Clinical trial NCT04540874
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2020-10-05; Completion date: 2020-11-12
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this trial is to investigate the safety, tolerability and pharmacokinetics of BI 894416 in healthy Japanese male subjects.

Detailed description:

Arms: arm 1: 1 tablet of 25 milligrams (mg) BI 894416 was administered orally as single dose with 240 milliliters of water after an overnight fast of at least 10 hours on day 1, followed by at least 48 hours close medical surveillance, followed by 2 weeks of follow-up period. arm 2: Matching placebo was administered orally as single dose with 240 milliliters of water after an overnight fast of at least 10 hours on day 1, followed by at least 48 hours close medical surveillance, followed by 2 weeks of follow-up period.
Interventions: intervention 1: BI 894416 intervention 2: Placebo
Intervention descriptions: intervention 1: BI 894416 intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (6.0)/Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c23040609-03
BI Trial No.
1371-0003
BI Investigational
Medicinal Product(s)
BI 894416
Title
Safety, tolerability and pharmacokinetics of single rising oral 
doses of BI 894416 versus placebo in healthy male Japanese
subjects (single-blind, randomized, placebo-controlled within 
dose group)
Lay Title
A study in healthy Japanese men to test how different doses of BI 
894416 are tolerated
Clinical Phase
I
Clinical Trial Leader
 
Telephone: 
, Fax: 
Principal 
Investigator
Telephone: 
, Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0
Date: 17 Aug 2020
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© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim (BI)
Protocol date
5 Jun 2020
Revision date
17 Aug 2020
BI trial number
1371-0003
Title of trial
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 894416 
versus placebo in healthy male Japanese subjects (single-blind, randomized, 
placebo-controlled within dose group)
Principal Investigator
Trial site
Clinical phase
I
Trial rationale
The objective of this trial is to investigate the safety, tolerability and 
pharmacokinetics of BI 894416 in healthy Japanese male subjects. The chosen 
population of healthy male subjects receiving single rising oral doses is considered 
adequate to provide the basis for the clinical development program of BI 894416 in 
Japan.
Trial objectives
To investigate safety, tolerability and pharmacokinetics following single rising 
doses of BI 894416
Trial endpoints
Primary endpoint
The percentage (%) of subjects with drug related adverse events
Secondary endpoints:
Cmax, AUC0-∞of BI 894416
Trial design
single-blind, randomised, placebo-controlled within dose groups
Number of subjects 
total entered
24
each treatment
8 per dose group (6 on BI 894416 and 2 on placebo) 
  
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 20 to 45 years (inclusive), body mass index (BMI) of 
18.5 to 25.0 kg/m2 (inclusive) 


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Test product(s)
BI 894416 as tablet formulation
dose
25 mg, 50 mg, 70 mg
mode of admin.
Oral with 240 mL of water 
Comparator product(s)
Matching placebo(s)
dose
Not applicable
mode of admin.
Oral with 240 mL of water
Duration of treatment
Single dose 1day
Statistical methods
Descriptive statistics will be calculated for all endpoints. 


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FLOW CHART
Visit
Day
Planned time (relative to 
BI 894416 or placebo 
administration [h:min])
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory6
PK blood 
8 ,10
PK urine
11
Medical Examination9
Neurological 
examination9
Vital signs (BP, PR)9
12-lead ECG,9,10
Continuous ECG 
monitoring
Questioning for AEs and 
concomitant therapy15
1
-28 to 
-1
Screening (SCR)1
A7
x
x
x
x
2
-1
-24:00
09:00
Ambulatory visit2
B2
x
x12
x
-12:00
21:00
Admission to trial site
1
-1:00
08:00
Allocation to treatment
C7
x
x
x
x
x
x13
x14
x
0:00
09:00
BI 894416 or placebo 
administration3
▲
│
▲
│
0:15
09:15
x
│
│
0:30
09:30
x
│
x
x13
│
x
0:45
09:45
x
│
x
│
x
1:00
10:00
x
│
x
x13
│
x
1:30
10:30
x
│
x
x13
│
x
2:00
11:00
240 mL fluid intake
x
│
x
x13
│
x
2:30
11:30
x
│
x
x13
│
x
3:00
12:00
x
│
x
x13
│
x
4:00
13:00
240 mL fluid intake, 
thereafter lunch4
B
x
┼
x
x
x13
▼
x
5:00
14:00
x
│
6:00
15:00
x
│
x
x13
x
8:00
17:00
Snack(voluntary)4
x
┼
x
x13
x
10:00
19:00
x
│
11:00
20:00
Dinner
│
12:00
21:00
x
┼
x
x13
x 
2
24:00
09:00
Breakfast4
C
x
┼
x
x
x13
x
28:00
13:00
Lunch4
│
x
32:00
17:00
Snack(voluntary)
│
34:00
18:00
x
│
x
x
x
35:00
19:00
Dinner
│
3
48:00
09:00
Discharge from trial site
B
x
▼
x
x
x
x
4
72:00
09:00
Ambulatory visit
x
x
x
x
5
96:00
09:00
Ambulatory visit
x
8
168:00
09:00
Ambulatory visit
C
x
x
3
15 to 
17
End of trial (EOT) 
examination5
C
x
x
x
x
x
PK: pharmacokinetics, ECG: electrocardiogram, BP: blood pressure, PR: pulse rate, AE: adverse event
1. Subject must be informed and written informed consent obtained prior to starting any screening procedures. 
Screening procedures include medical examination, neurological examination, check of vital signs, ECG 
(12-lead ECG and rhythm strip over at least 15 min), safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. 


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2. Safety laboratory to be taken and to be medically evaluated on Day -1 prior to administration of BI 894416; 
this ambulatory visit including safety laboratory, neurological exam, ECG and adverse event questioning can 
be omitted if the screening examination is performed on Day -3 or -2.
3. Oral with 240 mL of water after an overnight fast of at least 10 h; (please also refer to Section 4.2.2.2)
4. If several actions are indicated at the same time point, the intake of meals will be the last action.
5. EOT includes medical examination, neurological examination, vital signs, ECG, safety laboratory, recording 
of AEs and concomitant therapies.
6. Letters A, B and C describe different sets of safety laboratory examinations (see Section 5.2.3).
7. Drug screening will be performed at screening and prior to dosing at Day 1 of visit 2. A breath alcohol test 
and cotinine test will be performed during screening and prior to BI 894416 or placebo administration at 
Visit 2, and may be repeated at any time during the trial at the discretion of an investigator or designee. 
8.
PK samples for determination of plasma level of BI 894416 as detailed in Section 5.3.2 Sampling times and 
periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) including 
addition of samples and visits as long as the total blood volume taken does not exceed approximately 500 
mL per subject.
9. For allowed deviation from the scheduled time please refer to Section 6.1.
10. PK samplings and ECGs should be done in direct sequence to allow for a time-matched pair of ECG 
recordings and plasma concentration of BI 894416.
11. PK urine samples for determination of BI 894416 amount eliminated in urine are to be taken at following 
time intervals: a blank urine sample is to be obtained within 3 h prior to administration of trial medication;
other urine samples are to be collected over the stated post-dose intervals 0-4, 4-8, 8-12, 12-24 and 24-48 h 
(see Section 5.3.2.2).
12. Three triplicate ECGs are recorded within approximately 1 h. The recordings of each triplicates should be 
separated by at least 15 min (refer to the Section 5.2.4.1).
13. Triplicate ECG (refer to the Section 5.2.4.1).
14. Continuous ECG monitoring to be done starting at least 15 min before BI 894416, or placebo, administration 
and for at least 4 h following BI 894416, or placebo (3-lead ECG recording).
15. AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the 
time points indicated in the Flow Chart.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................14
Clinical Experience in Humans ...........................................................14
1.2.1
Summary of clinical trials........................................................14
1.2.1.1
Clinical pharmacokinetics........................................................15
1.2.1.2
Safety
...................................................................................16
1.2.1.3
Residual Effect Period..........................................................................18
1.2.2
Drug product.........................................................................................18
1.2.3
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................19
1.4
BENEFIT - RISK ASSESSMENT ...................................................................19
Procedure-related risks ........................................................................19
1.4.1
Drug -related risks and safety measures.............................................20
1.4.2
Overall assessment................................................................................23
1.4.3
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 24
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......24
Main objectives......................................................................................24
2.1.1
Primary endpoint..................................................................................24
2.1.2
Secondary endpoint ..............................................................................24
2.1.3
Safety and tolerability..............................................................24
2.2.2.1
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 26
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................26
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................28
3.3
SELECTION OF TRIAL POPULATION ......................................................29
Main diagnosis for trial entry..............................................................29
3.3.1
Inclusion criteria...................................................................................29
3.3.2
Exclusion criteria ..................................................................................30
3.3.3


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Withdrawal of subjects from treatment or assessments ...................31
3.3.4
Discontinuation of trial treatment............................................32
3.3.4.1
Withdrawal of consent to trial participation ............................32
3.3.4.2
Discontinuation of the trial by the sponsor..............................32
3.3.4.3
Replacement of subjects .......................................................................33
3.3.5
4.
TREATMENTS........................................................................................ 34
4.1
INVESTIGATIONAL TREATMENTS ..........................................................34
Identity of the Investigational Medicinal Products ...........................34
4.1.1
Selection of doses in the trial and dose modification .........................34
4.1.2
Method of assigning subjects to treatment groups ............................34
4.1.3
Drug assignment and administration of doses for each subject .......35
4.1.4
Blinding and procedures for unblinding ............................................36
4.1.5
Blinding ...................................................................................36
4.1.5.1
Unblinding and breaking the code...........................................36
4.1.5.2
Packaging, labelling, and re-supply ....................................................36
4.1.6
Storage conditions.................................................................................36
4.1.7
Drug accountability ..............................................................................37
4.1.8
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................37
Other treatments and emergency procedures....................................37
4.2.1
Restrictions............................................................................................38
4.2.2
Restrictions regarding concomitant treatment .........................38
4.2.2.1
Restrictions on diet and life style.............................................38
4.2.2.2
4.3
TREATMENT COMPLIANCE.......................................................................39
5.
ASSESSMENTS....................................................................................... 40
5.1
ASSESSMENT OF EFFICACY.......................................................................40
5.2
ASSESSMENT OF SAFETY............................................................................40
Medical examination.............................................................................40
5.2.1
Vital signs...............................................................................................40
5.2.2
Safety laboratory parameters..............................................................40
5.2.3
Electrocardiogram................................................................................43
5.2.4
12-lead resting ECG.................................................................43
5.2.4.1
Continuous ECG monitoring ...................................................45
5.2.4.2
Other safety parameters.......................................................................45
5.2.5
Neurological examination........................................................45
5.2.5.1
Assessment of adverse events...............................................................46
5.2.6
Definitions of adverse events...................................................46
5.2.6.1


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Adverse event ............................................................46
5.2.6.1.1
Serious adverse event ................................................46
5.2.6.1.2
AEs considered ‘Always Serious’.............................47
5.2.6.1.3
Adverse events of special interest .............................47
5.2.6.1.4
Intensity (severity) of AEs.........................................47
5.2.6.1.5
Causal relationship of AEs ........................................48
5.2.6.1.6
Adverse event collection and reporting ...................................48
5.2.6.2
AE collection.............................................................48
5.2.6.2.1
AE reporting to the sponsor and timelines ................49
5.2.6.2.2
Information required..................................................49
5.2.6.2.3
Pregnancy ..................................................................50
5.2.6.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................50
Assessment of pharmacokinetics .........................................................50
5.3.1
Methods of sample collection...............................................................50
5.3.2
Blood sampling for pharmacokinetic analysis.........................50
5.3.2.1
Urine sampling for pharmacokinetic analysis..........................51
5.3.2.2
5.4
ASSESSMENT OF BIOMARKER(S) .............................................................52
5.5
BIOBANKING ...................................................................................................52
5.6
OTHER ASSESSMENTS .................................................................................52
Pharmacogenomic evaluation..............................................................52
5.6.1
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................52
6.
INVESTIGATIONAL PLAN.................................................................. 53
6.1
VISIT SCHEDULE............................................................................................53
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................53
Screening period....................................................................................53
6.2.1
Treatment period ..................................................................................53
6.2.2
Follow-up period and trial completion ...............................................54
6.2.3
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 55
7.1
STATISTICAL DESIGN – MODEL ...............................................................55
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................55
7.3
PLANNED ANALYSES....................................................................................55
Primary endpoint analyses...................................................................56
7.3.1
Secondary endpoint analyses ...............................................................56
7.3.2
Safety analyses.......................................................................................57
7.3.4
Pharmacokinetic - pharmacodynamic analysis..................................58
7.3.5


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7.4
INTERIM ANALYSES .....................................................................................58
7.5
HANDLING OF MISSING DATA ..................................................................59
Safety......................................................................................................59
7.5.1
Pharmacokinetics..................................................................................59
7.5.2
7.6
RANDOMISATION ..........................................................................................59
7.7
DETERMINATION OF SAMPLE SIZE ........................................................59
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 60
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................60
8.2
DATA QUALITY ASSURANCE .....................................................................61
8.3
RECORDS..........................................................................................................61
Source documents .................................................................................61
8.3.1
Direct access to source data and documents.......................................62
8.3.2
Storage period of records.....................................................................62
8.3.3
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................63
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......63
Collection, storage and future use of biological samples and 
8.5.1
corresponding data ...............................................................................63
8.6
TRIAL MILESTONES .....................................................................................63
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................64
9.
REFERENCES......................................................................................... 65
9.1
PUBLISHED REFERENCES...........................................................................65
9.2
UNPUBLISHED REFERENCES.....................................................................66
10. APPENDICES .......................................................................................... 67
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 68
11.1
GLOBAL AMENDMENT 1 .............................................................................68
11.2
GLOBAL AMENDMENT 2 .............................................................................68


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
Aet1-t2
Amount of analyte eliminated in urine over the time interval t1 to t2
ALCOA
attributable, legible, contemporaneous, original, accurate (dimension of 
integrity)
ALT
Alanine transaminase
AP
Alkaline phosphatase
aPTT
Activated partial thromboplastin time 
AST
Aspartate transaminase
AUC
Area under the Curve
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to 24 hour after administration
AUC0-8
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to 8 hour after administration
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
AUCss
Area under the concentration-time curve of the analyte in plasma at
steady state
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUCτ
Area under the concentration-time curve of the analyte in plasma during a 
dosage interval
%AUCtz-∞
Percentage of AUCtz-∞ obtained by extrapolation
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CK
Creatine kinase
CK-MB
Creatine kinase-MB isozyme


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CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
CLR, t1-t2
Renal clearance of the analyte in plasma from the time point t1 to t2
Cmax
Maximum measured concentration of the analyte in plasma
Cmax, ss
Maximum measured concentration of the analyte in plasma at steady state
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CRO
Clinical research organization
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DILI
Drug Induced Liver Injury
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eDC
electronic Data Capture 
EOT
End of Trial
ESR
Erythrocyte Sedimentation Rate 
EU
European Union
FDA
Food and Drug Administration
fet1-t2
Fraction of administered drug excreted unchanged in urine over the time 
interval from t1 to t2
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase 
gMean
Geometric mean
GMP
Good Manufacturing Practice
GOT
Glutamic Oxaloacetic Transaminase
GPT
Glutamic Pyruvic Transaminase
IB
Investigator’s Brochure
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee


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INR
International Normalized Ratio
IPD
Important protocol deviation
IQRMP
Integrated Quality and Risk Management Plan
IRB
Institutional Review Board
ISF
Investigator Site File
K2EDTA
Dipotassium ethylenediaminetetraacetic acid 
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
multiple-rising dose 
MRTpo
Mean residence time of the analyte in the body after oral administration
NK
Natural killer
NOAEL
No observable adverse effect level
OCT2
Organic cation transporter 2
P-gp
P-glycoprotein 
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
RBC
Red blood cell
relative 
bioavailability
rel BA
REP
Residual Effect Period
SAE
Serious Adverse Event
SCR
Screening
SOP
Standard Operating Procedure
SRD
Single-rising dose
SYK
Spleen Tyrosine Kinase


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t1/2
Terminal half-life of the analyte in plasma
T2
T type 2 inflammation
tid
three times a day
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TMF
Trial Master File
TS
Treated set
TSAP
Trial Statistical Analysis Plan
TSH
Thyroid Stimulating Hormone 
tz
Time of last measurable concentration of the analyte in plasma
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WBC
White blood cell
WHO
World Health Organization
WOCBP
Woman of childbearing potential
XTC
Ecstasy
ZAP70
Zeta-chain-associated protein kinase of 70 kDa
β
Slope parameter of linear regression line
λz
Terminal rate constant in plasma


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1.
INTRODUCTION
BI 894416 is a selective inhibitor of the non-receptor protein tyrosine kinase SYK (spleen 
tyrosine kinase) and is under clinical development to be orally administered for the indication 
of uncontrolled severe persistent asthma.
This trial will be performed to investigate the safety, tolerability, and pharmacokinetics of 
single rising oral doses of BI 894416 versus placebo in healthy Japanese male subjects.
1.1
MEDICAL BACKGROUND
Asthma is a heterogeneous disease characterized by a chronic inflammatory process of the 
airways and is 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, natural killer (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-cells, 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, which are present 
on macrophages, dendritic cells, and neutrophils. Furthermore, SYK has important roles in B-
cell and T-cell development, having 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.
Clinical Experience in Humans
1.2.1
Summary of clinical trials
1.2.1.1
So far, BI 894416 was investigated in 4 phase I clinical trials in healthy male subjects and in 
one phase I clinical trial in mild asthma patients. Trial 1371-0001 was a first-in-man trial,
trial 1371-0004 was a trial to investigate drug-drug interaction, trial 1371-0021 investigated 
the effect of a high-fat, high-calorie breakfast on BI 894416 absorption and trial 1371-0005 


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investigated the drug-drug interaction of rifampicin on BI 894416 metabolism. Trial 1371-
0008 is an ongoing single-rising dose (SRD)/ multiple-rising dose (MRD) trial in mild 
asthma patients.
Trial 1371-0001 consisted of two parts. SRD part and a relative bioavailability (rel BA) part. 
Single-dose treatment up to 70 mg BI 894416, as an oral solution in the SRD part, as well as 
in the relative BA part, was safe and well tolerated. For details on safety and tolerability, as 
well as on pharmacokinetics and biomarker data of trial 1371-0001, refer to the IB 
[c03536505].
Trial 1371-0004 investigated the effect of strong inhibition of CYP3A, as well as the
inhibition of P glycoprotein, on the pharmacokinetics of oral single dose of BI 894416. In this
trial, 3 mg of BI 894416 was given in period 1. Period 2 consisted of a 3-day pre-treatment 
with 200 mg itraconazole being administered once a day, of a fourth dose of itraconazole 
being administered 1 h before BI 894416 administration, and of a fifth dose of itraconazole 
being administered 23 h after BI 894416 administration. Preliminary pharmacokinetic (PK)
data (based on planned time points) indicated that administration of itraconazole increased 
the geometric mean (gMean) of Cmax, AUC (area under the curve) 0-tz, and AUC0-∞of 
BI 894416 in plasma by 1.13, 1.42, and 1.43 fold respectively. BI 894416, alone or together 
with itraconazole, was assessed as safe and well-tolerated in trial 1371-0004. For more details 
refer to the IB [c03536505].
Trial 1371-0021 investigated the relative bioavailability of BI 894416 as tablet formulation 
following a high-fat, high calorie breakfast compared with administration in the fasting state. 
When 30 mg BI 894416 was administered as immediate release tablets after high-fat high 
calorie meal, Cmax was reduced by approximately 30% with a 2 h delay of tmax. AUC0-tz and 
AUC0-∞were not changed by food intake. BI 894416 immediate release tablets can therefore 
be taken under fasting and fed conditions. For more details refer to the IB [c03536505].
Drug interaction of BI 894416 at a dose of 50 mg with strong CYP3A4- and P-gp-inducer
Rifampicin has been investigated in trial 1371-0005. Relative bioavailability of BI 894416 
after 600 mg once daily Rifampicin administration decreased to 10.48% for AUC0-∞and 
30.03% for Cmax.
Trial 1371-0008 is a combined SRD and MRD trial conducted in mild asthma patients in 
Germany. As of May 2020, preliminary PK data are available for single doses up to 170 mg 
from the SRD part, and up to 50 mg tid. dosing in the MRD part. In the MRD part a single 
dose was administered on Day 1, followed by 7 d tid. dosing and a single dose on day 9. PK 
profiles were taken on Day 1 and on Day 9.
Clinical pharmacokinetics
1.2.1.2
In the 1371-0008 trial after each dose group, samples were analysed for BI 894416. A 
calculation of preliminary PK parameters was done based on planned sampling times; 
therefore PK parameters in the final Clinical Trial Report (CTR) might deviate. Preliminary 
PK parameters were assessed prior to each dose escalation to ensure that predicted gMean of 


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Cmax of patients did not exceed 5,233 nM, predicted gMean values for AUC0-24 did not 
exceed the maximum acceptable human exposure of 36,150 nM•h and that the upper limit of 
the 95% prediction interval for AUC0-24 of individual patients in the next dose group did not 
exceed 63,000 nM•h. Preliminary PK data from SRD part are shown in Table 1.2.1.2: 1 and 
from MRD part in Table 1.2.1.2: 2.
SRD part: AUC0-24 and Cmax increased dose proportionally with increasing doses. At 170 mg 
the gMean exposure limit for Cmax was met.
MRD part: trough values (data not shown) indicate that steady state was achieved after 4 
days. After 7 days of tid. dosing, Cmax,ss as well as AUCτ,ss increased with increasing dose and
were well below the exposure limits described above.
Table 1.2.1.2: 1
Preliminary PK data from SRD part in 1371-0008
Dose group
N
AUC0-24 [nM•h/L]
Cmax [nM]
75 mg qd
7
15200 (38.2)
2340 (29.7)
125 mg qd
7
25700 (29.9)
4128 (26.1)
170 mg qd
8
31700 (20.6)
5280 (24.3)
gMean (gCV%)
Table 1.2.1.2: 2
Preliminary PK data from MRD part in 1371-0008
Dose group
N
AUCτ,ss
[nM•h/L]
AUC0-24,ss* 
[nM•h/L]
Cmax [nM]
10 mg tid.
7
1470 (48.6)
4410
299 (42.7)
25 mg tid.
8
4800 (19.8)
14400
985 (19.4)
50 mg tid.
7
5400 (33.5)
16200
1290 (52.1)
gMean (gCV%)
*AUC0-24,ss is calculated with AUCτ,ss to get the daily exposure for tid. dosing under steady 
state conditions.
Safety
1.2.1.3
A total of 186 subjects and patients have completed treatment with BI 894416 as part of 
the Phase I trials. In the completed trials in healthy volunteers, the doses studied ranged 
from 3 mg to 70 mg BI 894416 given as single doses. In the patient trial 1371-0008, doses 
ranged from 75 mg to 170 mg BI 894416 administered as single doses and from 10 mg tid 
to 50 mg tid BI 894416 administered as multiple doses for 7 days.  
Phase I trials in healthy volunteers (1371-0001, 1371-0004, 1371-0005, 1371-0021)
No deaths, serious adverse event (SAE)s, AEs leading to discontinuation, protocol-
specified AESIs, or other significant AEs (according to ICH E3) were reported in the 
Phase I trials. No dose dependent increase in frequency of AEs or drug-related AEs was 
observed with increasing doses of BI 894416 across the range of 3 mg to 70 mg. For more 
details on AEs by individual dose group, please consult the IB [c03536505].  


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In the ongoing SRD/MRD trial in asthma patients, 46 of the planned 64 patients were 
exposed to BI 894416 and 12 of the planned 16 patients received placebo. A total of 7 
patients received 75 mg BI 894416,  8 patients received 125 mg BI 894416 and 8 patients 
received 170 mg BI 894416 in the single rising dose part of the trial (Table 1.2.1.3: 1). In 
addition, 7 patients received 10 mg tid BI 894416 while 8 patients in each arm of the 25 
mg tid and 50 mg tid BI in the MRD part received BI 894416. None of the patients in this 
trial had SAEs, AESIs (i.e. hepatic injury).
One patient had a severe AE of back pain in the 25 mg tid group. This event was not 
deemed related to trial medication. One patient in the 50 mg tid dose group had an event of 
panic attack which was moderate in intensity and led to discontinuation of trial medication
but was not deemed related to BI 894416. 
Taking into account the number of currently included patients, more patients on BI 894416 
were reported with AEs compared with placebo. The AE, which was most frequently 
reported after intake of BI 894416, was headache (overall 14 of 29 patients in the SRD
portion (48.3%) and 6 of 29 patients in the MRD portion (20.7%). Two patients on placebo in 
the MRD reported headache while the other reported events of headache were taking BI 
894416 in SRD and MRD parts. 
Nausea was reported in 2 of 29 patients in the SRD part (6.9%). Both events were reported in 
the 170 mg dose arm. Nausea was also reported in the MRD part for 1 of 29 patients (3.4%) 
in the 10 mg tid arm. Flatulence was reported for 4 of 29 patients (13.8%) in the 25 mg tid.
One patient reporting flatulence was taking placebo while the remaining three were taking BI 
894416. 
Two patients of 29 (6.9%) in the 25 mg tid dose group reported oropharyngeal pain and both 
patients were on active treatment.  Bronchospasm was reported in 1 patient in the 25 mg tid 
dose group and in 1 patient in the 50 mg tid dose group. Lower respiratory tract infection was 
reported in 1 patient in the 10 mg tid and in 1 patient in the 25 mg tid dose group. All other 
AEs were documented for at most 1 patient overall.
Likewise, headache was mostly classified as drug related by the investigator in 7 of 29 
patients in the SRD part (24.1%) and in 4 of 29 patients (13.8%) in the MRD part. The three 
events of nausea observed in the trial were reported as related to trial medication. Other drug-
related AEs were reported by at most 1 patient per preferred term and included tension 
headache, soft faeces and diarrhoea. 
The events of flatulence reported in the 25 mg tid dose arm were reported as related to trial
procedure as the patients received meals with higher fiber content than their normal diets.  
The safety information displayed for the 1371-0008 trial in patients is preliminary data taken 
from the ongoing trial. As such, the information reported in this protocol may differ slightly 
from the reported AEs in the clinical trial report.


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Table 1.2.1.3: 1
Overall summary of AEs in ongoing trial 1371-0008 – Treated set
SRD Part
MRD Part
Category of AE
Placebo
N (%)
75 mg
BI 894416
N(%)
125 mg
BI 894416
N(%)
170 mg
BI 894416
N(%)
Placebo
N(%)
10 mg
BI 894416
N(%)
25 mg
BI 894416
N(%)
50 mg
BI 894416
N (%)
Treated Patients
6 (100.0)
7 (100.0)
8 (100.0)
8 (100.0)
6 (100.0)
7 (100.0)
8 (100.0)
8 (100.0)
Any AE
1 (16.7)
5 (71.4)
5 (62.5)
7 (87.5)
4 (66.7)
5 (71.4)
5 (62.5)
5 (62.5)
Severe AEs1
0
0
0
0
0
0
1 (12.5)
0
Investigator defined 
drug−related AEs
0
2 (28.6)
3 (37.5)
4 (50.0)
1 (16.7)
2 (28.6)
0
2 (25.0)
AEs leading to 
discontinuation of trial 
medication
0
0
0
0
0
0
0
1 (12.5)
AEs of special interest
0
0
0
0
0
0
0
0
Serious AEs
0
0
0
0
0
0
0
0
Other significant AEs 
(ICH E3)
0
0
0
0
0
0
0
0
1
Worst intensity recorded
(c32087967)
Residual Effect Period
1.2.2
The Residual Effect Period (REP, i.e., the period after the last dose with measurable drug 
levels and/or with pharmacodynamic effects likely to be present) of BI 894416 has not been 
defined yet. However, the elimination half-life of BI 894416 is short (gMean terminal half-
life between 2.96 and 5.31 h in the SRD part of trial 1371-0001) and its mode of action is 
reversible. This suggests that the occurrence of any potential adverse effects would likely be 
limited to a short time period (i.e., few days).
Conservatively, a minimum period of 14 d after last administration of BI 894416, or placebo,
has been selected as the REP. Therefore, the individual subject’s end of trial will be 14 d 
following last dosing with BI 894416, or placebo, at the earliest. 
All adverse events (AE) reported between administration of trial medication and the 
individual subject’s end of trial will be counted as on-treatment AEs.
Drug product
1.2.3
Please refer to Section 4.1. For a more detailed description of the BI 894416 profile, please 
refer to the current IB [c03536505].


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1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 894416 is an SYK inhibitor that is being developed to be administered orally to treat
patients with severe asthma.
The first single rising dose trial was conducted in healthy volunteers (1371-0001). In trial 
1371-0001 doses of BI 894416 up to 70 mg were given and assessed as safe and well-
tolerated. 
The objective of this trial is to investigate the safety, tolerability, and pharmacokinetics of BI 
894416 in healthy Japanese male subjects. The chosen population of healthy male subjects 
receiving single rising oral doses is considered adequate to provide the basis for the clinical 
development program of BI 894416 in Japan.
In this trial it is intended to investigate the safety and tolerability of 25 mg, 50 mg, and 70 mg
single dose.
The dose range selected for this trial is expected to cover the potential therapeutic dose range 
in the further clinical development program of BI 894416.
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 trial procedures and risks related to the exposure to the trial 
medication.
Procedure-related risks
1.4.1
The use of an indwelling venous catheter or venepuncture for procedures such as blood 
sampling may result in mild bruising and, in rare cases, in transient inflammation of the wall 
of the vein, or in nerve injury that potentially results in paraesthesia, reduced sensibility, 
and/or in 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 trial will not exceed the 
volume of a normal blood donation (approximately 500 mL). No health-related risk to 
healthy subjects is expected from withdrawal of this volume of blood.
To ensure patient safety, all such events or symptoms reported will be managed according to 
the judgement of the Investigator.


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Drug -related risks and safety measures
1.4.2
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 of BI 894416 (see also IB [c03536505]).

Due to the reversible mode of action of BI 894416 with regards to SYK inhibition, 
any potential effect on immune cells are expected to be of transient nature.
Risk mitigation and monitoring: Subjects with a history or diagnosis of 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 C-Reactive Protein.
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 SYK inhibitor, BI 1002494, are in line with an absence of 
carcinogenic effect due to the inhibition of SYK enzymatic function [n00243171]. 
Risk mitigation and monitoring: Only male subjects are included in this trial and, in view that 
carcinogenesis is a process that develops over a long time span, single doses of BI 894416 are 
not considered a relevant carcinogenic risk to the male subjects participating in this trial. 
Accordingly, no further risk mitigation is required in this trial. 
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 Glycoprotein VI), but others 
are independent of SYK [R16-5240]. In vitro trials using human platelets demonstrated that,


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at concentrations up to 100 μM, BI 894416 had no effect on extrinsic or intrinsic coagulation 
pathways. Also, BI 894416 did not inhibit adenosine diphosphate-induced platelet 
aggregation up to 100 μM. However, BI 894416 inhibited collagen- and arachidonic acid-
induced platelet aggregation at 3 μM and 5 μM, respectively. 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. In line with this conclusion, data of previous trial 1371-0001 do not 
indicate any signs of an increased risk of bleeding.
Risk mitigation and monitoring: Use of any other concomitant drug that could reasonably 
inhibit platelet aggregation, or coagulation, such as acetylsalicylic acid, clopidogrel and 
warfarin, will be prohibited (see Sections 3.3.3 and 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 single doses of 
BI 894416. Due to the slow turnover of bone tissue, no relevant effect on bone density is 
expected due to single-dose administrations with BI 894416 in this trial, and no specific 
monitoring of bone density is necessary in this trial.
Mortality/morbidity in preclinical trials
Mortality/sacrifice due to morbidity occurred in CByB6F1 non-transgenic mice and in Wistar 
Han rats. Clinical signs preceding morbidity were similar in both rodent species and included 
respiratory changes (rapid, shallow, and/or labored breathing), decreased motor activity, 
ruffled fur, hunched or prostrate posture, eye changes (squinting, discharge) and/or 
hypothermia. One humane sacrifice due to overt neurotoxicity was done in one dog of the 
3-day escalation trial. For details see the current version of the IB [c03536505]. 
Risk mitigation and monitoring: Data of previous trial 1371-0001 indicate good safety and 
tolerability of BI 894416 at all investigated doses (single oral doses up to 70 mg). The dose of 
BI 894416 given in this trial is equivalent to or lower than doses given previously to healthy 
subjects. That means, BI 894416 plasma exposures that are expected in this trial are in the 
range measured previously in trial 1371-0001 and that were associated with good safety and 
tolerability. Moreover, subjects will be in-house at the trial site, under close medical 
observation for 48 h after administration of BI 894416. Vital signs and ECGs will be 
measured during the trial, and subjects will be instructed to report AEs spontaneously and 
will be asked, at time points defined in the Flow Chart for AEs. In case of AEs in need of 
treatment, the investigator can authorize symptomatic therapy. In those cases, subjects will be 
treated as necessary and, if required, kept under supervision at the trial site, or transferred to 
another hospital, until all medical evaluation results have returned to an acceptable level.
Neurotoxicity


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In dog toxicology trials, acute adverse neurological effects, such as tremor and movement 
disorder assessed as dyskinesia (paresis/rigidity), were observed at high exposures (see IB 
[c03536505]). One dog was euthanized due to overt neurotoxicity in 3-day escalation trial at 
90 mg/kg/day. In dose escalation trial in dogs with assessment of neurotoxicity [n00245394], 
all clinical signs of neurotoxicity were reversible with cessation of dosing. No structural 
changes were observed in histopathology. Peripheral nerve conduction velocity and 
electroencephalogram were unchanged. No specific mechanism causing the neurological
effects in dogs has been elucidated. Therefore, it has not been determined whether the 
neurological changes are species specific; however, external expert review considered this is 
most likely a channelopathy specific to dog and not likely to occur in man (see IB
[c03536505]). 
Risk mitigation and monitoring: Subjects with neurological disorder or medical history of 
relevant neurological disorder are excluded from trial participation (see Section 3.3.3). 
Neurological examinations, as described in Section 5.2.5.1, will be performed at screening, 
and subjects with clinically relevant findings in the neurological examination will be 
excluded from trial participation (see Section 3.3.3). If necessary according to the 
investigator, unscheduled neurological examinations may be performed at any time during 
the trial. Relevant findings in the neurological examination during the trial will be reported as 
AEs. If necessary, subjects may be sent for further, more specific evaluation and treatment to 
a local neurologist. 
Genotoxicity, reproductive and developmental toxicity
Genetic toxicology results indicate that BI 894416 is not mutagenic or clastogenic. In the 2-
week repeat dose range finding trial 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. 
Therefore, there is a theoretical risk of a sub therapeutic exposure to BI 894416, or its 
metabolites, for a woman of child bearing potential (WOCBP) via the semen of a trial
subject. Developmental and reproductive trials have not yet been conducted. Therefore, the 
effect of sub therapeutic concentrations of BI 894416, or its metabolites, with regards to 
embryofetal development has not been explored so far. 
Risk mitigation: In order to address the risk of exposing an WOCBP 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
Phototoxicity potential of BI 894416 was measured in the open-lid Neutral Red Uptake test.
There was no indication of phototoxicity by BI 894416. Subjects will be advised to avoid 
direct exposure to sun and UV light during the entire trial (see Section 4.2.2.2). Further 
protective measures would not be necessary given the low phototoxic potential of BI 894416
(see IB [c03536505]).


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Potential effects on QT interval
Preclinical trials suggested no proarrhythmic potential or cardiovascular liability with 
BI 894416. However, statistical results of first-in-man trial 1371-0001 suggested a 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% confidence interval (CI) was 10.5 ms). 
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 20), and subjects with a 
history of additional risk factors for Torsade de Pointes arrhythmia (Section 3.3.3, exclusion 
criterion 21) are excluded from trial participation. Moreover, subjects will be in-house under 
close observation for 48 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 1371-0003 due to potential effects on QT interval are 
considered minimal.
Liver toxicity
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by the sponsor. 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.
Overall assessment
1.4.3
BI 894416 is a highly specific SYK inhibitor that has been adequately characterised in pre-
clinical trials. The non-clinical safety package supports administration of BI 894416 for up to 
4 weeks duration to men. 
Data of trial 1371-0001 indicate good safety and tolerability of single oral doses of BI 
894416 at all dose levels 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 subjects (see IB [c03536505]).
BI 894416 plasma exposures in the current trial are expected to be within plasma exposure 
values that were observed in previous first-in-man trial 1371-0001 and SRD and MRD trial in 
mild asthma patients 1371-0008 and that were associated with good safety and tolerability.
Considering the medical need for treatment of uncontrolled severe persistent asthma and the 
potential advantage of a highly specific SYK, the sponsor considers that the benefit of this 
trial outweighs the potential risks.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
2.1.1
The main objectives of this trial are to investigate safety and tolerability of BI 894416 in 
healthy male subjects following oral administration of single rising doses.
Secondary objective is the exploration of PK of BI 894416.
Primary endpoint
2.1.2
The primary endpoint for assessment of safety and tolerability of BI 894416 is the percentage
[%] of subjects with drug related adverse events.
Secondary endpoint
2.1.3
The following pharmacokinetic parameters will be determined for BI 894416, if feasible:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
Safety and tolerability
2.2.2.1
Safety and tolerability of BI 894416 will be assessed based on:  
•
Adverse events (including clinically relevant findings from the medical examination,
neurological examination and continuous ECG monitoring)
•
Safety laboratory tests
•
12-lead ECG
•
Vital signs (blood pressure, pulse rate)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This single rising dose trial is designed as single-blind, randomised, and placebo-controlled 
within dose groups.
It is planned to include a total of 24 healthy male subjects in the trial. The subjects will be 
assigned to 3 groups consisting of 8 subjects per group; the groups will be dosed sequentially 
(see Table 3.1: 1).
The trial schedule and design is depicted in Figure 3.1: 1 and 3.1:2
Figure 3.1: 1 
Overview of trial schedule
Figure 3.1: 2
Trial design
Within each dose group, 6 subjects will receive BI 894416 and 2 will receive placebo. Only 
one dose is tested within each dose group.
The dose groups to be evaluated are outlined in Table 3.1: 1 below.


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Table 3.1: 1
Dose groups
Dose Group
1
2
3
Dose (mg)
25
50
70
Number of subjects
8
8
8
Subjects receiving placebo
2
2
2
Subjects receiving active drug
6
6
6
The groups will be dosed consecutively in ascending order of the doses, and a time interval of 
at least 7 d will be maintained between the last drug administration to subjects in the previous 
dose group (dose group N) and the first drug administration to subjects in the subsequent 
dose group (dose group N+1). The decision to treat the next dose group will be based upon 
safety and tolerability of all the preceding dose groups. The next dose group will only be 
treated if, in the opinion of the investigator (or authorised deputy, Sub Investigator), and 
Clinical trial leader (CTL), no safety concerns have arisen in the preceding dose groups, i.e. 
no dose-limiting events occurred, and if none of the pre-specified trial-specific stopping 
criteria have been met (refer to Section 3.3.4).
A documented safety review must take place prior to each dose escalation. Furthermore, an 
unscheduled safety review meeting can be requested anytime for any reasonable cause by the 
Principal Investigator, or an authorised deputy, Sub Investigator, or the sponsor of the trial,
e.g. in case of any unforeseen adverse events. Dose escalation will only be permitted if no 
safety concerns exist in the opinion of the Principal Investigator (or an authorised deputy,  
Sub Investigator) and the CTL.
Although no formal Safety Review meeting will take place within a given dose group, safety 
will be continuously monitored during this trial, and an individual will only be dosed in the 
absence of any safety concern, i.e. no dose-limiting events occurred, and if none of the pre-
specified trial-specific stopping criteria have been met (refer to Section 3.3.4).
At minimum, data from 4 subjects on active drug need to be available for escalation to a 
higher dose. The minimum data set for review consists of the following:

AEs in the current and preceding dose groups up to at least 7 d post dosing including 
clinically relevant findings from ancillary safety testing listed below (Note: AEs may 
be ongoing at the time of Safety Reviews and AE information may be subject to 
change prior to Database Lock)

Results from 12-lead ECG in the current and preceding dose groups up to at least 3 d
post dosing

Vital signs in the current and preceding dose groups up to at least 3 d post dosing.

Clinical laboratory tests in the current and preceding dose groups up to at least 7 d
post dosing

Review of criteria for stopping subject treatment as per Section 3.3.4.1


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The decision to escalate the dose will be made jointly by the Principal Investigator, or an 
authorised deputy, Sub Investigator, and the CTL after in-depth analysis of all available 
safety data, especially SAEs, AEs, and out-of-range laboratory results that are considered 
clinically significant by the investigator. Dose escalation will only be permitted if no safety 
concerns exist neither in the opinion of the Principal Investigator (or an authorised deputy, 
Sub Investigator) and the CTL. 
Safety Reviews can be conducted face-to-face or by video/telephone conference. The CTL is 
responsible for the organisation and minutes of the reviews. Minutes will be signed off by the 
Principal Investigator (or an authorised deputy, Sub Investigator) and CTL, and will be filed 
in the investigator site file (ISF) and trial master file (TMF). 
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
For single -rising dose trials, the sequential rising dose design described in Section 3.1 is 
viewed favourably under the provision not to expose the subjects to undue risks, since the 
main trial objective is to investigate safety and tolerability of BI 894416.
Single-blind conditions regarding the subject’s treatment (active or placebo) are maintained 
within each dose group. However, subjects and investigators will be aware of the dose of the 
drug administered. The disadvantage of this trial design is a possible observer bias with 
regard to the dose-dependent effects; in addition, the sequential dosing of groups could 
potentially result in time-related effects. However, as such effects are expected to be small 
relative to the differences between the doses in the broad range investigated, unbiased 
comparisons between treatments can still be expected.
It is standard in single rising dose trials involving healthy subjects to include a placebo group 
to control for safety and tolerability of the trial medication. Each dose group consists of 8 
subjects, with 6 on active treatment, and 2 on placebo. For data analysis purposes, the 
placebo control group will include all subjects that were treated with placebo, regardless of 
the groups they were treated. Six subjects per active treatment group are generally considered 
to be sufficient for the exploratory evaluation of pharmacokinetics.
For this trial, 25 mg has been selected as the minimum dose, which may be required to 
achieve therapeutic systemic exposure to BI 894416. However, higher doses might still be 
well tolerated while providing a larger magnitude of therapeutic effects. Finally, even if the 
therapeutic dose is determined to be as low as 25 mg, higher than therapeutic doses are 
typically explored in Phase I trials to provide a safety margin for following trials e.g., drug-
drug-interaction trials, trials with patients with impaired excretion function, etc., where 
substantial increases in exposure may be seen.
Also, 70 mg has been selected as the maximum dose, a dose that is expected to be high 
enough to obtain exposure in the therapeutic range. The human exposure cap was a Cmax
gMean value of 5,233 nmol/L, AUC0-24 gMean value of 36,150 nmol·h/L, AUC0-24 the upper 
limit of 95% prediction interval of 63,000 nmol·h/L. The exposure cap of AUC0-24 gMean 
corresponded to 3-fold below exposure at the dog NOAEL and 7-fold below the lowest 


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exposure in dogs where neurologic effects were observed (for more details, please see the 
current version of the Investigator’s Brochure (IB) [c3536505]). Cmax gMean, AUC gMean 
and the upper limit of 95% prediction interval value are predicted to be below the exposure 
cap (Table 3.2: 1); therefore, single administration of 70 mg are considered safe.
Table 3.2: 1
Predicted PK parameters 
Dose
AUC0-24
[nmol·h/L]
gMean
Exposure 
multiple1
AUC0-24
[nmol·h/L]
95%ile
Exposure 
multiple2
Cmax
[nmol/L]
gMean
Exposure 
multiple3
70 mg single
13973
2.59
26232
2.4
2177
2.4
Note: A population with a mean body weight of 65 kg (17% arithmetic coefficient of variation [CV]) was used in the 
simulations to predict the between subject variability.
1 in relation to AUC gMean exposure limit (36,150 nmol·h/L)
2 in relation to 95th percentile exposure limit (63,000 nmol·h/L)
3 in relation to Cmax gMean exposure limit (5,233 nmol/L)
3.3
SELECTION OF TRIAL POPULATION
It is planned that 24 healthy male subjects will enter the trial. These subjects will be recruited 
from the volunteers' pool of the trial site. 
Only male subjects will be included in the trial because no data on reproductive toxicology 
are available at this time.
A log of all subjects enrolled into the trial, i.e. who have signed informed consent, will be 
maintained in the ISF, irrespective of whether they have been treated with investigational 
drug or not.
Main diagnosis for trial entry 
3.3.1
Not applicable, as the trial will be performed in healthy subjects.
Inclusion criteria
3.3.2
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history, including a medical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests
2. Japanese ethnicity, according to the following criteria:
-
born in Japan, have lived outside of Japan <10 years, and have parents and 
grandparents who are Japanese
3. Age of 20 to 45 years (inclusive) at screening
4. BMI of 18.5 to 25.0 kg/m2 (inclusive) at screening
5. Signed and dated written informed consent prior to admission to the trial, in accordance 
with Good Clinical Practice (GCP) and local legislation


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6. Subjects who agree to minimize the risk of making their partner pregnant by fulfilling any
of the following criteria starting from the first administration of trial medication until 90
days after last administration of trial medication
-
Use of adequate contraception, any of the following methods plus condom:
intrauterine device, combined oral contraceptives that started at least 2 months
prior to the first drug administration.
-
Vasectomized (vasectomy at least 1 year prior to enrolment)
-
Surgical sterilization (including bilateral tubal occlusion, hysterectomy or bilateral
oophorectomy) of the subject’s female partner
Exclusion criteria
3.3.3
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication, except appendectomy or simple hernia repair
7. Diseases of the central nervous system, including but not limited to, any kind of seizures 
or stroke, and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections (Subjects who were positives to Hepatitis B surface 
antigen, Hepatitis B surface antibody, Hepatitis B core antibody, Hepatitis C antibodies, 
HIV-1 and HIV-2 antigen and/or antibody, T-SPOT and Syphilis test)
10. History of relevant allergy or hypersensitivity, including allergy to the trial medication or 
its excipients 
11. Use of drugs within 30 d 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 d 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 12 months prior to first planned 
administration of trial medication
14. Inability to refrain from smoking during trial
15. Alcohol abuse, i.e. consumption of more than 30 g per day
16. Drug abuse or positive drug screening


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17. Blood donation of more than 400 mL within 12 weeks, or 200 mL within 30 d, or plasma 
donation within 2 weeks prior to administration, or intended blood donation during the 
trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval, such as QTc intervals that are 
repeatedly greater than 450 ms, or any other relevant ECG finding at screening 
21. A history of additional risk factors for Torsade de Pointes, such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome 
22. Subject is assessed by the investigator as unsuitable for inclusion, because, for instance,
the subject is not considered able to understand and comply with trial requirements, or 
has a condition that would not allow safe participation in the trial
23. History of disease that affects the present situation
In addition, the following trial-specific exclusion criteria apply:
24. History of relevant neurological disorder affecting the peripheral or central nervous 
system, including, but not limited to, stroke, epilepsy, inflammatory or atrophic diseases 
affecting the nervous system, cluster headache or any cancer of the nervous system*
25. 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
26. History of cancer, except successfully treated basal cell carcinoma
27. Use of any drug that could reasonably inhibit platelet aggregation or coagulation, e.g. 
acetylsalicylic acid, within 10 d prior to administration of trial medication, or planned use 
during the trial or within 7 d after last dose of trial medication
* 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.
For trial restrictions, refer to Section 4.2.2.
Withdrawal of subjects from treatment or assessments
3.3.4
Subjects may discontinue trial treatment, or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’), with very different implications; please see sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from, or withdraws from, the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from, or 
withdraws from, the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR.
At the time of discontinuation, a complete end of trial examination will be performed, if 
possible, and the information will be recorded in the CRF. If the discontinuation occurs 


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before the end of the REP (see Section 1.2.2), the discontinued subject should, if possible, be 
questioned for AEs and concomitant therapies at, or after, the end of the REP in order to 
ensure collection of AEs and concomitant therapies throughout the REP, if not contrary to 
any consent withdrawal of the subject.
Discontinuation of trial treatment
3.3.4.1
An individual subject will be removed from the trial if:
1. The subject wants to discontinue trial treatment or trial participation , without the need to 
justify the decision
2. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
3. The subject can no longer able to participate trial for other medical reasons, such as 
surgery, adverse events (AE)s, or diseases
4. The subject has an elevation of AST and/or ALT ≥3-fold upper limit of normal (ULN)
and an elevation of total bilirubin ≥2-fold ULN, as measured in the same blood sample,
and/or needs to be followed up according to the DILI checklist provided in the ISF
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at trial assessments).
Withdrawal of consent to trial participation
3.3.4.2
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.
Discontinuation of the trial by the sponsor
3.3.4.3
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. Dose escalation will be terminated if more 
than 50% of the subjects at one dose level show clinically relevant drug-related adverse 
events of moderate or severe intensity, or if at least one drug-related serious adverse event 
is reported
3. Deviation from the clinical trial protocol (CTP), violation of GCP, or violation of the 
contract with BI, impairing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational product


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Addition to this, dose escalation will be stopped if at least 2 subjects on active treatment at 
one dose level have relevant individual QT prolongations, i.e. a QTc increase greater than 60 
ms from baseline in connection with an absolute QT or QTc greater than 500 ms, as
confirmed by a repeat ECG recording.
The investigator/trial site will be reimbursed for reasonable expenses incurred in case of trial 
termination, except if item 3 applies.
Replacement of subjects
3.3.5
If some subjects do not complete the trial, the CTL, together with the Trial 
Pharmacokineticist and the Trial Statistician, are to decide if and how many subjects will be 
replaced. A replacement subject will be assigned a unique trial subject number, and will be 
assigned to the same treatment as the subject he replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product BI 894416 as tablet formulation has been manufactured by BI 
Pharma GmbH & Co. KG.
Identity of the Investigational Medicinal Products
4.1.1
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 and 25 mg, 
Posology:
single dose
Route of administration:
oral
Duration of use:
Single dose
The characteristics of the reference product (placebo) are given below:
Substance:
Placebo 
Pharmaceutical formulation:
Tablet
Source:
BI Pharma GmbH & Co. KG, Germany 
Unit strength:
Not applicable
Posology:
single dose
Route of administration:
oral
Duration of use:
Single dose 
Selection of doses in the trial and dose modification
4.1.2
The dose range of BI 894416 for this trial was selected on the basis of the data obtained in the 
first-in-man SRD trials 1371-0001 and 1371-0008. So far, single doses up to 70 mg in 
healthy subjects and single doses up to 170 mg in asthma patients in fasting status was well 
tolerated.
Method of assigning subjects to treatment groups
4.1.3
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups 
according to their temporal availability. As soon as enough subjects are allocated to 1 of the 3 
dose groups, the following subjects will be allocated to one of the other dose groups and so 


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on until the dose groups are completed. Therefore, the allocation of subjects to dose groups is 
not influenced by trial personnel, but only by the subjects’ temporal availability. Because the 
trial is conducted on healthy subjects from a homogenous population, relevant imbalances 
between the dose groups are not expected. 
Subjects will be assigned to treatments (active treatment or placebo) prior to the first 
administration of trial medication. For this purpose, the randomisation list will be provided to 
the trial site in advance. Numbers of the randomization list will be allocated to subjects by the 
method ‘first come first served’. Subjects are then assigned to treatment 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.
Drug assignment and administration of doses for each subject
4.1.4
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The number of tablets for 
placebo corresponds to the number of tablets in the corresponding dose level.
Table 4.1.4: 1
BI 894416 and placebo* treatments, tablets 
Dose
group
Substance
Pharmaceutical 
form
BI 894416  10 mg
BI 894416  25 mg
Total dose of BI 894416
1
BI 894416
Tablet
0
1
25 mg
2
BI 894416
Tablet
0
2
50 mg
3
BI 894416
Tablet
2
2
70 mg
1-3
Placebo*
Tablet
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups
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. 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. 
During the first 4 h after drug administration, the subjects are not allowed to lie down, i.e. no 
declination of the upper body of more than 45 degrees from upright posture except for 
medical examination, or to sleep.
Subjects will be kept under close medical surveillance until 48 h after dosing.
For restrictions with regard to diet, see Section 4.2.2.2.


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Blinding and procedures for unblinding
4.1.5
Blinding
4.1.5.1
The trial is designed single-blind. The treatments administered (active or placebo) will be 
blinded to subjects, but will be known to the investigators (outcome assessors). Only the 
current dose level will be known to the subjects due to the rising dose design.
A single–blind design is considered acceptable, because the potential bias in this type of trial
seems to be low and, according to trial procedures, it is assured that the investigator's 
knowledge of the next treatment does not influence the decision to enter a subject. 
All trial data will be handled open label. This means that trial functions of the sponsor are 
unblinded, including clinical monitor, data manager, statistician, bioanalyst, 
pharmacokineticist, pharmacometrician, drug metabolism scientist, as well as dedicated 
personnel of the trial site. 
Within the central ECG lab, the staff involved with interval measurements will be blinded 
with respect to the treatment and also with regard to the recording date and time, as well as to 
the planned time points of the ECGs. The interval measurements for a given subject will be 
performed in a random and blinded sequence by a single technician.
If an interim safety analysis of ECG data is required, a part of the staff of the central ECG lab 
may be unblinded. This part of the staff will be strictly separated from the blinded staff 
members who will be involved with ECG interval measurements and assessments of ECGs.
Access to the randomisation schedule will be controlled and documented.
Unblinding and breaking the code
4.1.5.2
As this trial will be conducted single blind, subjects’ treatment assignments will be known to 
investigators. Therefore, no emergency envelopes will be provided.
Packaging, labelling, and re-supply
4.1.6
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 on packaging and for the description of the label, refer to the ISF.
The telephone number of the sponsor, as well as the name, address, and telephone number of 
the trial site are provided in the subject information form. Examples of the labels will be 
available in the ISF.
No re-supply is planned.
Storage conditions
4.1.7
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 


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Clinical Trial Manager (CTM), as provided in the list of contacts, is to be contacted 
immediately.
Drug accountability
4.1.8
The investigator, or a designee, will receive the investigational drugs from the sponsor when 
the following requirements are fulfilled:

Approval of the clinical trial protocol by the Institutional Review Board (IRB)

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/notification from the regulatory authority,  e.g. competent authority (CA)

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 adequately documenting that the subjects 
were provided the doses specified by the CTP and will 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 investigational medicinal product remains  in the 
investigator’s possession.
All unused trial medication will be disposed locally by the trial site upon written 
authorisation of the CTM. 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
Other treatments and emergency procedures
4.2.1
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can employ
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site, or transferred to another hospital, until all results of 
medical evaluations are acceptable.


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Restrictions
4.2.2
Restrictions regarding concomitant treatment
4.2.2.1
In principle, no concomitant therapy is allowed. All concomitant, or rescue therapies, will be 
recorded, including time of intake on trial days, on the appropriate pages of the CRF.
Acetylsalicylic acid, or other drugs that may inhibit platelet aggregation or coagulation,
should be avoided during the entire trial. If necessary, acetaminophen may be given 
occasionally, if required to treat an adverse event require.
Drugs that may increase exposure of BI 894416 should be avoided during the entire trial. 
Based on in vitro data, CYP3A is involved in the metabolism of BI 894416. In addition, BI 
894416 is substrate of P-glycoprotein in vitro. Data from the drug-drug interaction trial 1371-
0004 (see Section 1.2.1) indicate that inhibition of CYP3A and P-glycoprotein may cause 
mild increases of BI 894416 plasma concentrations. Therefore administration of CYP3A and 
P-glycoprotein inhibitors should be avoided during the entire trial.
BI 894416 is also a substrate of organic cation transporter 2 (OCT2). It is not excluded that 
inhibition of OCT2 could increase BI 894416 plasma exposure. Therefore administration of 
inhibitors of OCT2 should be avoided during the entire trial.
Restrictions on diet and life style
4.2.2.2
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 10 h before and 4 h after trial 
medication intake
One h before drug intake until 4 h after trial medication intake, fluid intake is restricted to the 
water administered with the trial medication, and an additional 240 mL of water served at 2 h 
and 4 h post-dose (mandatory for all subjects). From 4 h after drug intake on Day 1 until 24 h 
post-dose, fluid intake is restricted to 3 L.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges), as well as their 
juices, dietary supplements, and products containing St. John's wort (Hypericum perforatum) 
are not permitted from 7 d before the first administration of trial medication until after the last 
PK sample of each trial period is collected.
Poppy seed containing products should not be consumed starting 4 d before first 
investigational medicinal product administration until last PK sampling of the trial.
Methylxanthine-containing drinks or foods, such as coffee, tea, cola, energy drinks, or 
chocolate, are not allowed from 10 h before administration of trial medication until 24 h after 
administration of trial medication.
Smoking is not allowed during the trial.
Excessive physical activity, such as competitive sport, should be avoided from 7 d before the 
first administration of trial medication until the end of trial examination. 


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Direct exposure to the sun, or exposure to solarium radiation, should be avoided during the 
entire trial.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre and
under supervision of the investigating physician or a designee. The measured plasma 
concentrations and/or urinary excretion 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. 


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable. No efficacy endpoints will be evaluated in this trial.
5.2
ASSESSMENT OF SAFETY
Medical examination
5.2.1
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, medical examination, and neurological examination. At the end of trial examination, it 
will include review of vital signs, 12-lead ECG, laboratory tests, a medical examination and a 
neurological examination.
Vital signs
5.2.2
Systolic and diastolic blood pressures (BP), as well as pulse rate (PR), will be measured by a 
blood pressure monitor, 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 and on the same arm, if possible.
Safety laboratory parameters
5.2.3
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, except 4 h post dosing on Day 1. 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. 
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, and if clinically 
relevant in the opinion of the investigator, or if the investigator finds an abnormality in the 
urinalysis. 


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name (comment/abbreviation)
A1
B1
C1
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count (RBC) 
Reticulocytes (relative and absolute)
White Blood Cells (WBC) 
Platelet Count/Thrombocytes (quant)
Erythrocyte Sedimentation Rate (ESR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC differential, 
(relative)
Neutrophil; eosinophils; basophils; monocytes; 
lymphocytes
X
X
X
Manual differential WBC (if 
automatic
differential WBC is abnormal)
Polymorphnuclear neutrophils (segs), band neutrophils 
(stabs), eosinophils, basophils, monocytes, 
lymphocytes
Immunoglobulins in serum
IgA
IgE
IgG
IgM
X
X
X
X
--
--
--
--
X
X
X
X
Lymphocyte
differentiation (relative)
T cells (CD3+), T helper cells (CD3+CD4+), cytotoxic 
T cells (CD3+CD8+), B cells (CD19+), natural killer 
cells (CD16+CD56+CD3-), CD4:CD8 ratio
X
--
X
Coagulation
Activated partial thromboplastin time (aPTT) 
Prothrombin time (Quick’s test and INR)
Fibrinogen
X
X
X
X
X
X
X
X
X
Enzymes
AST (Aspartate transaminase)/GOT 
ALT (Alanine transaminase)/GPT
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT) 
Creatine kinase (CK); CK-MB only if CK is elevated 
Lactate dehydrogenase 
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
--
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone (TSH)
X
--
--
Substrates
Plasma glucose
Creatinine
Total bilirubin
Direct bilirubin
Total protein
C-Reactive Protein 
Uric acid
Total cholesterol
Triglycerides
X
X
X
X
X
X
X
X
X
X
X
X
X
--
X
--
--
--
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Calcium
Inorganic phosphate
X
X
X
X
X
X
X
--
X
X
X
X
1 A, B and C are different sets of laboratory values. The Flow Chart defines at what time point which set is to be investigated


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name (comment/abbreviation)
A1
B1
C1
Urinalysis (Stix)
Urine nitrite 
Urine protein 
Urine glucose 
Urine ketone 
Urobilinogen 
Urine bilirubin 
Urine erythrocytes
Urine leucocytes
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment1
(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 defines at what time point which set is to be investigated
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. Infectious serology is planned at screening only. Drug screening will be performed at 
screening and after admission to the trial site prior to dosing on Day 1 of visit 2.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/ Methylenedioxyamphetamine (MDA)
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methamphetamines/ Methylenedioxymethamphetamine 
(MDMA)/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B surface antibody (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antigen and/or antibody (qualitative)
T-SPOT
Syphilis test (RPR, TP antibody method)
Imaging test
Chest x-ray (For checking onset or history of tuberculosis) 
To encourage compliance with alcohol and smoking restrictions, a breath alcohol test and 
cotinine test will be performed during Screening Visit and before drug administration, and 


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may be repeated at any time during the trial 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 the local 
laboratory of the trial site or/and at a CRO designated by the sponsor. Laboratory data will be 
transmitted electronically from the site to BI.
Electrocardiogram
5.2.4
12-lead resting ECG
5.2.4.1
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph at the time points given in the Flow Chart. Precise electrode 
placement will be performed according to the method of 
and
,
modified by 
 and 
, i.e. hips and shoulders instead of ankles and wrists. Precise 
electrode placement will be marked with an indelible mark on the skin to allow reproducible 
placement throughout the trial.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment so that all subjects are at 
complete rest.
All ECGs will be recorded for 10 s after subjects have rested for at least 5 min in a supine 
position. ECG recording will always precede all other trial procedures scheduled for the same 
time, except for blood drawing from an intravenous cannula that is already in place, to avoid 
compromising ECG quality.
ECGs will be recorded as single ECGs or as triplicate ECGs, i.e. three single ECGs recorded 
within 180 s, as indicated in the Flow Chart.
ECGs may be repeated for quality reasons due to, for instance, alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs, the time 
window of 180 s applies as well. The repeat ECGs are assigned to the respective scheduled 
time point.
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point in the Sponsor’s database.
Storage
All ECGs will be stored electronically in the System provided by 
.
Data transfer
All triplicate ECGs will be transferred electronically to the central ECG laboratory 
 
 for evaluation.


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In case of ECGs repeated due to quality reasons, only the repeated ECG recordings will be 
transferred to the central ECG lab, whereas the initially recorded ECGs will be discarded. 
Unscheduled ECGs, i.e. those taken for safety reasons, will be transferred to the central ECG 
lab, but will not be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in a document that is filed 
in the TMF.
Evaluation
a) Central ECG lab
Central ECG lab evaluation will be performed (during the trial and/or after the trial) for 
first ECG of triplicate ECGs at every time point. For baseline, all three ECGs of the 
triplicate ECG at Day 1 pre-dose will be evaluated. This will include the determination of 
cardiac QRS-axis, as assessed by the ECG machine’s algorithm, as well as the intervals 
RR, PR, QRS, and QT measured semi-automatically. Heart rate (HR) and the QT interval 
corrected for HR, i.e. QTcF and QTcB, will be determined by the sponsor (see trial 
statistical analysis plan [TSAP] for details).
All semi-automatic interval measurements in one subject will be performed on the same 
lead. The intervals will be measured from four cardiac cycles (beats) in lead II. If lead II 
shows a flat T wave, or is not measurable for any reason, lead V5 will be used. If lead V5
is not measurable, then lead I will be used. The lead actually used will be reported in the 
CTR. For automatic interval measurements no lead will be provided
For blinding arrangements see Section 4.1.5.1. No more than two blinded readers will 
evaluate all ECGs of the trial. ECGs from a particular subject should be evaluated by a 
single reader. For quality assurance and control of the measurements, all ECGs of a 
subject will be subsequently reviewed by the ECG technician’s supervisor, or his/her 
designee, to assess the overall variance of the measured intervals, to detect accidental 
switching of leads and/or false subject assignments of the ECGs. After quality control, the 
fiducial point markings will be reviewed by the cardiologist assigned to the trial.
Evaluation of ECGs will comply with the ICH E14 guidance document and supplements 
[R07-4722, R16-0366] as well as the FDA requirements for annotated digital ECGs [R09-
4830].
b) Trial site 
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion, or exclusion, (see Section 3.3) of a subject and for the assessment of 
cardiac safety during the trial, the QT and QTcB values generated by the computerised 
ECG system, or their manual corrections by the investigators, will be used. In doubtful 
cases, ECGs may be sent upfront, i.e. prior to the regular data transfer, for cardiologic 
assessment by the central lab. In this case, these centrally measured results would 
overrule any other results obtained.


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Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 
clinically relevant by the investigator.
Any ECG abnormalities will be monitored carefully and, if necessary, the subject will be 
removed from the trial and will receive the appropriate medical treatment.
Continuous ECG monitoring
5.2.4.2
Cardiac rhythm, including heart rate, will be monitored by means of continuous 3-lead ECG 
recording for at least 15 min before drug administration, for baseline assessment, and for 4 h 
following drug administration. This continuous ECG monitoring supports the early detection 
of adverse events, such as clinically relevant bradycardia, tachycardia, or arrhythmia, at the 
trial site. Beyond this clinical evaluation at the trial site, no further data collection or analyses 
are performed based on continuous ECG monitoring.
ECG data from continuous ECG recording will not be transferred to the clinical trial database 
and will be evaluated by the investigator or a designee. Abnormal findings during continuous 
ECG recording will be recorded as AEs, if judged clinically relevant by the Investigator.
Other safety parameters
5.2.5
Neurological examination
5.2.5.1
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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Assessment of adverse events
5.2.6
Definitions of adverse events
5.2.6.1
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, medical 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. Adverse events deemed serious for any other 
reason are important medical events that, based upon appropriate medical judgment,  
jeopardise the patient and may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above. 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
An AE that possibly leads to disability will be ‘deemed serious for any other reason’ and 
reported as an SAE.


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AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
events regardless of the time since discontinuation of the trial medication and must be 
reported 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 meet the criteria of an SAE as defined 
above.
The latest list of ‘Always Serious AEs’ can be found in the electronic data capture (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, e.g. icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, etc.,
without lab results (ALT, AST, total bilirubin) available, the Investigator should make 
sure that these parameters are analysed, if necessary, in an unscheduled blood test. 
Should the results meet the criteria of hepatic injury alert, the procedures described in 
the DILI checklist should be followed.
Intensity (severity) of AEs
5.2.6.1.5
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


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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 investigational medicinal product
treatment continues or remains unchanged
Adverse event collection and reporting
5.2.6.2
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. 


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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 subjects, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial:
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and related SAEs and related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should, however, not be reported 
in the CRF
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs that are relevant for the 
reported SAE or AESI, on the BI SAE form via fax within 24 h to the sponsor’s unique entry 
point; the 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 AEs and SAEs, including those persisting after the individual subject’s end of trial, must 
be followed up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no 
further information can be obtained.


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Pregnancy
5.2.6.2.4
Once a male subject has been enrolled in the clinical trial and has taken trial medication, and 
if a partner of the male subject becomes pregnant, the investigator must report any drug 
exposure during pregnancy in this partner within 24 hours by means of Part A of the 
Pregnancy Monitoring Form to the sponsor’s unique entry point, after a written consent of the 
pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
5.3.1
Date and clock times of drug administration and pharmacokinetic sampling will be recorded
in Source data and in the CRFs.
Exact times of plasma sampling will be documented in the eCRFs by the medical personnel. 
The actual sampling times will be used for determination of pharmacokinetic parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. as a result of preliminary PK data), including addition of 
samples and visits, as long as the total blood volume taken per subject does not exceed 
approximately 500 mL. Such changes would be implemented via non-substantial CTP 
Amendments.
Methods of sample collection
5.3.2
Blood sampling for pharmacokinetic analysis
5.3.2.1
For quantification of BI 894416 concentrations in plasma, 3.0 mL of blood will be drawn 
from an antecubital or forearm vein into an K2EDTA (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.
Two plasma aliquots each having at least 0.5 mL will be obtained and stored in an upright 
position at approximately -20°C or below at the trial site until shipment on dry ice to the 


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analytical laboratory. Details on sample handling, processing and shipments are described in 
the lab manual.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. Further information such as matrix and analyte may also be provided. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g., for stability testing or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) 
will be generated by these additional investigations. The trial samples will be discarded after 
completion of the additional investigations, but not later than 5 years after the CTR is 
archived.
Urine sampling for pharmacokinetic analysis
5.3.2.2
A blank urine sample will be collected before administration of trial medication (within 3 h 
before drug dosing) and two 0.5 mL aliquots will be retained to check for analytical 
interference by concomitant or rescue medication.
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in 
urine containers and stored at room temperature. Subjects are told to empty their bladders at 
the end of each sampling interval. Details on sample handling, processing and shipments are 
described in the lab manual.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned collection time. Further information, such as matrix and analyte may also be 
provided.
Two urine aliquots each having at least 0.5 mL will be obtained and stored in an upright 
position at approximately -20°C or below at the trial site until shipment on dry ice to the 
analytical laboratory. Details on sample handling, processing and shipments are described in 
the lab manual.
The second aliquot will be transferred after the bioanalyst has acknowledged safe arrival of 
the first aliquot. At the analytical laboratory, the urine samples will be stored at 
approximately -20°C or below until analysis.
After completion of the trial, the urine samples may be used for further methodological 
investigations (e.g., for stability testing or assessment of metabolites). However, only data 
related to the analyte and/or its metabolite(s) will be generated by these additional 
investigations. The trial samples will be discarded after completion of the additional 
investigations but not later than 5 years after the CTR has been archived.


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5.4
ASSESSMENT OF BIOMARKER(S) 
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Pharmacogenomic evaluation
5.6.1
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 from each subject at Day -1. 
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.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic 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 2.1.3, 
2.2.2.2, and 5.3 are generally used assessments of drug exposure. 
Due to neurologic effects observed in dog trials, 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.
Trial measurements and assessments scheduled to occur ‘before’ trial medication 
administration at Day 1 are to be performed and completed within a 2 h-period prior to the 
investigational medicinal product administration (including blank values for PK). A blank 
urine sample for PK will be collected within 3 h before drug administration.
The acceptable deviation from the scheduled time for vital signs and ECG will be ± 10 min 
for the first 4 h after investigational medicinal product administration and ± 30 min 
thereafter. For laboratory test, the acceptable deviation is ± 30 min.
If several activities are scheduled at the same time point in the Flow chart, meal shoud be the 
last activity. Furthermore, if several measurements including venipuncture are scheduled for 
the same time, venipuncture should be the last of the measurements due to its inconvenience 
to the subject and possible influence on physiological parameters.
The acceptable deviation from the scheduled time for neurological tests is ± 45 min on Day 1 
and ± 90 min for other days.
For planned individual plasma concentration sampling times and urine collection intervals,
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for the determination of 
pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Screening period
6.2.1
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 trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital
signs, medical examination and neurological examination, refer to Sections 5.2.1 to 5.2.5. 
Genotyping will be performed (for details, see Section 5.6.1).
Treatment period
6.2.2
Each subject will receive one dose of trial medication (BI 894416 or placebo) at Visit 2.


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Trial medication will be taken orally by each subject under direct supervision of the 
investigator or 
designee. Details on treatments and procedures of administration are 
described in Section 4.1.4.
Trial participants will be admitted to the trial site in the evening of Day -1 and kept under 
close medical surveillance for at least 48 h following drug administration. The subjects will 
then be allowed to leave the trial site, after formal assessment and confirmation of their 
fitness by the investigator or
 designee. On all other trial days, subjects will be treated in 
an ambulatory fashion.
For details on time points and procedures for collection of plasma and urine 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.
Follow-up period and trial completion
6.2.3
For AE assessment, laboratory tests, recording of ECG and vital signs, medical 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 End of Trial 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 End of Trial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained. 
If a subject discontinues from the trial, the subject will be followed until the investigator, or 
sub-investigator, is convinced of the subject’s safety. If follow-up is not possible or comes to 
an end, follow-up should be formally completed after discussion with the sponsor. If a subject 
stops attending trial assessments, the investigator should assess the subject’s status as 
comprehensively as possible and the well-being of the subject should be monitored. 
However, if the subject withdraws from the trial, it is the subject’s choice whether or not to 
participate in further assessments; he cannot be compelled.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The primary objectives of this trial is to investigate the safety and tolerability of BI 894416
by using descriptive statistics for all endpoints  comparing active dose groups to placebo.
The primary endpoint is defined in Section 2.1.2. Inferential statistics is not planned (as 
explained in section 7.2)
Secondary objectives are the exploration of PK of BI 894416 endpoints as specified in 
section 2.1.3 by descriptive statistics.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of the different dose groups of BI 894416 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses. Instead, they will be described in their entirety and evaluated by 
descriptive statistical methods.
Any confidence intervals computed are to be interpreted in the perspective of the exploratory 
character of the trial; i.e., confidence intervals are considered as interval estimates for effects.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of investigational medicinal product. The treatment 
assignment will be determined based on the first treatment the subjects received. The 
treated set will be used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was not excluded due to a 
protocol violation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 
included in the PKS, even if he 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 specified in the TSAP, IPDs will be identified no later than in the 
Report Planning Meeting, and the IPD categories will be updated as needed.


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Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 will be calculated according to BI 
internal standard operating procedure (SOP). Noncompartmental pharmacokinetic parameters 
will be calculated based on actual sampling times using a validated pharmacokinetic software 
(e.g., Phoenix® WinNonlin®).
Plasma and urine concentration data and parameters of a subject will be included in the 
statistical PK analyses if they are not flagged for exclusion due to a protocol violation 
relevant to the evaluation of PK (to be decided no later than in the Report Planning Meeting) 
or due to PK non-evaluability (as revealed during data analysis, based on the criteria 
specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma and urine concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve.
Plasma/urine concentration data and parameters of a subject which is flagged for exclusion 
will be reported with its individual values but will not be included in the statistical analyses.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format as in the bioanalytical report (that is 
to the same number of decimal places provided in the bioanalytical report). 
Primary endpoint analyses
7.3.1
The primary endpoint as specified in Section 2.1.2 will be derived according to BI standards. 
The analysis will be based on the treated set (TS) and will be descriptive in nature.
Secondary endpoint analyses
7.3.2
Primary analyses
The secondary endpoints (refer to Section 2.1.3) will be analysed descriptively. Analyses will 
be performed for the parent drug.
Further exploratory analyses


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Dose proportionality will be explored via graphical checks and if applicable via the power 
model stated below. The analysis will be performed for the pharmacokinetic endpoints 
AUC0-∞/Cmax specified in Section 2.1.3.
The power model describes the functional relationship between the dose level and PK 
endpoint on the log scale via
 =  log (xkm) = μ +   β ∙ log (Dk) +  ekm ,
where 
ykm
logarithm of response (PK parameter) measured on subject m receiving dose k,
xkm
response (PK parameter) measured on subject m receiving dose k,
μ
the overall mean,
β
slope parameter of linear regression line,
D
level of dose k, k=1,…,3,
ekm
the random error associated with the mth subject who was administered dose k 
(e~(0, ) iid).
The slope parameter β together with its two-sided 90% confidence interval will be estimated. 
Additionally, the r-fold change  ! together with its 90% CI will be derived.
As some small doses at the beginning and/or some doses at the upper end might not 
contribute to the linear relationship between dose and PK, dose proportionality over the entire 
dose range investigated might not be shown. In that case an attempt will be made to identify a 
subrange of at least 3 consecutive doses where dose proportionality can be concluded.
Safety analyses
7.3.4
Safety will be assessed as defined by the endpoints listed in Section 2.1.2 and 2.2.2 based on 
the treated set (TS). Safety analyses will be descriptive in nature and will be based on BI 
standards. 
For all analyses the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. The placebo group in the safety evaluation 
will consist of all subjects treated with placebo, regardless of the dose group in which they 
were treated. The test treatment groups will be compared to the placebo group in a descriptive 


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way. Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.
Measurements (such as ECGs, vital signs, or laboratory parameters) or AEs will be assigned 
to treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment-emergent AEs). 
Therefore, measurements planned or AEs recorded prior to intake of trial medication will be 
assigned to the screening period, those between the trial medication intake and the individual 
subject’s end of REP (see Section 1.2.1) will be assigned to the treatment period. 
Events occurring after the REP but prior to trial termination date will be assigned to ’follow-
up’. These assignments including the corresponding time intervals will be defined in detail in 
the TSAP. Note that AEs occurring after the last per protocol contact but entered before 
database lock will be reported to Pharmacovigilance only and will not be captured in the trial 
database.
Additionally, further treatment intervals (called analysing treatments) may be defined in the 
TSAP in order to provide summary statistics for other than above periods, such as combined 
treatments, on-treatment totals, or periods without treatment effects (such as screening and 
post-trial 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 possibly clinically significant values 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. 
The ECG variables QT, HR, QTcF, QTcB, PR, QRS, and RR obtained from the centralised 
evaluation of 12-lead ECG recordings will be the basis for the derivation of quantitative and 
categorical ECG endpoints. These endpoints and their analyses will be described in the 
TSAP.
Pharmacokinetic - pharmacodynamic analysis
7.3.5
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
7.4
INTERIM ANALYSES
No interim analysis is planned.


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7.5
HANDLING OF MISSING DATA
Safety
7.5.1
It is not planned to impute missing values for safety parameters.
Pharmacokinetics
7.5.2
Handling of missing PK data will be performed according to the BI internal SOP.
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
The first 4 subjects per dose level will not be randomised to maintain a treatment sequence of 
active-placebo-active-active due to safety reasons. The remaining 4 subjects of each dose 
level will be randomised in a 3:1 ratio, which reflects the ratio of subjects receiving active 
drug to placebo.
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 include a total of 24 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 8 subjects per dose group (6 on active treatment, and 2 on 
placebo) is commonly used in single-rising dose trials of the present type and is in general 
considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics [R95-0013].


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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, the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) 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. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a 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 responsible 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 investigator or delegate must give a full explanation to trial subjects based on the subject 
information form. A language understandable to the subject should be chosen and technical 
terms and expressions avoided, if possible.
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. 


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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.
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.
Source documents
8.3.1
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.
Direct access to source data and documents
8.3.2
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.
Storage period of records
8.3.3
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY 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 World Health 
Organization (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.
Collection, storage and future use of biological samples and corresponding 
8.5.1
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
ICF.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the ‘date of the last visit of the last subject in 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.
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.


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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.
When the trial is completed, the investigator should inform the head of the trial site in writing 
of the completion of the trial, and the head of the trial site should promptly inform the IRB 
and sponsor in writing of the completion.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by 
The trial will be conducted at 
, 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 CTL, 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 CTM

Clinical Research Associates, and investigators of participating trial sites
The trial medication will be provided by the 
 
Safety laboratory tests will be performed by the local laboratory of the trial site.
Analyses of BI 894416 concentrations in plasma and urine will be performed at the 
 
 
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation 
 for evaluation during the trial or post trial.
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 CRO 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
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://.nhlbi.nih.gov; Bethesda: U.S. Department of Health and 
Human Services, National Institutes of Health, National Heart, Lung and 
Blood Institute (2007).
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) (2005).
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R14-4230
Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular 
approaches. Nature Med. 2012. 18(5): 716-725.
R15-4770
Blancato J, Graves A, Rashidi B, Moroni M, Tchobe L, Ozdemirli M, et.al. 
SYK Allelic Loss and the Role of Syk-Regulated Genes in Breast Cancer 
Survival. PloS ONE. 2014. 9(2): e87610.
R15-5470
Mocsai A, Ruland J, Tybulewicz VLJ. The SYK tyrosine kinase: a crucial 
player in diverse biological functions. Nat Rev Immunol. 2010. 10(6): 387-
402.
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. 2015: 879783.
R16-0366
E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs: questions & 
answers (R3) (current version dated 10 December 2015).
http://.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Effica
cy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2016) ; 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015).
R16-0945
Fahy JV. Type 2 inflammation in asthma - present in most, absent in many. 
Nat Rev Immunol. 2015. 15: 57-65.
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. 2015. 1853(1): 254-263.
R16-5240
Boylan B, Gao C, Rathore V, Gill JC, Newman DK, Newman PJ. 
Identification of FcγRIIa as the ITAM-bearing receptor mediating αIIbβ3 
outside-in integrin signaling in human platelets. 2008. 112(7): 2780-2786.
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. 2014. 193: 268-276.


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R95-0013
Broom C. Design of first-administration studies in healthy man. Early
Phase Drug Evaluation in Man. O'Grady J, Linet OI (Eds.), Macmillan 
Press: London, 1990, 206 213.
9.2
UNPUBLISHED REFERENCES
c03536505
 
 Investigator Brochure: BI 894416 Asthma. 
Current version.
c32087967
 Safety monitoring committee meeting clinical output of 1371-
0003. 1 Apr 2020.    
n00240179
 BI 894416: 
Exploratory 15 day oral (gavage) toxicity study in male rats. Nonclinical 
Report. 13B105. 29 June 2015.
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. Nonclinical Report. 2016-i-r-resp3-
report1. 11 July 2016.
n00245394
 BI 894416: Dose Escalation in Dogs with Assessment of 
Electroencephalography and Nerve Conduction Velocity. Nonclinical 
Report. 15R160. 21 February 2017.


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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
6 Jul 2020
BI Trial number
1371-0003
BI Investigational Medicinal 
Product(s)
BI 894416
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 894416 versus placebo in 
healthy male Japanese subjects (single-blind, 
randomized, placebo-controlled within dose group)
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
Section 5.2.3
Description of change
Safety Laboratory updated
Rationale for change
IgD cannot be measured at site.
T-SPOT test added to make sure subject safety.
11.2
GLOBAL AMENDMENT 2
Date of amendment
17 Aug 2020
BI Trial number
1371-0003
BI Investigational Medicinal 
Product(s)
BI 894416
Title of protocol
Safety, tolerability and pharmacokinetics of single 
rising oral doses of BI 894416 versus placebo in 
healthy male Japanese subjects (single-blind, 
randomized, placebo-controlled within dose group)
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
3.1
Description of change
Description adjustment about deputy of Principle 
investigator and CTL.


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Rationale for change
Based on comments from authority.
Section to be changed
3.3.2
Description of change
More detailed information about contraception 
methods were added.
Rationale for change
Based on comments from authority.
Section to be changed
3.3.3, Fig 5.2.3: 2 and Flowchart 
Description of change
Chest region x-ray and HBsAg test added.
Detailed condition about infection was added. 
Rationale for change
Based on comments from authority to make sure 
subject safety.
Section to be changed
NA
Description of change
Administrative description corrections
Rationale for change
Based on comments from authority.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c23040609
3.0
clinical-trial-protocol-version-03
Safety, tolerability and pharmacokinetics of single rising oral doses of BI 894416
versus placebo in healthy male Japanese subjects (single-blind, randomized,
placebo-controlled within dose group)
Author-Clinical Trial Leader
18 Aug 2020 02:53 CEST
Author-Trial Statistician
18 Aug 2020 09:02 CEST
Author-Trial Clinical
Pharmacokineticist
18 Aug 2020 10:57 CEST
Approval-Therapeutic Area
19 Aug 2020 11:36 CEST
Approval-Team Member Medicine
22 Aug 2020 06:00 CEST
Verification-Paper Signature
Completion
24 Aug 2020 04:59 CEST


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c23040609
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c34947384-01
BI Trial No.:
1371-0003
Title:
Safety, tolerability and pharmacokinetics of single rising oral 
doses of BI 894416 versus placebo in healthy male Japanese 
subjects (single-blind, randomized, placebo-controlled within 
dose group)
(Revised Protocol including Amendments 1-2 [c23040609-03])
Investigational
Product(s):
BI 894416
Responsible trial 
statistician(s):
Phone:
Fax:
Date of statistical 
analysis plan:
12 FEB 2021 SIGNED
Version:
1
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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...................................................................................................................3
2.
LIST OF ABBREVIATIONS ..............................................................................4
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINTS .........................................................................................................8
5.1
PRIMARY ENDPOINT .......................................................................................8
5.2
SECONDARY ENDPOINTS...............................................................................8
5.2.1
Key secondary endpoints......................................................................................8
5.2.2
Secondary endpoints.............................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........19
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................20
7.3
TREATMENT COMPLIANCE........................................................................20
7.4
PRIMARY ENDPOINT .....................................................................................20
7.5
SECONDARY ENDPOINTS.............................................................................20
7.5.1
Key secondary endpoints....................................................................................20
7.5.2
Secondary endpoint.............................................................................................20
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse Events ....................................................................................................22
7.8.2
Laboratory data ..................................................................................................23
7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................24
8.
REFERENCES....................................................................................................25


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10.
HISTORY TABLE..............................................................................................28
LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................11
Table 6.2: 1
Important protocol deviations ..........................................................................13
Table 6.3: 1
Subject sets analysed........................................................................................15
Table 6.7: 1
Time schedule of 12-lead ECG recordings ......................................................16
Table 10: 1
History table .....................................................................................................28


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
Website: http://glossary
Term
Definition / description
ALT
Alanine transaminase
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
CARE
Clinical data Analysis and Reporting Environment
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
gCV
Geometric coefficient of variation
gMean
Geometric mean
LLT
Lower level term
λz
Terminal rate constant of the analyte in plasma
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number of non-missing observations
P10
10th percentile
P90
90th percentile
po
Orally
PKS
Pharmacokinetic parameter analysis set
Q1
1st quartile
Q3
3rd quartile
qd
Once daily


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Term
Definition / description
RAGe
Report Appendix Generator system
REP
Residual effect period
SD
Standard deviation
SOC
System organ class
TS
Treated set
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1) the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This Trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data (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
The study was prematurely stopped after the first dose group (25mg BI 894416) due to a 
disadvantageous benefit risk ratio based on newly received data from another study with 
BI 894416.
Consequently, only a subset of the analyses planned in the CTP will be performed. Tables 
will be provided for disposition, demography, adverse events and standard safety analysis 
(including the primary endpoint) and for PK endpoints (including the secondary endpoints). 
For all study endpoints, listings will be provided. That means, for several variables, only 
listings will be provided and no descriptive analysis will be carried out. This applies to, for 
example, medical history, concomitant medication and non-drug procedures, laboratory data, 
vital signs and ECG.
As there is only one dose group available, no dose proportionality analysis will be done. 
Secondary endpoints (AUC0-∞and Cmax of BI 894416) will be analysed descriptively only.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Section 2.1.2 of the CTP: The primary endpoint for assessment of safety and tolerability of 
BI 894416 is the percentage [%] of subjects with drug related adverse events.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 2.1.3 of the CTP: 
The following pharmacokinetic parameters will be determined for BI 894416, if feasible:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatments and 
selection of doses, please see CTP, Section 4.
The study was performed as a single-blind, randomised, placebo-controlled study in healthy 
male Japanese subjects. It was planned that 24 subjects will be treated with a single dose of 
BI 894416 or Placebo. The study comprises 3 dose groups. Each dose group was planned to 
consist of 8 subjects randomised to active treatment or Placebo (6 on active treatment, 2 on 
Placebo).
Table 6.1: 1
Treatments and labels used in the analysis
Dose group
Treatment
Short label
P*
Placebo, tablet, qd
Placebo
A
25mg BI 894416 tablet, po, qd
BI 25mg
B
50mg BI 894416 tablet, po, qd
BI 50mg
C
70mg BI 894416 tablet, po, qd
BI 70mg
*The placebo control group will include all subjects that were treated with placebo, 
regardless of the groups they were treated.
The study was prematurely stopped after the first dose group (25mg BI 894416). Therefore, 
all analyses will be performed for this dose group only (Placebo n=2, BI 25mg n=6).
Section 1.2.2 of CTP:
The Residual Effect Period (REP (…)) of BI 894416 has not been defined yet. (…) 
Conservatively, a minimum period of 14 days after last administration of BI 894416, or 
placebo, has been selected as the REP. Therefore, the individual subject’s end of trial will be 
14 days following last dosing with BI 894416, or placebo, at the earliest.
All adverse events (AE) reported between administration of trial medication and the
individual subject’s end of trial will be counted as on-treatment AEs.
The following study phases will be defined for the analysis:


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
Screening (ranging from 0:00 h on day of informed consent until time of 
administration of trial medication (BI 894416 or Placebo))

On treatment (ranging from the time of administration of trial medication until 336 
hours (14 days) after time of administration)

Follow-up (F/U) (ranging from 336 hours (14 days) after administration of trial 
medication until 0:00 h on day after trial termination date)
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.
The following AE displays will be provided in the report:
Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov) of the CTR displays:
In these displays, the on-treatment phase will be analysed (labelled with the name of the 
study treatment (short label)). Screening and Follow up phases will not be included in this 
analysis. As the study was prematurely discontinued after one dose group, no additional totals 
will be provided.
In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays, screening and follow-up 
periods will be included.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewers guide. 
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 specified in 
the TSAP, 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 Report Planning Meeting (RPM). At this meeting, all 
manual deviations identified at the sites by the CRAs and deviations too complex to program 
will be reviewed by the trial team to decide which are considered important. For definition of 
important protocol deviations (iPD), and for the process of identification of these, refer to the 
Boehringer Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" 
(2).


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If any iPDs are identified, they are to be summarised into categories and will be captured in 
the decision log. Categories which are considered to be iPDs in this trial are defined in Table 
6.2: 1. The decision on exclusion of subjects from analysis sets will be made at the latest at 
the Report Planning Meeting, after discussion of exceptional cases and implications for 
analyses. If the data show other iPDs, the definition below will be supplemented accordingly 
by the time of the Report Planning Meeting and will be documented in the decision log and in 
the iPD specification file (3).
The iPDs will be listed in the CTR.
Table 6.2: 1
Important protocol deviations 
Category/
Code
Description
A
Eligibility Criteria
A1
Critical inclusion/exclusion criteria violated
A2
Withdrawal criteria as defined in the protocol met, but subject was not withdrawn
B
Informed Consent
B1
Required informed consent not available/not done
C
Trial Medication and Randomization
C1
Randomisation order not followed
C2
Critical trial medication procedure violated
D
Concomitant medication
D1
Improper medication washout
D2
Prohibited medication use
D3
Mandatory medication not taken/insufficient
E
Critical Study Procedure/Assessment
E1
Improper primary endpoint assessment
E2
Improper key secondary endpoint assessment
F
Safety Procedures/SAE Reporting
F1
Critical safety procedure not followed
G
Privacy/Data Protection
G1
Privacy and/or data protection violated
Q
Non-important COVID-19 Related
Q1
Missed examination
Q2
Missed visit
Q3
Drug shipment


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6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of investigational medicinal product. The treatment 
assignment will be determined based on the first treatment the subjects received. The 
treated set will be used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was not excluded due to a 
protocol violation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a subject will be 
included in the PKS, even if he contributes only one PK parameter value for one 
period to the statistical assessment. Descriptive […] analyses of PK parameters will 
be based on the PKS.
(…)
Pharmacokinetics
Plasma and urine concentration data and parameters of a subject will be included in the
statistical PK analyses if they are not flagged for exclusion due to a protocol violation 
relevant to the evaluation of PK (to be decided no later than in the Report Planning Meeting) 
or due to PK non-evaluability (as revealed during data analysis, based on the criteria 
specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma and urine concentrations and/or parameters of a subject will be considered as non-
evaluable, if for example

The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve.
Plasma/urine concentration data and parameters of a subject which is flagged for exclusion 
will be reported with its individual values but will not be included in the statistical analyses.


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Only concentration values within the validated concentration range and actual sampling 
times will be used for the calculation of pharmacokinetic parameters. Concentrations used in 
the pharmacokinetic calculations will be in the same format as in the bioanalytical report 
(that is to the same number of decimal places provided in the bioanalytical report).
The descriptive analysis of PK endpoints and concentrations will be based on the ADS ADPP 
and ADPC as described at the beginning of Section 7.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
PK endpoints 
X
Safety parameters 
X
ECG endpoints
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.
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 BI-KMED-BDS-
HTG-0035) (4).
Missing data and outliers of PK data are handled according to BI standards (see BI-KMED-
TMCP-MAN-0012 (5) and BI-KMED-TMCP-MAN-0014 (6)).


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before trial medication administration.
Section 6.1 of the CTP: Exact times of measurements outside the permitted time windows 
will be documented. The acceptable time windows for screening and the end of trial 
examination are provided in the CTP Flow Chart.
Trial measurements and assessments scheduled to occur ‘before’ trial medication 
administration at Day 1 are to be performed and completed within a 2 h-period prior to the 
investigational medicinal product administration (including blank values for PK). A blank 
urine sample for PK will be collected within 3 h before drug administration. 
The acceptable deviation from the scheduled time for vital signs and ECG will be ± 10 min 
for the first 4 h after investigational medicinal product administration and ± 30 min 
thereafter. For laboratory test, the acceptable deviation is ± 30 min.
(…)
The acceptable deviation from the scheduled time for neurological tests is ± 45 min on Day 1 
and ± 90 min for other days. 
Adherence to time windows will be checked via the consistency check listings at the RPM.
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. 
There will be a centralised evaluation of the 12-lead ECG recordings at the time points and 
for the ECG recordings specified in Table 6.7: 1 below:
Table 6.7: 1
Time schedule of 12-lead ECG recordings
Visit
Day
Planned time [hh:mm]
(relative to drug 
administration)
Study phase
Central evaluation
1
-28 to -1
Screening
NA
2
-1
-24:00
Pre-dose
Three triplicate ECGs**
1
-01:00
Baseline
Triplicate ECG*
00:30
On treatment
Triplicate ECG*
01:00
On treatment
Triplicate ECG*
01:30
On treatment
Triplicate ECG*
02:00
On treatment
Triplicate ECG*
02:30
On treatment
Triplicate ECG*


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03:00
On treatment
Triplicate ECG*
04:00
On treatment
Triplicate ECG*
06:00
On treatment
Triplicate ECG*
08:00
On treatment
Triplicate ECG*
12:00
On treatment
Triplicate ECG*
2
24:00
On treatment
Triplicate ECG*
34:00
On treatment
NA
3
48:00
On treatment
NA
4
72:00
On treatment
NA
3
15 to 17
End of trial 
examination
NA
* Central ECG lab evaluation will be performed for the first ECG of triplicate ECGs at every time point
** Will not be used for ECG analyses
Three triplicate ECGs will be recorded on Day -1 -24:00, but only the first triplicate will be 
transferred to the database. These values will not be used for the ECG analyses. 
At all other time points, triplicate ECGs will be recorded, but only the first ECG of the 
triplicate will be transferred to the data base. The baseline value of an ECG variable is 
defined as the first single ECG of the triplicate at Day 1 prior to drug administration (-1:00).


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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.
PK evaluation will be performed by 
 and monitored by the
and the descriptive 
statistics of PK endpoints and plasma concentrations will be presented in Section 15.6 of the 
CTR. Inferential statistical analyses of PK endpoints will not be applied in this trial due to the 
premature discontinuation.
The format of the listings and tables will follow BI standards (see BI-KMED-BDS-HTG-
0045 (7)) with the exception of those generated for PK evaluations following BI standards for 
PK/PD analysis (8).
The individual values of all subjects will be listed, sorted by treatment, subject number and 
visit. The listings of PK and other than PK will be included in Appendices 16.1.13.5 and 16.2
of the CTR, respectively.
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
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 


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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 (%). 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.
Exclusion of PK parameters
The ADS “ADPP” (PK parameters) contains column variables APEXC and APEXCO 
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for 
exclusion, that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS “ADPC” (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC 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 BI-KMED-TMCP-MAN-0014 “Noncompartmental 
Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” (6) and BI-KMED-
TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD Data Files” (9).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics for demographics are planned for this section of the report, based 
on the TS.
The data will be summarised by treatment and in total.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded using the latest version of the coding system of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA). Medications will be coded 
using the latest version of the World Health Organization Drug Dictionary (WHO-DD). The 
coding version number will be displayed as a footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the trial centre under supervision of the investigating physician or a designee. The 
measured plasma concentrations and/or urinary excretion 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 (cf. TSAP Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINT
Refer to TSAP Section 7.8 for a description of the analysis of safety and tolerability of
BI 894416.
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 endpoint
Section 7.3.2 of the CTP: The secondary endpoints (refer to CTP Section 2.1.3) will be 
analysed descriptively. Analyses will be performed for the parent drug.


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7.7
EXTENT OF EXPOSURE
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 “Analysis and Presentation of Adverse Event Data from Clinical Trials –
Display Template” [BI-KMED-BDS-HTG-0041] (10) and [BI-KMED-BDS-HTG-0066] 
(11). All analyses of AEs will be based on the number of subjects with AEs and not on the 
number of AEs.
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs will be assigned to ‘screening’, ‘on-treatment’ or ‘follow-up’ phases as defined 
in Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1. 
According to the clinical study protocol, adverse events of special interest (AESI) will be 
analysed:
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 
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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According to ICH E3 (12), in addition to Deaths and Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced 
or interrupted).
An overall summary of AEs 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
serious AEs, for subjects with drug-related AEs, for subjects with drug-related serious 
adverse events and for subjects with AESIs. In addition, the frequency of subjects with AEs 
will be summarised by treatment, worst intensity, primary system organ class (SOC) and 
preferred term (PT).
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.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on 
BI standards [BI-KMED-BDS-HTG-0042] (13). 
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.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significantly 
abnormal or not (at the RPM at the latest). 
7.8.3
Vital signs
For vital signs (blood pressure and pulse rate), listings including change from baseline will be 
presented 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.


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7.8.4
ECG
Continuous safety ECG monitoring:
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' (if they pre-exist prior to trial inclusion) or will be reported as AEs (if they 
occurred on treatment), and will be analysed as such. No separate ECG monitoring listing 
will be provided.
12-lead ECG:
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during 
the trial) if judged clinically relevant by the investigator, and will be analysed as such. 
Additionally, a dataset of quantitative and categorical ECG endpoints will be provided to 
 for analysis by an ECG programmer at BI.
Listings of individual data of ECG endpoints will be shown in Appendix 16.2. Occurrences 
of notable findings will be flagged. Comments regarding the ECGs will be listed.
7.8.5
Others
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition
(i.e., a condition already existent before intake of study drug) or as AE (if they occurred on
treatment) and will be summarised as such. No separate listing or analysis of physical 
examination findings will be prepared.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", 
current version, IDEA for CON.
3.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, current version, KMED.
4.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version; KMED.
5.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
6.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; KMED.
7.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project
Summaries”, current version; KMED.
8.
BI-KMED-TMCP-OTH-0003: “Graphs and Tables for Clinical Pharmacokinetics and 
Pharmacodynamic Noncompartmental Analyses”, current version, KMED.
9.
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; KMED.
10. BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
11. BI-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from clinical 
trials”, current version; KMED.
12. 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.
13. BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1
12-FEB-2021
None
This is the final TSAP