Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 14
Healthy volunteers: yes

Brief summary:
Investigate the relative bioavailability of BI 894416 as tablet formulation following a high-fat, high calorie breakfast (Test, T) compared with administration in the fasting state (Reference, R)

Detailed description:

Arms:
arm 1: 3 tablets with 10 milligram (mg) of BI 894416 (total: 30 mg) were administered as one single oral dose with 240 milliliter (mL) of water after a high-fat, high-calorie meal (fed conditions) as test treatment (T). arm 2: 3 tablets with 10 milligram (mg) of BI 894416 (total: 30 mg) were administered as one single oral dose with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (fasted conditions) as reference treatment (R).

Interventions: intervention 1: BI 894416
Intervention descriptions: intervention 1: 3 tablets with 10 milligram (mg) of BI 894416 (total: 30 mg) were administered as one single oral dose with 240 milliliter (mL) of water.

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c23506058-03
EudraCT No.
2018-004313-41
BI Trial No.
1371-0021
BI Investigational
Medicinal Product
BI 894416
Title
Relative bioavailability of BI 894416 as tablet formulation 
following a high-fat, high-calorie breakfast compared to 
administration in the fasting state in healthy male subjects 
(an open-label, randomised, single-dose, two-period, two-
sequence crossover study)
Lay Title
A study in healthy men to test whether food affects the amount of 
BI 894416 in the blood
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
Principal 
Investigator
Phone: 
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0
Date: 15 May 2019
Page 1 of 61
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© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
15 May 2019
Revision date
Not applicable
BI trial number
1371-0021
Title of trial
Relative bioavailability of BI 894416 as tablet formulation following a high-fat, 
high-calorie breakfast compared to administration in the fasting state in healthy 
male subjects (an open-label, randomised, single-dose, two-period, two-sequence 
crossover study)
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
This clinical trial will be performed to investigate the effect of food on 
bioavailability (assessed as relative bioavailability comparison of fed vs. fasting 
state) of BI 894416 as tablet formulation.
Trial objective
The main objective of this trial is to investigate the relative bioavailability of 
BI 894416 as tablet formulation following a high-fat, high calorie breakfast (Test, 
T) compared with administration in the fasting state (Reference, R).
Trial design
Randomised, open-label, two-way crossover design
Trial endpoints:
Primary endpoints: AUC0-tz and Cmax of BI 894416
Secondary endpoints: AUC0-of BI 894416
Number of subjects 
total entered
14
each treatment
14
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 50 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product
BI 894416 10 mg tablet
dose
30 mg


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mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h (treatment 
“Reference” (R)) or after a high-fat, high-calorie breakfast (treatment “Test” (T))
Duration of treatment
One day (single dose) for each treatment
Statistical methods
Relative bioavailability will be estimated by the ratios of the geometric means 
(test/reference) for the primary and secondary endpoints. Additionally, their two-
sided 90% confidence intervals (CIs) will be provided. This method corresponds to 
the two one-sided t-test procedure, each at a 5% significance level. Since the main 
focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified. The statistical model will be an analysis of 
variance (ANOVA) on the logarithmic scale including effects for sequence, subjects 
nested within sequences, period and treatment. CIs will be calculated based on the 
residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to 
drug administration)
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory8
PK blood
12-lead ECG
Neurological Examination7
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
A
x
x
x
1/2 (two identical periods separated by a wash-out interval of at least 5
days)
2/3
-5 to -1
-122:00
06:00
Ambulatory visit9
C9
x9
1
-2:00
06:00
Allocation to treatment2 (visit 2 
only)
x2,5
x2
x2
x2
x2
-0:30
07:30
High fat, high calorie breakfast 
(treatment T, only)
0:00
08:00
Drug administration
0:15
08:15
x
0:30
08:30
x
0:45
08:45
x
1:00
09:00
x
x
x
x
1:30
09:30
x
2:00
10:00
240 mL fluid intake
x
x
x
x
2:30
10:30
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
5:00
13:00
x
6:00
14:00
x
7:00
15:00
Snack (voluntary)3
8:00
16:00
x
10:00
18:00
Dinner3
x
12:00
20:00
x
x
2
24:00
08:00
Discharge from trial site, breakfast 
(voluntary)3
B
x
x
x
x
34:00
18:00
Ambulatory visit
x
x
3
48:00
08:00
Ambulatory visit
x
x
FU
4
8 to 15
End of trial (EoTrial) examination4
B
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, neurological examination, check of vital signs, ECG, safety laboratory 
(including drug screening), demographics (including determination of body height and weight, smoking status and 
alcohol history), 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 the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial (EoTrial) visit, the EoTrial examination includes physical examination, neurological examination, 
vital signs, ECG, safety laboratory, recording of AEs and concomitant therapies.
5.
Only urine drug screening and alcohol breath test will be done at this time
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
Unscheduled neurological examinations may be added at any time during the trial for individual volunteers or the whole 
treatment group, e.g., in case of neurological adverse events, if assessed as necessary by the investigator.
8.
Letters A, B, and C define different sets of safety laboratory examinations (see Section 5.2.3)
9.
Safety laboratory to be taken and to be medically evaluated within 5 days (within ~122 hours) prior to administration of 
study drug; this ambulatory visit including safety laboratory and adverse event questioning can be omitted if the 
screening examination is performed on Days -5, -4, -3, -2, or -1. Only prior to visit 2.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................5
ABBREVIATIONS.............................................................................................9
1.
INTRODUCTION.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILE...............................................................................................12
1.2.1
Residual Effect Period..........................................................................13
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................13
1.4
BENEFIT - RISK ASSESSMENT ...................................................................13
1.4.1
Expected benefit to the target population...........................................13
1.4.2
Procedure-related risks ........................................................................14
1.4.3
Drug-related risks and safety measures..............................................14
1.4.4
Overall assessment of benefit-risk ratio..............................................17
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 19
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......19
2.1.1
Main objectives......................................................................................19
2.1.2
Primary endpoints ................................................................................19
2.1.3
Secondary endpoint ..............................................................................19
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 21
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................21
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................21
3.3
SELECTION OF TRIAL POPULATION ......................................................21
3.3.1
Main diagnosis for trial entry..............................................................21
3.3.2
Inclusion criteria...................................................................................21
3.3.3
Exclusion criteria ..................................................................................22
3.3.4
Withdrawal of subjects from treatment or assessments ...................23
3.3.4.1
Discontinuation of trial treatment............................................24
3.3.4.2
Withdrawal of consent to trial participation ............................24
3.3.4.3
Discontinuation of the trial by the sponsor..............................24


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3.3.5
Replacement of subjects .......................................................................25
4.
TREATMENTS........................................................................................ 26
4.1
INVESTIGATIONAL TREATMENTS ..........................................................26
4.1.1
Identity of the Investigational Medicinal Products ...........................26
4.1.2
Selection of doses in the trial................................................................26
4.1.3
Method of assigning subjects to treatment groups ............................26
4.1.4
Drug assignment and administration of doses for each subject .......27
4.1.5
Blinding and procedures for unblinding ............................................28
4.1.6
Packaging, labelling, and re-supply ....................................................28
4.1.7
Storage conditions.................................................................................28
4.1.8
Drug accountability ..............................................................................29
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................29
4.2.1
Other treatments and emergency procedures....................................29
4.2.2
Restrictions............................................................................................29
4.2.2.1
Restrictions regarding concomitant treatment .........................29
4.2.2.2
Restrictions on diet and life style.............................................30
4.3
TREATMENT COMPLIANCE.......................................................................30
5.
ASSESSMENTS....................................................................................... 31
5.1
ASSESSMENT OF EFFICACY Not applicable..............................................31
5.2
ASSESSMENT OF SAFETY............................................................................31
5.2.1
Physical examination ............................................................................31
5.2.2
Vital signs...............................................................................................31
5.2.3
Safety laboratory parameters..............................................................31
5.2.4
Electrocardiogram................................................................................33
5.2.5
Other safety parameters.......................................................................34
5.2.5.1
Neurological examination........................................................34
5.2.6
Assessment of adverse events...............................................................35
5.2.6.1
Definitions of adverse events...................................................35
Adverse event ............................................................35
5.2.6.1.1
Serious adverse event ................................................35
5.2.6.1.2
AEs considered ‘Always Serious’.............................35
5.2.6.1.3
Adverse events of special interest .............................36
5.2.6.1.4
Intensity (severity) of AEs.........................................37
5.2.6.1.5
Causal relationship of AEs ........................................37
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................38
AE collection.............................................................38
5.2.6.2.1
AE reporting to the sponsor and timelines ................39
5.2.6.2.2
Information required..................................................39
5.2.6.2.3
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................39
5.3.1
Assessment of pharmacokinetics .........................................................39
5.3.2
Methods of sample collection...............................................................39


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5.3.2.1
Blood sampling for pharmacokinetic analysis.........................39
5.3.3
Analytical determinations ....................................................................40
5.3.3.1
Analytical determination of analyte plasma concentration......40
5.4
BIOBANKING ...................................................................................................40
5.5
OTHER ASSESSMENTS .................................................................................40
5.5.1
Pharmacogenomic evaluation..............................................................40
5.6
APPROPRIATENESS OF MEASUREMENTS.............................................40
6.
INVESTIGATIONAL PLAN.................................................................. 42
6.1
VISIT SCHEDULE............................................................................................42
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................42
6.2.1
Screening period....................................................................................42
6.2.2
Treatment periods.................................................................................42
6.2.3
Follow-up period and trial completion ...............................................43
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 44
7.1
STATISTICAL DESIGN – MODEL ...............................................................44
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................44
7.3
PLANNED ANALYSES....................................................................................44
7.3.1
Primary endpoint analyses...................................................................46
7.3.2
Secondary endpoint analyses ...............................................................47
7.3.4
Safety analyses.......................................................................................47
7.4
INTERIM ANALYSES .....................................................................................48
7.5
HANDLING OF MISSING DATA ..................................................................48
7.5.1
Safety......................................................................................................48
7.5.2
Pharmacokinetics..................................................................................49
7.6
RANDOMISATION ..........................................................................................49
7.7
DETERMINATION OF SAMPLE SIZE ........................................................49
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 51
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................51
8.2
DATA QUALITY ASSURANCE .....................................................................52
8.3
RECORDS..........................................................................................................52
8.3.1
Source documents .................................................................................52
8.3.2
Direct access to source data and documents.......................................53
8.3.3
Storage period of records.....................................................................53
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................54
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......54


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8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................54
8.6
TRIAL MILESTONES .....................................................................................54
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................55
9.
REFERENCES......................................................................................... 56
9.1
PUBLISHED REFERENCES...........................................................................56
9.2
UNPUBLISHED REFERENCES.....................................................................57
10. APPENDICES .......................................................................................... 58
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 59
11.1
GLOBAL AMENDMENT 1 .............................................................................59
11.2
GLOBAL AMENDMENT 2 – NOT APPLICABLE......................................60


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ALCOA
Attributable, legible, contemporaneous, original, and accurate
ANOVA
Analysis of variance
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 h
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BCS
Biopharmaceutics classification system
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
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, paper or electronic (sometimes referred to as ‘eCRF’)
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP3A
Cytochrome P450 subfamily 3A
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EEG
Electroencephalography
EoTrial
End of trial
EudraCT
European Clinical Trials Database
FU
Follow-up


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GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
HPC
Human Pharmacology Centre
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IPD
Important protocol deviation
IQRMP
Integrated quality and risk management plan
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRT,ex
Mean residence time of the analyte in the body, extravascular
NK
Natural killer
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
SYK
Spleen tyrosine kinase
T
Test product or treatment
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan


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ULN
Upper limit of normal
UV
Ultraviolet
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WHO
World Health Organization
WOCBP
Woman of child bearing potential
XTC
Ecstasy 
ZAP70
Zeta-chain-associated protein kinase of 70 kDa


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1.
INTRODUCTION
BI 894416 is an oral, selective non-receptor protein tyrosine kinase SYK (spleen tyrosine 
kinase) inhibitor under clinical development for the indication of uncontrolled severe asthma.
This trial will be performed to investigate the relative bioavailability of BI 894416 in plasma 
when given after a high-fat, high-calorie breakfast in comparison to when given in the fasting 
state.
1.1
MEDICAL BACKGROUND
Asthma is a heterogenous disease characterized by a chronic inflammatory process of the 
airways and driven by both the innate and adaptive immune pathways [R14-4230, P08-
01263]. In severe asthma, the T type 2 inflammation (T2) -high and T2-low, and the non-T2 
pathways are involved associated with a mixed pattern of inflammation involving eosinophil, 
basophil, mast, neutrophil, innate lymphoid and dendritic cells [R15-5888, R16-0945].
SYK is a non-receptor cytoplasmic tyrosine kinase that is predominantly expressed in cells of 
hematopoietic lineage, including B cells, T cells, monocytes, NK cells, mast cells, basophils, 
and neutrophils [R15-5470]. SYK is a key component of the signal transduction associated 
with the T2-high and T2-low, and non-T2 asthma pathways that is activated through 
interaction with allergens and a number of innate and adaptive immune receptors including 
Fc receptors on basophils, mast, B- and T cells. SYK is essential for the FcεR1-mediated 
activation and degranulation of mast cells and basophils. SYK is also important in the signal 
propagation of the dectin family of innate receptors, present on macrophages, dendritic cells 
and neutrophils. Furthermore, SYK has important roles in B-cell and T-cell development, 
with partially redundant functions with Zeta-chain-associated protein kinase of 70 kDa 
(ZAP70) [R15-5470, R16-5298].
For more details on medical background see the current version of the Investigator’s 
Brochure (IB) [c03536505].
1.2
DRUG PROFILE
BI 894416 is a potent and selective inhibitor of SYK. Based on pre-clinical in vitro and in 
vivo data, SYK inhibition is expected to have effect on the non-T2 and T2 inflammatory 
pathway components of severe asthma.
So far, BI 894416 was investigated in one clinical phase I first-in-man trial (BI study number 
1371-0001) in healthy male volunteers. Trial 1371-0001 consisted of two trial parts, a single-
rising dose (SRD) part and a relative bioavailability part. Single-dose treatment with up to 70 
mg BI 894416 or placebo as oral solution in the SRD part of trial 1371-0001 as well as 
administration of three single doses (10, 10, and 40 mg BI 894416) as tablet or oral solution 
in the relative bioavailability part was safe and well tolerated. 
For details on preliminary safety and tolerability as well as on pharmacokinetics and 
biomarker data of trial 1371-0001 refer to the IB [c03536505].


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For a more detailed description of the BI 894416 profile, please refer to the current 
Investigator’s Brochure (IB) [c03536505]. 
1.2.1
Residual Effect Period
The Residual Effect Period (REP, i.e., the period after the last dose with measurable drug 
levels and/or pharmacodynamic effects still likely to be present) of BI 894416 has not been 
defined yet. However, the elimination half-life of BI 894416 is short (gMean apparent 
terminal half-life between 3.0 and 5.8 h in the SRD part of trial 1371-0001), the mode of 
action is reversible, and safety and tolerability in trial 1371-0001 were good. This suggests 
that the occurrence of any potential adverse effects would likely be limited to a low number 
of days. 
The End-of-Trial visit is earliest on Day 8 following BI 894416 dosing in period 2. This is 
expected to cover the period during which any adverse effects could reasonably occur. 
1.3
RATIONALE FOR PERFORMING THE TRIAL
So far, BI 894416 has been administered to humans in the fasting state, only. In future trials, 
e.g., in multiple-dosing trials in patients, BI 894416 will be administered also in the non-
fasting state. However, so far it has not been investigated whether oral bioavailability of 
BI 894416 could be affected by food. 
This clinical trial will be performed to investigate the effect of food on bioavailability 
(assessed as relative bioavailability comparison of fed vs. fasting state) of BI 894416 as tablet 
formulation.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 894416. 
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
1.4.1
Expected benefit to the target population
Asthma is a heterogeneous disease that is driven by the innate and adaptive immune pathway.
In severe asthma, both the T2-high and T2-low, and the non-T2 inflammation pathways are 
involved, and associated with a mixed pattern of inflammation involving eosinophil, 
basophil, mast, neutrophil, innate lymphoid and dendritic cells. Up to 50% of severe asthma 
is driven by the non T2 and/or T2-low alone or in combination with the T2-high pathway. 
This non T2 / T2-low component represents an area of unmet medical need that does not 
respond to high dose inhaled corticosteroids or other current controller therapy, and is 
unlikely to respond to the T2-high monoclonal antibodies targeted therapies. 
SYK is a key component of signal transduction associated with the T2-high and T2-low, and
non-T2 asthma pathways that is activated through interaction with allergens and a number of
innate and adaptive immune receptors including Fc receptors on basophils, mast, B and T


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cells. SYK is also important in the signal propagation of the dectin family of innate receptors,
present on macrophages, dendritic cells and neutrophils.
Such a therapy would meet a substantial unmet need for severe asthma patients, especially
those with a non T2 and/or T2-low component, whether early/late-onset or steroid resistant,
and could become a safe and effective substitute used before high dose inhaled 
corticosteroids, oral systemic corticosteroids or T2-high biological monoclonal antibodies.
1.4.2
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
ECG electrodes may cause local and typically transient skin reactions.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
1.4.3
Drug-related risks and safety measures
Potential effects on immune cells
SYK is involved in the function of basophil, mast, neutrophil and dendritic cells. Moreover, 
SYK is implicated in the development and function of both T cells and B cells. For details 
refer to the IB [c03536505].
The risk for healthy volunteers due to effects of BI 894416 on immune cells is expected to be 
minimal, for the following reasons:

Inhibition of SYK is not expected to have a negative effect with regards to the 
immune response of innate immune cells to viral or bacterial infections due to
redundancy in the infection immune response. The key neutrophil and dendritic cell 
functions most likely will be triggered by alternative pathways.

Safety and tolerability data of trial 1371-0001 are not suggestive of an increased risk 
of infectious adverse events or of any relevant BI 894416-related findings in WBC, 
differential blood count, immunoglobulins, or lymphocyte subpopulations after single 
doses up to 70 mg BI 894416 (see IB [c03536505]).

Due to the reversible mode of action of BI 894416 with regards to SYK inhibition, 
any potential effects on immune cells are expected to be of transient nature.
Risk mitigation and monitoring: Subjects with a history or diagnosis of relevant 
immunological disease will be excluded from trial participation (see Section 3.3.3). Adverse 
events will be monitored for an increase in infectious adverse events. Safety laboratory 
contains WBC, differential blood count, and CRP.


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Tumour biology and carcinogenicity
The SYK pathway has been hypothesized to act as both a tumour suppressor and a tumour 
promoter in different types of human cancers [R16-4459]. An increased risk of 
carcinogenic/metastatic potential in epithelial cancers has been reported in the literature 
related to SYK knock-out, but not related to SYK inhibition. Allelic deletion of SYK has 
been associated with breast adenocarcinoma [R15-4770]. However, there is no evidence that 
pharmacologic inhibition of SYK will increase carcinogenicity or metastatic risk. Preclinical 
data with a potent and selective tool SYK inhibitor, BI 1002494, are in line with an absence 
of a carcinogenic effect due to inhibition of SYK enzymatic function [n00243171]. 
Risk mitigation and monitoring: Only male subjects are included in this trial. In view of the 
extended time necessary to induce a carcinogenic effect, two single doses of BI 894416 are 
not considered a relevant carcinogenic risk to male subjects participating in this study. 
Accordingly, no further risk mitigation is required in this study. 
Platelet aggregation and bleeding risk
A role of SYK in platelet function has been demonstrated in literature [R15-5470]. Several 
platelet functions rely on SYK signalling (e.g. collagen receptor GPVI) but others are 
independent of SYK [R16-5240]. In vitro studies using human platelets demonstrated that at 
concentrations up to 100 μM, BI 894416 had no effect on extrinsic or intrinsic coagulation 
pathways. Also, BI 894416 did not inhibit ADP-induced platelet aggregation up to 100 μM. 
However, BI 894416 inhibited collagen- and arachidonic acid-induced platelet aggregation at 
3 μM and 5 μM. However, platelet function as measured by bleeding time is not affected by a 
drug unless all the platelet pathways are inhibited due to redundancy within the system. 
Therefore, no risk for bleeding exists with regard to platelet inhibition unless a subject is also 
on another antiplatelet drug that blocks these other pathways. 
Risk mitigation and monitoring: Use of any other concomitant drug that could reasonably 
inhibit platelet aggregation or coagulation (e.g. acetylsalicylic acid) will be prohibited (see 
Section 4.2.2.1). Adverse events will be monitored for any signs of bleeding or bleeding-
related adverse events.
Bone density
SYK is reported to be involved in osteoclast differentiation, development and function. For 
details see the IB [c03536505]. In this trial, each subject is treated with two single doses of 
BI 894416. Due to comparatively slow turnover of bone tissue, no relevant effect on bone is 
expected due to two single-dose administrations with BI 894416 in this trial, and no specific 
monitoring of bone density is necessary or reasonable in this trial.


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Genotoxicity, reproductive and developmental toxicity
Genetic toxicology results by weight of evidence indicate that BI 894416 is not mutagenic or 
clastogenic. In the 2-week repeat dose range finding study in male rats [n00240179], 
degeneration of spermatids of the testes was observed at ≥400 mg/kg/day, which is 
considered a secondary effect, related to overt toxicity and morbidity. 
It is unknown whether BI 894416 or its metabolites are distributed into male semen. 
Theoretically there is therefore a risk for exposure of a study subject’s female partner who is 
a woman of child bearing potential (WOCBP) to subtherapeutic exposures of BI 894416 or 
its metabolites via male semen. Developmental and reproductive studies have not yet been 


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conducted, therefore the effect of subtherapeutic concentrations of BI 894416 or its 
metabolites with regards to embryofetal risk has not been explored so far.
Risk mitigation: In order to address the risk of exposure of a subject’s female WOCBP 
partner to BI 894416 or its metabolites via the subject’s seminal fluid, subjects need to use 
barrier contraception (condom) or abstinence (see Section 3.3.3).
Phototoxicity
Subjects will be advised to avoid direct exposure to sun and UV light during the entire study 
(see Section 4.2.2.2). Further protective measures would not be necessary given the low 
phototoxic potential of BI 894416.
Potential effects on QT interval
Preclinical studies suggested no proarrhythmic potential or cardiovascular liability with 
BI 894416. However, statistical results of first-in-man trial 1371-0001 showed a most-likely 
dose- and concentration-dependent increase of QTcF interval. At gMean Cmax of the 70 mg 
dose group, placebo- and baseline-corrected predicted mean QTcF increase was 5.9 ms 
(upper limit of the 90% CI was 10.5 ms). A dose- or concentration-dependent effect on heart 
rate was not observed. It is expected that plasma concentrations reached in current trial 1371-
0021 are lower than the maximal plasma concentrations reached in trial 1371-0001.
Risk mitigation: Subjects with cardiovascular disorders (Section 3.3.3, exclusion criterion 5), 
subjects who used drugs that cause QT/QTc prolongation (Section 3.3.3, exclusion criterion 
11), subjects that show a marked baseline prolongation of QT/QTc interval or any other 
relevant ECG finding at screening (Section 3.3.3, exclusion criterion 19), and subjects with a 
history of additional risk factors for Torsade de Pointes arrhythmia (Section 3.3.3, exclusion 
criterion 20) are excluded from trial participation. Moreover, subjects are in-house under 
close observation for 24 h following drug administration, and ECGs are done pre- and post-
dose at the time points given in the Flow Chart. Considering these risk-mitigating measures, 
the risks to subjects participating at trial 1371-0021 due to potential effects on QT interval are 
considered minimal.
Drug-induced liver injury
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also section 5.2.6.1.4, adverse events of special interest.
1.4.4
Overall assessment of benefit-risk ratio
BI 894416 is a highly specific SYK inhibitor that has been adequately characterised in pre-
clinical studies. The non-clinical safety package supports administration of BI 894416 for up 
to 4 weeks duration to men. 


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Data of trial 1371-0001 indicate good safety and tolerability of single oral doses of 
BI 894416 at all dose levels, i.e. up to 70 mg. In addition, data from oral administration of 
three SYK inhibitors are available and provide additional information on safety and 
tolerability of this class of drug in man. Published data indicate acceptable safety and 
tolerability of these three SYK inhibitors in healthy volunteers (see IB [c03536505]).
Plasma concentrations of BI 894416 in current trial 1371-0021 are expected to be in the range 
of the plasma concentrations that were measured in previous trial 1371-0001 and that were 
associated with good safety and tolerability.
Inhibition of SYK would meet a substantial unmet need for severe asthma patients, especially 
those with a non T2 and/or T2-low component, whether early/late-onset or steroid resistant, 
and could become a safe and effective substitute used before high dose inhaled 
corticosteroids, oral systemic corticosteroids or T2-high biological monoclonal antibodies.
This trial is required for the development of BI 894416. It is designed to assess the effect of 
food on bioavailability of BI 894416 as tablet formulation (in terms of relative bioavailability 
in fed vs. fasting state). The resulting data are planned to inform future trials regarding the 
administration of BI 894416 in relation to food intake.
Considering the medical need for an effective and safe treatment of uncontrolled severe 
asthma, the benefit of this trial is assessed to outweigh the potential risks.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the relative bioavailability of BI 894416 as 
tablet formulation following a high-fat, high calorie breakfast (Test, T) compared with 
administration in the fasting state (Reference, R).
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 894416:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for BI 894416:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as a randomised, open-label, two-way crossover trial in healthy 
male subjects in order to compare the test treatment (T) to the reference treatment (R). The 
treatments will be 30 mg BI 894416 as tablet formulation (3 tablets à 10 mg) following a 
high-fat, high-calorie breakfast (T) or 30 mg BI 894416 as tablet formulation (3 tablets à 
10 mg) administered in the fasting state (R). The subjects will be randomly allocated to the 2 
treatment sequences (T-R or R-T). For details, refer to Section 4.1.
There will be a washout period of at least 5 days between the treatments.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between treatments is based on 
an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529].
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analyte, which are not expected to be 
influenced by the knowledge of treatment received.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 14 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site.
Only male subjects will be included in the study because no data on reproductive toxicology 
are available at this time and because, until availability of data from the 26-week Tg.rasH2 
carcinogenicity study, study populations are restricted to male volunteers or patients (see IB 
[c03536505]).
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:


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1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests
2. Age of 18 to 50 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG and including the 
neurological examination) deviating from normal and assessed as clinically relevant by 
the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg,
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 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 assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (unless the subject quit smoking for at least 3 months prior to first planned 
administration of trial medication)
14. Alcohol abuse (consumption of more than 24 g per day)
15. Drug abuse or positive drug screening
16. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial


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17. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
18. Inability to comply with the dietary regimen of the trial site
19. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
20. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
21. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
22. History of relevant neurological disorder affecting the peripheral or central nervous 
system (this includes, but is not limited to: stroke, epilepsy, inflammatory or atrophic 
diseases affecting the nervous system, cluster headache or any cancer of the nervous 
system). Febrile seizures in childhood or adolescence, recovered carpal tunnel syndrome, 
recovered uncomplicated meningitis, recovered herpes zoster, tension headache, 
occasional benign tics (e.g. due to stress) or minor par- or dysesthesia (e.g. as a side effect 
of prior blood withdrawal) do not constitute a history of relevant neurological disorder.
23. History of immunological disease except allergy not relevant to the trial (such as mild hay 
fever or dust mite allergy) and except asthma in childhood or adolescence
24. History of cancer (other than successfully treated basal cell carcinoma)
25. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from time point of first administration of trial medication 
until 30 days after the last administration of trial medication
26. ALT (alanine transaminase), AST (aspartate transaminase), or creatinine exceed upper 
limit of normal range at screening, confirmed by a repeat test
27. Within 10 days prior to administration of trial medication, use of any drug that could 
reasonably inhibit platelet aggregation or coagulation (e.g., acetylsalicylic acid)
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 


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


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4. The sponsor decides to discontinue the further development of the investigational 
product.
3.3.5
Replacement of subjects
In case more than 2 subjects do not complete the trial, the Clinical Trial Leader together with 
the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects 
will be replaced. A replacement subject will be assigned a unique trial subject number, and 
will be assigned to the same treatment sequence as the subject he replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product has been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
BI 894416
Pharmaceutical formulation: Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
10 mg
Posology:
3-0-0
Route of administration:
oral
Duration of use:
1 day (in treatment R and T)
4.1.2
Selection of doses in the trial
For the current trial a dose of 30 mg BI 894416 is selected to ensure that, in case 
administration with food increases the bioavailability of BI 894416, BI 894416 plasma 
concentrations are in the range that were reached in previous first-in-man trial 1371-0001 and 
that were safe and well-tolerated.
BI 894416 is a BCS class I compound. As such, no relevant food effect is expected, however, 
until food effect results in man are available, we assume as a worst-case that an up to 2-fold 
increase of BI 894416 bioavailability when given with food cannot be fully excluded.
In first-in-man trial 1371-0001, single oral doses of 3 to 70 mg BI 894416 were given as oral 
solution, and doses of 10 and 40 mg were given as tablets. All doses in trial 1371-0001 were 
assessed as safe and well-tolerated. In trial 1371-0001, BI 894416 gMean plasma exposure at 
a dose of 30 mg was 527 nM for Cmax and 3140 nM*h for AUC0-24, and BI 894416 gMean 
plasma exposure at a dose of 70 mg was 2190 nM for Cmax and 11200 nM*h for AUC0-24
(preliminary data, see c03536505). That means, the ratios of gMean plasma exposure 
parameters at 70 mg and at 30 mg were approximately 4 for both Cmax and AUC0-24. These 
ratios are sufficient for the current trial to cover potential BI 894416 plasma exposure 
increases when given with food.
4.1.3
Method of assigning subjects to treatment groups
The randomisation list will be provided to the trial site in advance.
Subjects will be allocated to treatment sequences prior to the first administration of trial 
medication in the morning of Day 1 (Visit 2). For this purpose, numbers of the randomisation 


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list will be allocated to the subjects by drawing lots. Subjects are then assigned to a treatment 
sequence according to the randomisation list.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.6.
All subjects may be treated in one cohort, i.e. all subjects may receive treatment on the same 
calendar day. In case this is not feasible (e.g., due to logistical or recruitment reasons), the 
group may be split into several cohorts as required. Treatment of all subjects on the same 
calendar day is acceptable from a safety point of view (for safety margin to exposure in 
previous SRD trial 1371-0001 refer to Section 4.1.2; for discussion of study-associated risks 
and safety measures see Section 1.4).
4.1.4
Drug assignment and administration of doses for each subject
This trial is a 2-way crossover study. All subjects will receive the 2 treatments in randomised 
order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation Unit strength
Dosage
Total  dose
T (Test)
BI 894416
Tablet
10 mg
3 tablets (30 mg) as one single 
dose on Day 1 following a high-
fat, high-calorie breakfast
30 mg
R (Reference)
BI 894416
Tablet
10 mg
3 tablets (30 mg) as one single 
dose on Day 1 in the fasting state
30 mg
Administration of investigational medicinal product: The investigator (or authorised 
designee) will administer the trial medication as an oral dose together with about 240 mL of 
water to subjects who are in a sitting/standing position. For drug administration, the so-called 
four-eye principle (two-person rule) should be applied. For this, one authorised employee of 
the trial site should witness the administration of trial medication, and – if applicable – its 
preparation (e.g. reconstitution), if correct dosage cannot be ensured otherwise.
Treatment R: Administration of trial medication will be performed after subjects have fasted 
overnight; fasting is to start no later than 10 h before the scheduled dosing. 
Treatment T: Subjects are  to fast overnight prior to administration. Fasting is to start no later 
than 10 h before the scheduled dosing. A high-fat, high-calorie meal will be served 30 min
before drug administration. The subjects must completely consume the meal prior to drug 
intake. The composition of the standard high-fat, high-calorie meal is detailed in Table 
4.1.4: 2; this meal is in compliance with the FDA guidance ‘Food-Effect Bioavailability and 
Fed Bioequivalence Studies’ [R03-2269]. For restrictions with regard to diet, see Section 
4.2.2.2.


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Table 4.1.4: 2
Composition of the high-fat, high-calorie meal
Ingredients
kcal
2 chicken eggs (whole content) for scrambled eggs1
192
10 g butter for frying scrambled eggs
75
35 g fried bacon
186
2 toasted slices of wheat bread
130
15 g butter for buttering toast slices
113
115 g hash brown potatoes
132
240 mL whole milk (3.5% fat)
156
Sum2
984
1
Whole eggs or liquid egg may be used
2
The total caloric content is supplied approximately as following: 150 kcal as protein, 250 kcal as 
carbohydrate, and 500 to 600 kcal as fat. 
All treatments: Subjects will be kept under close medical surveillance until 24 h after drug 
administration. During the first 4 h after drug administration, subjects are not allowed to lie 
down (i.e. no declination of the upper body of more than 45 degrees from upright posture).
The treatments will be separated by a wash-out phase of at least 5 days.
4.1.5
Blinding and procedures for unblinding
This open label Phase I trial will be handled in an open fashion throughout (that is, during the 
conduct, including data cleaning and preparation of the analysis). This is considered
acceptable because the potential for bias seems to be low and does not outweigh practical 
considerations.
Emergency envelopes will not be provided, because the dose of trial medication and food 
condition is known to investigators and subjects.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 


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


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Acetylsalicylic acid or other drugs that may inhibit platelet aggregation or coagulation should 
be avoided during the entire study. 
Known inhibitors/inducers of CYP3A and P-glycoprotein activity should be avoided during 
the entire study.
4.2.2.2
Restrictions on diet and life style
Poppy-seeds containing foods should not be consumed starting 3 days before drug 
administration in each treatment period, in order to avoid false-positive results in the drug 
screen.
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake.
From 1 h before drug intake until lunch, fluid intake is restricted to the milk served with 
breakfast (treatment T, only; see Table 4.1.4: 2), the water administered with the drug, and an 
additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all subjects). From lunch 
until 24 h post-dose, total fluid intake is restricted to 3000 mL.
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products containing St. John's wort (Hypericum perforatum) are not permitted from 7 
days before the first administration of trial medication until after the last PK sample of the 
second study period is collected.
Alcoholic beverages are not permitted from 2 days before administration of trial medication 
in each period until after the last PK sample in the respective period is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 10 h before until 24 h after each administration of trial 
medication.
Smoking is not allowed during the trial.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, 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, a physical examination and a neurological examination. At the end of trial examination, 
it will include review of vital signs, 12-lead ECG, laboratory tests, and a physical 
examination.
5.2.2
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.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required. 
The parameters that will be determined are listed in Tables 5.2.3: 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.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; 
Basophils/ Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands;  Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, 
absol.; Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
Prothrombin time – INR (International Normalization 
Ratio)
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
X
X
--
--
Hormones
Thyroid Stimulating Hormone
X
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
X
X
X
X
X
X
X
X
X
X
X
X
--
X
X
--
--
X
Electrolytes
Sodium
Potassium
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
Urine 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)
1
A, B, and C are different sets of laboratory values. The Flow Chart details at which time point which 
set is to be investigated.


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The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and prior to each treatment period.
Table 5.2.3: 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
Cotinine test (urine)
Cotinine
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
7410, Dräger AG, Lübeck, Germany) will be performed prior to each treatment period, and 
may be repeated at any time during the study at the discretion of an investigator or designee. 
The results will not be included in the CTR
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at MVZ Labor 
Ravensburg GbR, Elisabethenstraße 11, 88212 Ravensburg, Germany, with the exception of 
drug screening tests. These tests will be performed at the trial site using M-10/14-PDT 
multiline test, or comparable test systems.
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 times provided in the Flow Chart. 
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 


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All ECGs will be stored electronically on the Muse CV Cardiology System (GE Medical 
Systems, Freiburg, Germany). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Neurological examination
At Screening, a physical neurological examination will be performed. Upon investigator 
judgment, additional neurological examinations may be added at any time during the trial, for 
individual subjects or for the whole treatment group.
The neurological examination will include the following assessments:
-
Eye movement
-
Pupil size and pupil reactivity
-
Reflexes 
-
Assessment of muscle strength
-
Gait
-
Romberg test
-
Tremor
-
Point-to-point movements
-
Sensitivity
Documentation, Assessment, and Reporting
Results will be documented in source data at the clinical trial site and assessed for clinical 
relevance by an investigator, deputy investigator or sub-investigator. Clinically relevant 
findings of the neurological examination will be reported as Adverse Events (during the trial) 
or as baseline conditions (at screening). Case narratives may be written if necessary.


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


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as described in 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
5.2.6.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.2.6.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.


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Intensity (severity) of AEs
5.2.6.1.5
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
5.2.6.1.6
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged


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5.2.6.2
Adverse event collection and reporting
AE collection
5.2.6.2.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of 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 any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF.


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AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 894416 concentrations in plasma, 2.7 mL of blood will be drawn 
from an antecubital or forearm vein into a K2-EDTA (dipotassium ethylenediaminetetraacetic
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venepuncture with a 
metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 90 min, with interim storage of blood samples and aliquots at room 
temperature. The time each aliquot was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.


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At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. Further information such as matrix may also be provided.
After completion of the quantification of BI 894416 in a plasma aliquot, the left-over and/or
back-up aliquot may be used for further methodological investigations (e.g. for stability 
testing or assessment of metabolites. However, only data related to the analyte and/or its 
metabolite(s) including anti-drug antibodies (if applicable) will be generated by these 
additional investigations. The study samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived.
5.3.3
Analytical determinations
5.3.3.1
Analytical determination of analyte plasma concentration
BI 894416 concentrations in plasma will be determined by a validated LC-MS/MS (liquid 
chromatography tandem mass spectrometry) assay. All details of the analytical method will 
be available prior to the start of sample analysis. 
5.4
BIOBANKING
Not applicable.
5.5
OTHER ASSESSMENTS
5.5.1
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
obtained at the screening examination from each subject whose genotype has not been 
previously determined. Separate informed consent for genotyping will be obtained from each 
volunteer prior to sampling.
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. 
The gene sequences to be determined include known and likely functional variations of key 
ADME genes and incorporate more than 90% of ADME-related genetic markers identified by 
the PharmaADME group (weblink.pharmaadme.org). It is not intended to include the 
pharmacogenomic data in the CTR. However, the data may be part of the CTR, if necessary.
5.6
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Sections 2.1.2, 
2.1.3, 2.2.2.1, and 5.3 are generally used assessments of drug exposure. 


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Due to neurologic effects observed in dog studies, a neurological examination is performed at 
Screening to ensure that no subject with a clinically relevant finding in the neurological 
examination is included into the trial. Upon investigator judgment, additional neurological 
examinations may be added at any time during the trial, for individual subjects or for the 
whole treatment group.


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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 the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG, and laboratory tests 
will be ± 1 h.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
Starting from 48 hours after BI 894416 administration a time window of ± 120 min will be 
allowed for all study activities.  
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, physical examination and neurological examination, refer to Sections 5.2.1 to 5.2.5.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.5.1).
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods (Days -5 to 3 in period 1 and 
Days 1, 2, and 3 in period 2). At least 5 days will separate drug administrations in the first 
and second treatment periods.


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On Day 1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration. The 
subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness. On all other study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
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 times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, physical examination 
and neurological examination during the follow-up period, see Sections 5.2.1 to 5.2.6.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained. 


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the effect of food on the relative 
bioavailability of BI 894416 administered as a single dose of 30 mg to healthy male 
volunteers. The drug administration after a standardised high fat, high caloric meal is 
regarded as the test treatment (T) while the intake of BI 894416 tablets under fasted 
conditions is the reference treatment (R). The trial is designed to allow intra-subject
comparisons between the fasted and fed condition and will be evaluated statistically by use of
an appropriate linear model.
A further objective is to evaluate and compare further pharmacokinetic parameters between 
the treatments. These pharmacokinetic parameters will be assessed by descriptive statistics.
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of BI 894416 formula tablet (30 mg) under fasted conditions (R) 
compared to BI 894416 formula tablets (30 mg) under fed conditions (T) will be estimated by 
the ratios of the geometric means (test/reference) for the primary and secondary PK 
endpoints. Additionally, their two-sided 90% confidence intervals (CIs) will be provided.
This method corresponds to the two one-sided t-test procedure, each at the 5% significance 
level. Since the main focus is on estimation and not testing, a formal hypothesis test and 
associated acceptance range is not specified.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of study drug. The treated set will be used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary and 
was not excluded due to a protocol deviation relevant to the evaluation of PK or due 
to PK non-evaluability (as specified in the following subsection ‘Pharmacokinetics’).
Thus, a subject will be included in the PKS, even if he contributes only one PK 
parameter value for one period to the statistical assessment. Descriptive and model 
based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(IPD) categories will be suggested in the Integrated Quality and Risk Management Plan 


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(IQRMP), IPDs will be identified no later than in the Report Planning Meeting, and the IPD
categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for drug BI 894416 will be calculated 
according to the relevant SOP of the Sponsor (001-MCS-36-472). 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis at or before two times median tmax. Median tmax is to 
be taken either from the median tmax for the reference treatment or from median tmax
for the test treatment, depending on whether the subject had experienced emesis after 
taken the test or the reference treatment. Median tmax is to be determined excluding the 
subjects experiencing emesis.

A predose concentration of BI 894416 is >5% Cmax value of that subject in the 
respective treatment period

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 


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7.3.1
Primary endpoint analyses
Statistical model
The statistical model used for the analysis of the primary (AUC0-tz and Cmax) and secondary 
(AUC0-∞) endpoints will be an analysis of variance (ANOVA) model on the logarithmic 
scale. This model will include effects accounting for sources of variation: ‘sequence’, 
‘subjects within sequences’, ‘period’ and ‘treatment’. The effect 'subjects within sequences' 
will be considered as random, whereas the other effects will be considered as fixed. For tests 
on subject, period, and treatment effects, the denominator sum of squares will be the sum of 
squares for error; while for tests on sequence effects, the denominator will be the sum of 
squares for subjects. The model is described by the following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response (AUC0-tz , Cmax and AUC0-∞) measured on subject m in 
sequence i receiving treatmentk in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2,
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2,
k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sim, eijkm are independent random 
variables.
Primary analysis
Point estimates of bioavailability, the ratios of the geometric means (test/reference) for the 
primary endpoints (see 2.1.2), and their two-sided 90% confidence intervals (CIs) will be 
provided.
The pharmacokinetic parameters (AUC0-tz and Cmax) will then be log transformed (natural
logarithm) prior to fitting the ANOVA model. The difference between the expected means
for test treatments and reference treatment log(T)-log(R), will be estimated by the difference
in the corresponding Least Square Means (point estimate) and two-sided 90% confidence
intervals based on the t-distribution will be computed. These quantities will then be back
transformed to the original scale to give the point estimator (geometric mean) and interval
estimates for the ratio between response under test/ fed condition and response under
reference/ fasted condition.


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Pharmacokinetic parameters of a subject will be included in the analysis unless the subject
has an important protocol deviation relevant for the evaluation. If an important protocol
deviation only affects one treatment period the analysis for the other period from this subject
is included anyway. Whether a protocol deviation is important will be decided no later than in
the Report Planning Meeting.
7.3.2
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will be assessed statistically using the same 
methods as described for the primary endpoints.
7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments under fed and under fasted condition will be compared in a descriptive way. 
Tabulations of frequencies/proportions will be used to evaluate categorical (qualitative) data, 
and tabulations of descriptive statistics will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period and those between trial medication intake and the trial
medication intake in the next treatment period or the EoTrial Visit (whatever comes next) 
will be assigned to the respective treatment. In case of two or more treatments, the follow-up 
will be summarized according to the previous treatment. These assignments including the 


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corresponding time intervals will be defined in detail in the TSAP. Note that AEs occurring 
after the last per protocol contact but entered before final database lock will be reported to 
Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
.
7.4
INTERIM ANALYSES
A preliminary, exploratory analysis of the PK parameters (AUC0-tz, AUC0-∞and Cmax of 
BI 894416) may be performed based on all evaluable data after last subject out and prior to 
data base lock. This may be necessary, e. g., in case the information is needed to inform other 
activities during the development of BI 894416 such as food intake in relation to BI 894416 
intake in other studies. In contrast to the final PK calculations, the preliminary, exploratory
analysis will be based on planned sampling times rather than on actual times, regardless of 
whether actual times were within the time windows or not. Therefore, minor deviations of 
preliminary and final results may occur. Results will be provided as individual values and 
geometric means as well as the adjusted gMean ratios determined according to the planned 
primary analysis described in Section 7.3.1. The preliminary, exploratory results will be 
distributed to the trial team.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.


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7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Subjects will be randomised to one of the two treatment sequences (RT or TR) in a 1:1 ratio.
The block size will be documented in the CTR.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 14 subjects in the trial, including up to 2 non PK evaluable 
subjects. The planned sample size is not based on a power calculation but is considered 
sufficient to achieve the aims of this exploratory trial. With this sample size, the following 
precision in estimating the ratio of geometric means (test/reference) can be expected with 
95% probability. Precision is defined as the ratio of upper CI limit to the relative BA 
estimate. Note that the precision is independent of the actual ratio of geometric means.
The intra-individual coefficient of variation (gCV) was estimated from inter-individual gCV 
from preliminary PK data of the SRD part of a previous trial using the 30 mg dose (data on 
file) which will also be used in this trial. The observed inter-individual gCV was roughly 
31% for Cmax and 26% for AUC0-tz. Assuming a within-subject correlation of 0.6 for Cmax and 
0.8 for AUC0-tz, the estimated upper 70% CI of the intra-individual gCV was roughly 27% for 
Cmax and 15% for AUC0-tz..
Assuming a gCV of 15% for BI 894416 and given a sample size of 12 subjects with 
evaluable data for primary analysis, the precision of the two-sided 90% confidence interval of 
the bioavailability ratio will be approximately 1.16 for a greater gCV of 27%, the precision 
would still be approximately 1.30. Table 7.7: 1 provides an overview of the achievable 
precision for estimating the ratio of geometric means (test/reference). For illustrative 
purposes, the expected 90% confidence intervals with 95% tolerance probability are 
displayed for different values of the ratios T/R of geometric means.


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Table 7.7: 1
Precision that can be expected with 95% tolerance probability and 
illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T/R) for different gCVs in a 2x2 crossover trial 
(N=12)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
21
1.23
100
81.22
123.12
21
1.23
150
121.83
184.68
21
1.23
200
162.44
246.24
21
1.23
400
324.89
492.47
27
1.30
100
76.68
130.42
27
1.30
150
115.02
195.63
27
1.30
200
153.35
260.84
27
1.30
400
306.71
521.67
33
1.38
100
72.48
137.97
33
1.38
150
108.72
206.96
33
1.38
200
144.96
275.94
33
1.38
400
289.91
551.89
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit,  = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.5.1.


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


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8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the Human Pharmacology Centre (HPC) – Boehringer Ingelheim's Phase I unit – the 
validated ClinBaseTM system is used 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
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:


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
Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data are entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial.


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Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (e.g., biomarker proposal, analysis plan and 
report) ensures compliant usage

If applicable, a fit for purpose approach will be used for assay/equipment validation 
depending on the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the
ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.


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Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the Human Pharmacology Centre (HPC) of BI Pharma GmbH 
& Co. KG, Biberach, Germany, under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

ensure appropriate training and information of Clinical Trial Managers (CTM), 
Clinical Research Associates, and investigators of participating trial sites
The trial medication will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany.
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
).
Analyses of BI 894416 concentrations in plasma will be performed at 
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research 
organization appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) , 1 - 9 
(2002)
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group (2010)
R14-4230
Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular 
approaches. Nature Med 18 (5), 716 - 725 (2012)
P08-01263
Expert panel report 3: guidelines for the diagnosis and management of 
asthma: full report 2007 (NIH publication no. 07-4051, revised August 
2007). http://www.nhlbi.nih.gov ; Bethesda: U.S. Department of Health and 
Human Services, National Institutes of Health, National Heart, Lung and 
Blood Institute (2007)
R15-5888
Pelaia G, Vatrella A, Busceti MT, Gallelli L, Calabrese C, Terracciano R, 
Maselli R. Cellular mechanisms underlying eosinophilic and neutrophilic 
airway inflammation in asthma. Mediators Inflamm 2015, 879783 (2015)
R16-0945
Fahy JV. Type 2 inflammation in asthma - present in most, absent in many.
Nat Rev Immunol 15, 57 - 65 (2015)
R15-5470
Mocsai A, Ruland J, Tybulewicz VLJ. The SYK tyrosine kinase: a crucial 
player in diverse biological functions. Nat Rev Immunol 10 (6), 387 - 402 
(2010)
R16-5298
Alsadeq A, Hobeika E, Medgyesi D, Klaesener K, Reth M. The role of the 
Syk/Shp-1 kinase-phosphatase equilibrium in B cell development and 
signaling. J Immunol 193, 268 - 276 (2014)
R16-4459
Krisenko MO, Geahlen RL. Calling in SYK: SYK's dual role as a tumor 
promoter and tumor suppressor in cancer. Biochim Biophys Acta Mol Cell 
Res 1853 (1), 254 - 263 (2015)
R15-4770
Blancato J, Graves A, Rashidi B, Moroni M, Tchobe L, Ozdemirli M, 
Kallakury B, Makambi KH, Marian C, Mueller SC. SYK allelic loss and 
the role of Syk-regulated genes in breast cancer survival. Plos One 9 (2), 
e87610 (2014)
R16-5240
Boylan B, Gao C, Rathore V, Gill JC, Newman DK, Newman PJ. 
Identification of FcgammaRIIa as the ITAM-bearing receptor mediating 
alphaIIbbeta3 outside-in integrin signaling in human platelets. Blood 112 
(7), 2780 - 2786 (2008)
R94-1529
Chow SC, Liu JP, Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc (1992)


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c03536505
 
. Investigator Brochure: BI 894416 Asthma
n00243171
. Assessment of pro-proliferative effects of the 
SYK inhibitor BI 1002494 on human breast cancer cell lines and in silico 
genetic evaluation of SYK for tumour suppressor characteristics using data 
from breast cancer patient databases. 11 Jul 2016
n00245394
. BI 894416: Dose Escalation in Dogs with Assessment of 
Electroencephalography and Nerve Conduction Velocity.
n00240179
. BI 894416: 
Exploratory 15 day oral (gavage) toxicity study in male rats. 29 Jun 2015


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
19 Feb 2019
EudraCT number
EU number
2018-004313-41
BI Trial number
1371-0021
BI Investigational Medicinal 
Product(s)
BI 894416
Title of protocol
Relative bioavailability of BI 894416 as tablet 
formulation following a high-fat, high-calorie 
breakfast compared to administration in the fasting 
state in healthy male subjects (an open-label, 
randomised, single-dose, two-period, two-sequence 
crossover study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1) Flow Chart
2) 3.3.3
3) 3.3.4.1
4) 4.1.3
5) 5.2.3
6) 6.2.2
7) 6.2.3
Description of change
1) Addition of safety laboratory and AE questioning 
within 5 days prior to administration in the first 
treatment period; change of post-dose ECG and 
VS time points post dose on Day 1 to +1:00 h and 
+2:00 h; addition of AE questioning on Day 1 at 
+1:00 h; addition of neurological examination to 
end-of-trial examination
2) Reduction of maximum allowable alcohol 
consumption to 24 g/day; addition of exclusion 
criteria 26 and 27
3) Addition of treatment discontinuation criterion 6
4) Clarification that all subjects may be treated on 
the same calendar day 
5) Addition of safety laboratory parameter set C


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6) Adaption of treatment period 1 duration
7) Addition of neurological examination 
Rationale for change
1) In response to IEC / Competent Authority 
objection
2) In response to IEC / Competent Authority 
objection
3) In response to IEC / Competent Authority 
objection
4) In response to IEC / Competent Authority 
objection
5) To detail parameters to be measured within 5 
days prior to first administration of trial drug (see 
point 1 above)
6) To account for addition of a safety laboratory 
examination prior to treatment period 1 (see point 
1 above)
7) In response to IEC / Competent Authority 
objection
11.2
GLOBAL AMENDMENT 2
Date of amendment
15 May 2019
EudraCT number
EU number
2018-004313-41
BI Trial number
1371-0021
BI Investigational Medicinal 
Product(s)
BI 894416
Title of protocol
Relative bioavailability of BI 894416 as tablet 
formulation following a high-fat, high-calorie 
breakfast compared to administration in the fasting 
state in healthy male subjects (an open-label, 
randomised, single-dose, two-period, two-sequence 
crossover study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Title Page
Description of change
Change of Clinical Trial Leader (CTL) “
 


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” instead of “
” and 
change of phone extension
Rationale for change
Change of Clinical Trial Leader (CTL)


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c23506058
3.0
clinical-trial-protocol-revision-2
Relative bioavailability of BI 894416 as tablet formulation following a high-fat,
high-calorie breakfast compared to administration in the fasting state in healthy male
subjects (an open-label, randomised, single-dose, two-period, twosequence crossover
study)
Approval-Clinical Pharmacokinetics
16 May 2019 10:56 CEST
Author-Trial Statistician
16 May 2019 10:57 CEST
Approval-Therapeutic Area 
16 May 2019 16:07 CEST
Author-Clinical Trial Manager
16 May 2019 16:14 CEST
Approval-Team Member Medicine
16 May 2019 21:23 CEST
Verification-Paper Signature
Completion
27 May 2019 10:41 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c23506058
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c28029008-01
BI Trial No.:
1371-0021
Title:
Relative bioavailability of BI 894416 as tablet formulation
following a high-fat, high-calorie breakfast compared to
administration in the fasting state in healthy male subjects (an 
open-label, randomised, single-dose, two-period, two-sequence
crossover study)
(including Protocol Amendments No.1[c23506058-02] and No. 2 
[c23506058-03])
Investigational
Product:
BI 894416
Responsible trial 
statisticians:
Phone:    
Fax:        
Phone:
Fax:
Date of statistical 
analysis plan:
03 JUN 2019 SIGNED
Version:
Final
Page 1 of 26
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2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
Secondary endpoint(s) ..........................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................13
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........17
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................18
7.4
PRIMARY ENDPOINTS...................................................................................18
7.4.1
Primary analysis of the primary endpoints......................................................18
7.5
SECONDARY ENDPOINTS.............................................................................20
7.5.1
Key secondary endpoints....................................................................................20
7.5.2
Secondary endpoints...........................................................................................20
7.7
EXTENT OF EXPOSURE.................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse Events ....................................................................................................21
7.8.2
Laboratory data ..................................................................................................23
7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG......................................................................................................................23
7.8.5
Others...................................................................................................................23
8.
REFERENCES....................................................................................................24


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10.
HISTORY TABLE..............................................................................................26


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................11
Table 6.3: 1
Subject sets analysed........................................................................................14
Table 10: 1
History table .....................................................................................................26


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
website: glossary
Term
Definition / description
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Aspartate transaminase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BMI
Body mass index
BWC
Bioavailability/Bioequivalence, within-subject design, time-controlled
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DILI
Drug induced liver injury
gCV
Geometric coefficient of variation
gMean
Geometric mean
LLT
Lower level term
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PKS
PK parameter set
Q1
1st quartile
Q3
3rd quartile
R / Ref
Reference treatment
RAGe
Report Appendix Generator system


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Term
Definition / description
SD
Standard deviation
SOC
System organ class
T
Test treatment
TS
Treated set
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 (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher, Certara USA Inc., Princeton, NJ, USA).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP: The following pharmacokinetic parameters will be determined for
BI 894416:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 2.1.3 of the CTP: The following pharmacokinetic parameter will be determined for
BI 894416:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatment sequences 
and selection of doses, please see CTP, Sections 3 and 4.
The study will be performed as a randomised, open-label, two-way crossover trial with two 
treatments (T and R) and two treatment sequences (TR or RT). 
In total, it was planned to assign 14 healthy male subjects to the two treatment sequences in a 
1:1 ratio.
For details of dosage and formulation see Table 6.1: 1 below:
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
Short label for footnote
R
BI 894416, 3*10 mg tablet, qd, fasted
BI 30mg fast
BI 894416 30mg fast
T
BI 894416, 3*10 mg tablet, qd, fed
BI 30mg fed
BI 894416 30mg fed
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from 0:00 h on day of informed consent until first administration 
time of study drug)

On treatment (separately for each treatment; i.e. ranging from the time of 
administration of the respective treatment until next drug administration or 0:00 h on 
the day after trial termination date) 
Displays of AEs will be presented separately for the treatments described in Table 6.1: 1
above


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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 will not be included in this analysis. 
The following total will be provided in addition (Section 15.3 only):

a total over all on treatment phases included in this analysis ("Total on treatment")
B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of 
the CTR displays:
Screening
On treatment (labelled with the name of the study treatment (short label))
In Section 16.1.13.1.8 AE tables, the following totals will be provided in addition:
a total over all study phases ("Total")
For detailed information on the handling of the treatments refer to Technical TSAP ADS plan
and Analysis Data Reviewers guide. 


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Section 7.3 of the CTP: Important protocol deviation (IPD) categories will be suggested in 
the Integrated Quality and Risk Management Plan (IQRMP), IPDs will be identified no later 
than in the Report Planning Meeting, and the IPD categories will be updated as needed.
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the combined report planning and database lock meeting
(RPM/DBLM). At this meeting, all manual deviations identified at the sites by the CRAs and 
deviations too complex to program will be reviewed by the trial team to decide which are 
considered important. For definition of important protocol deviations (iPD), and for the 
process of identification of these, refer to the Boehringer Ingelheim (BI) SOP "Identify and 
Manage Important Protocol Deviations (iPD)" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM minutes via an accompanying Excel spreadsheet (3). 
The iPDs will be summarised and listed.
6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:

Treated set (TS): The treated set includes all subjects who were treated with at least one 
dose of study drug. The treated set will be used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary and 
was not excluded due to a protocol deviation relevant to the evaluation of PK or due to 
PK non-evaluability (as specified in the following subsection ‘Pharmacokinetics’). Thus, 
a subject will be included in the PKS, even if he contributes only one PK parameter 
value for one period to the statistical assessment. Descriptive and model based analyses 
of PK parameters will be based on the PKS.
[…]
Plasma concentration data and parameters of a subject will be included in the statistical
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.


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Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if
for example

The subject experienced emesis at or before two times median tmax. Median tmax is to 
be taken either from the median tmax for the reference treatment or from median tmax
for the test treatment, depending on whether the subject had experienced emesis after 
taken the test or the reference treatment. Median tmax is to be determined excluding 
the subjects experiencing emesis.

A predose concentration of BI 894416 is >5% Cmax value of that subject in the 
respective treatment period

Missing samples/concentration data at important phases of PK disposition curve
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Analyses of PK endpoints 
X
Safety parameters
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (4)).
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, the baseline is defined as the last measurement before administration of 
BI 894416 in each period.
For laboratory, the baseline is defined as the measurement prior to first drug administration 
(in Visit 2).
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 the end of trial 
examination are provided in the Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication
administration on Day 1 are to be performed and completed within a 3 h-period prior to the
trial drug administration. The acceptable deviation from the scheduled time for vital signs, 
ECG, and laboratory tests will be ± 1 h.
[…]
Starting from 48 hours after BI 894416 administration a time window of ± 120 min will be
allowed for all study activities.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.
Unscheduled measurements of laboratory data and vital signs data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement. 


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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 endpoints and concentrations will be performed by the 
department Translational Medicine and Clinical Pharmacology (TMCP) at BI and will be 
presented in Section 15.6 of the CTR.
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of Clinical Trials and Project Summaries” [001-MCG-159] (6) with the 
exception of those generated for PK-calculations (7).
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number, visit and actual treatment (if appropriate). 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile


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


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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.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM. 
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The
measured plasma concentrations of trial medication will provide additional confirmation of 
compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM/DBLM (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
Relative bioavailability is to be determined on the basis of the primary pharmacokinetic 
endpoints (see Section 5.1). 
7.4.1
Primary analysis of the primary endpoints
Section 7.3.1 of the CTP: The statistical model used for the analysis of the primary (AUC0-tz
and Cmax) and secondary (AUC0-∞) endpoints will be an analysis of variance (ANOVA) model 
on the logarithmic scale. This model will include effects accounting for sources of variation: 
‘sequence’, ‘subjects within sequences’, ‘period’ and ‘treatment’. The effect 'subjects within 
sequences' will be considered as random, whereas the other effects will be considered as 
fixed. For tests on subject, period, and treatment effects, the denominator sum of squares will 
be the sum of squares for error; while for tests on sequence effects, the denominator will be 
the sum of squares for subjects. The model is described by the following equation:


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yijkm = + ζi + sim + j + k + eijkm, where
yijkm = logarithm of response (AUC0-tz , Cmax and AUC0-∞) measured on subject m in
sequence i receiving treatmentk in period j,
= the overall mean,
ζi = the ith sequence effect, i = 1, 2
sim = the effect associated with the mth subject in the ith sequence, 
m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2
k = the kth treatment effect, k = 1, 2
eijkm = the random error associated with the mth subject in sequence i who received 
treatment k in period j.
[…]
The pharmacokinetic parameters (AUC0-tz and Cmax and AUC0-∞) will then be log 
transformed (natural logarithm) prior to fitting the ANOVA model. The difference between 
the expected means for test treatments and reference treatment log(T)-log(R), will be 
estimated by the difference in the corresponding Least Square Means (point estimate) and 
two-sided 90% confidence intervals based on the t-distribution will be computed. These 
quantities will then be back transformed to the original scale to give the point estimator 
(geometric mean) and interval estimates for the ratio between response under test/ fed 
condition and response under reference/ fasted condition.
The implementation for this analysis will be accomplished by using the XPKISTAT macro, 
based on PKS, and option BWC (Bioavailability/Bioequivalence, within-subject design, time-
controlled).
Note, that the computed CIs must be interpreted in the context exploratory character, i.e. 
confidence intervals are considered as interval estimates for effects.
Since the main focus is on estimation and not testing, an acceptance range was not specified, 
that is, no hypothesis will be tested.


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
The secondary PK parameter AUC0-∞(AUCINF_pred) will be assessed using the same 
methods as described for the primary endpoints.
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.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. 
The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in the corporate guideline: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials” [001-MCG-156] (8).
The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 
For analysis, multiple AE occurrence data on the case report form (CRF) will be collapsed 
into one AE provided that all of the following applies:

All AE attributes are identical (lower level term (LLT), intensity, action taken, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
two occurrences is given if the second occurrence started within one hour after end of 
the first occurrence).
For further details on summarization of AE data, please refer to [001-MCG-156] (8).
Section 5.2.6.1.4 of the CTP: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the 'DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 


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encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events.
Section 1.2.1 of the CTP: The Residual Effect Period (REP, i.e., the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present) 
of BI 894416 has not been defined yet. […]
Therefore, all AEs reported until the end of trial examination (last per protocol contact) will 
be considered as on treatment.
Section 7.3.4 of the CTP: Note that AEs occurring after the last per protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
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, 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 SOCs and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on 
BI standards [001-MCG-157] (10). 
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 possibly
clinically significant will be flagged in the data listings.
It is the investigator's responsibility to decide whether a lab value is clinically significantly 
abnormal or not (at the RPM/DBLM at the latest). 
Descriptive statistics of laboratory data will be calculated by planned time point based on the 
worst value of the subject at that planned time point (or assigned to that planned time point).
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate). In the listing the difference from baseline will also be 
displayed.
For vital signs, descriptive statistics will be calculated by planned time point based on the last 
value of the subject at that planned time point (or assigned to that planned time point).
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as AEs (when they 
occurred during treatment).
7.8.5
Others
This section is not applicable as no other variables have been specified in the protocol.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, IDEA for CON.
3.
BI-KMED-COPS-TMP-0001: "iPD log", current version; IDEA for GEN.
4.
001-MCG-156_RD-01: “Handling of Missing and Incomplete AE Dates”, current 
version; IDEA for CON.
5.
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic/Pharmacodynamic
Analyses of Clinical Studies”, current version; IDEA for CON.
6.
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current version; 
IDEA for CON.
7.
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
8.
001-MCG-156: “Analysis and Presentation of Adverse Event Data from Clinical Trials”, 
current version; IDEA for CON.
9.
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version.
10. 001-MCG-157: “Handling, Display and Analysis of Laboratory Data”, current version; 
IDEA for CON.
11. 001-MCS-36-472_RD-03: “Description of Analytical Transfer Files and PK/PD Data 
Files”, current version; IDEA for CON.


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