Clinical trial NCT03505151
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2018-04-27; Completion date: 2018-05-19
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this trial is to investigate the absolute bioavailability of BI 409306. The secondary objective is the evaluation and comparison of several pharmacokinetic parameters for the different treatments.

Detailed description:

Arms: arm 1: On day 1, subjects were administered the Test treatment (T): a single dose of 50 milligram (mg) of BI 409306 film-coated tablet orally with 240 milliliter (mL) of water, followed 30 minutes (min) later by the Reference treatment (R): 0.1 mg isotope BI 409306 (C-13/N-15) as intravenous (i.v.) infusion over 30 minutes.

Both treatments were given in fasted state.
Interventions: intervention 1: BI 409306 (C-13/N-15) intervention 2: BI 409306
Intervention descriptions: intervention 1: i.v solution intervention 2: Film-coated tablet

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c09116705-03
EudraCT No.:
BI Trial No.:
2017-004798-14
1289-0025
BI Investigational
Product:
BI 409306
Title:
Absolute bioavailability and pharmacokinetics of BI 409306 using a 
single oral dose of BI 409306 co-administered with an intravenous
stable labeled isotope BI 409306 (C-13/N-15) in healthy male and 
female subjects (Non-Randomised, open-label, single arm, single 
period design)
Lay Title:
This study in healthy men and women tests how the body takes up 
BI 409306
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax:
Principal Investigator:
Phone: 
Fax:
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date:
Version: 3.0
Date: 04 May 2018
Page 1 of 63
Proprietary confidential information
© 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 409306
Protocol date:
Trial number:
Revision date:
04 May 2018
14 February 2018
1289-0025
Title of trial:
Absolute bioavailability and pharmacokinetics of BI 409306 using a single oral dose 
of BI 409306 co-administered with an intravenous stable labeled isotope BI 409306 
(C-13/N-15) in healthy male and female subjects (Non-Randomised, open-label, 
single arm, single period design)
Principal Investigator:
Trial site:
Clinical phase:
I
Objective:
To investigate the absolute bioavailability of BI 409306 
Methodology:
Non-Randomised, open-label, single arm, single period design 
No. of subjects: 
Total entered:
Up to 12
6 subjects with CYP 2C19 non-PM status and up to 6 subjects with 2C19 PM status
Each treatment:
Up to 12
6 subjects with CYP 2C19 non-PM status and up to 6 subjects with 2C19 PM status
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male/female subjects, age of 18 to 55 years, body mass index (BMI) of 18.5 
to 29.9 kg/m2, known CYP2C19 metabolizer status
Reference product:
Stable labeled isotope BI 409306 (C-13/N-15) Solution for infusion 6mL (0.1 mg/mL)
(R)
dose:
0.1 mg 
mode of admin.:
intravenous (infusion over 30 minutes)
Test product:
BI 409306 film-coated tablets, 1 tablet containing 50 mg (T)
dose:
1 x 50 mg 
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment: One day (single dose) for each treatment


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 409306
Protocol date:
Trial number:
Revision date:
04 May 2018
14 February 2018
1289-0025
Criteria for 
pharmacokinetics:
Primary endpoints: AUC0-and Cmax for BI 409306 and stable labeled isotope 
BI 409306 (C-13/N-15) (after oral and intravenous administration)
Secondary endpoints:
t1/2, tmax. for BI 409306 and stable labeled isotope BI 409306 (C-13/N-15). 
Cl (total clearance of the analyte) and Vz (Apparent volume of distribution during the 
terminal phase after intravascular administration) for stable labeled isotope 
BI 409306 (C-13/N-15), 
F (absolute bioavailability) for BI 409306
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the physical 
examination, safety laboratory tests, 12-lead electrocardiogram (ECG), vital signs 
(blood pressure [BP], pulse rate [PR]) 
Statistical methods:
Absolute bioavailability (F) will be estimated by the ratios of the geometric means 
(test/reference) for the dose normalized primary endpoints AUC0-∞and Cmax. 
Additionally, their two-sided 90% confidence intervals (CI) will be provided. This 
method corresponds to the two one-sided t-tests procedure, each at the 5% 
significance level. Since the main focus is on estimation and not testing, an 
acceptance range was not specified. The statistical model will be an ANOVA on the 
logarithmic scale including the fixed effect for ‘formulation’ and ‘subject’ as a 
random effect. CIs will be calculated based on the residual error from ANOVA.
Descriptive statistics will be calculated for all endpoints


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FLOW CHART
Period
Visit
Day
Planned time (relative to oral drug administration 
[h:min]
Approximate clock time  of actual day [h:min]
Event and comment
Safety laboratory
PK blood BI 409306  
BI 409306 (C-13/N-15)
Intravenous infusion
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
x
x
x
1
2
-1
-12:00
20:00
Admission to trial site10
x5
x
1
-1:30
06:30
Allocation to treatment
x2
x2
x2
x2
x2
0:00
08:00
50 mg BI 409306 p.o.
0:10
08:10
x
0:20
08:20
x
x
0:30
08:30
0.1 mg BI 409306 i.v.
x8
▲
┼
0:35
08:35
x
│
0:45
08:45
x
x
│
0:50
08:50
x
│
1:00
09:00
x9
x9
┼
▼
1:10
09:10
x
1:20
09:20
x
x
x
x7
1:30
09:30
x
1:45
09:45
x
x
2:00
10:00
240 mL fluid intake
x
x
x
x
x
2:30
10:30
x
x
3:00
11:00
x
x
3:30
11:30
x
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x
x
5:00
13:00
x
x
6:00
14:00
x
x
7:00
15:00
x
x
8:00
16:00
Snack (voluntary)3
x
x
9:00
17:00
x
x
10:00
18:00
x
x
11:00
19:00
Dinner
12:00
20:00
x
x
x
x
2
24:00
08:00
Discharge from trial site
Breakfast (voluntary) 3
x
x
x7
EOT
3
2
n.a.
n.a.
End of trial (EOT) examination4
x4
x4
x4
x4


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1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures includes physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history and pregnancy 
test in women), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria.
Pharmacogenetic samples will be collected if needed
2.
The time is approximate; the procedure is to be performed and completed within 3 h prior to (oral) drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, vital signs, ECG, safety laboratory including pregnancy test in 
women, recording of AEs and concomitant therapies
Date of EOT coincides with day 2 of visit 2. All EOT activities take place after the formal discharge from the trial 
site. Exception: blood for the EOT safety lab is taken in the context of the 24:00 hours post-dose sampling to avoid two 
separate punctures
5.
Only urine drug screening and alcohol breath test, and pregnancy test in women.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
includes assessment of local tolerability
8.
PK sampling within 2 minutes prior start of infusion 
9. 
PK sampling within 2 minutes prior to end of infusion
10.  Admission to the trial site should not be later than 10 hours prior to oral drug administration


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TABLE OF CONTENTS
TITLE PAGE...................................................................................................... 1
CLINICAL TRIAL PROTOCOL SYNOPSIS................................................ 2
FLOW CHART .................................................................................................. 4
TABLE OF CONTENTS................................................................................... 6
ABBREVIATIONS .......................................................................................... 10
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 22
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................22
3.1.1
Administrative structure of the trial...................................................22
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................23
3.3
SELECTION OF TRIAL POPULATION ......................................................23
3.3.1
Main diagnosis for study entry............................................................23
3.3.2
Inclusion criteria...................................................................................23
3.3.3
Exclusion criteria ..................................................................................24
3.3.4
Removal of subjects from therapy or assessments.............................25
3.3.4.1
Removal of individual subjects................................................25
3.3.4.2
Discontinuation of the trial by the sponsor..............................26
4.
TREATMENTS........................................................................................ 27
4.1
TREATMENTS TO BE ADMINISTERED....................................................27
4.1.1
Identity of BI investigational products ...............................................27
4.1.2
Method of assigning subjects to treatment groups ............................28
4.1.3
Selection of doses in the trial................................................................28
4.1.4
Drug assignment and administration of doses for each subject .......28
4.1.5
Blinding and procedures for unblinding ............................................29
4.1.6
Packaging, labelling, and re-supply ....................................................29
4.1.7
Storage conditions.................................................................................29


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4.1.8
Drug accountability ..............................................................................30
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................30
4.2.1
Other treatments and emergency procedures....................................30
4.2.2
Restrictions............................................................................................30
4.2.2.1
Restrictions regarding concomitant treatment .........................30
4.2.2.2
Restrictions on diet and life style.............................................31
4.3
TREATMENT COMPLIANCE.......................................................................31
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 32
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................32
5.1.1
Endpoints of efficacy.............................................................................32
5.1.2
Assessment of efficacy...........................................................................32
5.2
SAFETY..............................................................................................................32
5.2.1
Endpoints of safety................................................................................32
5.2.2
Assessment of adverse events...............................................................32
5.2.2.1
Definitions of adverse events...................................................32
5.2.2.2
Adverse event collection and reporting ...................................35
5.2.3
Assessment of safety laboratory parameters......................................37
5.2.4
Electrocardiogram................................................................................39
5.2.5
Assessment of other safety parameters...............................................40
5.2.5.1
Vital signs ................................................................................40
5.2.5.2
Medical examinations..............................................................40
5.2.5.3
Local tolerability......................................................................40
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................41
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................41
5.5.1
Pharmacokinetic endpoints..................................................................41
5.5.1.1
Primary endpoint......................................................................41
5.5.1.2
Secondary endpoints................................................................41
5.5.2
Methods of sample collection...............................................................43
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................43
5.5.3
Analytical determinations ....................................................................44
5.5.3.1
Analytical determination of BI 409306 and the BI 409306 (C-
13/N-15) plasma concentration................................................44
6.
INVESTIGATIONAL PLAN.................................................................. 45
6.1
VISIT SCHEDULE............................................................................................45
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................45


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6.2.1
Screening period....................................................................................45
6.2.2
Treatment period ..................................................................................45
6.2.3
End of trial period.................................................................................46
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE ......................................................................................... 47
7.1
STATISTICAL DESIGN – MODEL ...............................................................47
7.1.1
Objectives...............................................................................................47
7.1.2
Endpoints...............................................................................................47
7.1.3
Model......................................................................................................47
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................48
7.3
PLANNED ANALYSES....................................................................................48
7.3.1
Primary analyses...................................................................................48
7.3.2
Secondary analyses ...............................................................................50
7.3.3
Safety analyses.......................................................................................50
7.3.4
Interim analyses ....................................................................................51
7.3.5
Pharmacokinetic analyses ....................................................................51
7.4
HANDLING OF MISSING DATA ..................................................................51
7.4.1
Safety......................................................................................................51
7.4.2
Plasma drug concentration - time profiles..........................................51
7.4.3
Pharmacokinetic parameters...............................................................51
7.5
RANDOMISATION ..........................................................................................51
7.6
DETERMINATION OF SAMPLE SIZE ........................................................52
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS................................................................................................. 53
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................53
8.2
DATA QUALITY ASSURANCE .....................................................................54
8.3
RECORDS..........................................................................................................54
8.3.1
Source documents .................................................................................54
8.3.2
Direct access to source data and documents.......................................55
8.3.3
Storage period of records.....................................................................55
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................55
8.5
STATEMENT OF CONFIDENTIALITY.......................................................55
8.6
COMPLETION OF TRIAL..............................................................................55
9.
REFERENCES ......................................................................................... 56
9.1
PUBLISHED REFERENCES...........................................................................56
9.2
UNPUBLISHED REFERENCES.....................................................................57
10. APPENDICES........................................................................................... 59
10.1
DRUG SUPPLY AND EQUIPMENT..............................................................59
10.1.1 Drug supply ...........................................................................................59


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10.1.2 Disposables.............................................................................................59
10.1.3 Technical equipment.............................................................................59
10.2
HANDLING INSTRUCTION ..........................................................................60
10.2.1 Overview................................................................................................60
10.2.2 Preparation of i.v. solution for continuous infusion via syringe 
pump
..................................................................................................60
10.2.3 In-use stability.......................................................................................60
10.2.4 Mode of application ..............................................................................61
10.2.5 General remarks – important..............................................................61
11. DESCRIPTION OF GLOBAL AMENDMENT(S) .............................. 62


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ABBREVIATIONS
AD
Alzheimer’s Disease
ADME
Absorption, Distribution, Metabolism and Excretion
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
APS
Attenuated Psychosis Syndrome
AUC0-24h
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 – 24 h
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BA
Bioavailability
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
bpm
Beats per minute
CA
Competent authority
cGMP
Cyclic guanosine monophosphate
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
CYP
Cytochrom P 450
DILI
Drug induced liver injury
ECG
Electrocardiogram
EDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EM
Extensive metabolizer
EOT
End of trial
F
Absolute bioavailability factor
GCP
Good Clinical Practice


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GLP
Good laboratory Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
HPC
Human Pharmacology Centre
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LTP
Long term potentiation
MedDRA
Medical Dictionary for Regulatory Activities
MRT
Mean residence time of the analyte in the body after intravenous bolus 
administration
MRTpo
Mean residence time of the analyte in the body after oral administration
NMDA
N-methyl-D-aspartate
NOA
Not analysed
NOAEL
No adverse effect level
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PDE
Phosphodiesterase
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter analysis set
PM
Poor metabolizer
PR
Pulse rate
QD
Quaque die, once daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard Operating Procedure
SRD
Single-rising dose
Ss
(at) steady state
T
Test product or treatment


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TDMAP
Trial Data Management and Analysis Plan
TMF
Trial master file
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
Vss
Apparent volume of distribution at steady state after intravascular 
administration
Vz
Apparent volume of distribution during the terminal phase after
intravascular administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
YLD
Years lived with disability


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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 non-randomised, open-label, single arm, single period trial
in healthy male and female subjects in order to compare the test treatment (T) to the reference 
treatment (R).
The treatments will be 0.1 mg isotope BI 409306 (C-13/N-15), intravenous administration (R)
and one 50 mg film-coated tablet BI 409306, oral administration (T). Both treatments are 
given in fasted state. 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.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The trial medication will be provided by the 
 
 
The trial will be conducted at the
 under the supervision of the Principal Investigator. Safety 
laboratory tests will be performed by
 
The prespecified genotyping of CYP2C19 will be performed at the
The analyses of BI 409306 concentrations in plasma will be performed
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI. Data management will be done by BI according to BI SOPs.
Statistical tasks and programming will be performed by
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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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
To investigate the absolute bioavailability, a single arm, single period trial design using a 
microtracer approach* was considered as more favourable design as compared to the 
traditional cross-over design used for absolute bioavailability studies for the following 
reasons: 

Day to day variability within a subject is eliminated as potential confounding variable 
in addition to the intrasubject variabilities in drug dissolution, absorption rate, and 
metabolism

Expected favourable safety due to very low exposures after an intravenous microdose 

Radiopharmacy is not required with the stable isotopes. Subjects are not exposed to 
radioactivity. The stable isotope labeled compound used in this study, BI 409306
(C-13/N-15)-BI 409306 is unlikely to exhibit any detectable isotope effects (see 
section 2.3).

Reduced duration of the clinical trial 
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analyte.
_____________
*In this context ‘microtracer’ is defined as an intravenous dose of an isotopically labeled drug in an absolute 
bioavailability study administered as 1% of the pharmacologic dose or 0.1 mg, whichever is the lower. [R17-
1799]
3.3
SELECTION OF TRIAL POPULATION
It is planned that up to 12 healthy male and female subjects will enter the study. They will be 
recruited from the volunteers' pool of the trial site.
To explore potential differences in absolute bioavailability based on 2C19 metabolizer status, 
it is planned to include 6 subjects with CYP2C19 non-PM status, and up to 6 subjects with 
2C19 PM status, if feasible.
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The study will be performed in male and female healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:


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1. Healthy male or female subjects according to the assessment of the investigator, based on 
a complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
5. Known CYP 2C19 metabolizer status
6. Male subjects, or female subjects who meet any of the following criteria starting from at 
least 30 days before the first administration of trial medication and until 30 days after trial 
completion:
-
Use of adequate contraception, e.g. non-hormonal intrauterine device plus condom.
-
Sexually abstinent
-
A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) 
-
Surgically sterilised (including hysterectomy)
-
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea 
(in questionable cases a blood sample with simultaneous levels of FSH (follicle 
stimulating hormone) above 40 U/L and estradiol below 30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)


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12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
13. Current smoker or ex-smoker who quit smoking less than 30 days prior to screening
14. Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for
males)
15. Drug abuse or positive drug screening
16. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
17. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
18. Inability to comply with dietary regimen of trial site
19. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 msec in males or repeatedly greater than 470 msec in females)
or any other relevant ECG finding at screening
20. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
21. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
Female subjects will not be allowed to participate if any of the following applies:
22. Positive pregnancy test, pregnancy or plans to become pregnant within 30 days after study 
completion
23. Lactation period
24. Concomitant use of hormonal replacement therapy or hormonal contraceptives
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as pregnancy, 
surgery, adverse events, or diseases)


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4. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time of 
discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent withdrawal 
of the subject. These discontinuations will be discussed in the CTR.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication has to be stopped immediately, and the subject has to be removed from the trial. 
The subject is to be followed until she has given birth or until the end of pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the clinical trial report. For reporting of pregnancy and events refer to Section 
5.2.2.2.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP by a trial site or investigator, disturbing the appropriate 
conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational product.
 
 


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational products have been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of BI investigational products
The characteristics of the test product are given below:
Substance:
BI 409306
Pharmaceutical formulation: film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
50 mg
Posology:
1-0-0
Route of administration:
p.o.
The characteristics of the reference product are given below:
Substance:
stable labeled isotope BI 409306 (C-13/N-15) Solution for 
infusion
Pharmaceutical formulation: i.v. solution
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
6 mL (0.1 mg/mL, 0.6mg/vial)
Posology:
0.1 mg-0-0
Route of administration:
i.v.
Duration of use:
intravenous infusion over 30 min
BI 409306 (C-13/N-15) is a ready for use i.v. solution provided in a glass vial. Sodium 
chloride (0.9%) has been chosen as tonicifier for the BI 409306 (C-13/N-15) solution. The 
aseptically prepared solution is tested for sterility and bacterial endotoxins as part of the 
release testing. 
BI 409306 (C-13/N-15) will be administered as short infusion using a syringe infusion pump 
(Perfusor fm® B.Braun, Melsungen, Germany) based on the handling instructions (see 
section 10). For intravenous drug administration and PK sampling two different intravenous 
cannulas will be used. They must not be on the same arm during the drug administration.


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4.1.2
Method of assigning subjects to treatment groups
The allocation of subjects to study subject numbers will be performed prior to the first
administration of trial medication in the morning of Day 1 (Visit 2). For this purpose, the 
subjects will be allocated to a study subject number by drawing lots. 
Once a subject number has been assigned, it cannot be reassigned to any other subject.
4.1.3
Selection of doses in the trial
The oral dose of 50 mg BI 409306 was selected since it is expected to be a therapeutic dose 
and was well tolerated in previous studies (section 1.2).
Using the microtracer approach for investigating the absolute bioavailability the intravenous 
dose should not significantly add to the systemic drug concentrations arising from the oral 
administration [R17-1799].
The oral dose (50 mg BI 409306) is 500 times higher than the intravenously infused dose 
(0.1 mg BI 409306 [C-13/N-15]). Therefore the exposure to BI 409306 (C-13/N-15)
originating from the infused microdose is considered negligible (see section 2.3).
With the bioanalytical methods described in section 5.5.3, the anticipated drug concentrations
are expected to be detectable. 
4.1.4
Drug assignment and administration of doses for each subject
This trial is a non-randomised, open-label, single arm, single period study. All subjects will 
receive both treatments, orally administered BI 409306 (T) as well as intravenously 
administered BI 409306 (C-13/N-15) (R). 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
R (Reference)
BI 409306 (C-13/N-15)
i.v. solution
0.1 mg/mL
1 ml
0.1 mg
T (Test)
BI 409306
film-coated tablet
50 mg
50 mg single dose
50 mg
The oral medication will be administered as a single dose together with about 240 mL of 
water to a subject in the sitting or standing position under supervision of the investigating 
physician or an authorised designee. 
During the first 2 h after oral drug administration, they are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture).
The intravenous medication will be administered as a continuous intravenous infusion over 
30 minutes  under supervision of the investigating physician or an authorised designee. Start 
and end time of the infusion will be recorded.
The so-called four-eye principle (two-person rule) should be applied for administration of trial 
medication and – if applicable – its preparation, if correct dosage cannot be ensured 


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otherwise. Administration will be performed following an overnight fast starting no later than 
10 h before scheduled dosing. 
4.1.5
Blinding and procedures for unblinding
No blinding was performed because the treatments are distinguishable from each other. 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, since all subjects receive the same dose of 
different formulations in an open label design.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labeled
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. The clinical trial supply 
containers will be labeled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Batch number
The telephone number of the sponsor and name, address and telephone number of the trial site
are given in the subject information form. The EudraCT number is indicated on the title page 
of this protocol as well as on the subject information and informed consent forms. Examples 
of the labels will be available in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labeled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.


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4.1.8
Drug accountability
The investigator will receive the investigational drugs delivered by the sponsor when the 
following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee 

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 
written authorisation by the clinical monitor. Receipt, usage and disposal must be documented 
on the respective forms. Account must be given for any discrepancies. 
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each subject, and the disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
investigator will maintain records that document adequately that the subjects were provided 
the doses specified by the CTP, and that reconcile all investigational products received from 
the sponsor. At the time of disposal, the investigator must verify that all unused or partially 
used drug supplies have been returned by the clinical trial subject and that no remaining 
supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is
planned. However, in case of adverse events in need of treatment, the investigator can 
authorise symptomatic therapy. In those cases, subjects will be treated as necessary and, if 
required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
CYP2C19 or 1A2 inhibitors or inducers are not allowed due to their interaction potential with 
BI 409306. Acetylsalicylic acid is not allowed due to potential for CYP2C19 induction.
Ibuprofen may be used as analgesic drug if need be.


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4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 4 h after oral drug intake.
From 1 h before oral drug intake until lunch, fluid intake is restricted to 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 including St. John's wort (Hypericum perforatum) are not 
permitted starting 7 days before the first administration of trial medication until after the last 
PK sample of each study period is collected.
Smoking is not allowed.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 24 h before until 24 h after oral trial medication.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the oral 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.
If female subjects of child bearing potential are included, adequate contraception is to be 
maintained throughout the course of the trial (see Section 3.3.2 for adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/or urinary excretion will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Safety and tolerability of the investigational drug will be assessed based on: 

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)
These parameters will be evaluated in a descriptive way only, and are therefore considered to 
be ‘further parameters of interest’. A confirmatory analysis is not planned (see Section 7.3). 
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have to 
have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the following 
criteria:

results in death, 

is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 


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
requires inpatient hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect, 
or 

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’
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.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
The latest list of ‘Always Serious AEs’ can be found in the eDC (electronic data capture)
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 in chapter 5.2.2.2.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see section 5.2.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/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 


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


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
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AEs collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’ Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
If subjects report a change in perception or any vision-related AE, site staff must record the 
subject’s verbatim description in the source documents to be reported in the eCRF.
A local ophthalmology assessment will be required if any visual AE is rated as severe by the 
subject or at the discretion of the principal investigator. The ophthalmologist will act as a 
consultant to the Investigator and may offer advice on the proper management and treatment 
for the reaction.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs in 
Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report related SAEs and related AESIs of which the investigator 
may become aware of by any means of communication, e.g. phone call. Those 
AEs should, however, not be reported in the CRF.


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Figure 5.2.2.2: 1
Collection of AEs and AESIs
 
The REP refers to 
the oral drug administration. The REP of the BI 409306 (13-C/15-N) is considered to be 
negligible. Therefore, all AEs that occur through the treatment phase and throughout the REP 
will be considered as on treatment (without differentiation of intravenous or oral 
administration); please see Section 7.3.3. Events that occur after the REP until the end of trial 
examination will be considered to be follow-up events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs that are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). The 
same timeline applies if follow-up information becomes available. In specific occasions the 
Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
Upon receipt of any further information relevant to the reported AEs, the investigator is to 
provide a follow-up SAE form to the sponsor. For follow-up information, the same rules and 
timelines apply as for the initial information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. 
The following should also be recorded as an (S)AE in the CRF and on the 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


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If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions.
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 characterised, or no further 
information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in the
clinical trial and has taken trial medication, the investigator must report any drug exposure
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
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).
Pregnancy itself is not an AE. In the absence of an accompanying SAE and/or AESI, only the 
Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be completed. If 
there is an SAE and/or AESI associated with the pregnancy, an SAE form must be completed 
as well.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designee for 
retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, 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. Creatine kinase-MB will only be performed if creatine kinase is increased.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Screening
End-of- trial
Haematology
Haematocrit
Haemoglobin
Red blood cell count /Erythrocytes
White blood cell count /Leucocytes
Platelet count/Thrombocytes/ (quant)
x
x
x
x
x
x
x
x
x
x
Automatic WBC 
differential 
(relative and absolute)
Neutrophils/Leucocytes
Eosinophils/Leucocytes
Basophils/Leucocytes
Monocytes/Leucocytes
Lymphocytes/Leucocytes
x
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 
x
x
x
x
x
x
x
x
Hormones
Thyroid stimulating hormone 
x
-
Substrates
Glucose Plasma
Creatinine 
Bilirubin total
Bilirubin direct
C-Reactive Protein (Quant)
x
x
x
x
x
x
x
x
x
x
Electrolytes
Sodium
Potassium
x
x
x
x
Urinalysis (Stix)
Urine Nitrite (qual)
Urine protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine erythrocytes (qual)
Urine leukocytes (qual)
Urine pH
x
x
x
x
x
x
x
x
x
-
-
-
-
-
-
-
-
-
Urine sediment
(microscopic examination 
if erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (for 
instance, the presence of sediment bacteria, casts 
in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
x
-
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy test and drug screening, it is planned to perform these tests during 
screening only. 
Pregnancy testing in women will be performed at screening, after admission to the trial site on 
day -1, and as part of the end of trial examination. 
Drug screening will be performed at screening and after admission to the trial site on day -1.


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed prior to treatment and may be repeated at 
any time during the study at the discretion of an investigator or designee. The results will not 
be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
 with the exception of 
the drug screening and pregnancy tests. These tests will be performed at the trial site using M-
10/14-PDT test and HCG-K20 test, respectively.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
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 time points given in the Flow Chart.
All ECGs will be recorded for a 10-sec duration after the subjects have rested for at least 5
min in a supine position. ECG assessment will always precede all other study procedures of 
the same time point (except blood drawing from an intravenous cannula which is already in 
place) to avoid impact of sampling on the ECG quality. 
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. ECGs may be repeated for quality reasons (like alternating current
artefacts, muscle movements, electrode dislocation) and the repeated ECG will be used for 
analysis. Additional (unscheduled) ECGs may be collected by the investigator for safety 
reasons. 


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Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) 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. Additional (unscheduled) BP data may be collected 
by the investigator for safety reasons. However, BP measurement on the arm where i.v. drug 
is administered must be avoided during the 30 min infusion period. 
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 
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.
5.2.5.3
Local tolerability
Local tolerability at the injection site will be assessed by the investigator according to 
‘swelling’, ‘induration’, ‘heat’, ‘redness’, ‘pain’, or ‘other findings’ as specified in the 
flowchart.
 
 
 
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic 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 and intravenously administered drug, and are 
widely used in clinical trials. The pharmacokinetic parameters and measurements outlined in 
Section 5.5 are generally used assessments of drug exposure. 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded.
Exact time points of plasma sampling will be derived from the study management system 
ClinBase™ and documented in the CRFs by the medical personnel or sent as electronic files
to the trial data manager. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoint
The following primary endpoints will be determined for BI 409306 and 
BI 409306 (C-13/N-15):

AUC0-∞and Cmax
5.5.1.2
Secondary endpoints
The following secondary endpoints will be evaluated.
For BI 409306 and BI 409306 (C-13/N-15):


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
t1/2 (terminal half-life of the analyte in plasma)

tmax (time from dosing to maximum measured concentration of the analyte in plasma)
For BI 409306 (C-13/N-15):

CL (total clearance of the analyte)

Vz (Apparent volume of distribution during the terminal phase after intravascular 
administration)
For BI 409306

F (absolute bioavailability)
 
 
 
 
 


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
BI 409306
For quantification of BI 409306 plasma concentrations and its metabolites (CD 13896 and 
CD 14084), 4.9 mL of blood will be taken from an antecubital or forearm vein into a K3-
EDTA (tripotassium ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the 
times indicated in the Flow Chart. Blood will be withdrawn by means of either an indwelling 
venous catheter or by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2000 g to 4000 g and at 4 to 8 °C. Three plasma aliquots will be obtained and stored in 
polypropylene tubes. The first and second aliquot should contain at least 0.5 mL plasma
whereas the third aliquot should contain the remaining plasma (0.5 mL or less). The process 
from blood collection until transfer of plasma aliquots into the freezer should be completed 
within 120 minutes, with interim storage of blood samples and aliquots at room temperature.
For each aliquot the time when the sample was placed in the freezer will be documented.
Until transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
about -20°C or below at the trial site. The third aliquot will be transferred to the analytical 
laboratory after the bioanalyst has acknowledged safe arrival of the first and second aliquot.
At the analytical laboratory the plasma samples will be stored at about -20°C or below until 
analysis.
BI 409306 (C-13/N-15)
For quantification of the BI 409306 (C-13/N-15) plasma concentrations, 4.9 mL of blood will 
be taken from an antecubital or forearm vein into a K3-EDTA (tripotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and stored in 
polypropylene tubes. The first aliquot should contain at least 1 mL plasma whereas the second 
aliquot should contain 1 mL or less plasma. The process from blood collection until transfer 
of plasma aliquots into the freezer should be completed within 120 min, with interim storage 
of blood samples and aliquots at room temperature. For each aliquot the time when the sample 
was placed in the freezer will be documented. Until transfer on dry ice to the analytical 
laboratory, the aliquots will be stored upright at about -20°C or below at the trial site. The 
second aliquot will be transferred to the analytical laboratory after the bioanalyst has 
acknowledged safe arrival of the first aliquot. At the analytical laboratory the plasma samples 
will be stored at about -20°C or below until analysis.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, and planned sampling time. Further information such as matrix and 
analyte may also be provided. 


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After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years upon the final study 
report has been signed.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 409306 and the BI 409306 (C-13/N-15) plasma 
concentration
Analyte concentrations in plasma will be determined by validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assays [All details of the analytical method will 
be available prior to the start of sample analysis.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial oral drug administration. 
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 30 min for the first 4 hours after oral drug administration and ± 45 min thereafter.
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 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological
parameters.
For planned individual plasma concentration sampling times refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for determination of pharmacokinetic parameter.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including pregnancy test, drug and virus 
screening), ECG, vital signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
Pharmacogenomic genotyping will be performed in those volunteers whose genotypes are not 
known (for details see Section 5.3).
6.2.2
Treatment period
Each subject is expected to participate in one treatment period (Days -1, 1, and 2). 
On Day -1 study participants will be admitted to the trial site in the evening prior to drug 
administration. Study participants will be kept under close medical surveillance for at least 
24 hours following oral drug administration (Day 1). The subjects will then be allowed to 
leave the trial site after formal assessment and confirmation of their fitness on day 2. 


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Due to the short half-life of BI 409306, end-of-trial examination will take place on day 2. (see 
6.2.3). 
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period
Due to the short half-life of BI 409306, end-of-trial examination will take place on day 2 after 
the last PK sample has been taken. 
For AE assessment, laboratory tests (including pregnancy test in women), recording of ECG 
and vital signs, and physical examination during the end of trial period, see Sections 5.2.2 to 
5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed up 
until they have resolved, have been sufficiently characterised, or no further information can be 
obtained. The end of the trial as a whole is defined by the ‘last regular visit completed by last 
subject’ or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE 
has been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the absolute bioavailability of BI 409306 
by comparing 50 mg of orally administered unlabeled BI 409306 (Test, T ) with 0.1 mg 
intravenously administered stable labeled isotope BI 409306 (C-13/N-15) (Reference, R). The 
trial is designed to allow intra-subject comparisons and will be evaluated statistically by use 
of an appropriate linear model.
The secondary objective is the evaluation and comparison of several pharmacokinetic 
parameters between the formulations. The secondary objectives will be assessed by 
descriptive statistics.
The assessment of safety and tolerability will be an additional objective of this trial, and will 
be evaluated by descriptive statistics.
7.1.2
Endpoints
Absolute bioavailability is to be determined on the basis of the dose normalized primary 
pharmacokinetic endpoints (see Section 5.5.1.1). All pharmacokinetic endpoints (see Section 
5.5.1) will be calculated and analysed descriptively.
Safety and tolerability will be determined on the basis of the parameters specified in Section 
5.2.1.
7.1.3
Model
The statistical model used for the analysis of the primary endpoints will be an ANOVA 
(analysis of variance) model on the logarithmic scale. This model will include effects 
accounting for the following sources of variation: ‘subjects’ and ‘formulation’. The effect 
‘subjects’ will be considered as random, whereas ‘formulation’ will be considered as fixed. 
The model is described by the following equation:
ykm
= + sm + k + ekm, where
ykm
= logarithm of response (dose normalized primary endpoint, see Section 
5.5.1.1) measured on subject m receiving formulation k,

= the overall mean,
sm
= the effect associated with the mth subject m = 1, 2, ..., n
k
= the kth formulation effect (either tablet or i.v.), k = 1, 2,
ekm
= the random error associated with the mth subject who received formulation k.


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7.2
NULL AND ALTERNATIVE HYPOTHESES
The absolute bioavailability of 50 mg of orally administered unlabeled BI 409306 compared 
to 0.1 mg intravenously administered stable labeled isotope BI 409306 (C-13/N-15) will be 
estimated by the ratios of the geometric means (test/reference) for the dose normalized 
primary PK endpoints. Additionally, their two-sided 90% confidence interval (CI) will be 
provided. This method corresponds to the two one-sided t-tests procedure, each at the 5% 
significance level. Since the main focus is on estimation and not testing, an acceptance range 
was not specified, that is, no hypothesis will be tested.
Confidence intervals and p-values will be computed, but have to be interpreted in the 
perspective of the exploratory character of the study, i.e. confidence intervals are considered 
as interval estimates for effects, while p-values are considered as an exploratory measure of 
evidence for effects in the present data.
7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The primary pharmacokinetic endpoints (see Section 5.5.1.1) will be calculated according to 
the BI Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed 
within Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analysis 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 pre-dose concentration is >5% of the Cmax value of that subject 

missing samples/concentration data at important phases of PK disposition curve.


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The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one primary PK parameter that was not excluded according to the description 
above. Thus, a subject will be included in the PKS, even if he/she contributes only one PK 
parameter value for one formulation to the statistical assessment. 
Subjects who are not included in the PKS will be reported with their individual plasma 
concentrations and individual pharmacokinetic parameters; however, they will not be included 
in descriptive statistics for plasma concentrations, pharmacokinetic parameters or other 
statistical assessment.
Concentrations will be used for graphs and calculations in the format that is reported in the 
bioanalytical report. Only concentrations within the validated concentration range and actual 
sampling times will be used for the calculation of PK 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).
Plasma concentrations will be plotted graphically versus time for all subjects as listed in the 
drug plasma concentration-time tables. For the presentation of the mean profiles, the 
arithmetic mean, geometric mean and the planned blood sampling times will be used.
If a pre-dose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidance. The individual pharmacokinetic parameters of such a subject will be calculated and 
listed separately. If a pre-dose concentration is above BLQ, but less than or equal to 5% of the 
subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
Point estimates of bioavailability, the intra-subject ratios of the geometric means 
(test/reference) for the dose normalized primary endpoints (see Section 5.5.1.1), and the 
corresponding two-sided 90% CIs will be provided.
To this end, the dose normalized PK endpoints will be log transformed (natural logarithm) 
prior to fitting the ANOVA model (cf. Section 7.1.3). 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 (LeastSquares Means), and a two-sided 90% CI based on the 
t-distribution will be computed. These quantities will then be back-transformed to the original 
scale to provide the point estimate and 90% CI for each endpoint.
The response variables used in the ANOVA model are the following:
for Cmax: Cmax, norm, po and Cmax, norm,iv
for AUC: AUC0-∞, norm, po and AUC0-∞, norm,iv
The primary analysis will be based on the pharmacokinetic analysis set (see Section 7.3).


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7.3.2
Secondary analyses
As a sensitivity analysis, the ANOVA performed as primary analysis will be repeated with 
subject as fixed effect instead of random effect. The results will be presented in the same 
manner as for the primary analyses.
If an adequate number of PM subjects is reached within the study a subgroup analysis will be 
done for the primary PK endpoints to compare PM subjects with non-PM subjects.
The following descriptive statistics will be calculated for primary and secondary PK 
parameters and for further endpoints: N, arithmetic mean, standard deviation, minimum, 
median, maximum, arithmetic coefficient of variation, geometric mean, and geometric 
coefficient of variation. 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 3 significant digits in the clinical trial report.
The secondary parameters (refer to Section 5.5.1.2) will be calculated according to the BI 
SOP ‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472).
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is, 
all subjects who received at least one dose of study drug), will be included in the safety 
evaluation. Safety analyses will be descriptive in nature and will be based on BI standards.
The analyses will be done by ‘treatment at onset’.
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used for the evaluation of categorical (qualitative) data, and tabulations of descriptive 
statistics will be used to analyse continuous (quantitative) data.
Measurements (such as 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 'screening', those between first trial medication intake until end of the residual 
effect period (see Section 5.2.2.2) will be assigned to the treatment period. Events after the 
residual effect period but prior to next intake or end of trial examination will be summarized 
as ‘follow-up’. These assignments including the corresponding time intervals will be defined 
in detail in the TSAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, intensity and causal relationship of AEs will be tabulated by 
treatment, primary system organ class and preferred term. SAEs and other significant AEs 
(according to ICH E3), and AESIs will be listed separately (see Section 5.2.2.1). 


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Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be flagged. Additionally, differences from baseline (screening measurements) will 
be evaluated.
For vital signs, the differences from baseline (last value before oral drug administration) will 
be evaluated.
Relevant ECG findings will be reported as AEs.
7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
For the analysis of pharmacokinetic parameters please refer to Section 7.3.1.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant Corporate Procedure 
of the Sponsor (001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the pre-dose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit. 
7.5
RANDOMISATION
Randomisation is not applicable in this open-label, single arm, single period clinical study. 
All subjects will receive the same treatment. A list of consecutive subject numbers will be 
provided for procedural reasons (see Section 4.1.2).


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7.6
DETERMINATION OF SAMPLE SIZE
It is planned to enter up to 12 subjects in the trial: 6 subjects with CYP2C19 non-PM status, 
and up to 6 subjects with CYP2C19 PM status. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
As a general rule, no trial results should be published prior to finalisation of the CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 


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personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance auditor 
will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.8.
ClinBaseTM
In the Human Pharmacology Centre (HPC) – Boehringer Ingelheim's Phase I unit – the 
validated ClinBaseTM system is operated for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as data base. Instead of being entered into CRFs, selected data are directly 
entered into the system.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data is entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.


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8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities, i.e. the CA.
8.6
COMPLETION OF TRIAL
The ethics committee / competent authority in each participating EU member state needs to be
notified about the end of the trial (last subject / subject out, unless specified differently in 
Section 6.2.3 of the CTP) or early termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R10-5109
Bliss TVP, Collingridge GL. A synaptic model of memory: long-term 
potentiation in the hippocampus. Nature 1993;361:31-39.
R10-5092
Cooke SF, Bliss TVP. Plasticity in the human central nervous system. Brain 
2006;129:1659-1673.
R10-5102
Reymann KG, Frey JU. The late maintenance of hippocampal LTP: 
requirements, phases, 'synaptic tagging', 'late-associativity' and implications. 
Neuropharmacology 2007;52:24-40.
R15-0594
European Medicines Agency (EMA). ICH guideline M3(R2) on non-clinical
safety studies for the conduct of human clinical trials and marketing 
authorisation for pharmaceuticals: step 5 (December 2009, 
EMA/CPMP/ICH/286/1995). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideli
ne/2009/0 9/WC500002720.pdf (access date: 5 February 2015) ; London: 
European Medicines Agency (EMA) ; 2009.
R15-1442
Calkins ME, Moore TM, Merikangas KR, Burstein M, Saterthwaite TD, 
Bilker WB, et al. The psychosis spectrum in a young U.S. community 
sample: findings from the Philadelphia Neurodevelopmental Cohort. World 
Psychiatry 2014;13 (3) :296-305.
R15-4424
American Psychiatric Association. Diagnostic and statistical manual of 
mental disorders (DSM-5). 5th ed. Arlington: American Psychiatric 
Association; 2013.
R17-1799
Lappin G. Approaches to intravenous clinical pharmacokinetics: recent 
developments with isotopic microtracers. J Clin Pharmacol 2016;56 (1) :11-
23.
R10-5095
Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. 
Alzheimer's Disease International. Global prevalence of dementia: a Delphi 
consensus study. Lancet 2005;366:2112-2117.
R10-5106
Wimo A, Winblad B, Aguero-Torres H, Strauss E von. The magnitude of 
dementia occurrence in the world. Alzheimer Dis Assoc Disord 
2003;17(2):63-67.
R16-5173
The world health report: 2001: mental health: new understanding, new hope. 
http://www.who.int/whr/2001/en/whr01_en.pdf (access date: 10 November 
2016) ; Geneva: World Health Organization; 2001.


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R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
U12-1034-01
A randomised, double-blind,
placebo-controlled (within dose groups) Phase I study to assess the safety,
tolerability and pharmacokinetics of single rising doses 0.5 mg to 500 mg of
BI 409306 administered orally in healthy male volunteers. 1289.1. Clinical 
Trial Report. 19 January 2012
c01694347-09
 BI 409306 in Alzheimer's Disease and Cognitive 
Impairment associated with Schizophrenia. Investigator's Brochure. 01 June 
2017
U13-1182-01
Safety, tolerability, 
pharmacokinetics, and pharmacodynamics of multiple-rising doses of BI 
409306 film-coated tablets given orally q.d. or bid for 14 days in young 
healthy and elderly healthy male/female volunteers (randomised, double-
blind, placebo-controlled within dose groups Phase I study). 1289.2. 
Clinical Trial Report. 20 February 2013
U12-2165-01
 Randomised, double-
blind, placebo-controlled, parallel-group proof of mechanism study to assess 
the pharmacokinetics and to evaluate the pharmacodynamic effect of 
different single oral doses of BI 409306 in healthy male volunteers. 1289.3. 
Clinical Trial Report. 17 September 2012
c02098989-02
Safety, tolerability and 
pharmacokinetics of single oral doses of BI 409306 (tablet) in healthy 
Chinese and Japanese male volunteers and multiple oral doses of BI 409306 
(tablet) in healthy Japanese male volunteers (randomised, double-blind, 
placebocontrolled within dose groups). 1289.4. Clinical Trial Report.
13 March 2014.
c03131799-01
Open, randomised, two-way 
crossover study to assess the effect of a high fat, high caloric meal on the 
pharmacokinetics of BI 409306, followed by a fixed sequence period to 
investigate the pharmacokinetics of BI 409306 after a single oral dose given 
at bed time in healthy male and female volunteers. 1289.22. Clinical Trial 
Report. 10 September 2015


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c03183204-01
 Open-label, randomised, two-way 
crossover study to assess the effect of once daily Itraconazole on the 
pharmacokinetics of BI 409306 after a single oral dose in healthy male 
volunteers genotyped as poor and extensive metabolisers of CYP2C19.
1289.23. Clinical Trial Report. 14 August 2015
c09564954-01
 A study to investigate the 
pharmacokinetic drug-drug interaction following oral administration of 
BI 409306 and donepezil in healthy male and female subjects. 1289.24. 
Clinical Trial Report. 29 November 2016
c03808525-02
A randomized, double-blind, double 
dummy, placebo-controlled, three-way crossover study to assess cardiac 
effects after single oral doses of BI 409306 under resting and exercise 
conditions in healthy male volunteers. 1289.28. Clinical Trial Report.
04 September 2017.
c13128239-01
 Influence of fluvoxamine on the 
pharmacokinetics of BI 409306 after oral administration (randomized, open-
label, two-treatment, two-sequence, two-period crossover study). 1289.35.
Clinical Trial Report. 19 July 2017
c18976961
Effect of rifampicin on 
the pharmacokinetics of BI 409306 following oral administration in healthy 
male subjects (an open-label, two-period, fixed sequence trial). 1289.44. 
Clinical Trial Report, Draft Report available.
c09055140-01
Metabolism and 
pharmacokinetics of [14C]-BI 409306 after administration of 25 mg [14C]-
BI 409306 as oral solution in healthy male volunteers. 1289.26. Clinical 
Trial Report. 27 September 2016


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10.
APPENDICES
Section 10.1 and 10.2 provides information on preparation of the intravenous stable labeled
isotope BI 409306 (C-13/N-15) for infusion and its application.
10.1
DRUG SUPPLY AND EQUIPMENT
10.1.1
Drug supply
BI 409306 (C-13/ N-15) solution for infusion is an intravenous solution consisting of 6 mL of 
a sterile, clear, colourless solution, containing 0.1 mg/mL BI 409306 BS (C-13/N-15), and 
presented in a colourless glass vial sealed with a rubber stopper and an aluminum flip-off seal. 
10.1.2
Disposables
Material
REF
Company
Mini-Spike®  1)
4550242
B Braun
Omnifix® 10 mL Luer Lock Solo  2)
4617100V
B Braun
Original Perfusor® Line 
Type: IV-Standard-PE, Luer Lock 150 cm  3)
8722935
B Braun
Discofix®3SC  4)
4095111
B Braun
Introcan Safety® W Winged-FEP 18G 5)
4254562-01
B Braun
Combi-Stopper6)
4495101
B Braun
1) Mini-Spike is a vented dispensing pin for withdrawing fluids from medication vials. Its 
integrated air-venting channel makes pressure-balancing techniques unnecessary.
2) Omnifix 10 mL ,Luer Lock Solo – is a hypodermic syringe for single use with Luer Lock 
connection to allow the connection with the Perfusor® line.
3) Original Perfusor® Line – tube for use with syringe pump “Perfusor® fm”
4) Dicofix®3SC is a stopcock system with axially and radially movable swivel lock for secure 
and speedy connection.
5) Introcan Safety® is an intravenous catheter with protection against needlestick injuries.
6) Combi-Stopper: sterile closing
Please note: only CE certified disposables are to be used.
10.1.3
Technical equipment


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10.2
HANDLING INSTRUCTION
10.2.1
Overview
Prior to intravenous drug administration, 6 mL of the solution is withdrawn from the vials into 
a syringe “Omnifix® 10 mL Luer Lock Solo”. The application system is flushed with the 
solution for infusion.
Subsequently, 1 mL (i.e. 0.1 mg) of solution for infusion is administered over 30 minutes. 
Residual solution for infusion is discarded. 
The following description provides a step by step instruction.
10.2.2
Preparation of i.v. solution for continuous infusion via syringe pump
Step 1: Remove the flip-off seal from the glass vial containing BI 409306 BS
(C-13/N-15)
Step 2: Attach the Minispike® on the vial and mount the Omnifix® 10 mL Luer Lock 
Solo
Step 3: Withdraw 6 ml i.v. solution completely 
Step 4: Disconnect the syringe from the Minispike®
Step 5: Remove air bubbles from the Omnifix® 10 mL Luer Lock Solo if applicable 
Step 6: Connect the Perfusor® line with the filled Omnifix® 10 mL Luer Lock Solo
Step 7: Connect the Discofix®3SC at the end of the Perfusor® line
Step 8: Remove the air from the Perfusor® line by pushing the syringe plunger and fill 
the Perfusor® line and the Discofix®3SC completely with i.v. solution.
Step 9: Put a Combi-Stopper to the Discofix®3SC for safe storage of the system until 
administration 
Step 10: Place the filled Omnifix® 10 mL Luer Lock Solo into the syringe pump 
Perfusor® fm
Step 11: Flush the Perfusor® line with 1 mL via Perfusor® fm
Step 12: Enter administration data into syringe pump Perfusor® fm: 
              1 ml solution is to be administered over 30 min. 
Please note: The deadspace volume of  Introcan Safety® W Winged-FEP 18G was 
determined as 0.1 mL. Therefore, the volume settings at the syringe pump must be 
increased from 1.0 mL to 1.1 mL (infusion duration 30 minutes).
The solution for infusion is ready for administration.
10.2.3
In-use stability
After withdrawal of i.v. solution from the glass vial, storage of vial and solution in the 
Omnifix® 10 mL Luer Lock Solo (including filled Perfusor® line ) is allowed for 24 hours at 


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room temperature. Vial and syringe shall be protected from direct sun exposure. No additional 
light protection measures are required. 
10.2.4
Mode of application
The vials are for single use only. Remnants in vial and syringe must be discarded. 
10.2.5
General remarks – important
The solution in the vial is ready for use. Because of lacking analytical coverage beyond the 
preparation procedure described in this document, no further dilutions of the solution is 
allowed.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
24 April 2018
EudraCT number
2017-004798-14
BI Trial number
1289-0025
BI Investigational Product(s)
BI 409306
Title of protocol
Absolute bioavailability and pharmacokinetics of 
BI 409306 using a single oral dose of BI 409306 
co-administered with an intravenous stable 
labeled isotope BI 409306 (C-13/N-15) in healthy 
male and female subjects (Non-Randomised, 
open-label, single arm, single period design)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1.
5.5.2.1
2.
4.1.4
Description of change
1.
The term “dipotassium”was 
replaced with the correct term 
“tripotassium”
2.
Clarification of position after oral 
drug administration
Rationale for change
1.
Correction
2.
Correction


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BI Trial No.: 1289-0025
c09116705-03
Trial Protocol
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001-MCS-40-106-RD-13 (5.0) / Saved on: 15 Jul 2014
Number of global amendment
2
Date of CTP revision
04 May 2018
EudraCT number
2017-004798-14
BI Trial number
1289-0025
BI Investigational Product(s)
BI 409306
Title of protocol
Absolute bioavailability and pharmacokinetics of 
BI 409306 using a single oral dose of BI 409306 
co-administered with an intravenous stable 
labeled isotope BI 409306 (C-13/N-15) in healthy 
male and female subjects (Non-Randomised, 
open-label, single arm, single period design)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1.
10.2.2
2.
3.3.3
Description of change
1.
Information of amount of 
deadspace volume of 
intravenous cather was 
inserted
2.
In exclusion criterion 12 
the missing last word
( “drug” ) was added 
already in the context of 
global amendment No 1 but 
not listed on the description 
of changes.  
Rationale for change
1.
Clarification 
2.
Correction


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09116705
3.0
clinical-trial-protocol-revision-2
Absolute bioavailability and pharmacokinetics of BI 409306 using a single oral dose
of BI 409306 co-administered with an intravenous stable labeled isotope BI 409306
(C-13/N-15) in healthy male and female subjects (Non-Randomised, open-label,
single arm, single period design)
Author-Trial Statistician
07 May 2018 11:34 CEST
Author-Clinical Pharmacokineticist
07 May 2018 11:39 CEST
Approval-Therapeutic Area
07 May 2018 12:32 CEST
Author-Trial Clinical Monitor
07 May 2018 14:46 CEST
Verification-Paper Signature
Completion
07 May 2018 17:44 CEST
Approval-Team Member Medicine
09 May 2018 16:44 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09116705
3.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c23833856-01
BI Trial No.:
1289-0025
Title:
Absolute bioavailability and pharmacokinetics of BI 409306 using a
single oral dose of BI 409306 co-administered with an intravenous 
stable labeled isotope BI 409306 (C-13/N-15) in healthy male and 
female subjects (Non-Randomised, open-label, single arm, single
period design)
Investigational
Products:
BI 409306
Responsible trial 
statisticians:
Phone:
Fax:
Phone:
Fax:
Date of statistical 
analysis plan:
26 JUN 2018 SIGNED
Version:
FINAL
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2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
5.3
FURTHER ENDPOINTS.....................................................................................9
5.4
OTHER VARIABLES........................................................................................10
5.4.1 
Demographic and other baseline characteristics .............................................10
5.4.2
Pharmacogenomic evaluation............................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATION......................................................12
6.3
PATIENT 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 ...................15
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...........................................................................................21
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse events.....................................................................................................21
7.8.2
Laboratory data ..................................................................................................23
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 of AEs, safety laboratory data 
and vital signs as well as demographics...........................................................11
Table 6.1: 2
Overview of treatments for intra-individual comparison.................................11
Table 6.2: 1
Important protocol violations...........................................................................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
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
BI
Boehringer Ingelheim
BWU
Bioavailability/Bioequivalence, within-subject design, uncontrolled w.r.t 
time
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case report form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DILI
Drug induced liver injury
DNA
Desoxyribonucleic acid
ECG
Electrocardiogram 
EudraCT
European Union Drug Regulating Authorities Clinical Trials
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference on Harmonisation
iv
intravenous
LLT
Lower level term
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number non-missing observations
O*C
Oracle Clinical


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Term
Definition / description
PK
Pharmacokinetics
PKS
PK parameter analysis set
PM
Poor metabolizer
po
Per os
PT
Preferred term
PV
Protocol violation
qd
Quaque die (daily)
R
Reference treatment
RAGe
Report Appendix Generator system
REP
Residual effect period
RPM
Report planning meeting
SAS®
Statistical Analysis System
SD
Standard deviation
SOC
System organ class
T
Test treatment
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary
XPKISTAT
Library of SAS® Macros for PK analysis


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This Trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP). 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, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SAS® (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 5.5.1.1 of the CTP: The following primary endpoints will be determined for 
BI 409306 and BI 409306 (C-13/N-15):

AUC0-∞and Cmax
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
Secondary endpoints are pharmacokinetic parameters. For more details see CTP Section 
5.5.1.2.
5.3
FURTHER ENDPOINTS
 
Safety:
Section 5.2.1 of the CTP: Safety and tolerability of the investigational drug will be assessed 
based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)

Local tolerability
Section 5.2.1 of the CTP: These parameters will be evaluated in a descriptive way only, and 
are therefore considered to be ‘further parameters of interest’. A confirmatory analysis is not 
planned.


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5.4
OTHER VARIABLES
5.4.1 
Demographic and other baseline characteristics
Section 5.2.5.2 of the CTP: At screening, the medical examination will include 
demographics including height and body weight, smoking and alcohol history, relevant 
medical history and concomitant therapy […].
Age [years] will be determined as the difference between year of informed consent and year 
of birth.
BMI will be calculated as weight [kg] / (0.01 * height [cm])2.
5.4.2
Pharmacogenomic evaluation
Section 5.3.1 of the CTP: [..] a sample of at most 10 mL of blood will be taken at the 
screening examination if a subject’s CYP2C19 genotype has not been previously determined. 
Pharmacogenetic results of CYP2C19 will be included in the final report. 
If a separate informed consent is signed, the extracted DNA of this sample will be used to 
determine a panel of genes coding for proteins that are involved in the Absorption,
Distribution, Metabolism and Excretion (ADME) of drugs. The panel contains a list of known
and likely functional variations present in key genes and covers more than 90% of the current
ADME related genetic markers as defined by the PharmaADME group
(website.pharmaadme.org). It is not intended to include these data in the final report.
However, the data may be part of the report if necessary.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatments, and 
selection of doses, please see CTP, Sections 3 and 4.
The study will be performed as a non-randomised, open-label, single arm, single period trial 
with 2 treatments (T and R). 
In total, it was planned to assign up to 12 healthy male and female subjects (6 subjects with 
CYP 2C19 non-PM status and up to 6 subjects with 2C19 PM status).
For details of dosage and formulation see Table 6.1: 1 and Table 6.1: 2 below:
Table 6.1: 1
Treatments and labels used in the analysis of AEs, safety laboratory data and 
vital signs as well as demographics
Treatment
Short label
A
BI 409306 50mg tab + 0.1mg i.v.
BI tab + iv
Table 6.1: 2
Overview of treatments for intra-individual comparison
Treatment
Short label
T
BI 409306, 50 mg tablet, qd
BI 50mg tab
R
BI 409306 (C-13/N-15), 0.1 mg/mL i.v. 
solution 0.1 mg, qd
BI 0.1mg iv
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 (including residual effect period (REP); 

Follow-up (ranging from end of on treatment phase until 0:00 h on the day after trial
termination date)
Displays of AEs will be presented without differentiation of intravenous or oral 
administration during on treatment phase.


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Two types of AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT 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. 
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of the 
CTR displays:

Screening 

On treatment (labelled with the name of the study treatment (short label))

Follow-up
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:

a total over all study phases ("Total")
Tables of vital signs and laboratory values will present results by the above mentioned on
treatment phase.
For detailed information on the handling of the treatments in the O*C views refer to 
Technical TSAP ADS plan. In particular, AEs will be counted for treatment if they occur up 
to the end of the residual effect period (REP) of 24 hours after oral administration.
6.2
IMPORTANT PROTOCOL VIOLATION
Data discrepancies and deviations from the CTP will be identified for all randomised
subjects. Listings of protocol deviations and of unresolved discrepancies will be provided to 
be discussed at the combined report planning and database lock meeting (RPM/DBLM), e.g. 
deviations in drug administration, in blood sampling etc. At this meeting, it will be decided 
whether the discrepant data can be used as they are or whether the data have to be corrected 
in the clinical database.
Each protocol deviation must be assessed to determine whether it is an important protocol 
violation. A protocol violation (PV) is important if it affects the rights or safety of the study 
subjects or if it can potentially influence the primary outcome measure(s) for the respective 
subjects in a way that is neither negligible nor in accordance with the study objectives. This 
last category of important PV forms the basis for the decision of whether a subject does or 
does not belong to an analysis set. PVs that do not influence the subject's rights and safety or 
the evaluability of the subjects for the main study objectives are called non-important PVs. 
These are only considered when checking the trial quality in general.
If any important PVs are identified, they are to be summarised into categories and will be 
captured in the RPM/DBLM minutes via an accompanying Excel spreadsheet [001-MCS-50-


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413_RD-02] (2). The following table contains the categories which are considered to be 
important protocol violations in this trial. If the data show other important PVs, this table will 
be supplemented accordingly by the time of the RPM/DBLM.
Table 6.2: 1
Important protocol violations
Category
/Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C2
Non-compliance
D
Concomitant medication
D1
Concomitant medication with the potential to affect the assessment of the trial 
medication
E
Missing data 
E1
Certain violations of procedures used to measure primary data
F
Incorrect timing1
F1
Certain violations of time schedule used to measure primary data
G
Other trial specific important violations
G1
PVs affecting safety and rights
1 Time deviations will only be flagged as important PV, when leading to exclusion of the entire subject from an analysis set
Source: ‘Protocol Violation Handling Definitions’ [001-MCS-50-413_RD-01] (3)


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6.3
PATIENT SETS ANALYSED

Treated set (TS):
This subject set includes all subjects who were documented to have received 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 7.3.1 of the CTP: Plasma concentration data and parameters of a subject will be 
included in the statistical pharmacokinetic (PK) analysis 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 experiences emesis that occurred at or before 2 times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

a pre-dose concentration is >5% Cmax value of that subject

missing samples/concentration data at important phases of PK disposition curve

PK parameter analysis set (PKS): 
This subject set includes all subjects from the TS who provide at least one primary PK 
parameter that was not excluded according to the description above. Thus, a subject will 
be included in the PKS, even if he/she contributes only one PK parameter value for one 
formulation to the statistical assessment.
The descriptive analysis of PK concentrations will be based on the analysis data set (ADS) 
ADPC as described at the beginning of Section 7.


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Table 6.3: 1
Subject sets analysed
Analysis set
Class of endpoint
TS
PKS
Analyses of PK endpoints 
X
Safety endpoints 
X
Demographic/baseline endpoints
X
Important protocol violations
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
Data of screened subjects who were withdrawn from the trial prior to first administration of 
any study drug will not be reported in the CTR.
Handling of missing data and outliers will be performed as described in the CTP, Section 7.4.
The only exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (5).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For vital signs and laboratory parameters the baseline is defined as the last measurement prior 
to first study drug administration.
Section 6.1 of the CTP: Exact times of measurements outside the permitted time windows 
will be documented. The acceptable time windows for screening and end-of-trial examination 
are given in the CTP Flow Chart.


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Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial oral drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 30 min for the first 4 hours after oral drug administration and ± 45 min thereafter.
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 BI and 
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.
The individual values of all subjects will be listed, sorted by treatment, subject number and
visit. The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations 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
The descriptive statistics of PK parameters will be calculated using the individual values with 
the number of decimal places as provided by the evaluation program. Then the individual 
values as well as the descriptive statistics will be reported with three significant digits in the 
CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment group. Percentages will be rounded to one decimal place and will be based on all 
subjects in the respective subject set whether they have non-missing values or not. The 
category 'missing' will be displayed only if there are actually missing values.


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Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
Exclusion of PK parameters
The ADS ADPP (PK parameters) contains column variables APEXC and APEXCO
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for 
exclusion, that is 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 or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’ the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (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 for both formulations together (BI tab + iv).
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.


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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 and/or urinary excretion 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
Absolute bioavailability is to be determined on the basis of the dose normalized primary
pharmacokinetic endpoints (see Section 5.1). 
Primary analysis
The statistical model used for the analysis of the primary endpoints will be an ANOVA
(analysis of variance) model on the logarithmic scale. This model will include effects 
accounting for the following sources of variation: ‘subjects’ and ‘formulation’. The effect 
‘subjects’ will be considered as random, whereas ‘formulation’ will be considered as fixed.
The model is described by the following equation:
ykm = µ + sm + τk + ekm, where
ykm = logarithm of response (dose normalized primary endpoint, see Section 5.1) 
measured on subject m receiving formulation k,
µ = the overall mean,
sm = the effect associated with the mth subject m = 1, 2, ..., n
τk = the kth formulation effect (either tablet or i.v.), k = 1, 2,
ekm = the random error associated with the mth subject who received formulation k.
The implementation for this analysis will be accomplished by using the XPKISTAT macro, 
based on PKS, and option BWU (Bioavailability/Bioequivalence, within-subject design, 
uncontrolled w.r.t. time).
Section 7.3.1 of the CTP: […] the dose normalized PK endpoints will be log transformed 
(natural logarithm) prior to fitting the ANOVA model […] For each endpoint, the difference 


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between the expected means for log(T)-log(R), will be estimated by the difference in the 
corresponding adjusted means (Least Squares Means), and a two-sided 90% confidence 
interval (CI) based on the t-distribution will be computed. These quantities will then be back-
transformed to the original scale to provide the point estimate and 90% CIs for each 
endpoint. 
The response variables used in the ANOVA model are the following:
for Cmax: Cmax, norm, po and Cmax, norm,iv
for AUC: AUC0-∞, norm, po and AUC0-∞, norm,iv
Further analysis
Section 7.3.2 of the CTP: As a sensitivity analysis, the ANOVA performed as primary 
analysis will be repeated with subject as fixed effect instead of random effect. The results will 
be presented in the same manner as for the primary analyses.
Furthermore, the input dataset will be restricted in such a way that treatments not relevant for 
the comparison of interest will be deleted. 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; 
MODEL logkp = treatment subject; 
LSMEANS treatment / PDIFF=CONTROL(“Ref_trt”) CL ALPHA=0.1; 
RUN;
Section 7.3.2 of the CTP: If an adequate number of PM subjects is reached within the study 
a subgroup analysis will be done for the primary PK endpoints to compare PM subjects with 
non-PM subjects.
This subgroup analysis will be done using the same model and parameters as for the primary 
analysis but including the PM status as a covariate (fixed effect).
The implementation for this analysis will be accomplished by using the XPKISTAT macro, 
based on PKS, option BWU (Bioavailability/Bioequivalence, within-subject design, 
uncontrolled w.r.t. time), and CLASSFIX=PM status.
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.


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7.5.2
Secondary endpoints
Descriptive statistics of plasma concentrations and PK endpoints will be done by department 
Translational Medicine and Clinical Pharmacology at BI and will be presented in 
Section 15.6 of the CTR.
The analysis of PK parameters as well as the tables and graphs for the pharmacokinetic non-
compartmental analyses will follow specific definitions of this TSAP or, otherwise, the BI 
standard procedure “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics” [001-MCS-36-472] (7).
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).


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The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:

All AE attributes are identical (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 
2 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 5.2.2.1 of the CTP: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/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 5.2.2.2 of the CTP:
 
 
The REP refers to the oral drug administration. The REP of the BI 409306 (13-C/15-
N) is considered to be negligible. Therefore, all AEs that occur through the treatment phase 
and throughout the REP will be considered as on treatment (without differentiation of 
intravenous or oral administration) […].


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All adverse events occurring before first drug administration will be assigned to ‘screening’, 
those between intake of trial medication and end of the 24-hour REP will be assigned to
treatment (‘on treatment’). AEs occurring after the REP but prior to termination date will be 
assigned to ‘follow-up’. 
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 = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant
therapy as identified by the Clinical Monitor/Investigator at the Report Planning Meeting. 
An overall summary of AEs (including AESIs) will be presented.
The frequency of subjects with AEs will be summarised by treatment (BI tab + iv), 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. The MedDRA version number will be 
displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
Descriptive statistics will be calculated for screening and post examination visits as well as 
for the difference from baseline (=screening). The summary statistics will be provided in 
total. 
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 clinically 
relevant will be flagged in the data listings.
Frequency tables of changes with respect to the reference range between screening and post 
examination will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator’s comments on the eCRF or at the RPM/DBLM at the latest. It is the 
investigator's responsibility to decide whether a lab value is clinically significantly abnormal 


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or not. Standard or project-specific rules for flagging clinically significant values will not be 
applied in this study.
The analyses of laboratory data will be based on BI standards [001-MCG-157] (10).
7.8.3
Vital signs
Descriptive statistics over time and for the changes from baseline will be performed for vital 
signs (blood pressure and pulse rate) for both formulations together (BI tab + iv).
Section 7.3.3 of the CTP: For vital signs, the differences from baseline (last value before 
oral drug administration) will be evaluated.
In the listing the difference from baseline will also be displayed.
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 adverse events 
(when they occurred during treatment).
7.8.5
Others
Local tolerability
Local tolerability at the injection site will be assessed by the investigator according to
‘swelling’, ‘induration’, ‘heat’, ‘redness’, ‘pain’, or ‘other findings’.
A frequency table using the worst assessment will be provided.


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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-50-413_RD-02: “Important Manual Protocol Violations Spreadsheet”, current 
version, IDEA for CON.
3
001-MCS-50-413_RD-01: “Protocol Violation Handling Definitions”, current version, 
IDEA for CON.
4
001-MCG-156_RD-01: “Handling of Missing and Incomplete AE Dates”, current 
version; IDEA for CON.
5
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic
Analyses of Clinical Studies”, current version; IDEA for CON.
6
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current version; 
IDEA for CON.
7
001-MCS-36-472: "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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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
26-JUN-18
None
This is the final TSAP without any 
modification