Clinical trial NCT03802331
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2019-01-28; Completion date: 2019-03-03
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main objective of this trial is to assess the effect of food on the pharmacokinetics of an oral tablet formulation of BI 1323495 by investigating the relative bioavailability following single dose administration under fed and fasted conditions.

Detailed description:

Arms: arm 1: fed arm 2: fasted
Interventions: intervention 1: BI 1323495,
Intervention descriptions: intervention 1: single oral doses

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c24401085-02
EudraCT No.
2018-002792-18
BI Trial No.
1405-0007
BI Investigational
Medicinal Product
BI 1323495
Title
Relative bioavailability of BI 1323495 following oral 
administration under fed and fasted conditions in healthy male 
subjects (an open-label, randomised, single-dose, two-period, 
two-sequence crossover study)
Lay Title
A study to test how food influences the amount of BI 1323495 in 
the blood of healthy men
Clinical Phase
I
Trial Clinical 
Monitor
Phone:
Fax: 
Principal Investigator
 
Phone: 
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 1))
Version and Date
Version: 2.0
Date: 22 November 2018
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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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
1 August 2018
Revision date
22 November 2018
BI trial number
1405-0007
Title of trial
Relative bioavailability of BI 1323495 following oral administration under fed and 
fasted conditions in healthy male subjects (an open-label, randomised, single-dose, 
two-period, two-sequence crossover study)
Principal Investigator
 
Trial site
 
Clinical phase
I
Trial rationale
This food interaction study will generate pharmacokinetic information under fed 
conditions versus the fasted state to support the future development in patients.
Trial objective
To investigate the relative bioavailability of a single oral dose of BI 1323495 under 
fed and fasted conditions
Trial design
Randomised, open-label, two-way crossover design
Trial endpoints
Primary endpoints: AUC0-tz and Cmax of BI 1323495
Secondary endpoints: AUC0-of BI 1323495
Number of subjects 
total entered
12
each treatment
12
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 45 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product
BI 1323495 tablet formulation
dose
mode of admin.
Oral with 240 mL of water following a high fat, high calorie meal (treatment test 
(T)) and after an overnight fast of at least 10 h (treatment reference (R)) 


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Duration of treatment
One day (single dose) for each treatment
Statistical methods
Relative bioavailability will be estimated by the ratios of the geometric means 
(test/reference) for the primary and secondary endpoints. Additionally, their two-
sided 90% confidence intervals (CIs) will be provided. This method corresponds to 
the two one-sided t-test procedure, each at a 5% significance level. Since the main 
focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified. The statistical model will be an analysis of 
variance (ANOVA) on the logarithmic scale including effects for sequence, subjects 
nested within sequences, period and treatment. CIs will be calculated based on the 
residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................5
ABBREVIATIONS.............................................................................................9
1.
INTRODUCTION.................................................................................... 11
1.1
MEDICAL BACKGROUND............................................................................11
1.2
DRUG PROFILE...............................................................................................12
1.2.4
Clinical experience in humans.............................................................14
1.2.4.1
Clinical experience with BI 1323495 ......................................14
1.2.5
Residual Effect Period..........................................................................19
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................19
1.4
BENEFIT - RISK ASSESSMENT ...................................................................19
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......22
2.1.1
Main objectives......................................................................................22
2.1.2
Primary endpoints ................................................................................22
2.1.3
Secondary endpoint ..............................................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 24
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................24
3.3
SELECTION OF TRIAL POPULATION ......................................................24
3.3.1
Main diagnosis for trial entry..............................................................24
3.3.2
Inclusion criteria...................................................................................24
3.3.3
Exclusion criteria ..................................................................................25
3.3.4
Withdrawal of subjects from treatment or assessments ...................26
3.3.4.1
Discontinuation of trial treatment............................................27


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3.3.4.2
Withdrawal of consent to trial participation ............................27
3.3.4.3
Discontinuation of the trial by the sponsor..............................27
3.3.5
Replacement of subjects .......................................................................28
4.
TREATMENTS........................................................................................ 29
4.1
INVESTIGATIONAL TREATMENTS ..........................................................29
4.1.1
Identity of the Investigational Medicinal Products ...........................29
4.1.2
Selection of doses in the trial and dose modifications........................29
4.1.3
Method of assigning subjects to treatment groups ............................30
4.1.4
Drug assignment and administration of doses for each subject .......30
4.1.5
Blinding and procedures for unblinding ............................................31
4.1.6
Packaging, labelling, and re-supply ....................................................31
4.1.7
Storage conditions.................................................................................32
4.1.8
Drug accountability ..............................................................................32
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................32
4.2.1
Other treatments and emergency procedures....................................32
4.2.2
Restrictions............................................................................................33
4.2.2.1
Restrictions regarding concomitant treatment .........................33
4.2.2.2
Restrictions on diet and life style.............................................33
4.3
TREATMENT COMPLIANCE.......................................................................33
5.
ASSESSMENTS....................................................................................... 34
5.1
ASSESSMENT OF SAFETY............................................................................34
5.1.1
Physical examination ............................................................................34
5.1.2
Vital signs...............................................................................................34
5.1.3
Safety laboratory parameters..............................................................34
5.1.4
Electrocardiogram................................................................................37
5.1.5
Assessment of adverse events...............................................................37
5.1.5.1
Definitions of adverse events...................................................37
Adverse event ............................................................37
5.1.5.1.1
Serious adverse event ................................................38
5.1.5.1.2
AEs considered ‘Always Serious’.............................38
5.1.5.1.3
Adverse events of special interest .............................39
5.1.5.1.4
Intensity (severity) of AEs.........................................39
5.1.5.1.5
Causal relationship of AEs ........................................39
5.1.5.1.6
5.1.5.2
Adverse event collection and reporting ...................................40
AE collection.............................................................40
5.1.5.2.1
AE reporting to the sponsor and timelines ................41
5.1.5.2.2
Information required..................................................41
5.1.5.2.3
Pregnancy ..................................................................41
5.1.5.2.4
5.2
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................42
5.2.1
Assessment of pharmacokinetics .........................................................42
5.2.2
Methods of sample collection...............................................................42


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5.2.2.1
Blood sampling for pharmacokinetic analysis.........................42
5.2.3
Analytical determinations ....................................................................42
5.2.4
Pharmacokinetic - pharmacodynamic relationship...........................43
5.3
BIOBANKING ...................................................................................................43
5.4
OTHER ASSESSMENTS .................................................................................43
5.5
APPROPRIATENESS OF MEASUREMENTS.............................................43
6.
INVESTIGATIONAL PLAN.................................................................. 44
6.1
VISIT SCHEDULE............................................................................................44
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................44
6.2.1
Screening................................................................................................44
6.2.2
Treatment periods.................................................................................44
6.2.3
Follow-up period and trial completion ...............................................45
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 46
7.1
STATISTICAL DESIGN – MODEL ...............................................................46
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................46
7.3
PLANNED ANALYSES....................................................................................46
7.3.1
Primary endpoint analyses...................................................................47
7.3.2
Secondary endpoint analyses ...............................................................48
7.3.4
Safety analyses.......................................................................................49
7.4
INTERIM ANALYSES .....................................................................................49
7.5
HANDLING OF MISSING DATA ..................................................................50
7.5.1
Safety......................................................................................................50
7.5.2
Pharmacokinetics..................................................................................50
7.6
RANDOMISATION ..........................................................................................50
7.7
DETERMINATION OF SAMPLE SIZE ........................................................50
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 51
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................51
8.2
DATA QUALITY ASSURANCE .....................................................................52
8.3
RECORDS..........................................................................................................52
8.3.1
Source documents .................................................................................52
8.3.2
Direct access to source data and documents.......................................53
8.3.3
Storage period of records.....................................................................53
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................54
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......54


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8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................54
8.6
TRIAL MILESTONES .....................................................................................54
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................55
9.
REFERENCES......................................................................................... 56
9.1
PUBLISHED REFERENCES...........................................................................56
9.2
UNPUBLISHED REFERENCES.....................................................................58
10. APPENDICES .......................................................................................... 59
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 60
11.1
GLOBAL AMENDMENT 1 .............................................................................60


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CML
Clinical Monitor Local
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials Database
FU
Follow-up
GCP
Good Clinical Practice


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HR
Heart rate
IB
Investigator’s brochure
IC50
Half-maximal inhibitory concentration
IEC
Independent Ethics Committee
IPV
Important protocol violation
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
No observed adverse effect level
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
T
Test product or treatment
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
XTC
Ecstasy 


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1.
INTRODUCTION
 
 
 This trial will investigate the effect of food on pharmacokinetics of 
BI 1323495.
1.1
MEDICAL BACKGROUND


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1.2
DRUG PROFILE


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For a more detailed description of the BI 1323495 profile, please refer to the current 
Investigator’s Brochure (IB) (c21238478-01).
1.2.4
Clinical experience in humans
1.2.4.1
Clinical experience with BI 1323495
At the time of CTA submission of this trial, the first in man study 1405-0001 had been 
initiated. This partially randomized within dose groups, placebo-controlled trial investigates 
the safety, tolerability, pharmacokinetics and pharmacodynamics of single rising oral doses 
of BI 1323495 as tablet formulation. As of 14 November 2018, the clinical part has been
completed as planned. A total of 63 subjects were randomized to treatment with either 


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placebo (N=15) or single ascending doses of 
 
BI 1323495 (N=6 per dose). An overview on preliminary results of this 
trial is given in the following.
Treatments with BI 1323495 tablets or placebo were safe and well tolerated at all doses 
investigated. Overall, 16 out of 48 subjects treated with BI 1323495 (33.3%) and 2 out of 15
subjects treated with placebo (13.3%) were reported with at least 1 AE following drug 
administration. No dose dependency was observed for the different BI 1323495 treatment 
groups. The most frequently reported AE was headache, observed in 6 subjects (12.5%) 
dosed with BI 1323495 and 2 subjects (13.3%) on placebo. The incidence of headache
appeared similar between the different BI 1323495 dose groups and placebo.
AEs were generally of short duration and mild in intensity apart from 1 case of moderate 
headache 
moderate common cold reported by 
one subject 
, and 1 case of moderate rhinitis 
 
. Severe or serious AEs were not reported. All AEs were followed-up until 
resolved.
A summary of AEs reported following study drug treatment is shown in Table 1.2.4.1: 1.
Table 1.2.4.1: 1
Number (percentage) of subjects with AEs following administration 
of BI 1323495 or placebo in SRD trial 1405-0001
AE reported 
term
Placebo
BI 1323495
Total BI
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
No. of subjects
15 
(100.0)
6
(100.0)
6
(100.0)
6
(100.0)
6
(100.0)
6
(100.0)
6
(100.0)
6
(100.0)
6 
(100.0)
48 
(100.0)
Total with on 
treatment AEs
2 (13.3)
3 (50.0) 2 (33.3) 1 (16.7) 2 (33.3) 1 (16.7) 2 (33.3) 3 (50.0) 2 (33.3) 16
(33.3)
Headache
2 (13.3)
3 (50.0) 1 (16.7) -
-
-
-
1 (16.7) 1 (16.7) 6 (12.5)
Tiredness
-
-
-
1 (16.7) 1 (16.7) -
-
-
2 (4.2)
Diarrhoea
-
-
1 (16.7) -
-
-
-
1 (16.7) -
2 (4.2)
Stiff neck
-
-
-
-
1 (16.7) -
-
-
1 (2.1)
Malaise
-
-
-
-
-
1 (16.7) -
-
1 (2.1)
Common cold
-
-
-
-
-
-
1 (16.7) -
-
1 (2.1)
Improved 
breathing
-
-
-
-
-
-
-
1 (16.7) -
1 (2.1)
ALT increase
-
-
-
-
-
-
1 (16.7) -
-
1 (2.1)
GLDH increase
-
-
-
-
-
-
1 (16.7) -
-
1 (2.1)
Rhinitis
-
-
-
-
-
-
-
-
1 
(16.79
1 (2.1)
Clinically relevant changes in ECGs, vital signs (BP, pulse) or safety laboratory parameters 
were to be reported as adverse events. 


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No adverse events based on ECG or vital signs were reported. Also no trends of changes 
were observed.
Noteworthy: Subject 
(
 BI 1323495) presented with an increase in pulse rate 
compared to baseline from 5h to 12h postdose, i.e. after the end of bed rest period. Systolic 
blood pressure showed also a trend to higher values in the same period. This is explained by 
increased physical activity and not considered as clinically relevant. Furthermore, subject 
 
who was randomised to placebo, had single ECGs with absolute QT of 502 ms (2/3 ECGs at 
2h p.a.) and 500 ms (1/3 ECGs at 3h p.a.). Change from baseline was below 60 ms and QTc 
below 430 ms.
The clinical laboratory evaluation included the analysis of haematology, coagulation, 
enzymes, substrates, electrolytes, urinalysis, and inflammatory parameters. In general, values 
of measured laboratory parameters were within or only slightly outside the respective 
reference ranges. There were no hints for relevant changes over time and no relevant 
differences between the treatment groups (including placebo) in any of the safety laboratory 
parameters measured.
Noteworthy: Subject 
 (
 BI 1323495) presented with mild elevation of ALT and 
GLDH. Highest value for ALT was seen 4 days after drug administration (96 U/L, ULN=50 
U/L); follow-up measurements were done until returned to almost normalized value of 51 
U/L at 16 days postdose. Highest value for GLDH was already seen at 4h p.a. (11 U/L, 
ULN= 7.0 U/L). GLDH value returned to normal range 5 days after drug administration.
Both laboratory findings are reported as adverse events of mild intensity and potentially 
related to the administration of BI 1323495.
Pharmacokinetic results:
Plasma samples were taken up to 96 h after drug administration. Preliminary PK data analysis 
for BI 1323495 used planned vs actual sampling times for all dose groups. Bioanalytical data 
of BI 1323495 and PK calculation is preliminary and subject to change.


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1.2.5
Residual Effect Period
The Residual Effect Period (REP) of BI 1323495, i.e., the time interval when measurable 
drug levels or PD effects are still likely to be present after administration, is not yet known. 
Therefore, all AEs with an onset between start of treatment and the end of trial examination 
(last per protocol contact) will be considered on treatment.
1.3
RATIONALE FOR PERFORMING THE TRIAL
In the ongoing single rising dose study, only pharmacokinetic data under fasted conditions 
are investigated for BI 1323495. The planned food interaction study will generate 
pharmacokinetic information under fed conditions to support the future development in 
patients.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of a new orally 
available drug, which might improve the therapy in patients with COPD and emphysema. 
The subjects are exposed to the risks of the study procedures and the risks related to the 
exposure to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures


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In this food effect trial, subjects will receive two single doses of 
 once under fasted 
and once under fed conditions. Administration of BI 1323495 under fed conditions may cause 
an increase of plasma concentrations of BI 1323495. However, based on modelling data for 
the tablet formulation used in the SRD trial and this food effect trial only a minimal food 
effect is expected for a dose of
resulting in plasma concentrations below those 
exposures seen in the SRD trial following doses of 
and above. 


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to assess the effect of food on the pharmacokinetics of an 
oral tablet formulation 
 of BI 1323495 by investigating the relative 
bioavailability following single dose administration under fed and fasted conditions.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 1323495:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for BI 1323495:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, open-label, two-way crossover trial in healthy 
male subjects in order to compare the test treatment (T) to the reference treatment (R). The 
treatments will be two single oral doses of 
 BI 1323495 separated by a washout period 
 between the treatments:
Treatment T:
 tablets of BI 1323495, fed
Treatment R:
 tablets of BI 1323495, fasted
The subjects will be randomly allocated to the 2 treatment sequences (T-R or R-T). For 
details, refer to Section 4.1.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between treatments is based on 
an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments (R94-1529).
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analyte, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 12 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site.
Only male subjects will be included in the study because no data on reproductive toxicology 
are available at this time.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:


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1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 45 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
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 30 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial


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18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
greater than 450 ms, if confirmed by a 2nd ECG recording) or any other relevant ECG
finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
23. Subjects with female partner of childbearing potential who are unwilling to use male 
contraception (condom or sexual abstinence) from the first administration of trial 
medication until 30 days after last administration of trial
24. Current or history of relevant kidney, urinary tract diseases or abnormalities (e.g. 
nephrolithiasis, hydronephrosis, acute or chronic nephritis, renal injury, renal failure)
25. Estimated glomerular filtration rate according to CKD-EPI formula < 90 mL/min at 
screening
26. Within 10 days prior to administration of trial medication, use of any drug that could 
reasonably inhibit platelet aggregation or coagulation (e.g., acetylsalicylic acid)
27. Liver enzyme (ALT, AST, GGT) values above upper limit of normal at the screening 
examination
For study restrictions, refer to Section 4.2.2.
3.3.4
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, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.5), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 
and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.


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3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold upper limit of normal (ULN)
and an elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) 
and/or needs to be followed up according to the DILI checklist provided in the ISF.
6. The subject experiences a drug-related serious adverse event or drug-related severe 
adverse event. AEs will be considered as drug-related unless clearly unrelated (e.g. events 
prior to administration of study drug), see Section 5.1.5.1.6.
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
or suspended if more than 50% of the subjects have drug-related and clinically relevant 
adverse events of moderate or severe intensity, if more than two subjects have drug-
related non-serious adverse events of severe intensity or if at least 1 drug-related serious 
adverse event is reported. AEs will be considered as drug-related unless clearly unrelated 
(e.g., events prior to administration of study drug), see Section 5.1.5.1.6. 
Any further dosing is only possible after an analysis and evaluation of the harm, review of 


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the risk-benefit analysis, submission of a substantial amendment for further dosage and 
approval by the competent authority and ethics committee.
3. Violation of GCP or the CTP impairing the appropriate conduct of the trial-
4. The sponsor decides to discontinue the further development of the investigational product
3.3.5
Replacement of subjects
Subjects withdrawn due to drug related adverse events will not be replaced. In case some
subjects do not complete the trial for any other reason, the Trial Clinical Monitor together 
with the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many 
subjects will be replaced. A replacement subject will be assigned a unique trial subject 
number, and will be assigned to the same treatment as the subject 
 replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product has been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
BI 1323495
Pharmaceutical formulation: Tablet, film-coated
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Posology:
2-0-0
Route of administration:
oral
Duration of use:
single dose in treatment T and R
4.1.2
Selection of doses in the trial and dose modifications
In the ongoing first in man trial (1405-0001) it is planned to investigate single doses up to 
 BI 1323495. In this food effect trial, it is intended to administer two single doses of 
 BI 1323495. This dose has been chosen as it corresponds to the assumed therapeutic 
dose (see Section 1.2.2).
The investigator in this trial 1405-0007 will be informed by the sponsor in writing about the 
outcome of the documented safety review meeting scheduled after completion of the 
 
dose group in trial 1405-0001.


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Based on the experience gained during trial 1405-0001, a lower dose of BI 1323495 may be 
tested in this trial. If the lower dose is selected for safety reasons, this will be implemented 
via substantial amendment only.
4.1.3
Method of assigning subjects to treatment groups
The randomisation list will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). For this purpose, numbers of the randomisation 
list will be allocated to the subjects by drawing lots. Subjects are then assigned to a treatment 
sequence according to the randomisation list.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
All subjects may be treated in one cohort, i.e. all subjects may receive treatment on the same 
calendar day. In case this is not feasible (e.g., due to logistical or recruitment reasons), the 
group may be split into several cohorts as required. Treatment of all subjects on the same 
calendar day is acceptable (for safety margin to exposure reached in SRD trial 1405-0001 and
for discussion of study-associated risks and safety measures, see Section 1.4).
The randomisation procedure is described in Section 7.6.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a 2-way crossover study. All subjects will receive the 2 treatments in randomised 
order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total  dose
T (Test)
BI 1323495
Tablet, film-
coated
 as single dose, 
fed state
R (Reference)
BI 1323495
Tablet, film-
coated
 as single dose, 
fasted state
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. 
In treatment T, a high-fat, high-calorie meal will be served within 30 min before drug 
administration. The subjects must completely consume the meal prior to drug intake. The 
composition of the standard high-fat, high-calorie meal is detailed in Table 4.1.4: 2; this meal 
is in compliance with the FDA guidance ‘Food-Effect Bioavailability and Fed 
Bioequivalence Studies’ (R03-2269). For restrictions with regard to diet, see Section 4.2.2.2.
Table 4.1.4: 2
Composition of the high-fat, high-calorie meal
Ingredients
kcal
2 chicken eggs (whole content) for scrambled eggs
192
10 g butter for frying scrambled eggs
75


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Ingredients
kcal
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum1
984
1
The total caloric content was supplied approximately as following: 150 kcal as protein, 250 kcal 
as carbohydrate, and 500 to 600 kcal as fat. 
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a standing position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
Subjects will be kept under close medical surveillance until 24 h after drug administration. 
During the first 4 h after drug administration, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture).
The treatments will be separated by a wash-out phase of at least 6 days.
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
No re-supply is planned.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Approval/notification of the regulatory authority,  e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
Acetylsalicylic acid or other drugs that may inhibit platelet aggregation or coagulation should 
be avoided during the entire study. If necessary, short term use of ibuprofen or paracetamol is 
acceptable.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (see Table 4.1.4: 2), the water administered with the drug, and an additional 
240 mL of water at 2 h and 4 h post-dose (mandatory for all subjects). From lunch until 24 h 
post-dose, total fluid intake is restricted to 3000 mL.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication until after the last PK 
sample is collected.
Smoking as well as methylxanthine-containing drinks or foods (such as coffee, tea, cola, 
energy drinks, or chocolate) are not allowed during in-house confinement.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF SAFETY
5.1.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results of smoking and alcohol history not mandatory to be 
entered into CRF or to be reported), relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
laboratory tests, and a physical examination. At the end of trial examination, it will include 
review of vital signs, 12-lead ECG, laboratory tests, and a physical examination.
5.1.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100, GE Medical Systems, Freiburg, Germany) at the times indicated in the 
Flow Chart, after subjects have rested for at least 5 min in a supine position. All recordings 
should be made using the same type of blood pressure recording instrument on the same arm, 
if possible.
5.1.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
The parameters that will be determined are listed in Tables 5.1.3: 1 and 5.1.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.1.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands;  Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
X1
X1
X1
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
Lipase
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 
X
--
--
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI2
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
C-Reactive Protein (Quant)  
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
X
--
--
--
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
X
X
X
X
X
X
1 if automatic differential WBC is abnormal
2 estimated glomerular filtration rate according to CKD-EPI formula (R12-1392)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visits 2 and 3 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 4 (end of trial examination)


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Table 5.1.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment3
(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)
X3
--
X3
3 if erythrocytes, leukocytes nitrite or protein are abnormal in urinalysis
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visits 2 and 3 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 4 (end of trial examination)
The tests listed in Table 5.1.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and prior to each treatment period.
Table 5.1.3: 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 (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
7410, Dräger AG, Lübeck, Germany) will be performed prior to each treatment period, and 


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may be repeated at any time during the study at the discretion of an investigator or designee. 
The results will not be included in the CTR.
The laboratory tests listed in Tables 5.1.3: 1 and 5.1.3: 2 will be performed 
 
 with the exception of 
drug screening tests. These tests will be performed at the trial site using M-10/14-PDT test or 
a comparable test system.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.1.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the times provided in the Flow Chart. 
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for 10 sec duration after subjects have rested for at least 5 min in a 
supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (GE Medical 
Systems, Freiburg, Germany). 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).
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.1.5
Assessment of adverse events
5.1.5.1
Definitions of adverse events
Adverse event
5.1.5.1.1
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.


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The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
5.1.5.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation  

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.1.5.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.1.5.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.


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Adverse events of special interest
5.1.5.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.1.5.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
Intensity (severity) of AEs
5.1.5.1.5
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
5.1.5.1.6
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure


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
Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.1.5.2
Adverse event collection and reporting
AE collection
5.1.5.2.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 


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o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.
AE reporting to the sponsor and timelines
5.1.5.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.1.5.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
Pregnancy
5.1.5.2.4
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 


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is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.2
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.2.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.2.2
Methods of sample collection
5.2.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 1323495 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic 
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venepuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and at 4 to 8 °C. Two plasma aliquots will be obtained 
and stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. 
The process from blood collection until transfer of plasma aliquots into the freezer should be
completed within 60 min, with interim storage of blood samples at room temperature. The 
time each aliquot was placed in the freezer will be documented. Until transfer on dry ice to 
the analytical laboratory, the aliquots will be stored upright at approximately -20°C or below 
at the trial site. The second aliquot will be transferred to the analytical laboratory after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory, the 
plasma samples will be stored at approximately -20°C or below until analysis. 
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g. for stability testing or assessment of metabolites. However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the CTR is 
archived.
5.2.3
Analytical determinations
BI 1323495 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis. 


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During sample analysis, the bioanalyst will be blinded to subject allocation and will have no 
access to the randomisation code.
5.2.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
5.3
BIOBANKING
Not applicable.
5.4
OTHER ASSESSMENTS
5.4.1
Pharmacogenomic evaluation
5.5
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used assessments of drug exposure. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening, for measurements and assessments scheduled to 
occur ‘before’ trial medication administration on Day 1, and the end of trial examination are 
provided in the Flow Chart.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 15 min for the first 4 h after trial drug administration and ± 30 min thereafter. 
Starting from 48 h post administration a deviation from the scheduled time for vital signs, 
ECG and laboratory tests of ±120 min is acceptable.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements
including venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.1.1 to 5.1.4.
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Days -1, 1, 2, 3, 4 and 5 in each 
period). In addition, an ambulatory visit will be necessary within 3 days prior to the first 
study drug administration for safety laboratory. At least 6 days will separate drug 
administrations in the first and second treatment periods. 
In the evening of Day -1 of each treatment period, study participants will be admitted to the 
trial site and kept under close medical surveillance for at least 24 h following drug 


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administration. The subjects will then be allowed to leave the trial site after formal 
assessment and confirmation of their fitness. All following trial assessments will be 
performed in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.2.2.
The safety measurements performed during the treatment period are specified in Section 5.1
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.1.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained. 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the relative bioavailability of 
 
BI 1323495 administered as tablet formulation in the fed state (Test, T) compared to 
 
 BI 1323495 administered as tablet formulation in the fasted state (Reference, R) on the 
basis of the primary and secondary pharmacokinetic endpoints, as listed in Section 2.1.2 and 
2.1.3. The trial is designed to allow intra-subject comparisons and will be evaluated 
statistically by use of a linear model for logarithmically transformed PK endpoints. 
A further objective is to evaluate and compare further pharmacokinetic parameters between 
the treatments. These pharmacokinetic parameters will be assessed by descriptive statistics.
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of BI 1323495 under fed and fasted conditions will be estimated 
by the ratios of the geometric means (test/reference), and their corresponding 2-sided 90% 
confidence intervals (CIs) will be provided. This method corresponds to the two one-sided t-
test procedure, each at the 5% significance level. Since the main focus is on estimation and 
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for safety 
analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol violation relevant to the evaluation
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he/she 
contributes only one PK parameter value for one period to the statistical assessment.
Descriptive and model based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol violation 
(IPV) categories will be suggested in the TSAP, IPVs will be identified no later than in the 
Report Planning Meeting, and the IPV categories will be updated as needed.


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Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for BI 1323495 will be calculated 
according to the relevant Standard Operating Procedure (SOP) of the Sponsor 
. 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
violation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis)

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.3.1
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: sequence, subjects within 
sequences, period and treatment. The effect 'subjects within sequences' will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment  


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k in period j,
= 
the overall mean,
i = 
the ith sequence effect, i = 1, 2,
sim = the effect associated with the mth subject in the ith sequence, m = 1, 2,…,6
j = 
the jth period effect, j = 1, 2,
k = 
the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means).
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, ‘treatment’) 
considered as fixed effects.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.3.2
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ 
 and will be assessed statistically using the same 
methods as described for the primary endpoints.


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7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.3) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between first trial medication intake and end of 
trial termination date will be assigned to the treatment period. These assignments including 
the corresponding time intervals will be defined in detail in the TSAP. Note that AEs 
occurring after the last per protocol contact but entered before final database lock will be 
reported to Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.5.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No interim analysis is planned.


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7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure 
.
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Subjects will be randomised to one of the 2 treatment sequences in a 1:1 ratio. The block size 
will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 12 subjects in the trial, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial. 


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form 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. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:


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
Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial.


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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 patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage 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 (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage

If applicable, 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 
ICF.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.


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Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the 
 
, under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates, and investigators of participating trial sites
The trial medication will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
Analyses of BI 1323495 concentrations in plasma will be performed 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER) 
2002:1-9.
R12-1392
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
Kusek JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI). A new equation to 
estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604-612.


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R94-1529
Chow SC, Liu JP. Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc; 1992.


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9.2
UNPUBLISHED REFERENCES
c21238478-01
Investigator’s Brochure BI 1323495. 
 05 Apr 2018.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
22 November 2018
EudraCT number
EU number
2018-002792-18
BI Trial number
1405-0007
BI Investigational Medicinal 
Product(s)
BI 1323495
Title of protocol
Relative bioavailability of BI 1323495 following 
oral administration under fed and fasted conditions 
in healthy male subjects (an open-label, randomised, 
single-dose, two-period, two-sequence crossover 
study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1
Flow Chart
2
Section 1.2.4 Clinical experience in humans
3
Section 1.4 Benefit – Risk Assessment
4
Section 3.3.3 Exclusion criteria
5
Section 3.3.4.1 Discontinuation of trial treatment
6
Section 3.3.4.3 Discontinuation of the trial by the 
sponsor
7
Section 3.3.5 Replacement of subjects
8
Section 4.1.3 Method of assigning subjects to 
treatment groups
9
Section 5.1.3 Safety laboratory parameters
10
Section 5.2.2.1 Blood sampling for pharmacokinetic 
analysis


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Description of change
1
PK sampling schedule adapted based on SRD data;
additional ECG/VS at 2h postdose
2
Preliminary data from SRD trial 1405-0001 
amended
3
Benefit – risk assessment amended based on data 
gained in SRD trial.
4
Exclusion criterion 20 more precisely described
5
Additional criterion for individual treatment 
discontinuation introduced.
6
Discontinuation of the trial by the sponsor, point 2 
clarified by more detailed description.
7
Clarification: subjects withdrawn for drug related 
AEs will not be replaced.
8
Explanation that all subjects may be dosed in one 
cohort on the same calendar day.
9
Test name of drug screen corrected.
10
PK blood samples may be stored at room 
temperature until centrifuged.
Rationale for change
1
In the SRD trial, maximum plasma concentrations 
were reached earlier than expected based on 
preclinical data; therefore the sampling schedule for 
PK was adapted accordingly
2/3
To address request by competent authority / ethics 
committee; to give sound ground for dose selection, 
trial design, and safety measures.
4
Clarification requested by ethics committee.
5
Addition requested by FDA (protocol was submitted 
to FDA to open IND).
6
To address request by competent authority.
7
To address request by competent authority.
8
Clarification requested by competent authority.
9
Name of drug screen test was incorrect.
10
Interim storage on ice not necessary according to 
stability data.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c24401085
2.0
clinical-trial-protocol-revision-1
Relative bioavailability of BI 1323495 following oral administration under fed and
fasted conditions in healthy male subjects (an open-label, randomised, single-dose,
two-period, two-sequence crossover study)
Author-Trial Statistician
22 Nov 2018 13:44 CET
Author-Clinical Trial Leader
22 Nov 2018 13:51 CET
Author-Trial Clinical
Pharmacokineticist
22 Nov 2018 14:14 CET
Approval-Therapeutic Area 
23 Nov 2018 10:44 CET
Approval-Team Member Medicine
23 Nov 2018 11:39 CET
Verification-Paper Signature
Completion
26 Nov 2018 09:13 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c24401085
2.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
C26496666-01
BI Trial No.:
1405-0007
Title:
Relative bioavailability of BI 1323495 following oral administration 
under fed and fasted conditions in healthy male subjects (an open-
label, randomised, single-dose, two-period, two-sequence crossover 
study)
Including Global Amendment 1 [c24401085-02]
Investigational
Products:
BI 1323495 tablet formulation 
 fasted and after a high fat, 
high calorie meal
Responsible trial 
statisticians:
 
Phone:
Fax:
Phone:
Fax:
Date of statistical 
analysis plan:
11 APR 2019 SIGNED
Version:
final
Page 1 of 27
Proprietary confidential information
2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim
TSAP for BI Trial No: 1405-0007
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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.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINTS...................................................................................10
5.2
SECONDARY ENDPOINTS.............................................................................10
5.2.1
Key secondary endpoints....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................13
6.1
TREATMENTS...................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................19
7.4
PRIMARY ENDPOINTS...................................................................................19
7.5
SECONDARY ENDPOINTS.............................................................................20
7.5.1
Key secondary endpoints....................................................................................20
7.5.2
Secondary endpoints...........................................................................................20
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse events.....................................................................................................21
7.8.2
Laboratory data ..................................................................................................24
7.8.3
Vital signs.............................................................................................................24
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................24
8.
REFERENCES....................................................................................................25


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10.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................13
Table 6.3: 1
Subject sets analysed........................................................................................15
Table 10: 1
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Aspartate transaminase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BMI
Body mass index
BP
Blood pressure
BWC
Bioavailability/Bioequivalence, within-subject design, time-controlled
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CRA
Clinical research associate
CRF
Case report form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DILI
Drug induced liver injury
ECG
Electrocardiogram 
EDC
Electronic data capture
EudraCT
European Union Drug Regulating Authorities Clinical Trials


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Term
Definition / description
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference on Harmonisation
iPD
Important Protocol Deviation
ISF
Investigator site file
LLT
Lower level term
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number non-missing observations
O*C
Oracle Clinical
P10
10th percentile
P90
90th percentile
PK
Pharmacokinetics
PKS
PK parameter analysis set
PR
Pulse rate
PT
Preferred term
Q1
1st quartile
Q3
3rd quartile
R
Reference treatment
RAGe
Report Appendix Generator system
REP
Residual effect period
RPM
Report planning meeting
SASTM
Statistical Analysis System
SD
Standard deviation
SOC
System organ class
SOP
Standard operating procedure
T
Test treatment


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Term
Definition / description
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary
XPKISTAT
Library of SAS® Macros for PK analysis


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


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP. No changes compared to the protocol were made.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP: The following pharmacokinetic parameters will be determined for 
BI 1323495: 

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Pharmacokinetic (PK):
Section 2.1.3 of the CTP: The following pharmacokinetic parameter will be determined for 
BI 1323495:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
There are two methods by which AUC0-∞is calculated:

AUCINF_obs: Area under the plasma concentration time curve from time zero to time 
infinity with extrapolated area from time tz to infinity based on last observed 
concentration at time tz

AUCINF_pred: Area under the plasma concentration time curve from time zero to 
time infinity with extrapolated area from time tz to infinity based on the concentration 
predicted by regression for the time tz
Analysis will be performed on all methods available in the data.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatment sequences, 
and selection of doses, please see CTP, Sections 3 and 4.
The study will be performed as a randomised, open-label, two-way crossover trial with two
treatments (T and R) and two treatment sequences (T-R or R-T). 
In total, it was planned to assign 12 healthy male subjects to the two treatment sequences in a 
1:1 ratio.
For details of dosage and formulation see Table 6.1: 1 below:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
Short label for footnote
T
 tablets of BI 1323495, 
fed
BI fed
BI 1323495 
 fed
R
 tablets of BI 1323495, 
fasted
BI fasted
BI 1323495 
 fasted
The following separate study phases will be defined for the analyses of AEs:
Screening (ranging from 0:00 h on day of informed consent until first administration 
time of study drug)
On treatment (separately for each treatment, ranging from the time of administration 
of the respective treatment until next drug administration of 0:00 h or on the day after 
trial termination date) 
Please note that all AEs reported between start of trial drug administration and the last per-
protocol contact will be considered on treatment (i.e. no follow-up period is considered in this 
trial).
Displays of AEs will be presented separately for the treatments described in Table 6.1: 1
above.
For detailed information on the handling of the treatments in the O*C views refer to 
Technical TSAP ADS plan and Data Reviewers guide. 


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the combined report planning and database lock meeting 
(RPM/DBLM). At this meeting, all manual deviations identified at the sites by the CRAs and 
deviations too complex to program will be reviewed by the trial team to decide which are 
considered important. For definition of important protocol deviations (iPD), and for the 
process of identification of these, refer to the Boehringer Ingelheim (BI) SOP "Identify and 
Manage Important Protocol Deviations (iPD)" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM minutes via an accompanying Excel spreadsheet (3). 
For a description of categories which are considered to be iPDs in this trial, please refer to the 
IQRM plan.
6.3
SUBJECT SETS ANALYSED

Treated set (TS):
This subject set includes all subjects who were dispensed study medication and were 
documented to have taken at least one dose of study drug.
This is the full analysis set population in the sense of ICH-E9 (1).
It is used for safety analyses.
Section 7.3 of the CTP: Plasma concentration data and parameters of a subject will be 
included in the statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion 
due to a protocol violation relevant to the evaluation of PK (to be decided no later than in the 
Report Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, 
based on the criteria specified below). Exclusion of a subject’s data will be documented in 
the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis)

A predose concentration is >5% Cmax value of that subject


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
Missing samples/concentration data at important phases of PK disposition curve

PK parameter analysis set (PKS): 
This subject set includes all subjects in the TS who provide at least one primary or 
secondary PK parameter that was not excluded according to the description above. 
Thus, a subject will be included in the PKS, even if he contributes only one PK 
parameter value for one period to the statistical assessment.
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.
The following Table 6.3: 1 contains the information which subject is used for which class of 
endpoint:
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Analyses of primary and secondary PK endpoints 
X
Safety endpoints 
X
Demographic/baseline endpoints
X
Important protocol deviations
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).


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Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For vital signs baseline for Period 1 is defined as the last measurement prior to first drug 
administration, and baseline for Period 2 is defined as the last measurement prior to first drug 
administration in Period 2.
For laboratory parameters baseline for Period 1 and Period 2 is defined as the last 
measurement prior to first drug administration, as the REP of BI 1323495 is not known.
Section 6.1 of the CTP: Exact times of measurements outside the permitted time windows 
will be documented. The acceptable time windows for screening, for measurements and 
assessments scheduled to occur ’before’ trial medication administration on Day 1, and the 
end of trial examination are provided in the Flow Chart.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 15 min for the first 4 h after trial drug administration and ± 30 min thereafter. 
Starting from 48 h post administration a deviation from the scheduled time for vital signs, 
ECG and laboratory tests of ±120 min is acceptable.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Section 7.4 and Section 7.5.2) will 
also be performed by 
and will be presented in Section 15.5 of 
the CTR and in Appendix 16.1.13.3.
Descriptive data analysis of PK parameters and concentrations will be performed by the 
department Translational Medicine and Clin. Pharmacology at BI and will be presented in 
Section 15.6 of the CTR.
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of Clinical Trials and Project Summaries” [001-MCG-159] (6) with the 
exception of those generated for PK-calculations (7).
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number, visit and actual treatment (if appropriate). 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations 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
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90
90th percentile
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.


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Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment sequence/group. Percentages will be rounded to one decimal place and will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not. The category 'missing' will be displayed only if there are actually missing values.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
Exclusion of PK parameters
The ADS ADPP (PK parameters) contains column variables indicating inclusion/exclusion 
(APEXC) of a PK parameter and an analysis flag comment (APEXCO). All analyses based 
on the PKS will include parameters if they are not flagged for exclusion, that is APEXCO is 
equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC and ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (11).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by treatment sequence and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 


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Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM. 
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The 
measured plasma concentrations of trial medication will provide additional confirmation of 
compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM/DBLM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
Relative bioavailability of BI 1323495 is to be determined on the basis of the primary and 
secondary pharmacokinetic endpoints (see Section 5.1). 
Section 7.3.1 of the CTP:
Primary analysis
The statistical model used for the analysis of primary and secondary endpoints will be an 
analysis of variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will 
be log-transformed (natural logarithm) prior to fitting the ANOVA model. This model will 
include effects accounting for the following sources of variation: sequence, subjects within 
sequences, period and treatment. The effect ‘subjects within sequences’ will be considered as 
random, whereas the other effects will be considered as fixed. The model is described by the 
following equation:
yijkm = + ζi + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving treatment 
k in period j,
= the overall mean,
ζi = the ith sequence effect, i = 1, 2
sim = the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., 6


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j = the jth period effect, j = 1, 2
k = the kth treatment effect, k = 1, 2
eijkm = the random error associated with the mth subject in sequence i who received 
treatment k in period j.
The implementation for this analysis will be accomplished by using the XPKISTAT macro, 
based on PKS, and option BWC (Bioavailability/Bioequivalence, within-subject design, time-
controlled).
Section 7.3.1 of the CTP: For each endpoint, the difference between the expected means for 
log(T)-log(R), will be estimated by the difference in the corresponding adjusted means (Least 
Squares Means). Additionally, their two-sided 90% confidence intervals will be calculated 
based on the residual error from the ANOVA and quantiles from the t-distribution. These 
quantities will then be back-transformed to the original scale to provide the point estimate 
and 90% CIs for each endpoint. 
Further exploratory analyses
As a sensitivity analysis, this ANOVA will be repeated for the primary and secondary 
endpoints with all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, 
‘treatment’) considered as fixed effects. This analysis will be done using PROC GLM.
The following SAS code can be used to fit the model:
PROC GLM DATA=indata; 
CLASS subject treatment sequence period; 
MODEL logkp = treatment sequence period subject(sequence); 
LSMEANS treatment / PDIFF=CONTROL(“Ref_trt”) CL ALPHA=0.1; 
RUN;
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 secondary PK parameter AUC0-∞will be assessed using the same methods as described 
for the primary endpoints.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (8).
The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 
For analysis, multiple AE occurrence data on the case report form (CRF) will be collapsed 
into one AE provided that all of the following applies:


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
All AE attributes are identical (lower level term (LLT), intensity, action taken, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
two occurrences is given if the second occurrence started within one hour after end of 
the first occurrence).
For further details on summarization of AE data, please refer to [001-MCG-156] (8,4).
Section 5.1.5.1.4 of the CTP: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
an elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-
fold ULN measured in the same blood sample, or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients 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.
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events.
Section 1.2.5 of the CTP: The residual effect period (REP) of BI 1323495, i.e. the time 
interval when measurable drug levels or PD effects are still likely to be present, is not yet 
known. Therefore, all AEs with an onset between start of treatment and the end of trial 
examination (last per protocol contact) will be considered on treatment.
All adverse events occurring before first drug administration will be assigned to ‘screening’, 
those between intake of trial medication and prior to next drug administration or termination 
date will be assigned to the corresponding treatment (‘on treatment’). 


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Section 7.3.4 of the CTP: 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.
For more detail see the TSAP ADS plan.
According to ICH E3 (9), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken with trial drug = discontinuation’ or ‘action taken with trial drug = reduced’, 
or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant
therapy as identified by the Clinical Monitor/Investigator at the Report Planning Meeting. 
An overall summary of AEs (including AESIs) will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with other 
significant AEs according to ICH E3 (9), for subjects with serious AEs, for subjects with 
drug-related AEs, for subjects with drug related serious adverse events and for subjects with 
AESIs.
The SOC and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) of the 
CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening and follow-up periods will not be included in this analysis. 
The following total will be provided in addition (Section 15.3 only):

a total over all on treatment phases included in this analysis ("Total on treatment")
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of the 
CTR displays:


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
Screening 

On treatment (labelled with the name of the study treatment (short label))
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:

a total over all study phases ("Total")
7.8.2
Laboratory data
Descriptive statistics will be calculated by treatment including change from baseline. Due to 
an unknown REP, baseline of period 1 will be used as baseline of both periods. The 
timepoints V3 -2:00 and post-exam and their change from baseline will be determined for the 
treatment in Period 2.
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possible 
clinically significant will be flagged in the data listings.
It is the investigator's responsibility to decide whether a lab value is clinically significantly
abnormal or not(at the RPM/DBLM at the latest).
The analyses of laboratory data will be based on BI standards [001-MCG-157] (10).
7.8.3
Vital signs
Descriptive statistics including change from baseline will be performed for vital signs (blood 
pressure and pulse rate) by treatment.
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as AEs (when they 
occurred during treatment).
7.8.5
Others
This section is not applicable as no other variables have been specified in the protocol.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, IDEA for CON.
3
BI-KMED-COPS-TMP-0001: "iPD log", current version; IDEA for GEN.
4
001-MCG-156_RD-01: “Handling of Missing and Incomplete AE Dates”, current 
version; IDEA for CON.
5
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic
Analyses of Clinical Studies”, current version; IDEA for CON.
6
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current version; 
IDEA for CON.
7
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
8
001-MCG-156: “Analysis and Presentation of Adverse Event Data from Clinical 
Trials”, current version; IDEA for CON.
9
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.
10
001-MCG-157: “Handling, Display and Analysis of Laboratory Data”, current version; 
IDEA for CON.
11
001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.


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TSAP for BI Trial No: 1405-0007
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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
11-APR-19
 
None
This is the final TSAP without any 
modification