer genotype (*1/*1 or *1/*2)

Part II: UGT2B17 poor metabolizer genotype (*2/*2)
Test product 1
BI 1323495 film-coated tablets (dose strengths 10, 50, and 150 mg)
dose
Part I in extensive metabolizer subjects: 6 ascending doses

10 mg, 30 mg, 70 mg, 150 mg and an intermediate dose of 120 mg,
as multiple twice daily doses,

120 mg as multiple once daily dose
Part II in poor metabolizer subjects: 2 ascending doses

10 mg and 30 mg as multiple twice daily doses
mode of 
administration
Oral with 240 mL of water and within 30 minutes of a meal
Comparator product
Matching placebo
dose
Not applicable
mode of
administration
Oral with 240 mL of water and within 30 minutes of a meal
Test product 2
Midazolam solution for injection, diluted for use as oral solution
(target concentration of dilution: 50 µg/mL midazolam)
dose
75 µg
mode of 
administration
Oral followed by 240 mL of water and within 30 minutes after a 
standard breakfast
Duration of treatment BI 1323495
11 days, 10 days twice daily (bid) dosing, or once daily dosing for 
120 mg qd dose group, and single dose on day 11
Midazolam solution:
Single dose in the 3 highest bid dose groups of Part I on day -1 and day 
11
Statistical methods
Descriptive statistics will be calculated for all endpoints.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
TABLE OF CONTENTS ......................................................................................................25
ABBREVIATIONS................................................................................................................29
1.
INTRODUCTION...............................................................................................32
1.1
MEDICAL BACKGROUND.............................................................................32
1.2
DRUG PROFILE................................................................................................33
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................46
1.4
BENEFIT - RISK ASSESSMENT.....................................................................48
1.4.1
Benefits.................................................................................................................48
1.4.2
Risks .....................................................................................................................48
1.4.2.1
Risks related to study medication (Investigational Medicinal Product BI 1323495)
...............................................................................................................................48
1.4.2.2
Risks related to microdose midazolam .................................................................52
1.4.2.3
Procedure-related risks..........................................................................................52
1.4.3
Discussion.............................................................................................................53
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................56
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........56
2.1.1
Main objectives....................................................................................................56
2.1.2
Primary endpoint................................................................................................56
2.1.3
Secondary endpoints...........................................................................................56


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2.2.2.1
Safety and tolerability...........................................................................................57
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................60
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................60
3.1.1
Dose Escalation Committee review ...................................................................63
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP...........................................................................................64
3.3
SELECTION OF TRIAL POPULATION .......................................................65
3.3.1
Main diagnosis for trial entry ............................................................................66
3.3.2
Inclusion criteria .................................................................................................66
3.3.3
Exclusion criteria ................................................................................................66
3.3.4
Withdrawal of subjects from treatment or assessments..................................68
3.3.4.1
Discontinuation of trial treatment .........................................................................69
3.3.4.2
Withdrawal of consent to trial participation .........................................................69
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................69
3.3.5
Replacement of trial participants......................................................................70
4.
TREATMENTS...................................................................................................71
4.1
INVESTIGATIONAL TREATMENTS ...........................................................71
4.1.1
Identity of the Investigational Medicinal Products and Matching Placebo ..71
4.1.2
Selection of doses in the trial and dose modifications......................................73
4.1.3
Method of assigning subjects to treatment groups ..........................................77
4.1.4
Drug assignment and administration of doses for each subject .....................77
4.1.5
Blinding and procedures for unblinding...........................................................79
4.1.5.1
Blinding.................................................................................................................79
4.1.5.2
Unblinding and breaking the code ........................................................................80
4.1.6
Packaging, labelling, and re-supply...................................................................80
4.1.7
Storage conditions...............................................................................................81
4.1.8
Drug accountability.............................................................................................81
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................83
4.2.1
Other treatments and emergency procedures..................................................83
4.2.2
Restrictions ..........................................................................................................83
4.2.2.1
Restrictions regarding concomitant treatment ......................................................83
4.2.2.2
Restrictions on diet and life style..........................................................................83
4.2.2.3
Contraception requirements..................................................................................84
4.3
TREATMENT COMPLIANCE........................................................................84
5.
ASSESSMENTS..................................................................................................86
5.1
ASSESSMENT OF EFFICACY........................................................................86
5.2
ASSESSMENT OF SAFETY.............................................................................86
5.2.1
Physical examination ..........................................................................................86
5.2.2
Vital signs.............................................................................................................86
5.2.3
Safety laboratory parameters ............................................................................86
5.2.4
Electrocardiogram ..............................................................................................90


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5.2.4.1
12 –lead resting ECG............................................................................................90
5.2.5
Other safety parameters.....................................................................................92
5.2.6
Assessment of adverse events.............................................................................92
5.2.6.1
Definitions of AEs ................................................................................................92
5.2.6.2
Adverse event collection and reporting ................................................................94
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................96
5.3.1
Assessment of pharmacokinetics .......................................................................96
5.3.2
Methods of sample collection .............................................................................96
5.3.2.1
Plasma sampling for pharmacokinetic analysis ....................................................96
5.3.2.2
Plasma sampling for metabolism analysis ............................................................97
5.3.2.3
Urine sampling for pharmacokinetic analysis.......................................................97
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................98
5.4.1
Biochemical and cellular biomarkers................................................................98
5.4.1.1
Methods of sample collection ...............................................................................98
5.5
BIOBANKING ....................................................................................................99
5.6
OTHER ASSESSMENTS...................................................................................99
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................99
6.
INVESTIGATIONAL PLAN...........................................................................100
6.1
VISIT SCHEDULE...........................................................................................100
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ...............100
6.2.1
Screening............................................................................................................100
6.2.1.1
Screening Period .................................................................................................100
6.2.2
Treatment period ..............................................................................................101
6.2.3
Follow up period and trial completion............................................................102
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
.............................................................................................................................103
7.1
NULL AND ALTERNATIVE HYPOTHESES .............................................103
7.2
PLANNED ANALYSES...................................................................................103
7.2.1
General considerations .....................................................................................103
7.2.2
Primary endpoint analyses...............................................................................104
7.2.3
Secondary endpoint analyses ...........................................................................104
7.2.5
Safety analyses...................................................................................................107
7.2.6
Other analyses ...................................................................................................108
7.2.7
Interim analyses ................................................................................................108
7.3
HANDLING OF MISSING DATA .................................................................108
7.3.1
Safety..................................................................................................................108
7.3.2
Plasma/urine drug concentration - time profiles ...........................................108
7.3.3
Pharmacokinetics..............................................................................................109
7.4
RANDOMISATION .........................................................................................109
7.5
DETERMINATION OF SAMPLE SIZE .......................................................109


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ......110
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT .........................................................................................................110
8.2
DATA QUALITY ASSURANCE ....................................................................111
8.3
RECORDS.........................................................................................................111
8.3.1
Source documents .............................................................................................111
8.3.2
Direct access to source data and documents...................................................112
8.3.3
Storage period of records .................................................................................112
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ................................112
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY......112
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.....................................................................................................................113
8.6
TRIAL MILESTONES.....................................................................................113
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL .................................113
9.
REFERENCES..................................................................................................116
9.1
PUBLISHED REFERENCES..........................................................................116
9.2
UNPUBLISHED REFERENCES....................................................................118
10.
APPENDICES...................................................................................................119
10.1
INSTRUCTIONS FOR USE............................................................................119
10.2
PHARMACOKINETIC METHODS AND ANALYSES..............................119
10.3
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.......................................................................................................119
10.4
TRIAL BIOMARKER PLAN..........................................................................119
10.5
ADDITIONAL INFORMATION REGARDING IN/EXCLUSION 
CRITERIA.........................................................................................................119
11.
DESCRIPTION OF GLOBAL AMENDMENT............................................120
11.1
GLOBAL AMENDMENT 1 ............................................................................120
11.2
GLOBAL AMENDMENT 2 ............................................................................121
11.3
GLOBAL AMENDMENT 3 ............................................................................123
11.4
GLOBAL AMENDMENT 4 ............................................................................124
11.5
GLOBAL AMENDMENT 5 ............................................................................126
11.6
GLOBAL AMENDMENT 6 ............................................................................127
11.7
GLOBAL AMENDMENT 7 ............................................................................129


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area under the Curve
bid
bis in die (twice daily dosing)
BI
Boehringer Ingelheim
BM
Biomarker
BP
Blood Pressure
CA
Competent Authority
CatC
Cathepsin C
CatG
Cathepsin G
CF
Cystic Fibrosis
CFTR
Cystic Fibrosis Transmembrane Conductance Regulator
CI
Confidence Interval
CKD-EPI
Chronic Kidney Disease-Epidemiology Collaboration
Cmax
Maximum Plasma Concentration
CNS
Central Nervous System
COPD
Chronic Obstructive Pulmonary Disease
COVID
Coronavirus disease
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organization
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP450
Cytochrome P450
DEC
Dose Escalation Committee
DG
Dose Group
DILI
Drug Induced Liver Injury
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED
Effective Dose
eDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic Acid


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eGRF
estimated Glomerular Filtration Rate
EM
Extensive metabolizer(s)
EoS
End of Study
EoT
End of Treatment
EudraCT
European Clinical Trials Database
FC
Flow Chart
FDA
Food and Drug Administration (United States of America)
GCP
Good Clinical Practice
gCV
geometric Coefficient of Variation
GLDH
Glutamate dehydrogenase
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
GPV
Global Pharmacovigilance
GSH
Glutathione
hERG
human Ether-à-go-go-Related Gene
HR
Heart Rate
IB
Investigator’s Brochure
IC50
Concentration at which 50% inhibition of target occurs
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IQRMP
Integrated Quality and Risk Management Plan
IRB
Institutional Review Board
ISF
Investigator Site File
LSLT
Last Subject Last Treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRD
Multiple Rising Dose
MRT
Mean Residence Time
NA
Not applicable
NE
Neutrophil Elastase
NOAEL
No Observed Adverse Effect Level
NSP
Neutrophil Serine Protease
OPU
Operative Unit
p.o.
per os (oral)
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PM
Poor metabolizer(s)


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PMDA
Pharmaceuticals and Medical Devices Agency (Japan)
PTF
Peak-Trough Fluctuation
PTS
Peak-Trough Swing
qd
quaque die (once a day)
REP
Residual Effect Period
SAE
Serious Adverse Event
SCR
Screening
SOP
Standard Operating Procedure
SRD
Single Rising Dose
SUSAR
Suspected Unexpected Serious Adverse Reaction
TIMP
Tissue Inhibitor of Metalloproteinase
tmax
Timepoint of Maximum Plasma Concentration
TMF
Trial Master File
TMM
Team Member Medicine
TSAP
Trial Statistical Analysis Plan
TSTAT
Trial Statistician
UDP
Uridine 5’-diphosphate
UGT
UDP Glucuronosyltransferase
UGT2B17
UDP Glucuronosyltransferase family 2 member B17
ULN
Upper Limit of Normal
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
In this study, for the first time multiple doses of BI 1323495 will be administered. Safety, 
tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of 
BI 1323495 will be investigated.
1.1
MEDICAL BACKGROUND


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1.2
DRUG PROFILE


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1.3
RATIONALE FOR PERFORMING THE TRIAL
In this trial, for the first time the effects of multiple doses of BI 1323495 will be assessed in 
humans. This will be done in healthy subjects. 
 


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1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation in the study, however, is of major importance for the development of a 
new orally available drug, 
 
1.4.2
Risks
Trial subjects are exposed to risks related to the exposure to the trial medication and to risks 
of the study procedures.
At the time of completion of EM DG 2 in this trial, the COVID-19 pandemic emerged with 
worldwide impact on daily life. To allow for thorough evaluation of potential additional risks 
to trial participants in the course of this pandemic, the trial was temporarily put on hold after 
completion of EM DG 2 and prior to the start of EM DG 3. Potential additional risks for 
study participants with regard to COVID-19 have been evaluated and risk management 
measures implemented in ctp version 4.0 (see Sections 1.4.2.1.1 and 1.4.2.3)
1.4.2.1
Risks related to study medication (Investigational Medicinal Product BI 1323495)
Risk factors may derive from particular knowledge or the lack thereof, regarding the mode of
action, the nature of the target, and/or findings in non-clinical safety studies.


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1.4.2.1.4
Patient data
The substance has not been administered to patients so far.
1.4.2.1.5
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. Laboratory findings of an elevation of AST and/or ALT ≥3-fold ULN combined with 
an elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) or findings 
of elevations of ALT and/or AST ≥10 fold ULN constitute a hepatic injury alert, and a trial 
subject showing these lab abnormalities needs to be followed up according to the ‘DILI 
checklist’ provided in the ISF. See also Section 5.2.6.1.4, adverse events of special interest.
1.4.2.2
Risks related to microdose midazolam
The evaluation of a potential CYP3A4 interaction with BI 1323495 using a microdose of 
midazolam is acceptable. The administered dose is 1/100th of a therapeutic dose and not 
expected to have any pharmacological effects. Microdoses of midazolam have been
administered orally as a microdose in previous clinical studies without any reports of AEs 
[R17-3022, R17-3023]. Therefore, subjects are not exposed to undue risks. Also, the safety 
and tolerability evaluation of BI 1323495 should not be influenced.
1.4.2.3
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, and can cause syncopation. 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 be less than 
500 ml and thus not exceed the volume of a normal blood donation (500 mL). No health-
related risk to healthy subjects is expected from blood withdrawals.
During Covid-19 pandemic, within the usual phase I settings, where subjects stay stationary 
at the site for several days in small groups, there is a potential risk for spreading the infection 
within the group/to the site staff, if an infected subject was enrolled into the trial. Also, there 
are trial procedures, e.g. collecting blood samples, recording of ECG, or assessing vital signs, 
that are impossible to perform from a distance of 1.5 to 2 meters, which is the generally 


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recommended distance to keep between humans, in order to prevent the transmission of 
SARS-CoV-2.
Risk mitigation:

A risk management plan has been set up at the site detailing specific cautionary measures, 
e.g. hygiene rules, wearing of face masks and physical distance which is filed in the ISF. 

In addition, a screening on SARS-CoV-2 has been implemented, to be performed as part 
of the safety assessments on Day -4 to -2. Subjects positive in the SARS-CoV-2 test will 
be informed about the test result and that they are not eligible to the trial in accordance to 
exclusion criterion #24, prior to coming to the site for stationary admission.

In case COVID-19 is suspected in a subject during trial participation, SARS-CoV-2 
testing is to be initiated without delay to enable treatment discontinuation according to the 
extended withdrawal criteria, i.e., based on a confirmed COVID-19 infection (see Section 
3.3.4.1).
1.4.3
Discussion
The following general safety measures are planned to mitigate potential risks associated with 
the IMP BI 1323495:

Dose selection for this trial is based on PK predictions derived from clinical data of a 
single rising dose trial (1405-0001) and a food effect trial (1405-0007), as well as
preclinical data (see IB and Section 4.1.2).
 

exposures may exceed exposures that have as yet been observed in healthy volunteers in
the single rising dose trial 1405-0001. In that trial, due to the less than linear increase of 
exposures with dose, the expected human therapeutic exposure range could just be 
reached for Cmax, without establishing a safety margin, and could not be reached for 
AUC0-24, in UGT2B17 EMs. Therefore, careful dose escalation (see Section 3.1) will be 
used to explore exposures above the limited SRD exposures. This will allow assessment 
of higher exposures that may be required for efficacy (also covering AUC and Cmin). Dose 


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escalations will occur in the setting of a multiple rising dose trial under clinically tightly 
monitored conditions, in a fashion similar to that obtained in the first in man study 1405-
0001.

A Dose Escalation Committee (DEC) will be constituted which will ensure appropriate 
and documented safety review before deciding on each dose escalation step (see Sections 
3.1 and 8.7). Only if the respective dose of BI 1323495 was safe and showed acceptable 
tolerability, also considering gender differences, and if no stopping criterion was met (see 
Section 3.3.4.2) within a dose group, the next dose group will be started at least 7 days 
after last subject completed End of Treatment of the previous dose group.

Estimation of exposures for subsequent dose groups will be done based on preliminary 
PK values of preceding dose groups 
 

To reduce PK variability, UGT2B17 EMs and PMs will be included in separate parts 
(Part I: EMs; Part II: PMs) of the study and will be administered different dose ranges. 

Part of the subjects within each dose group will be treated with placebo, which is 
considered standard in phase I trials, to allow for a reliable assessment of safety and 
tolerability.

For safety reasons, each dose group of 12 subjects in Part I (9 on active, 3 on placebo) 
and 8 subjects in Part II (6 on active and 2 on placebo) will be divided into two cohorts. 
The first (“sentinel”) cohort will consist of 4 subjects for Part I and Part II (3 on active, 1 
on placebo). The second cohort will consist of 8 subjects in Part I (6 on active, 2 on 
placebo) and 4 subjects in Part II (3 on active, 1 on placebo). These two cohorts will be
separated by at least 7 days (between first dose of the last subject of 1st cohort and first 
dose of the first subject of 2nd cohort) which is expected to cover the period until 
pharmacokinetic steady state is reached. Both cohorts will be dosed in a randomised 
fashion.

Extensive safety laboratory assessments will be performed (see Section 5.2.3), 
particularly including parameters to monitor liver and renal function as well as infection.

A thorough ECG monitoring comprised of repetitive 12-lead ECGs will be performed. 


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
Potential effects of BI 1323495 on embryo-fetal development have not yet been assessed, 
and no data are available from its use in pregnant women. Therefore BI 1323495 should 
not be administered to pregnant women and should not be used in women of child-
bearing potential without adequate contraception.

Upon start of treatment until Day 12, subjects will stay at the site being kept under 
medical surveillance under stationary conditions, and monitored for both expected and 
unexpected adverse events (see Flow Chart 1/2/3/4).

Healthy subjects up to ≤ 70 years of age will be enrolled in this trial. Accordingly, 
exclusion criteria have been defined in order not to expose subjects within this age range 
to a particular risk due to the presence of concomitant conditions. In particular, subjects 
with a history of cardiovascular disease or evidence of clinically relevant ECG alterations 
will be excluded from participating in this trial. Neither non-clinical toxicity testing nor 
clinical safety in the first-in-human trial 1405-0001 have revealed a potential of 
BI 1323495 to be associated with cardiovascular adverse effects. The general risk-
mitigation measures in this trial, i.e., step-wise dose escalations, dosing in two subcohorts 
within each dose level, and close medical surveillance during stationary stay during the 
entire treatment period, also serve to ensure that healthy subjects up to ≤ 70 years of age 
will not be exposed to any undue risks.

Potential risks for the subject in relation to the COVID-19 pandemic situation have been 
evaluated together with the principle investigator. With regard to study treatment, no 
relevant impact is expected on the subject’s health condition (like e.g. increased 
susceptibility to infections, immune suppression, or impaired lung function). In the very 
unlikely case that despite all implemented measures a COVID-19 case occurs in a trial 
subject while in the study, the withdrawal criterion for subjects experiencing an infection 
has been extended to also cover discontinuation of treatment in case of laboratory-
confirmed COVID-19 disease.

To minimize the risk that infected subjects take part in the trial, who might spread the 
infection to others, subjects are only to be admitted to the site for Visit 2 if fulfilling the 
strict criteria laid out by the Robert Koch Institute (RKI) in the current national testing 
strategy regarding admission or re-admission of patients to hospital, see: 
https://www.rki.de, particularly 
https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Teststrategie/Nat-
Teststrat.html. This includes a negative PCR test (see Section 5.2.3), and patients need to 
confirm a symptom-free interval of 48 hours. As RKI recommendations may be subject to 
change, current recommendations will be re-assessed on a periodic basis and trial 
procedures adapted accordingly, if applicable.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 1323495 in 
healthy subjects following bid or qd oral administration of multiple rising doses, each over 
an 11 day treatment period.
Secondary objectives are the exploration of the pharmacokinetics (PK),
 
 This includes 
exploration of a therapeutic exposure range, a range not adequately achieved in the single-
rising dose trial 1405-0001.
2.1.2
Primary endpoint
The primary endpoint to assess safety and tolerability of BI 1323495 is the percentage of 
subjects with treatment-emergent drug related Adverse Events. The timeframe for primary 
endpoint is from the first drug administration, until 7 days after the last drug administration, 
up to 18 days.
2.1.3
Secondary endpoints
The following pharmacokinetic endpoints are considered as secondary endpoints and will be 
determined if feasible:
After the first dose of BI 1323495:

AUC0-12 (area under the concentration-time curve of the analyte in plasma over a time 
interval of 12 h after administration of the first dose)

Cmax (maximum measured concentration of the analyte in plasma after the first dose)

Only for qd dosing: AUC0-24 (area under the concentration-time curve of the analyte 
in plasma over a uniform dosing interval of 24 h after administration of the first dose)
The time frame for secondary endpoints after the first dose of BI 1323495: Before the first 
drug administration and 20 minutes (min), 40 min, 1 hour (h), 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 
9h, and 12h after drug administration on Day1. For the qd dose group (EM DG7), an 
additional time point at 24h after drug administration on Day1 is considered.
After the last dose of BI 1323495:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)
The time frame for secondary endpoints after the last dose of BI 1323495: Before the last 
drug administration and 20 min, 40 min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, and 12h after 


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the last drug administration on Day11. For the qd dose group (EM DG7), an additional time 
point at 24h after the last drug administration on Day11 is considered.
2.2.2.1
Safety and tolerability
Safety and tolerability of BI 1323495 will be assessed based on:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate, aural body temperature)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This multiple rising-dose trial will be randomised, double-blind within dose groups, and 
placebo controlled. Eligible population are healthy subjects of both genders and aged ≥18 
and ≤ 70 years. 
The trial consists of two parts. An overview on the main characteristics of the two parts is 
provided in the below table. 
Table 3.1:1 Comparison of main characteristics of Part I and Part II of the trial
Topic
Part I
Part II
Eligibility
UGT2B17 genotypes *1/*1 and 
*1/*2
“Extensive Metabolizer (EM)” 
subjects
UGT2B17 genotype *2/*2
“Poor Metabolizer (PM)” subjects
Dose groups
6 EM dose groups: 
5 bid dose groups: 10 mg, 30 mg, 
70 mg, 120 mg*, 150 mg
1 qd dose group**: 120 mg
2 PM dose groups:
10 mg, 30 mg bid
Sample size 
per dose group
9 subjects will receive BI 1323495
3 subjects will receive placebo
6 subjects will receive BI 1323495
2 subjects will receive placebo
Gender 
proportion 
requirement
Minimum 4 female subjects 
required per dose group
No restrictions for either gender 
applicable
Midazolam 
microdosing
Within the three highest bid dose 
groups
Not applicable
Assessment of 
biomarkers 
(PD)
As specified in the flowchart and in 
Section 5.4.
Not applicable
BI 1323495 
metabolite 
sampling
In EM Dose Group 4
In PM Dose Group 2
* with global amendment 6, an intermediate dose of 120 mg bid was added
** with global amendment 7, a 120 mg qd dose group was added; and decision to finally not 
use the initially planned 300 mg bid dose group was implemented (see Section 4.1.2)
Start of the Part II dose groups is possible only after EM DG 3 is completed and the 
subsequent DEC meeting has come to a positive decision (see Section 3.1.1). Separate DEC 


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meetings will be held after completion of dose groups for trial parts I and II, allowing to 
independently decide for each part on further dose escalations. However, the totality of 
clinical safety and pharmacokinetic data available at the respective time point from both trial 
parts will be considered for the dose escalation decision.
Subjects will be enrolled (screened) in the trial once they have signed the informed consent. 
Subjects who are suitable after screening and who still meet the inclusion/exclusion criteria 
will be randomised into the treatment period in which they will receive either BI 1323495 or 
placebo. No concomitant therapy is allowed (restrictions see Section 4.2.2).
A total of 88 healthy male and female subjects will participate in the trial (Part I: 6 sequential 
groups of 12 subjects each, Part II: 2 sequential groups of 8 subjects each). 
Note: with global amendment 6, an intermediate dose of 120 mg bid (DG 6) in EMs was 
added.
Note: with global amendment 7, a 120 mg qd dose group (DG 7) in EMs was added, and 
decision to finally not use the initially planned 300 mg bid dose group (DG 5) in EMs was 
implemented (see Section 4.1.2).
The addition of a dose group for the evaluation of safety findings would require a substantial 
amendment and could only be implemented after approval.
Only one dose is tested within each dose group.
Additionally, the potential for DDI with a CYP3A4 substrate will be assessed in the three 
highest bid dose groups of Part I. This will be conducted in parallel to BI 1323495
administration, using a microdose of midazolam (a sensitive CYP3A4 substrate) administered 
at 2 different time points (on Day -1 and Day 11/EoT) to examine potential CYP3A4
induction effects of BI 1323495.
The following figures show an overview over the visit structure. Detailed schedules of all 
relevant trial activities are provided in the Flow Charts 1, 2 and 3.
Table 3.1:2
Overview over visit structure for EM DG 1, EM DG 2, EM DG 7, PM 
DG 1 and PM DG 2 (without Midazolam), for details see Flow Charts 
1/3/4.


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Table 3.1:3
Overview over visit structure for EM DG 3, EM DG 4, and EM DG 6 
(with Midazolam), for details see Flow Chart 2.
For safety reasons, each dose group will consist of 2 cohorts. The trial medication will be 
administered accordingly:
Part I:

Cohort 1: 3 subjects on active treatment and 1 subject on placebo (in total 4 subjects)

Cohort 2: 6 subjects on active treatment and 2 subjects on placebo (in total 8 subjects)
Part II: 

Cohort 1: 3 subjects on active treatment and 1 subject on placebo (in total 4 subjects)

Cohort 2: 3 subjects on active treatment and 1 subject on placebo (in total 4 subjects)
Between start of the last subject of the first cohort and start of second cohort there will be a 
time interval of at least 7 days (see Section 6.2.2). 
Two cohorts (within one dose group) are considered as appropriate based on the clinical data 
from the first-in-man single-rising dose trial that investigated and confirmed the safety of 
single doses up to 600 mg. No acute effects were observed at exposures expected in this trial.
Within each trial part, treatment in the next higher dose group will only be started if the 
treatment in the preceding dose groups was safe and showed acceptable tolerability.
The dose groups to be evaluated are outlined in Table 3.1: 4 below.


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Table 3.1:4
Dose groups 
Dose Group
EM DG 1, 
PM DG 1
EM DG 2, 
PM DG 2
EM DG 3* EM DG 4* EM DG 6*
EM DG 7#
Total daily dose (mg)
20
60
140
300
240
120
Dose strength (mg)
10
10
50+10
150
50+10
50+10
Posology§
1-0-1
(3)-0-(3)
(1+2)-0-
(1+2)
1-0-1
(2+2)-0-
(2+2)
(2+2)-0-0
No. of subjects per 
DG
EM DGs:12, PM DGs: 8
No. of subjects 
receiving active drug
EM DGs:  9, PM DGs: 6
No. of subjects 
receiving placebo
EM DGs:  3, PM DGs: 2
* Subjects in the three highest EM bid dose groups will receive a microdose of midazolam (75 µg) on Day -1 (prior to the 
first administration of study medication) and at Day 11.
# with global amendment 7, a 120 mg qd dose group (DG 7) was added; and decision to finally not use the initially planned 
300 mg bid dose group (DG 5) was implemented (see Section 4.1.2)
§ At day 11 only qd administration in all dose groups
The end of the trial is defined as “last subject completed” (i.e. EoS completed by the last 
subject in the trial). For further details regarding the definition of the end of the trial, please 
see Section 8.6.
3.1.1
Dose Escalation Committee review
The different dose groups will be investigated, within each study part, consecutively in 
ascending order of daily doses, maintaining a time interval of at least 7 days between last 
drug administration in the preceding dose group and first drug administration of the 
subsequent dose group. The decision to proceed to the next dose level, no matter if in Part I 
or Part II of the trial, will be based upon the safety and tolerability data of all preceding dose
levels, which will be assessed by a Dose Escalation Committee (DEC, see Section 8.7). The 
next dose will only be given if, in the documented opinion of the DEC, no safety concerns 
arise in the previous dose groups (i.e. no dose-limiting events occur) and if none of the pre-
specified trial-specific stopping criteria are met (Section 3.3.4.1).
The minimum data set for DEC review consists of the following data:

Adverse events of the current and preceding dose levels (including clinically relevant 
findings from ancillary safety testing listed below) (Note: AEs may be ongoing at the 
time of safety reviews and AE information may change prior to Database Lock).

Results from 12-lead EGG of the current and preceding dose levels.

Vital signs of the current and preceding dose levels.

Clinical laboratory tests of the current and preceding dose levels.

Check of criteria for stopping subject treatment as per Section 3.3.4.

Preliminary PK data 
 from at least 5 subjects on active 
treatment
 
from previous dose group and exposure predictions for 
subsequent dose group, to make sure the next applied dose regimen will not exceed 
the predefined exposure limits. 


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The DEC will review unblinded data. As the DEC is reviewing data only retrospectively, i.e.,
after the relevant subjects have completed the trial, this is not considered as having impact on 
the Principal Investigator’s blinded assessment of subjects during their trial participation.
Furthermore, an unscheduled safety review by the DEC can be requested anytime for any 
reasonable cause by the Principal Investigator or the sponsor of the study, e.g. because of any
unforeseen adverse events.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
This trial will investigate the safety and tolerability as well as pharmacokinetics of multiple 
rising doses of BI 1323495, administered twice daily or once daily together with a meal. As 
the therapeutic exposure range has not been reached following administration of single doses 
in trial 1405-0001 in UGT2B17 extensive metabolizers, 
 
 dose levels in this multiple-rising dose trial have been 
selected to explore necessary exposures in a Phase I setting.
With the rising-dose design, double-blind conditions regarding the subjects' treatment 
allocation (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 potential dose-dependent effects, but this design, also 
involving review of the data from each dose group by a Dose Escalation Committee (see 
Section 3.1.1), is inevitable when sequentially studying ascending doses in order to minimize 
subject risk.
Due to the small number of subjects, the study will not allow for hypothesis testing but will 
allow for gathering safety, PK, and PD data for decision on the definition and possible 
limitation of the number of dose levels to be explored in later clinical development trials.


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The control group will be treated with placebo, which is considered standard in phase I trials, 
to allow for a reliable assessment of safety and tolerability and PD.
The group size (9 subjects in Part I and 6 subjects in Part II per active treatment group) is in 
general considered sufficient for the assessment of safety and tolerability as well as for the 
exploratory evaluation of pharmacokinetics, but will only allow for a descriptive analysis of 
pharmacodynamic effects (in Part I) (see Section 7.5). The number of 4 females per dose 
group in Part I (3 on active, 1 on placebo) is considered adequate to allow for an assessment 
of the effect of gender on pharmacokinetic parameters and on safety.
The treatment period of 11 days is considered adequate for collection of safety,
pharmacokinetic, and pharmacodynamic data after multiple dosing at steady state to inform 
subsequent studies along the clinical development path. The treatment period is adequately 
covered by non-clinical toxicology data from animal studies.
A strong PK/PD relationship has been observed in the SRD trial. 
 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 88 healthy subjects will be randomised. Subjects will be recruited from the 
volunteers' pool of the trial site.
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.
No data on reproductive toxicology are available at this time, therefore male subjects will be 
included and female subjects either not of childbearing potential (i.e. postmenopausal or 
surgically sterilised) or women of childbearing potential willing and able to use a highly 
effective method of contraception as described in Section 4.2.2.3. The age range has been 
selected to allow the identification of postmenopausal women for the purpose of stratification 
by gender in the EM dose groups. The defined age range also enables the inclusion of healthy 
subjects representative for the typical age ranges of patients of both targeted indications, i.e., 
COPD and CF, which differ substantially: COPD is a disease of advanced age, with 
populations of typical large clinical trials in COPD having a mean age of > 60 years. Among 
CF patients, on the other hand, only few reach an age of > 50 years. Therefore, in order to 
also cover females of a CF-adequate age range, it is allowed that women of child-bearing 
potential are enrolled if they are willing and able to use adequate, non-hormonal 
contraception methods, as defined in Section 4.2.2.3. This is also expected to facilitate the 
identification of a sufficient number of female subjects to be recruited. The selected age 


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range will make the safety/tolerability information to be collected during this trial more 
meaningful.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy subjects according to the assessment of the investigator, as based on a complete 
medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and 
clinical laboratory tests.
2. Age of 18 to 70 years (inclusive).
3. BMI of 18.5 to 29.9 kg/m2 (inclusive).
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation.
5. For Part I: Subjects genotyped as UGT2B17 extensive metabolizers, i.e., carrying at least 
one functional allele of the UGT2B17 gene (*1/*1 or *1/*2).
For Part II: Subjects genotyped as UGT2B17 poor metabolizers, i.e., carrying no 
functional allele of the UGT2B17 gene (*2/*2).
6. Male or female subjects.

For ‘female subjects not of childbearing potential’ at least one of the following 
criteria must be fulfilled:
-
Permanently sterile (permanent sterilisation methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy)
-
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea without an 
alternative medical cause (in questionable cases a blood sample with FSH above 
40 U/L and estradiol below 30 ng/L is confirmatory)

Female subjects of childbearing potential must use a highly effective contraception 
method from at least 30 days before the first administration of trial medication until 
14 days after trial completion as described in Section 4.2.2.3.
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR, or ECG) deviating from 
normal and assessed as clinically relevant by the investigator. In particular a marked 
baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms in males or repeatedly greater than 470 ms in females) at screening.
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; safety laboratory screening evaluation can be repeated a maximum of 
two times.


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4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator 
or at risk of requiring concomitant drug therapy, e.g., gastrointestinal, hepatic, renal, 
respiratory, cardiovascular, metabolic, immunological, or hormonal disorder, diseases of 
the central nervous system (including, but not limited to any kind of seizures or stroke), 
and other relevant neurological or psychiatric disorders.
5. History of cholecystectomy or other surgery of the gastrointestinal tract that could 
interfere with the pharmacokinetics of the trial medication (except appendectomy or 
simple hernia repair).
6. History of relevant orthostatic hypotension, fainting spells, or blackouts.
7. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients); mild seasonal allergy adequately managed by topic administration of 
drugs to eyes or nose is not excluded.
8. Subjects with a documented active malignancy, or malignancy for which the subject has 
undergone resection, radiation therapy, or drug therapy (e.g., cytostatic, protein kinase 
inhibitor, or immune checkpoint inhibitor therapy), within the last 5 years.
9. Subjects who have been previously randomised in this study.
10. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval 
prolongation).
11. Intake of an investigational drug in another clinical trial within 60 days, or within 5 half-
lives of the investigational drug (whichever is longer), of planned administration of 
investigational drug in the current trial, or concurrent participation in another clinical 
trial in which investigational drug is administered.
12. Major surgery (major according to the investigator’s assessment) performed within 6 
weeks prior to randomisation or planned within 3 months after screening, e.g. hip 
replacement.
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day), also inability to refrain 
from smoking during in-house confinement.
14. Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for 
males) or any other drug abuse or positive drug screening.
15. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial.
16. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial.
17. Inability to comply with the dietary regimen of the trial site.
18. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome).
19. Subjects with veins unsuited for venipuncture (for instance, veins which are difficult to 
locate, access or puncture, veins with a tendency to rupture during or after puncture) as 
assessed by the investigator.
20. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study.
In addition, the following trial-specific exclusion criteria apply:
21. Male subjects with ‘women of childbearing potential’ (WOCBP) partner who are
unwilling to use male contraception (condom or sexual abstinence) from the first


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administration of trial medication until 30 days after the last administration of trial
medication
22. Known relevant immunodeficiency, as judged by the investigator
23. Chronic or relevant acute infections
24. History and/or presence of tuberculosis; positive result for interferon gamma release 
assay (IGRA) (i.e., QuantiFERON TB-Gold), or history of pneumococcal infection
25. Positive results for Hepatitis B antigen, Hepatitis C antibodies, and/or human 
immunodeficiency virus (HIV) 1 antigen or HIV1/2 antibodies, at screening
26. Aural body temperature of more than 37.7°C on Day -3 to -1, or Day -4 to -2 for subjects 
receiving Midazolam microdosing.
27. Subjects who have received live or live-attenuated vaccine in the 4 weeks prior to dosing
28. C-reactive protein above upper limit of laboratory reference range at screening and/or on 
Day -3 to -1, or Day -4 to -2 for subjects receiving Midazolam microdosing.
29. Subjects with signs of current gingivitis/periodontitis. Inspection of the oral cavity will 
be performed by the investigator.
30. Current or history of relevant kidney, urinary tract diseases or abnormalities (e.g. 
nephrolithiasis, hydronephrosis, acute or chronic nephritis, renal injury, renal failure), 
according to investigator.
31. Estimated glomerular filtration rate (eGFR) according to CKD-EPI formula < 80 mL/min 
at screening.
32. Known clinically relevant impairment of liver function or clinically relevant laboratory 
abnormality at the screening visit (V1) regarding liver aminotransferases, alkaline 
phosphatase, gamma glutamyl transferase, bilirubin, serum albumin, as judged by the 
investigator.
33. Subjects with a known coagulopathy or abnormal coagulation laboratory parameters at 
screening, or subjects who, within 10 days prior to administration of trial medication, 
used any drug that could reasonably inhibit coagulation.
34. Females with a positive pregnancy test or breastfeeding.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR.
At the time of discontinuation, an End of Treatment examination followed by an End of 
Study Visit will be performed as indicated in the Flow Chart 1/2/3/4, if possible, and the 
information will be recorded in the CRF.
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the subject files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Sections 5.2.6.2.1 and 
5.2.6.2).


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If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The 
subject is to be followed until she has given birth or until the end of the pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the CTR. For reporting of pregnancy and associated events, refer to Section 
5.2.6.2.4.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:

The subject wants to discontinue trial treatment, without the need to justify the decision.

The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future. 

The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment (see Section 4.2.2).

The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).

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.

The subject experiences an infection with SARS-CoV-2 (as confirmed by PCR Test, see 
Section 5.2.3) or an infection requiring systemic antibiotic treatment.
In addition to these criteria, the physician may discontinue a subject at any time based on his 
or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the FC and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for the following 
reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial.
3. The sponsor decides to discontinue the further development of the investigational 
product.
4. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment.


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5. Dosing will be stopped upon occurrence of a serious adverse reaction or of severe non-
serious adverse events considered as drug related by the investigator in 2 subjects on 
active treatment of the same dose group. No further subjects will be treated without 
thorough re-evaluation of the benefit-risk ratio.
6. Dosing will be stopped if at least 2 subjects on active treatment at one dose level have
relevant individual QT prolongations, i.e. a QTc increase of greater than 60 ms from 
baseline or absolute QT or QTc greater than 500 ms, as confirmed by a repeat ECG 
recording.
7. Dose escalation will be stopped if, based on preliminary PK results of preceding dose 
groups, the estimated systemic exposure (group gMean values) of the next dose level is 
expected to exceed a Cmax of 1900 nM or an AUC0-24 of 11500 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.
8. Dose escalation will be stopped (within the relevant study Part, I or II) if at least one 
subject of the preceding dose group exceeds individual exposures of a Cmax of 1900 nM or 
an AUC0-24 of 11500 nM*h.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the second reason).
3.3.5
Replacement of trial participants
In case some subjects do not complete the trial or there is not a sufficient number of subjects 
on active treatment within one dose group (see Section 3.1), the Clinical Trial Leader 
together with the Trial Clinical 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 or she 
replaces.
Subjects withdrawn due to drug-related adverse events will not be replaced. In addition, the 
subjects will not be replaced in the following cases:
1.
If a subject within the first cohort discontinues trial medication prior to reaching the 
decision point (at PK steady state) for the initiation of the second cohort of the current 
dose group, the safety decision would still be valid based on three subjects (of which 
at least 2 have to be on active treatment). No replacement is necessary to complete the
first cohort. 
2.
Within a dose group, subjects will not be replaced, if at least 5 subjects on active 
treatment (for Part I: at least two per each gender) complete the trial.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products and Matching Placebo
The investigational products used in this trial are manufactured by Boehringer Ingelheim 


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4.1.2
Selection of doses in the trial and dose modifications


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Midazolam
For testing the potential of BI 1323495 to induce CYP3A, an oral dose of 75 µg midazolam 
has been chosen to be administered once in the absence of BI 1323495 and once at PK steady 
state following multiple doses of BI 1323495. This dose is within the definition of a 
microdose (1/100th of the therapeutic dose, or 100 µg, whichever is smaller). Since 
midazolam exposures have been shown to be dose proportional over the microdose-to-
therapeutic-dose range, the microdose is considered adequate to accurately assess the CYP3A 
induction potential, while remaining below a pharmacologically active and toxicologically 
relevant concentration of midazolam.
For oral administration of midazolam, the preparation of the dose by dilution of the marketed 
solution for IV administration has been selected instead of preparation from the marketed oral 
solution. This decision was made as the preparation of a microdose of 75 µg with adequate
precision and reproducibility requires dilution from the more highly concentrated original 
solution. Whereas data regarding the stability and compatibility of a dilution prepared from 
the solution for IV administration are available, this is not the case for a dilution prepared 
from the solution for oral administration. Furthermore, the IV solution contains midazolam in 
isotonic saline solution, while the oral solution has added excipients, which would result in 
additional elements of risk. Finally, there is the aspect of feasibility, whereby the oral 


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solution would need to be diluted 1:400, which may not be possible to be accurately 
achieved, while the IV solution requires a dilution of only 1:200. The IV solution of 
midazolam has been successfully diluted and administered orally as a microdose in previous 
clinical studies without any reports of AEs.
4.1.3
Method of assigning subjects to treatment groups
Prior to screening visit, subjects will be contacted in writing and informed about the planned 
visit dates. The subjects willing to participate will be recruited to dose groups (2 cohorts per 
dose group) according to their temporal availability.
In this trial a sentinel cohort design is used within each Dose Group. As soon as enough 
subjects have been allocated to the first cohort, the following subjects will be allocated to the 
second cohort of the respective dose group. Therefore, the allocation of subjects to cohorts is 
not influenced by trial personnel, but only by the subjects’ temporal availability.
Prior to first administration of trial medication, eligible subjects will be randomised to receive 
active compound (BI 1323495) or matching placebo in a 3:1 ratio according to a 
randomisation plan. 
The list of subject and medication numbers will be provided to the trial site in advance. The 
allocation of subjects to trial subject numbers will be performed prior to the first 
administration of trial medication. For this purpose, the subjects will be allocated to a subject
number by the method ‘first come-first served’. Once a subject number has been assigned, it 
cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.5.
Subjects will first be randomised into Dose Group 1. Randomisation into a following dose 
group will only be possible after the DEC has cleared the next dose group for randomisation
after assessment of all available data from the subjects of the preceding dose group (see
Section 3.1). 
In- and exclusion criteria are applicable for all dose groups. 
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 group of the active 
substance.


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On Day 11, Subjects will receive a single dose in the morning only. On all other trial days,
BI 1323495 will be administered bid (except for 120 mg qd dose group).
For safety reasons, each dose group will consist of 2 cohorts. The trial medication will be 
administered accordingly:

Cohort 1 (“sentinel”): 3 subjects on active treatment and 1 subject on placebo (in total 4 
subjects)

Cohort 2: For Part I, 6 subjects on active treatment and 2 subjects on placebo (in total 8 
subjects); for Part II, 3 subjects on active treatment and 1 subject on placebo (in total 4 
subjects)
Between start of last subject of cohort 1 and start of cohort 2 there will be a time interval of at 
least 7 days. This ensures that the safety of subjects in cohort 1 who have reached 
pharmacokinetic steady state of BI 1323495
 will have been evaluated before subjects 
of cohort 2 start treatment.
In case safety data cannot be assessed for all 4 subjects of the first cohort of a dose group, 
safety data of at least two subjects on active study drug must be available for safety 
evaluation.


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In the following paragraphs of this chapter, information regarding the evening dose (time, 
food intake etc.) is applicable for all bid dose groups. For the DG 7 with 120 mg qd, drug 
administration takes place only in the morning.
Subjects who qualify will be randomised to either BI 1323495 or placebo and will be 
instructed to self-administer the trial medication depending on the dose group that is open for 
randomisation at that timepoint. The morning dose will be administered to the subjects at the 
site under supervision of authorized site staff. Generally, subjects should take the study drug
while in a standing or sitting position, as an oral dose together with about 240 mL of water.
On first day of treatment (Day 1) and last day of treatment (Day 11), where PK profile 
sampling takes place, administration of BI 1323495 and administration of midazolam (Day -
1, Day 11, Part I DG 3, 4, and 6) in the morning will be performed following a standardized
breakfast, which is to start and be completed within 30 minutes before the scheduled dosing. 
On all other treatment days and in the evening of Day 1, subjects should take the study 
medication with food, preferably within 30 min after a meal. On treatment days, breakfast 
will be provided 30 minutes prior to the morning dose administration and dinner will be 
provided 30 minutes prior to the evening dose administration.
Subjects should take their morning doses on all treatment days at the same time as on the first 
day, +/- 1 hour. The evening dose should be taken 12 hours +/-1 hour after the scheduled time 
of the morning dose.
Following the first administration of trial medication, subjects will stay in inhouse 
confinement until Day 12. During the first 2 h after drug administration, and in Part I DG 3, 
4, and 6 in the first 2 h after midazolam administration on Day -1, 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 trial is designed double-blind with regard to the subjects and the investigator (as well as 
the research staff at the trial site) in order to eliminate observer or performance bias. This 
means avoiding systematic differences in assessments regarding the subject’s treatment 
(active or placebo). According to the rising dose design, the current dose level will be known 
to subjects and investigators.
At the trial site, access to the randomisation schedule is restricted to unblinded pharmacist. 
The unblinded pharmacist together with a further staff member will assign the medication 
numbers to the random numbers. Access to the codes will be controlled and documented by a 
signed confidentiality statement, which will be stored in the TMF. Persons directly involved 
in the clinical conduct of the trial will not have access to the treatment allocation prior to 
database lock.
Regarding the sponsor, the database of this trial will be handled open-label, meaning that the 
trial functions of the sponsor are unblinded (including clinical trial leader, clinical trial 
manager, data manager, statistician, bioanalyst, pharmacokineticist, pharmacometrician, drug 


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metabolism scientist as well as dedicated CRO personnel if not involved in the clinical 
conduct of the trial). The objective of the trial is not expected to be affected.
DEC Members will receive unblinded data, for details see Section 3.1.1.
Within the central ECG lab, the staff involved with interval measurements and morphological 
analyses will be blinded with respect to the treatment and also with regard to the recording 
date and time as well as planned time points of the ECGs. The interval measurements for a 
given subject will be performed in a random and blinded sequence by a single technician. No 
more than two different blinded readers will evaluate the ECGs of the study.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via contact to the unblinded 
pharmacist or, in exceptional case of non-availability, by calling the emergency unblinding 
provider contracted for the trial (Global Emergency Unblinding & Medical Support in 
Clinical Trials). Instructions will be provided in the ISF, and subjects will receive the contact 
information on their Trial Identification Card. It must only be used in an emergency situation 
when the identity of the trial drug must be known to the investigator in order to provide 
appropriate medical treatment or otherwise assure safety of trial participants. The sponsor 
must be informed immediately. The reason for unblinding must be documented in the source 
documents and/or appropriate CRF page along with the date and the initials of the person 
who unblinded.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from
to 
access the randomisation code for individual subjects during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives and not be shared 
further. 
4.1.6
Packaging, labelling, and re-supply
BI 1323495
Drug supplies will be provided by the 
 
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 
as Annex 13/EU GMP Guideline will be provided on the containers. 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


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
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.
Re-supply will be provided if applicable, e.g. in case of prolonged study timelines with 
regard to expiry dates. For details of packaging and the description of the label, refer to the 
ISF.
Midazolam solution for injection
Midazolam solution for injection will be obtained by the clinical trial site from a public 
pharmacy. The drug will be used out of the original, unmodified packages in order to prepare 
a dilution for oral administration. Instructions for dilution and application of Midazolam are 
provided in the ISF.
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 storage conditions recommended on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Trial 
Manager (as provided in the list of contacts in the ISF) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Subjects should be instructed to return 
unused investigational drug.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
subjects. The investigator or designee will maintain records that document adequately that the 
subjects were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. All unused medication will 


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be disposed locally by the trial site upon written authorisation by the Clinical Trial Manager. 
The investigator or designee must verify that all unused or partially used drug supplies have 
been returned by the subjects and that no remaining supplies are in the investigator’s 
possession.
Source data documentation and full drug accountability in regard to dispensed and returned 
medication to investigational site and to subjects is required.


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
No special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. In particular, drugs must be avoided which 
are known to induce CYP3A4. Strong inhibitors of CYP3A4/P-gp have to be avoided in Part 
I, since a modest effect of the strong CYP3A4/P-gp inhibitor itraconazole on the PK of 
BI 1323495 has been observed (see Section 1.2.4). For PM subjects participating in Part II of 
the trial, inhibitors of CYP3A4/P-gp have to be avoided in general.
Live or live-attenuated vaccine should be avoided during the trial.
All concomitant therapy will be recorded (including time of intake on study days) on the 
appropriate pages of the CRF. 
4.2.2.2
Restrictions on diet and life style
On Day 1 and Day 11 where PK profile sampling is performed, while admitted to the trial 
site, the subjects are restricted from consuming any other foods or beverages than those 
provided by the site staff. Standardised meals will be served at the time points described in 
Flow Chart 1/2/3/4. A standardized normal caloric breakfast (e.g., a roll with cheese or 
sausage, including some dietary fat) should be served and finished within 30 minutes prior to 
dose administration. In addition, in Part I DG 3, 4, 6, and 7, breakfast will be served 30 
minutes before midazolam intake on Day -1 and should be finished within 30 minutes prior to 
dose administration.
In the evening of Day 1 and on Days 2 to 10, drug intake should occur with food. Breakfast 
will be provided 30 minutes prior to the morning dose administration and dinner will be 
provided 30 minutes prior to the evening dose administration (for DG 7 with qd dosing, 
instructions regarding evening dose are not applicable).
On Days 1 and 11, 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 24 h post-dose, total fluid intake is 
restricted to 3.0 litres.
On Day -1 in Part I DG 3, 4, and 6, from 1 h before midazolam intake until 4 h after 
midazolam intake, fluid intake is restricted to the water administered with midazolam and an 
additional 240 mL of water served at 2 h and 4 h after midazolam (mandatory for all 
subjects).
During the days of urine collection, total fluid intake should be at least 1.5 litres and should 
not exceed 3.5 litres.


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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.
Methylxanthine-containing beverages or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 4 h before until 4 h after each administration of trial 
medication.
Smoking is not allowed during in-house confinement while admitted to the trial site.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the administration of trial medication until the EoS Visit. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.2.2.3
Contraception requirements
Women of child-bearing potential (WOCBP) must use one of the following highly effective 
methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per 
year when used consistently and correctly, from at least 30 days before the first 
administration of trial medication until 14 days after trial completion:

Use of intrauterine device (IUD) plus condom (Note: intrauterine hormone-releasing 
systems (IUS) will not be allowed).

Sexual abstinence: This is defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. Periodic abstinence e.g. calendar, 
ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable.

A vasectomised sexual partner who received medical assessment of the surgical 
success (documented absence of sperm) (see Section 3.3.2).
The investigator should take care to inform WOCBP that hormonal contraception methods 
are not considered highly effective in this trial. However, female subjects regularly taking
hormonal contraception are not required to interrupt administration during the trial, as long as 
they are aware that the effectiveness of hormonal contraception may be reduced (see also 
Section 1.2.4), and another method (as described above) has to be used in addition.
Men able to father a child must use highly effective methods of birth control per ICH M3 
(R2) that result in a low failure rate of less than 1% per year when used consistently and 
correctly. A list of contraception methods meeting these criteria is provided in the subject 
information.
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. Subjects who are non-compliant (for 
instance, who do not appear for scheduled visits or violate trial restrictions) may be removed 


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from the trial and the CRF will be completed accordingly (for further procedures, please see 
Section 3.3.4.1). 


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable. No efficacy endpoints will be evaluated in this trial.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart 1/2/3/4 including inspection of the oral cavity. 
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart 1/2/3/4.
The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart 1/2/3/4, prior to 
blood sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a supine position after at least 5 minutes of rest. The results 
must be included in the source documents available at the site.
Aural body temperature will be measured at the time points indicated in the Flow Chart
1/2/3/4.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. For the 
sampling time points please see the Flow Chart 1/2/3/4. Reference ranges will be filed in the 
ISF.
Blood and urine samples will be analysed by the local laboratory of the site. Laboratory data 
will be collected and captured in the eCRF. Manual differential white blood cell count or 
urine sediment examinations will only be performed if there is an abnormality in the 
automated blood cell count or if erythrocytes, leukocytes, nitrite, or protein are abnormal in 
the urinalysis, respectively.
It is the responsibility of the investigator to evaluate the laboratory reports received from the 
local laboratory. Clinically relevant abnormal findings as judged by the investigator will be 
reported as adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1 and the DILI Checklist provided in the ISF). In this 
case, the amount of blood taken from the subject concerned will be increased due to the
additional sampling.


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Table 5.2.3:1 
Safety laboratory tests
Functional lab group
Test name
A1
B1
C1
D1
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes (RBC)
Reticulocyte count
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 (per Leukocytes) and 
absolute 
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Manual differential WBC 
relative (per Leukocytes)
(if automated differential 
WBC is abnormal)
Polymorphonuclear neutrophils (segs)
Band neutrophils
Eosinophils
Basophils 
Monocytes 
Lymphocytes
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
Activated Partial Thromboplastin Time (aPTT)
Prothrombin time – INR (International Normalized Ratio)
Fibrinogen
X
X
X
X
X
X
X
X
X
-
-
-
Enzymes
Aspartate transaminase (AST/GOT) 
Alanine transaminase (ALT/GPT)
Alkaline Phosphatase [AP]
Gamma-Glutamyl Transferase (GGT)
Glutamate Dehydrogenase (GLDH)
Creatine Kinase (CK)
Creatine Kinase Isoenzyme MB (CK-MB), if CK is 
elevated
Lactate Dehydrogenase (LDH)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
-
-
-
-
-
-
Hormones
Thyroid Stimulating Hormone (TSH)
X
-
-
-
Substrates
Plasma glucose
Creatinine
GFR/ CKD-EPI
Total bilirubin
Direct bilirubin
Total protein
Albumin
C-Reactive Protein (CRP) 
Uric Acid
Urea
Total cholesterol
Triglycerides
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
X
-
X
-
-
-
X
X
X
X
X
-
X
X
X
X
X
-
-
-
-
-
-
-
-
-
-
-
-
Electrolytes
Sodium
Potassium
Chloride
Calcium
X
X
X
X
X
X
X
X
X
X
X
X
-
-
-
-


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Table 5.2.3:1 (continued) 
Safety laboratory tests 
Functional lab group
Test name
A1
B1
C1
D1
Urinalysis2 (Stix)
Urine nitrite (qual)
Urine protein (qual)
Urine glucose (qual)
Urine ketone (qual)
Urobilinogen (qual)
Urine bilirubin (qual)
Urine RBC/erythrocytes (qual)
Urine WBC/leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
-
-
-
-
-
-
-
-
-
Urine sediment2
(microscopic examination, if 
erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
X
X
X
-
1 A, B, C, and D are different sets of laboratory assessments. The Flow Chart 1/2/3/4 defines at what time point 
which set is to be investigated
2 Urinalysis/urine sediment only at screening, Day 11 and Visit 3.
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which are planned during 
screening only, but may be repeated as required. The results will not be entered in the 
CRF/database and will not be reported in the CTR. Except for pregnancy tests and drug 
screening, it is planned to perform these tests at screening only. Pregnancy testing in women 
will be performed at screening, prior to each treatment start, and as part of the end of study 
examination. Drug screening will be performed at screening and prior to treatment start.


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
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)
Immunology*
Interferon-ɣ release assay to tuberculosis (qualitative), e.g. 
QuantiFERON®-TB-Gold Test
Molecular Diagnostics**
PCR test for detection of SARS-CoV-2 according to 
recommendations of Robert-Koch-Institute in Germany 
(https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Corona
virus/Entlassmanagement.html)
i.e. performed on two swabs obtained at the same time from 
oro- and nasopharynx (single PCR test sufficient after transfer 
of two swabs from oro- and nasopharynx to the same 
transport media, or use of the same swab in both oro- and 
nasopharynx)
*Test results already available for a subject do not have to be repeated, if assessment took place within 4 weeks 
before randomisation 
**Applicable to Part I DG 3, DG 4, DG 5, and DG 6; and Part II DG 1 and DG 2, to be performed on Visit 2 
Day -4 to -2, and at any time if COVID-19 infection is suspected
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest® 
7410, 
) 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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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 system at the time points given in the Flow Chart 1/2/3/4. Electrode placement 
will be performed according to the method of Wilson, Goldberger and Einthoven modified by 
Mason and Likar (hips and shoulders instead of ankles and wrists). Precise electrode 
placement will be marked with an indelible mark on the skin to allow reproducible placement 
throughout the study.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG recording will always precede all other study procedures scheduled 
for the same time (except for blood drawing from an intravenous cannula that is already in 
place) to avoid compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs (i.e. three single ECGs recorded 
within 180 sec) as indicated in the Flow Chart 1/2/3/4. Recording time points may be adapted 
based on information obtained during the trial. Such changes would be implemented as non-
substantial amendment.
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 system provided by 
. Screening 
and EoS ECGs will not be transferred to central ECG lab.
Data transfer
For time points specified in the Flow Chart 1/2/3/4, ECGs will be transferred electronically to 
the central ECG lab (
) for evaluation.
In case of repeat ECGs due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab.
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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Evaluation
a) Central ECG laboratory
Central ECG lab evaluation will be performed for the first of three replicate ECGs per 
time point as specified in the Flow Chart 1/2/3/4.
RR and QT intervals will be determined semi-automatically, whereas PR, QRS 
intervals, and QRS-axis are measured automatically by a validated GE 12-SL-
algorithm or equivalent.
Heart rate (HR) and the QT interval corrected for HR (QTc, e.g. QTcF and QTcB) 
will be determined by the sponsor (see TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the 
same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. 
If lead II shows a flat T wave or is not measurable for any reason, lead V5 will be 
used, or if that lead is not measurable, then lead I will be used. The lead actually used 
will be reported in the CTR.
For automatic interval measurements no lead will be provided. After quality control, 
the fiducial point markings will be reviewed by the cardiologist assigned to the study.
For blinding arrangements see Section 4.1.5. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular subject should be evaluated by 
a single reader. For quality assurance and control of the measurements, all ECGs of a 
subject will be subsequently reviewed by the ECG technician supervisor or his/her 
designee to assess the overall variance of the measured intervals and to detect 
accidental switching of leads and/or false subject assignments of the ECGs. After 
quality control, the fiducial point markings will be reviewed by the cardiologist 
assigned to the study.
Evaluation of ECGs will comply with the ICH E14 guidance document and 
supplements [R07-4722, R16-0366] as well as the FDA requirements for annotated 
digital ECGs [R09-4830].
b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of 
cardiac safety during the study, the QT and QTcB values generated by the 
computerised ECG system or their manual corrections by the investigators will be 
used.
In doubtful cases, ECGs may be sent upfront (i.e. prior to the regular data transfer) for 
cardiologic assessment by the central lab. In this case, these centrally measured results 
would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 
clinically relevant by the investigator.
Any ECG abnormalities will be monitored carefully and, if necessary, the subject will be 
removed from the trial and will receive the appropriate medical treatment.


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5.2.5
Other safety parameters
This section is not applicable.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation,
-
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 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
5.2.6.1.3
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 


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as described in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
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.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST (aspartate transaminase) and/or ALT (alanine transaminase) ≥3 fold 
ULN combined with an elevation of total bilirubin ≥2 fold ULN measured in the same 
blood draw sample, or

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 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.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 


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confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-existing
or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end 
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart 1/2/3/4. 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.


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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 the 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: 
The investigator does not need to actively monitor the subject for new AEs but should 
only report any occurrence of cancer and related SAEs and related AESIs of which the 
investigator may become aware of by any means of communication, e.g. phone call.
Those AEs should however not be reported in the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific contact details will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
5.2.6.2.3
Information required
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been assessed as “chronic” or “stable” , or no further 
information can be obtained.
5.2.6.2.4
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner.


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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 B) as 
well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Date and exact clock time of drug administration and pharmacokinetic sampling for 
BI 1323495 and Midazolam will be recorded in the eCRF.
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.
If a subject has to be withdrawn from treatment at one of the above mentioned time points 
and the PK sample was already obtained, this PK sample might be registered as EOS sample 
instead. It will be collected and analysed accordingly.
5.3.2
Methods of sample collection
5.3.2.1
Plasma sampling for pharmacokinetic analysis
BI 1323495
For quantification of BI 1323495 plasma concentrations, blood will be taken from an 
antecubital or forearm vein into an EDTA (dipotassium ethylenediaminetetraacetic acid)-
anticoagulant blood drawing tube at the times indicated in the Flow Charts 1/2/3. Blood will
be withdrawn by means of either an indwelling venous catheter or by venipuncture with a
metal needle.
For details, please see lab manual/ISF:
Midazolam
For quantification of midazolam and 1-OH midazolam plasma concentrations, blood will be 
taken from an antecubital or forearm vein into a K-EDTA (potassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart 2. Blood will be withdrawn by means of either an indwelling venous catheter 
or by venipuncture with a metal needle.
For details, please see lab manual/ISF:


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BI 1323495, Midazolam and 1-OH midazolam
After completion of the trial, the plasma samples may be used for further methodological
investigations, e.g. for stability testing, assessment of metabolites. However, only data related
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be
generated by these additional investigations. The study samples will be discarded after
completion of the additional investigations but not later than 5 years upon the final study
report has been signed.
5.3.2.2
Plasma sampling for metabolism analysis
Additional EDTA plasma samples for the identification of drug metabolites will be
investigated in the 150 mg bid EM dose group (DG4 in Part I) and 30 mg bid PM dose group 
(DG2 in Part II) and will be pooled per dose group.
Based on the knowledge gained during the trial conduct, e.g. from preliminary PK results, the 
dose group may be changed to a different one. The change would be implemented via a non-
substantial CTP Amendment.
The blood samples will be drawn in parallel to PK samples at Day 11 including the 24 h 
sample (see Flow Chart 2/3). At each of these time points, approx. 3 ml blood will be needed 
for metabolite analysis. The blood samples will be processed in the same way as the PK 
samples described in the lab manual.
Only data related to the parent compound and its metabolites will be acquired. Evaluation of
the drug metabolism will be reported separately but not included in the CTR of this trial. The
study samples will be discarded after completion of the experiments but not later than 5 years
after the final study report has been signed.
5.3.2.3
Urine sampling for pharmacokinetic analysis
A blank urine sample will be collected before administration of trial medication (within 3 h
before drug dosing) and two 0.5 mL aliquots will be retained to check for analytical
interference by concomitant or rescue medication.
All urine voided during the sampling intervals indicated in the Flow Chart 1/2/3/4 will be 
collected in 2 L polyethylene (PE) containers and stored at room temperature. Subjects are 
told to empty their bladders at the end of each sampling interval.
The urine weight/volume for each collection interval will be documented (however, no
correction for the specific gravity of urine is done, i.e. 1 L is defined to be equal to 1 kg).
For details please see lab manual/ISF.


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5.4
ASSESSMENT OF BIOMARKER(S)
5.4.1
Biochemical and cellular biomarkers
Biomarkers will be assessed to monitor pharmacodynamic drug effects over the course of the 
observation time. Assessment of biomarkers in blood will be done in all subjects.
Direct target engagement of BI 1323495 in blood will be evaluated in Part I of the trial 
 
5.4.1.1
Methods of sample collection
Blood samples will be taken at time points indicated in the Flow Chart 1/2/4.
A maximum of approximately 20 ml blood will be collected per biomarker sampling time-
point per subject for the pre-specified biomarker analyses. This sums up to a total blood 
volume of approximately 60 mL collected for biomarker analyses over the 3 weeks 
observational period.
Detailed instructions for biomarker blood sampling, processing, storage and shipment of the 
different biofluids will be provided in the lab manual/site’s ISF.


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5.5
BIOBANKING
This section is not applicable.
5.6
OTHER ASSESSMENTS
This section is not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic and 
pharmacodynamic parameters in an adequate way allowing for appropriate risk mitigation in 
a clinical trial during the early clinical development phase when only limited information is 
available yet on the IMP. The scheduled measurements will allow monitoring of changes in 
vital signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. 
The safety assessments are standard, are accepted for evaluation of safety and tolerability of 
an orally administered drug, and are widely used in clinical trials. The pharmacokinetic 
parameters and measurements outlined in Section 5.3 are established assessments of drug 
exposure. The biomarkers and pharmacodynamic parameters and measurements outlined in 
Sections 5.4 are of exploratory nature.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The trial consists of a screening period, an 11 days multiple dose treatment and a Follow-up 
period. The acceptable time windows for visits and trial procedures are given in the Flow 
Chart 1/2/3/4. Exact times of measurements outside the permitted time windows will be 
documented. 
Screening Visit and Day -3 to -1 (or Day -2 to -4 for midazolam dose groups) may be 
combined if feasible. 
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 and Day 11 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, PK 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, except for V3 (EoS 
Visit), where a deviation of -120 min to + 72 h is acceptable. 
If several activities are scheduled at the same time point in the Flow Chart 1/2/3/4, ECG 
should be the first and meal the last activity. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological 
parameters.
For planned individual plasma concentration sampling times and urine collection intervals 
refer to Flow Chart 1/2/3/4. 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
6.2.1.1
Screening Period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local regulations prior to enrolment in the study and 
before any study procedures are started. 
Screening procedures include a complete medical examination (including documentation of 
demographics, smoking and alcohol history, medical history, inclusion/exclusion criteria, 
concomitant therapy), measurement of blood pressure, heart rate, body weight and height, 12-


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lead ECG, as well as an assessment of laboratory values including drug and virological 
screening, and pregnancy testing in females will be performed. 
If V1 takes place within the last three days before first drug administration, or first 
midazolam administration, respectively, and all required assessments are completed before 
V2/Day 1, the visit Day -3 to -1 (resp. Day -4 to -2 in the midazolam groups) and related 
assessments may be skipped.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.4.
The subject should be recorded on the enrolment log as screened.
6.2.2
Treatment period
In any case, within the last three days before single dose administration, or midazolam 
administration, as applicable, subjects will visit the site and main eligibility criteria will be 
reviewed and safety lab performed. 
Subjects will be admitted to the site in the evening before first drug administration on Day 1
(Part I: DG 1, DG 2 and DG 7, and Part II), and in the evening before first midazolam 
administration on Day -1 (Part I: DG 3, DG 4 and DG 6), respectively. A subject who is 
eligible for the study will be randomised into the current dose group and receive the first dose
of BI 1323495 or placebo on Day 1. During treatment phase up to Day 10, each subject will 
receive multiple bid doses of BI 1323495 or placebo, or multiple qd doses of BI 1323495 or 
placebo in DG 7, and a last single dose on Day 11.
Trial medication will be taken orally by each subject under direct supervision of the 
investigator or 
designee. 
Study participants will stay at the site under medical surveillance during the treatment phase.
The subjects will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness by the investigator or 
 designee, and return to further visits as 
indicated in the Flow Chart 1/2/3/4.
For details on time points and procedures for collection of blood and urine samples for PK 
analysis, refer to Flow Chart 1/2/3/4 and Section 5.3.2. 
The safety assessments performed during the treatment period are specified in Section 5.2 of 
this protocol and in the Flow Chart 1/2/3/4.
For details on time points for all other trial procedures, refer to the Flow Chart 1/2/3/4. AEs 
and concomitant therapy will be assessed continuously from screening until the end of trial 
examination.
Safety evaluation between 1st and 2nd cohort of each Dose Group
Between start of the last patient of cohort 1 and start of cohort 2 there will be a time interval 
of at least 7 days. Subjects of cohort 2 will only enter treatment if the following safety-
relevant data from the subjects in cohort 1, who are expected to have reached PK steady state 
 have been evaluated:

Adverse events as recorded at that time


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
Any findings from physical examination, vital signs, ECG assessment, or safety 
laboratory testing
Day 11 (End of Treatment)
On Day 11 in the morning, subjects will take their last dose of trial medication. For AE 
assessment, laboratory tests, ECG measurements, vital signs, and physical examination 
during the end of trial period, see Sections 5.2.1 to 5.2.6.
Male subjects with ‘women of childbearing potential’ (WOCBP) partner will be reminded to 
use male contraception (condom or sexual abstinence) until 30 days after the last 
administration of trial medication.
6.2.3
Follow up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.1 to 5.2.6.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the End of Study 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. All visit procedures of the Visits during Follow-up period Day 12 to Day 16
and at Visit 3 (Day 18 to 21) (EoS) Visit have to be completed as indicated in the Flow Chart 
1/2/3/4.
Male subjects with ‘women of childbearing potential’ (WOCBP) partner will be reminded to 
use male contraception (condom or sexual abstinence) until 30 days after the last 
administration of trial medication.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 6 different dose groups of BI 1323495 in Part I and two different 
dose groups in Part II 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 be interpreted in the perspective of the 
exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.2
PLANNED ANALYSES
7.2.1
General considerations
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomised and 
treated with at least one dose of study drug. The treatment assignment will be 
determined based on the first treatment the subjects received. The treated set will be 
used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was not excluded due to a 
protocol deviation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 
included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment. Descriptive and model based analyses of PK 
parameters will be based on the PKS.
Further PK and PD sets for different strata may be defined in TSAP, if needed. 
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be specified in the Integrated Quality and Risk Management Plan 
(IQRMP). IPDs will be identified no later than in the Blinded Report Planning Meeting, and 
the iPD categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2 for drug BI 1323495 or 
midazolam and 1-OH midazolam will be calculated according to the relevant BI internal 
procedures.
Plasma and urine concentration data and parameters of a subject will be included in the 
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol deviation relevant to the evaluation of PK (to be decided no later than in the Blinded 


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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 deviation 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 and urine concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects experiencing 
emesis),

Missing samples/concentration data at important phases of PK disposition curve.
Plasma/urine concentration data and parameters of a subject which is flagged for exclusion 
will be reported with its individual values but will not be included in the statistical analyses.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format as in the bioanalytical report (that is 
to the same number of decimal places provided in the bioanalytical report). 
7.2.2
Primary endpoint analyses
The primary endpoint as specified in Section 2.1.2 will be derived according to BI standards. 
Inferential statistics is not planned here. The analysis will be based on the treated set (TS) and 
will be descriptive in nature. For Part I only, this analysis will be repeated for all categories 
of stratification factor (gender). 
7.2.3
Secondary endpoint analyses
Primary analyses
The secondary endpoints (refer to Section 2.1.3) will be analysed descriptively. Analyses will 
be performed for the parent drug.
Further exploratory analyses


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7.2.5
Safety analyses
All treated subjects will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
For all analyses the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Blinded Report Planning Meeting).
Treatments will be compared in a descriptive way. The placebo group in the safety evaluation 
will consist of all subjects treated with placebo, regardless of the dose group in which they 
were treated. The test treatment groups will be compared to the placebo group in a descriptive 
way. Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.
Measurements (such as ECGs, vital signs, or laboratory parameters) or AEs will be assigned 
to treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment-emergent AEs). 
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between the first trial medication intake and end of 
REP (see Section 1.2.6) will be assigned to the treatment period. Events occurring after the 
REP but prior to trial termination date will be assigned to ’follow-up’. These assignments 
including the corresponding time intervals will be defined in detail in the TSAP. Note that 
AEs occurring after the last per protocol contact but entered before database lock will be 
reported to Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (called analysing treatments) may be defined in the
TSAP in order to provide summary statistics for other than above periods, such as combined 
treatments, on-treatment totals, or periods without treatment effects (such as screening and 
post-study intervals). 
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 


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regard to frequency and percentage of subjects with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-study evaluation will be assessed 
with regard to possible changes compared to findings before start of treatment.
7.2.6
Other analyses
This section is not applicable.
7.2.7
Interim analyses
No interim analysis is planned for this trial.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Plasma/urine drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant BI internal 
procedure. Drug concentration data identified with NOS (no sample available), NOR (no 
valid result), NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no 
peak detectable) will be displayed as such and not replaced by zero at any time point (this 
rule applies also to the lag phase, including the predose values).


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7.3.3
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedure.
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.4
RANDOMISATION
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to 3.3.5).
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 88 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 8-12 subjects per dose group is commonly used in 
multiple-rising dose studies of the present type and is in general considered as sufficient for 
the exploratory evaluation of multiple dose safety and pharmacokinetics. The sample size in 
the PM dose groups of 8 subjects (6 on active treatment and 2 on placebo) is lower than in the 
EM dose groups (12, of which 9 on active treatment and 3 on placebo), as an additional 
objective in the EM dose groups is the assessment of potential gender effects on exposures 
with BI 1323495. It is assumed that stratification by gender in each EM dose group leads to 8 
trial subjects being males (6 on active treatment and 2 on placebo), whereas 4 will be females 
(3 on active treatment and 1 on placebo). Hence, the sample size of the PM dose groups, that 
do not look at potential gender effects, is equivalent to the sample size of the larger male 
subpopulation in the EM dose groups.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations. Investigators and site staff must adhere to 
these principles. Deviation from the protocol, the principles of ICH GCP or applicable 
regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the subject.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the subjects, and is
stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective 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 subject participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.”
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.


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8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial subject. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. 
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: gender, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

ECG results (original or copies of printouts)

Adverse events and outcome events (onset date (mandatory), and end date (if available))


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
Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the subject eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site


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as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as well 
as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as specified in 
the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial
(“Last Subject Completed”).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last subject
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).


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The Principal Investigator is responsible to coordinate tasks and responsibilities at the site as
defined in a contract. 
BI has appointed a Clinical Trial Leader (CTL), responsible for coordinating all required 
activities, in order to 

manage the trial in accordance with applicable regulations and internal SOPs,

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate training and information of Clinical Trial Managers (CTMs), Clinical 
Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
The trial medication will be provided by the 
 
 
Midazolam-
 solution for injection will be obtained by the clinical trial site from a 
public pharmacy.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
The genotype assessment for eligibility determination will be performed by a central 
laboratory.
Logistics for PK, PD and biomarker samples will be coordinated by the site.
Safety laboratory tests will be performed in local laboratories selected by the investigational 
site.
All other laboratory analyses, i.e. PK and biomarker assessments, will be handled by central 
laboratory facilities.
The digitally recorded 12-lead ECGs will be submitted to a specialised contract research 
organisation for evaluation.
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
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.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
Dose Escalation Committee
A Dose Escalation Committee (DEC) composed of Principal Investigator, the Team Member 
Medicine (TMM), the Trial Clinical Pharmacokineticist (TCPK), and the Clinical Trial 
Leader (CTL) will be established to review individual and aggregated safety data at regular 
intervals to determine the safety profile and risk/benefit ratio and decide on each dose 
escalation step.


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Details of the DEC responsibilities and procedures are described in the DEC charter (see also 
Section 3.1.1).


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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A nanogram dose of the CYP3A probe substrate midazolam to evaluate 
drug interactions. Clin Pharmacol Ther. 2013. 93(6):564-571.
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Hohmann N, Kocheise F, Carls A, Burhenne J, Haefeli WE, Mikus G. 
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CYP3A activity in humans. Br J Clin Pharmacol 2014;79(2):278-285.
R17-3101
Sorensen OE, Clemmensen SN, Dahl SL, Ostergaard O, Heegaard NH, 
Glenthoj A, et al. Papillon-Lefevre syndrome patient reveals species-
dependent requirements for neutrophil defenses. J Clin Invest 
2014;124(10):4539-4548.


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R18-0132
Ilumets H, Rytila PH, Sovijarvi AR, Tervahartiala T, Myllarniemi M, 
Sorsa TA, et al. Transient elevation of neutrophil proteinases in induced 
sputum during COPD exacerbation. Scand J Clin Lab Invest 
2008;68(7):618-623.
R18-0467
Clinical trial results: a phase IIa, randomized, double-blind, placebo-
controlled, parallel group study to assess the safety and efficacy of 28 day 
oral administration of BAY 85-8501 in patients with non-cystic fibrosis 
bronchiectasis (EudraCT number: 2012-004491-18 version 1). 
https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-004491-
18/results (access date: 2 February 2018) ; EU Clinical Trials Register; 
2016.
R18-0468
Stapels DAC, Geisbrecht BV, Rooijakkers SHM. Neutrophil serine 
proteases in antibacterial defense. Curr Opin Microbiol 2015;23(3):42-48.
R18-0515
Nussbaum F von, Li VMJ. Neutrophil elastase inhibitors for the treatment 
of (cardio) pulmonary diseases: into clinical testing with pre-adaptive 
pharmacophores. Bioorg Med Chem Lett 2015;25:4370-4381.
R18-1291
Nagelschmitz J, Kaufel D, Stephan S, Nussbaum F von, Li V, Delbeck M, 
et al. The novel elastase inhibitor BAY 85-8501 provides a new approach 
in the treatment of pulmonary diseases. 24th Ann Cong of the European 
Respiratory Society (ERS), Munich, 6 - 10 Sep 2014. Eur Respir J 
2014;44 (Suppl 58)
R19-1804 
Bhatt et al, Hepatic Abundance and Activity of Androgen- and Drug-
Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, 
and Sex, Drug Meb Dispos 46:888-896, 2018
R19-1805 
Xue et al., Adaptive Evolution of UGT2B17 Copy-Number Variation. 
Am. J. Hum. Genet. 2008; 83: 337–346
R19-1806 
Wang et al, UGT2B17 Genetic Polymorphisms dramatically affect the 
pharmacokinetics of MK-7246 in healthy patients in a fist-in-human 
study, Nature 92:1;2012,96-102
R19-1961
Midazolam-ratiopharm 2 mg/ml orale Loesung (ratiopharm) 
(Fachinformation, Stand der Information: August 2018).
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
001-MCG-312
Biomarker Assessments on Trial Level. Current version.
c21238478
Investigator’s Brochure BI 1323495. COPD. Current version.


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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
This section is not applicable.
10.2
PHARMACOKINETIC METHODS AND ANALYSES
This section is not applicable in the trial.
10.3
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING
This section is not applicable.
10.4
TRIAL BIOMARKER PLAN
This section is not applicable.
10.5
ADDITIONAL INFORMATION REGARDING IN/EXCLUSION 
CRITERIA
Calculation of number of pack years
          Pack years =
Number of cigarettes/day
X      years of smoking
20


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11.
DESCRIPTION OF GLOBAL AMENDMENT
11.1
GLOBAL AMENDMENT 1
Date of amendment
4 Oct 2019
EudraCT number
EU number
2018-004238-13
BI Trial number
1405-0002
BI Investigational 
Medicinal Product(s)
BI 1323495
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of multiple rising oral doses of 
BI 1323495 versus placebo in healthy subjects, including 
an investigation of drug-drug interaction with microdose 
midazolam (double-blind, randomised, placebo-controlled 
[within dose groups] trial)
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Flowchart 1 and Flowchart 2, sections 4.1.4 and 6.2.2, 
other minor locations within the document
Description of change
Previous visit schedule included ambulatory visits from 
Day 5 to Day 10. In the current visit schedule, all visits 
during treatment phase will be stationary. All relevant 
parts of the CTP have been updated accordingly.
Rationale for change
Due to competent authority request, to minimize safety or 
compliance related risks.
Section to be changed
3.1,
other minor locations within the document
Description of change
Clarification that the implementation of an intermediate
dose group via non-substantial amendment is possible if 
based on preliminary PK data if still within approved 
ranges, but not due to safety findings.
Rationale for change
Due to competent authority request.
Section to be changed
3.3.3
Description of change
Exclusion criteria, wording clarified for criterion #13 and 


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adding a further condition to criterion #25.
Rationale for change
Due to competent authority request.
Section to be changed
3.3.4.3
Description of change
Clarification of criteria for trial discontinuation.
Rationale for change
Due to competent authority request.
11.2
GLOBAL AMENDMENT 2
Date of amendment
04 Mar 2020
EudraCT number
EU number
2018-004238-13
BI Trial number
1405-0002
BI Investigational 
Medicinal Product(s)
BI 1323495
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of multiple rising oral doses of 
BI 1323495 versus placebo in healthy subjects, including 
an investigation of drug-drug interaction with microdose 
midazolam (double-blind, randomised, placebo-controlled 
[within dose groups] trial)
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Synopsis, 1.3, 1.4.2.1.2, 1.4.3, 3.3, 3.3.2 incl. crit. #6, 3.3.3 
excl. crit. #35, 3.3.4, 5.2.6.2.4
Description of change
Inclusion of female subjects either not of child-bearing 
potential, or not pregnant/not breastfeeding and willing 
and able to use adequate highly effective contraception 
methods.
Rationale for change
Recruitment of female healthy volunteers not of child 
bearing potential only, as per the initial protocol, turned 
out to be a major challenge for the trial. BI 1323495 
should not be administered to pregnant women and should 
not be used in women of child-bearing potential without 
adequate contraception. 
1. Potential effects of BI 1323495 on embryo-fetal 


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development have not yet been assessed, and no data are 
available from its use in pregnant women. There is no 
evidence indicating human teratogenicity or fetotoxity, 
2. Short term exposure of only 10.5 days in this trial under 
adequate contraception appears justifiable. 
3. This will allow including also females representing the 
age range of the relevant target population of patients with 
cystic fibrosis.
Section to be changed
Flowchart 1 and Flowchart 2, both footnote 12, 6.1
Description of change
Time to perform procedures prior to drug administration 
on Day 1 and Day 11 changed from 2 h to 3 h.
Rationale for change
Minor administrative change to facilitate conduct of trial 
procedures at the site.
Section to be changed
1.2.4, 1.2.7, 4.2.2.1
Description of change
Added new information from trial 1405-0009: modest 
effect on BI 1323495 exposure upon co-administration of 
a strong CYP3A4 inhibitor, with the consequence that
concomitant treatment only with strong (not all)
CYP3A4/P-gp inhibitors is to be avoided, no safety issues 
reported.
Rationale for change
New information available
Section to be changed
1.4.3, 4.2.2.3
Description of change
Added instruction on adequate, non-hormonal 
contraception methods
Rationale for change
Inclusion of WOCBP is only justifiable with adequate 
highly effective contraception. Due to potential CYP3A4 
induction by BI 1323495, hormonal contraception might 
be less effective, thus instruction on acceptable highly 
effective contraception methods is provided.
Section to be changed
3.1.1
Description of change
Added details on how the population PK model is updated 
to predict exposure in the next dose group.
Rationale for change
Clarification of procedures for exposure predictions for 
subsequent dose groups
Section to be changed
Table 3.1:1, Table 3.1:2
Description of change
Correction of screening phase start from -84 days to -21 
days
Rationale for change
Correction
Section to be changed
3.3.3 Excl. crit. #7


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Description of change
Added that mild seasonal allergy adequately managed by 
topic administration of drugs to eyes or nose is not 
excluded.
Rationale for change
Clarification of exclusion criterion.
Section to be changed
Table 4.1.4:1
Description of change
Number of units per administration in Dose Group 1 
changed from 2 tablets bid to 1 tablet bid
Rationale for change
Correction
Section to be changed
Table 5.2.3:2
Description of change
Added Immunology lab group/ tuberculosis assay
Rationale for change
Clarification (in alignment to 3.3.3, excl. crit. #25)
Section to be changed
5.2.6.2.2
Description of change
Removed “via fax” from SAE reporting instruction
Rationale for change
More flexible wording, to adapt to potential future 
reporting procedure
11.3
GLOBAL AMENDMENT 3
Date of amendment
06 May 2020
EudraCT number
EU number
2018-004238-13
BI Trial number
1405-0002
BI Investigational 
Medicinal Product(s)
BI 1323495
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of multiple rising oral doses of 
BI 1323495 versus placebo in healthy subjects, including 
an investigation of drug-drug interaction with microdose 
midazolam (double-blind, randomised, placebo-controlled 
[within dose groups] trial)
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Flowchart 2, 1.4.2 Risks, 1.4.2.1.1 Mode of action, 1.4.2.3 


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Procedure related risks, 1.4.3 Discussion, 3.3.4.1 
Discontinuation of trial treatment, 5.2.3 Safety laboratory
parameters
Description of change
Implementation of risk assessment and risk mitigation 
procedures with regard to Covid-19 pandemic.
Rationale for change
At the time of completion Part I DG 2 in this trial, the 
COVID-19 pandemic emerged with worldwide impact on 
daily life. To allow for thorough evaluation of potential 
additional risks to trial participants in the course of this 
pandemic, the trial was temporarily put on hold after 
completion of Part I DG 2 and prior to the start of Part I 
DG 3. Potential additional risks for study participants with 
regard to COVID-19 have been evaluated and risk 
management measures implemented within the sections
cited above.
11.4
GLOBAL AMENDMENT 4
Date of amendment
04 Jun 2020
EudraCT number
EU number
2018-004238-13
BI Trial number
1405-0002
BI Investigational 
Medicinal Product(s)
BI 1323495
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of multiple rising oral doses of 
BI 1323495 versus placebo in healthy subjects, including 
an investigation of drug-drug interaction with microdose 
midazolam (double-blind, randomised, placebo-controlled 
[within dose groups] trial)
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Throughout the whole document
Description of change
Extending the subject population with subjects 
characterised by the genotype UGT2B17 *2/*2, so called 
“Poor Metabolizers”, i.e. including the investigation of 


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safety and PK in these subjects in two dose groups. 
Previous Dose Groups are named Part I or EM Dose 
Groups, new Dose Groups are named Part II or PM Dose 
Groups. In the whole document the allocation of dose 
groups to either Part I or Part II of the trial was specified. 
Procedures or analyses only applicable to certain dose 
groups were clearly indicated.
Rationale for change
Extending the subject population by additional two dose 
groups to include poor metabolizers will allow the drug 
exposure to be effectively explored. Most other procedures 
remain unchanged.
Section to be changed
Flowchart 1, 2; Table 3.1:2; Table 3.1:3
Description of change
Screening window changed from 21 to 28 days
Rationale for change
Improve feasibility regarding subject recruitment
Section to be changed
Flow Chart 2, 4.1.3, 6.2.2
Description of change
Wording updated to clarify that allocation to treatment is 
not restricted to Day 1 (i.e. for Midazolam dose groups on 
Day -1)
Rationale for change
Correction/clarification
Section to be changed
Flowchart 3
Description of change
Flowchart added for the 2 additional PM dose groups
Rationale for change
The new Flowchart lists slightly different procedures for 
trial Part II
Section to be changed
1.2.7 
Description of change
Addition new information from current trials
Rationale for change
New information available
Section to be changed
1.2.7.1, 4.2.2.1
Description of change
Inclusion of a statement that the effects of CYP3A4/P-gp 
inhibition in PM subjects have not yet been assessed, 
therefore treatment with drugs known to inhibit CYP3A4 
must be avoided
Rationale for change
Specific information related to new subject sub-population
Section to be changed
1.4.2.1.3, 1.4.3
Description of change
The start of the first PM DG depends on the decision of 
DEC upon completion of EM DG 3
Rationale for change
The risk assessment performed prior to the start of PM 
DG1 1 should be based on the most current data


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Section to be changed
2.1.2, 2.2.2.1
Description of change
“number” of subjects was replaced with “percentage”; 
Listing of safety assessment was moved to Section 2.2.1
Rationale for change
As number of subjects in EM and PM dose groups are 
different, percentage will be a better unit to compare 
results of primary endpoint for all dosing groups
Section to be changed
3.1
Description of change
Overview table included to highlight difference between 
Part I and Part II of the trial
Rationale for change
Inclusion of overview to enhance clarity
Section to be changed
3.2
Description of change
Addition of an evaluation regarding the inclusion of PM 
dose groups
Rationale for change
Relevant for rationale of current amendment
Section to be changed
Table 4.1.1:1 Test product
Description of change
Posology descriptions: information for PM dose groups 
added, posology entry for Midazolam corrected
Rationale for change
Update regarding inclusion of PM dose groups, correction 
of mistake
Section to be changed
4.1.6 
Description of change
Wording changed to state that re-supply of study 
medication will be provided if applicable
Rationale for change
Update necessary due to prolonged trial duration e.g. due 
to additional dose groups
Section to be changed
Table 5.2.3:1
Description of change
Removed absolute values for manual differential WBC
Rationale for change
Test not required
11.5
GLOBAL AMENDMENT 5
Date of amendment
29 Sep 2020
EudraCT number
EU number
2018-004238-13
BI Trial number
1405-0002


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BI Investigational 
Medicinal Product(s)
BI 1323495
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of multiple rising oral doses of 
BI 1323495 versus placebo in healthy subjects, including 
an investigation of drug-drug interaction with microdose 
midazolam (double-blind, randomised, placebo-controlled 
[within dose groups] trial)
Global Amendment due to urgent safety reasons
Global Amendment
Comment: This protocol amendment implements administrative changes and does not 
meet the criteria of a substantial amendment according to sec. 10 (1) of the German
GCP ordinance, or Article 10 a EU Directive 2001/20/EC
Section to be changed
Flowchart 1/2/3, Table 3.1:2, Table 3.1:3, Table 5.2.3:1 
footnote 2, Section 6.2.3
Description of change
A time window of +3 days was implemented to the End of 
Study Visit (Visit 3), changing the definition of the EoS 
Visit from “Day 18” to “Day 18 to 21”.
Rationale for change
For site and subjects the time window allows for more 
flexibility in planning the last study visit.
11.6
GLOBAL AMENDMENT 6
Date of amendment
04 Nov 2020
EudraCT number
EU number
2018-004238-13
BI Trial number
1405-0002
BI Investigational 
Medicinal Product(s)
BI 1323495
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of multiple rising oral doses of 
BI 1323495 versus placebo in healthy subjects, including 
an investigation of drug-drug interaction with microdose 
midazolam (double-blind, randomised, placebo-controlled 
[within dose groups] trial)


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Global Amendment due to urgent safety reasons
Global Amendment
Comment: This non-substantial amendment is implemented to add an intermediate dose 
group following provisions as given in earlier versions of the protocol:
“Additional subjects may be entered to allow testing of an additional (intermediate) dose 
based on preliminary PK data). The approved highest dose for each of the two trial parts will 
not be exceeded. Thus, the actual number of subjects entered may exceed 76, but will not 
exceed 96 subjects. Such a change would be implemented as a non-substantial CTP 
amendment.”
Section to be changed
4.1.2 Selection of doses
Description of Changes
Addition of a rationale for introduction of an intermediate 
dose group (EM DG 6, 120 mg bid).
Rationale For Changes
Requirement to provide a rationale for introduction of the 
intermediate dose group.
Section to be changed
Synopsis
Flowchart 2
2.2.1 Further objectives
2.2.2.2 Further pharmacokinetic endpoints
2.2.2.3 Pharmacodynamic endpoints in Part I
3.1 Overall trial design and plan
4.1.1 Identity of IMP
4.1.4 Drug assignment
4.2.2.2 Restrictions on diet and lifestyle
Table 5.2.3:2 Exclusionary laboratory tests
6.2.2 Treatment period
7.2.4 Further endpoint analyses
7.1 Null and alternative hypotheses
7.2.7 Interim analyses
Description of Changes
Addition of dose group 6 at text locations where the 
different dose groups are mentioned or listed.
Rationale For Changes
Introduction of an intermediate dose group (EM DG 6, 120 
mg bid).
Section to be changed
1.2.7 Clinical Studies
1.2.7.1 Clinical Pharmacokinetics
1.2.7.2 Clinical Pharmacodynamics
1.2.7.3 Preliminary clinical safety data
Table 4.1.2:1
Description of Changes
Addition of data and findings from new clinical data (from 
the completed dose groups of this trial).
Rationale For Changes
Provision of data to support the rationale for introduction 
of the intermediate dose group.


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Section to be changed
1.4.3 Discussion
7.2.7 Interim analyses 
7.2.3 Secondary endpoint analyses
7.2.4 Further endpoint analyses
Description of Changes
Minor changes of wording, addition of a further endpoint.
Rationale For Changes
New wording implemented for clarification/definition 
purposes.
11.7
GLOBAL AMENDMENT 7
Date of amendment
10 Dec 2020
EudraCT number
2018-004238-13
BI Trial number
1405-0002
BI Investigational 
Medicinal Product(s)
BI 1323495
Title of protocol
Safety, tolerability, pharmacokinetics, and 
pharmacodynamics of multiple rising oral doses of 
BI 1323495 versus placebo in healthy subjects, including 
an investigation of drug-drug interaction with microdose 
midazolam (double-blind, randomised, placebo-controlled 
[within dose groups] trial)
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Synopsis 
Flowchart
1.3 Rationale for performing the trial
2.2.1 Further objectives
2.2.2.2 Further pharmacokinetic endpoints
3.1 Overall trial design and plan
3.2 3.2 Discussion of trial design, including the choice of 
control group
4.1.1 Identity of IMP
4.1.2 Selection of doses in the trial and dose modifications
4.1.4 Drug assignment
4.2.2.2 Restrictions on diet and lifestyle
6.2.2 Treatment period


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7.2.4 Further endpoint analyses
Description of Changes
At text locations where the different dose groups are 
mentioned or listed, 
1.
a 120 mg qd dose group (DG 7) in EMs has been
implemented, and 
2.
in parallel it was clarified that the initially planned 
300 mg bid dose group (DG 5) in EMs will not be 
used.
At several of these text locations, wording was adapted to 
clarify that qd dosing takes place only in the morning, 
compared to bid dosing in the morning and in the evening.
Rationale For Changes
Section to be changed
Synopsis
2.1.3 Secondary endpoints 
2.2.2.2 Further pharmacokinetic endpoints
7.2.3 Secondary endpoint analysis
Description of Changes
Wording was updated with regard to the qd dose group, in 
particular a new secondary endpoint AUC0-24 was added 
only applicable for qd dosing.
Rationale For Changes
Adaptation was required due to different dosing scheme in 
the new qd dose group.
Section to be changed
Synopsis
3.1 Overall trial design
3.3 Selection of trial population
7.5 Determination of sample size
Description of Changes
The sample size was updated to planned 88 healthy 
subjects, and wording regarding the possibility to 
implement additional (intermediate) dose groups based on 
preliminary PK values via non-substantial amendment was 
removed.
Rationale For Changes
Based on the available data from completed dose groups, 
the flexibility to implement additional dose groups is no 


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longer relevant.
Section to be changed
Synopsis
3.1 Overall trial design and plan
3.3 Selection of trial population
7.5 Determination of sample size
Description of Changes
Wording was removed which described the possibility to 
increase the sample size by adding an (intermediate) dose 
group, via non-substantial amendment.
Rationale For Changes
Based on the currently available data, no further dose 
group will be implemented based on the initial protocol.
Section to be changed
Flowchart
Description of Changes
Flowchart 4 was added indicating times of drug 
administration and sampling for qd dose group
Rationale For Changes
Specific information on qd dosing and sampling times was 
implemented in line with the addition of a qd dose group.
Section to be changed
1.2.7.1 Clinical pharmacokinetics
Description of Changes
Data from the current trial was added, including the 
rationale to use a once-daily dosing schedule.
Rationale For Changes
New information from already completed dose groups 
were added as they had become available at the time of the 
amendment.
Section to be changed
1.2.7.3 Clinical safety
Description of Changes
Content in this section, particularly the overview on 
number of subjects per dose group reporting treatment-
emergent AEs in the current multiple-rising dose trial 
1405-0002 (Table 1.2.7.3: 1), was updated.
Rationale For Changes
New data from already completed dose groups were 
included as they had become available at the time of the 
amendment.
Section to be changed
1.4.3 Discussion
Description of Changes
Reference regarding COVID-19 testing of trial subjects 
was updated.
Rationale For Changes
Updated information/advice on COVID-19 test strategy is 
available from Robert-Koch-Institute.


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Section to be changed
4.1.2 Selection of doses
Description of Changes
PK predictions for qd dosing were included.
Rationale For Changes
PK predictions for qd dosing were added to provide the 
basis for dose selection in EM DG 7.
Section to be changed
7.2.1 General considerations, 
7.3.2 Plasma/urine drug concentration – time profiles
7.3.3 Pharmacokinetics
Description of Changes
The references to specific BI Standard Operation 
Procedures was changed.
Rationale For Changes
The initial references have been changed at BI.
Section to be changed
Throughout the document
Description of Changes
Administrative updates or clarifications were 
implemented, reference to flow chart 4 was included.
Rationale For Changes
The mentioned updates were implemented where 
applicable.


 
 
 
 
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clinical-trial-protocol-version-08
Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising oral
doses of BI 1323495 versus placebo in healthy subjects, including an investigation of
drug-drug interaction with microdose midazolam (double-blind, randomised,
placebo-controlled [within dose groups] trial)
Author-Clinical Trial Leader
11 Dec 2020 11:38 CET
Approval-Therapeutic Area 
11 Dec 2020 11:42 CET
Approval-Team Member Medicine
11 Dec 2020 12:24 CET
Author-Trial Clinical
Pharmacokineticist
11 Dec 2020 15:44 CET
Author-Trial Statistician
11 Dec 2020 15:47 CET
Verification-Paper Signature
Completion
14 Dec 2020 11:34 CET


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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c35122034-01
BI Trial No.:
1405-0002
Title:
Safety, tolerability, pharmacokinetics, and pharmacodynamics of 
multiple rising oral doses of BI 1323495 versus placebo in healthy 
subjects, including an investigation of drug-drug interaction with 
microdose midazolam (double-blind, randomised, placebo-
controlled [within dose groups] trial)
Revised Protocol #08
Investigational
Product:
BI 1323495
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
08-Apr-2021 SIGNED
Version:
Final
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
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 ...................16
7.
PLANNED ANALYSIS......................................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........20
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................20
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINTS...................................................................................20
7.4.1
Primary analysis of the primary endpoints......................................................20
7.5
SECONDARY ENDPOINTS.............................................................................20
7.5.1
Key secondary endpoints....................................................................................20
7.5.2
Secondary endpoints...........................................................................................20


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7.7
EXTENT OF EXPOSURE.................................................................................24
7.8
SAFETY ANALYSIS..........................................................................................24
7.8.1
Adverse Events ....................................................................................................24
7.8.2
Laboratory data ..................................................................................................26
7.8.3
Vital signs.............................................................................................................26
7.8.4
ECG......................................................................................................................27
7.8.5
Others...................................................................................................................29
8.
REFERENCES....................................................................................................30
10.
HISTORY TABLE..............................................................................................38


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LIST OF TABLES
Table 6.1: 1
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data and vital signs .......................................................13
Table 6.3: 1
Subject sets analysed........................................................................................15
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation ..........17
Table 10: 1
History table .....................................................................................................38


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-12
Area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval of 12 h after administration of the first dose
AUC0-24
Area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval of 24 h after administration of the first dose
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady
state over a uniform dosing interval τ
BI 
Boehringer Ingelheim
BLQ
Below limit of quantification
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ
COVID
Coronavirus disease
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
ECGPCS
ECG plasma concentration set
eCRF
Electronic case report form
EM
Extensive metabolizer
gCV
Geometric coefficient of variation
gMean
Geometric mean
HR
Heart rate
ICH
International Conference on Harmonisation
IPD
Important protocol deviations
IQRMP
Integrated quality and risk management plan


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Term
Definition / description
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
NE
Neutrophil elastase
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter analysis set
PM
Poor metabolizer
PR
Pulse rate
QRS 
complex
Combination of the Q, R, and S waves in an electrocardiogram
QT interval
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval, heart rate corrected
QTcB
QT interval, heart rate corrected according to Bazett’s formula
QTcF
QT interval, heart rate corrected according to Fridericia’s formula
RAGe
Report appendix generator
RPM
Report planning meeting
RR interval
ECG interval from the peak of the R wave to the peak of the subsequent R 
wave
SAE
Serious adverse event
SD
Standard deviation
SOC
System organ class
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal


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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 revised CTP, 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) and its 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 revised 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 Medidata Rave system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version Phoenix 6.3, 
.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The CTP uses the term “gender”, but means “sex” (as it is meanwhile named according to BI 
standards). The CTP did not mean “gender identity” (a concept that has meanwhile been 
developed), so “gender identity” was not collected in this trial, but “sex” was collected in the 
eCRF. This TSAP and the statistical analysis will use the term “sex” where the CTP uses the 
term “gender”.
The CTP states: “Dose proportionality may be repeated for different categories of gender 
and/or genotype, separately.” Since no trend for sex or genotype was seen, this analysis will 
not be conducted.
All analyses described in this TSAP are in accordance with the statistical methods described 
in the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Primary endpoint is the percentage of subjects with treatment-emergent drug-related adverse 
events.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
Secondary endpoints are PK endpoints of BI 1323495, as defined in Section 2.1.3 of the CTP:
After the first dose of BI 1323495:

AUC0-12 (area under the concentration-time curve of the analyte in plasma over a 
uniform time interval of 12 h after administration of the first dose)

Cmax (maximum measured concentration of the analyte in plasma after the first dose)

Only for qd dosing: AUC0-24 (area under the concentration-time curve of the analyte 
in plasma over a uniform dosing interval of 24 h after administration of the first dose)
[…] After the last dose of BI 1323495:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment 
groups, and selection of doses, cf. Section 4 of the CTP.
EM subjects (Part I) were planned to be treated with 

doses of 10 mg bid, 30 mg bid, 70 mg bid, 120 mg bid, 120 mg qd, or 150 mg bid
of BI 1323495 (test treatments)
or

matching placebo (reference treatment)
PM subjects (Part II) were planned to be treated with 

doses of 10 mg bid or 30 mg bid of BI 1323495 (test treatments)
or

matching placebo (reference treatment)
In the 3 highest EM bid dose groups (70 mg bid, 120 mg bid and 150 mg bid of BI 1323495), 
subjects were planned to receive a single dose of microdose midazolam solution on Day -1 
and Day 11.
All placebo subjects will be analysed in one pooled placebo group (i.e. no distinction between 
dose groups will be made for placebo subjects).
For statistical analysis of AEs, the following analysis phases for each subject are provided in 
Table 6.1: 1.


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Table 6.1: 1
Analysis phases for statistical analysis of AEs, and actual treatment for 
analysis of laboratory data and vital signs
Study analysis 
phase
Label
Start
End
Screening1
Screening
Date of informed 
consent
Date/time of first administration 
of BI drug or midazolam 
(whichever occurs first)
On treatment2
Mid alone
Date/time of first 
administration of 
midazolam
Date/time of first administration 
of BI drug
On treatment
Placebo/Placebo+Mid,
10 mg bid EM,
10 mg bid PM,
30 mg bid EM,
30 mg bid PM,
70 mg bid+Mid EM,
120 mg bid+Mid EM,
120 mg qd EM, or
150 mg bid+Mid EM,
respectively
Date/time of first 
administration of BI 
drug
Date/time of last administration of 
BI drug + residual effect period 
(7 days, i.e., 7 * 24 h)
or
12:00 a.m. on day after last 
contact date
(whichever occurs first)
Follow-up3
F/U Placebo/Placebo+Mid,
F/U 10 mg bid EM,
F/U 10 mg bid PM,
F/U 30 mg bid EM,
F/U 30 mg bid PM,
F/U 70 mg bid+Mid EM,
F/U 120 mg bid+Mid EM,
F/U 120 mg qd EM, or
F/U 150 mg bid+Mid EM,
respectively
Date/time of last
administration of BI 
drug + 7 * 24 h
12:00 a.m. on day after last 
contact date
1 See Section 6.7 for definition of baseline, which will be used in the statistical analyses of safety laboratory data, ECG and 
vital signs.
2 This phase exists only in those subjects who have received Midazolam.
3 This phase exists only in those subjects who have last contact 7 or more days after last BI drug. 
AE displays in CTR Section 15.3, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 will 
present results for the on-treatment phase only.
In AE tables in CTR Section 15.3 (but not in Appendix 16.1.13.1.8.2 and Appendix 
16.1.13.1.8.3 AE tables), the following totals will be presented in addition: 

"Total BI", defined as the total over all on-treatment phases involving BI

"Total BI EM", defined as the total over all on-treatment phases in EM subjects, 
involving BI

"Total BI PM", defined as the total over all on-treatment phases in PM subjects, 
involving BI

"Total on-trt ", defined as the total over all on-treatment phases (involving BI,
placebo and midazolam alone)


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Safety laboratory data, ECG and vital signs will be statistically analysed based on dose 
groups (not on analysis phases defined above), with clear differentiation between baseline (cf. 
Section 6.7) and on-treatment measurements. Measurements will be considered on-treatment, 
if they were taken within the on-treatment phases as defined in Table 6.1: 1. Analysis results 
will be labelled with the applicable dose group, as follows:

Placebo/Placebo+Mid

10 mg bid EM

10 mg bid PM

30 mg bid EM

30 mg bid PM

70 mg bid+Mid EM

120 mg bid+Mid EM

120 mg qd EM

150 mg bid+Mid EM
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from 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. At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important PD (IPD). For definition of IPDs, and for the process of 
identification of these, refer to the BI reference document "Identify and Manage Important 
Protocol Deviations (IPD)" (2).
If any IPDs are identified, they are to be summarised into categories and will be captured in 
the decision log. Categories which are considered to be IPDs in this trial are defined in the 
integrated quality and risk management plan (IQRMP). If the data show other IPDs, the 
definition in the IQRMP will be supplemented accordingly by the time of the Report 
Planning Meeting.
IPDs will be summarized and listed. Which kind of IPDs could potentially lead to exclusion 
from which analysis set is specified in the DV domain template. The decision on exclusion of 
subjects from analysis sets will be made at the latest at the Report Planning Meeting, after 
discussion of exceptional cases and implications for analyses. If the data show other IPDs, 
this table will be supplemented accordingly by the time of the Report Planning Meeting.
Non-important COVID-19 related PDs will only be listed.


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6.3
SUBJECT SETS ANALYSED
The treated set (TS) and pharmacokinetic parameter analysis set (PKS) will be used as 
defined in the CTP, Section 7.2.1.
In addition, the following subject set for a certain analysis of ECG data will be used.
All ECG analyses are performed on the TS, except for the exposure-response analyses, which 
are performed on the ECGPCS defined below.

ECG plasma concentration set (ECGPCS):
This subject set includes all subjects from the TS who provide at least one pair of a 
valid drug plasma concentration and a corresponding (i.e. time-matched) ECG 
endpoint to be used in the exposure-response analyses. For placebo subjects, the 
plasma concentration is set to zero and hence always considered as valid. The 
decision whether a time deviation between PK blood sampling and ECG recording is 
acceptable (and thus whether the pair of values will be used) is to be made no later 
than at the RPM before data base lock.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
ECGPCS
Primary endpoint
X
Secondary PK endpoints 
X
Further PK endpoints 
X
Further PD endpoint
X
X1
Safety parameters 
(except for exposure-response 
analyses of ECG data)
X
Exposure-response analyses of 
ECG data
X
Demographic/baseline 
characteristics
X
Treatment exposure
X
1 In analysis of further PD endpoints, PKS will only be used for Emax model analysis


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6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
CTP: If a subject is removed from or withdraws from the trial prior to the first 
administration of trial medication, the data of this subject will not be entered in the case 
report form (CRF) and will not be reported in the clinical trial report (CTR). 
If a subject is removed from or withdraws from the trial after the first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, the data will be included in the CRF and will be reported in the CTR.
CTP: It is not planned to impute missing values for safety parameters.
One exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).
No imputation will be done for ECG endpoints. If replicate ECG recordings are missing, the 
arithmetic means per time point will be computed with the reduced (1 or 2) number of 
recordings. If single cardiac cycles (also denoted as beats or waveforms) are missing, the 
arithmetic mean per single ECG will be computed with the reduced (1, 2 or 3) number of 
cardiac cycles.
For the classification of the on-treatment QTc/QT intervals into ‘no new onset’ / ‘new onset’ 
categories, the handling of missing value is described in Additional Section 9.3.
For the exposure-response analyses subjects on active drug, missing plasma concentration 
values with ‘BLQ’ in the comment field will be replaced by ½ LLOQ. For placebo subjects, 
the missing plasma concentration values will be replaced by 0 for the exposure-response 
analyses. 
Missing data and outliers of PK data are handled according to BI standards (4) and (5).
CTP: PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For all parameters, except for ECG, the last non-missing value determined prior to first 
administration of BI 1323495 will be defined as baseline. 
A centralised evaluation of 12-lead ECG recordings is performed at the time points specified 
in Table 6.7: 1. Three triplicate ECGs will be recorded as the baseline before the first drug 
administration and at planned time point 239:00, but only the first ECG of each of the 3 
baseline triplicates will be transferred to the database. All other ECGs for centralized 
evaluation are recorded as one triplicate ECGs (i.e. three single ECGs recorded within 180 


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sec), but only the first single ECG of the triplicate will be transferred to the database. Central 
ECG lab evaluation will be performed for the first of three replicate ECGs per 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. 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.
The baseline value of an ECG variable is defined as the mean of the ECG variable values 
with centralised evaluation prior to first study drug administration. 
Table 6.7: 1
Time schedule of 12-lead ECG recordings with centralised evaluation
Visit
Day
Planned time [hh:mm]
- relative to first drug administration
Study phase
2
1
-01:00
Baseline
01:00
On-treatment
02:00
04:00
06:00
08:00
12:00
2
23:301
5
95:301
8
167:151
11
239:001
241:00
242:00
244:00
246:00
248:00
252:00
12
264:00
1 According to CTP flow chart, there is no time-matched PK sample for the ECG measurements at planned times 23:30, 
95:30, 167:15 and 239:00 These ECG measurements will be paired with the PK measurements from planned times 24:00, 
96:00, 168:00 and 240:00 respectively in the exposure-response model, which will be applied to time matched pairs of ECG 
measurements and PK samples.
For the exposure response analyses, pairs of ECG variables and corresponding plasma
concentrations will be built using the same planned time points, e.g., the HR change from 
baseline and the plasma concentration measured at planned time 1:00 will build one pair. 
Whether a time deviation between PK blood sampling time and corresponding ECG 


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recording is too big for a reliable assessment and the pair has to be excluded from the 
analysis will be decided no later than at the RPM.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the Report Planning Meeting.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (6).
The individual values of all subjects will be listed. Listings will be sorted by treatment group, 
subject number and visit (if visit is applicable in the respective listing). AE listings will be 
sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma 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 (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary. Concomitant non-drug therapies will be coded 
according to the most recent version of MedDRA.
Only descriptive statistics are planned for this section of the CTR.
A medication will be considered concomitant to a dose group, if it

is ongoing at the time of study drug administration, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases). 
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the Report Planning Meeting (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINTS
7.4.1
Primary analysis of the primary endpoints
Refer to Section 7.8.1 for a description of the analysis of AEs, and in particular the analysis 
of the percentage of subjects with treatment-emergent drug related AEs, which is the primary 
endpoint of this trial.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
The analysis of secondary endpoints will be based on the PKS.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
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. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.


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For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs will be assigned to screening, on-treatment or follow-up phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of AESIs.
CTP: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
○
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold ULN 
measured in the same blood draw sample, or 
○
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8), in addition to Deaths and Serious Adverse Events, ‘other
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced
or interrupted).
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related will be 
summarised separately once overall and, additionally, stratified by sex only for EM dose 
groups. Separate tables will also be provided for subjects with SAEs and subjects with 
AESIs. AEs will also be summarized by maximum intensity.
The SOCs and preferred terms within SOCs will be sorted by descending frequency over all 
treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will 
also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarized.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards "Display and Analysis of Laboratory Data" (9).
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
Results from the pregnancy tests will only be listed.
Unscheduled measurements of laboratory data will be assumed to be repeat measurements of 
the most recent scheduled measurement (e.g. for follow-up or confirmation of a particular 
value). Therefore, unscheduled measurements will be assigned to the planned time point of 
the previous scheduled measurement. Descriptive statistics will be calculated by planned time 
point based on the worst value of the subject at that planned time point (or assigned to that 
planned time point).
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as possibly clinically significant values will be highlighted in the listings.
Clinically relevant findings in laboratory data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment) 
if judged clinically relevant by the investigator, and will be analysed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Body weight and aural body temperature will be listed, including its change from baseline.
Unscheduled measurements of vital signs will be assigned to planned time points in the same 
way as described above for laboratory data. However, for vital signs, descriptive statistics 
will be calculated by planned time point based on the last value of the subject at that planned 
time point (or assigned to that planned time point).
Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment) 
if judged clinically relevant by the investigator, and will be analysed as such.


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7.8.4
ECG
Abnormal findings will be reported as baseline conditions (prior to first study drug 
administration) or as AEs (from first study drug administration onwards) if judged clinically 
relevant by the investigator. 
Descriptive analysis of ECG endpoints will be based on the TS. The evaluation of the 
relationship between plasma concentration and change in ECG endpoints (exposure-response 
analysis) will be based on the ECGPCS.
ECG measurements will not be included in the statistical analysis if one of the following 
applies:

No date or time available for ECG measurement

Pre-dose measurement done after first drug administration

On-treatment measurement done before first drug administration

Measurement is a repeated measurement

More than 3 single ECGs (i.e., measurements from 4th single ECG onwards will not 
be included)

Unscheduled measurements
Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR, only listings will be provided. Occurrences of notable findings will be flagged.
Comments regarding the ECGs will be listed.
Categorical endpoints
For the categorical endpoints, frequency tables will be provided.
For all subjects with any notable finding in quantitative ECG recordings, a separate listing 
will be created as end-of-text display (based on the same display template as in 
Appendix 16.2), and the corresponding time profiles will be shown.
For subjects with notable findings, the individual time courses of QTcF, QT, HR, PR and 
QRS of these subjects will be presented in figures. Additionally a corresponding listing will 
be provided.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the absolute 
values and changes from baseline over time of QTcF, HR, QT, PR and QRS. The time 
profiles of mean and SD for the changes from baseline on treatment will be displayed 
graphically by treatment for PR, QT and QRS. Similar plots (not showing SD) are defined for 
QTcF and HR below, in context of the exposure-response analysis. 


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Exposure-response analysis
For QTcF and HR changes from baseline, the relationship to the corresponding plasma 
concentrations will be evaluated using a random coefficient model. For subjects in the 
ECGPCS, all time points with available ECG endpoints and valid time-matched drug plasma 
concentrations will be included. For the handling of missing values, see Section 6.6.
The response variable will be the change from baseline in QTcF (ΔQTcF). The placebo 
subjects will be included in the analysis, setting their plasma concentrations to zero.
As a first step, it is investigated if there is a potential delayed or accelerated (e.g. due to 
metabolites) effect of the drug on QTcF. A general visual impression will be provided by 
overlaying time profiles of plasma concentrations and QTcF changes from baseline (ΔQTcF). 
These figures will be generated for each subject (presented in the Statistical Appendix of the 
CTR), as well as for means per dose group (presented in the End-of-Text part of the CTR).
The relationship between BI 1323495 plasma concentrations and QTcF changes from 
baseline will be investigated in an exploratory manner using a random coefficient model to 
estimate the difference in mean QTcF change from baseline between BI 1323495 and placebo 
and its 90% confidence interval at the geometric mean of Cmax for each dose group. 
Additionally, the estimated overall slope with its 90% confidence interval will be provided. 
The used random coefficient model is based on a white paper from Garnett et. 
al. [R18-0143] (10) with ΔQTcF as response variable, centered baseline QTcF and plasma 
concentration as continuous covariates, treatment, time and day as fixed categorical effects, 
and a random intercept and slope for each subject. For more details refer to Additional 
Section 9.4.
For visualization, a scatterplot of the BI 1323495 plasma concentration against the following 
individual QTcF values will be provided: For each subject on active treatment and each time 
point, subtract the mean value of all individual observed ΔQTcF values from the placebo 
group for this time point from the individual observed ΔQTcF value for this subject and time 
point. This results in estimates for “individual ΔΔQTcF” values, which should only be used 
for plotting purposes. The corresponding regression line and its pointwise confidence bands 
as well as the geometric mean of Cmax for each dose will additionally be displayed in the plot.
The goodness of fit of the above model will be checked. The visual checks will include the 
inspection of concentration-QTcF quantile plots (see [R18-0143]) and residual plots.
To check model assumptions, the conditional residuals will be plotted and presented in the 
Statistical Appendix of the CTR. In case of non-linearity or if there is evidence for a delayed 
effect, further models will be explored in order to better characterise the PK-ECG 
relationship (e.g. effect compartment models, non-linear models, etc.).
All of the above described graphical and statistical analyses for the exposure-response 
analysis will be also performed for HR in place of QTcF.


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Appropriateness of heart rate correction methods of QT interval
To evaluate the appropriateness of the heart rate correction methods, the slope of the 
relationship of QTcF interval versus RR interval will be estimated separately for off-drug 
values and active treatment, by applying the random coefficient model described in 
Additional Section 9.2 using the QTcF and RR variable values per time point. A scatterplot 
of QTcF vs RR including the overall regression lines will be included in the Statistical 
Appendix of the CTR. The resulting (fixed effect) slope together with two-sided 95% 
confidence intervals will be included in the footnote for this plot.
7.8.5
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(if a condition already exists before first administration of study treatment) or as AE (if 
condition emerges after first administration of study treatment) and will be summarized 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 Design, Conduct, Analysis and Evaluation of 
Clinical Trials, current version
2
001-MCS-40-413_1.0: "Identify and Manage Important Protocol Deviations 
(iPD)", current version; IDEA for CON
3
KM Asset BI-KMED-BDS-HTG-0035: "Handling of missing and incomplete AE 
dates", current version; KMED
4
KM Asset BI-KMED-TMCP-MAN-0014: "Noncompartmental PK/PD Analyses of 
Clinical Studies", current version; KMED
5
KM Asset BI-KMED-TMCP-MAN-0010: "Description of Analytical Transfer Files, 
PK/PD Data files and ADA files", current version; KMED
6
KM Asset BI-KMED-BDS-HTG-0045: "Reporting of Clinical Trials and Project 
Summaries", current version; KMED
7
KM Asset BI-KMED-BDS-HTG-0041: "Analysis and Presentation of Adverse 
Event Data from Clinical Trials", current version; KMED
8
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
9
KM Asset BI-KMED-BDS-HTG-0042: "Display and Analysis of Laboratory Data", 
current version; KMED
10
Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white 
paper on concentration-QTc modeling. J Pharmacokinet Pharmacodyn. 2018. 
45(3): 383-397. [R18-0143]


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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
08-APR-2021
None
This is the final TSAP