Clinical trial NCT03722173
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2018-11-13; Completion date: 2018-12-18
Enrollment: 14 participants; Allocation: NA; Intervention model: CROSSOVER

Brief summary:
The main objective of this trial is to investigate the relative bioavailability of BI 894416 in plasma when given as oral single dose together with multiple oral doses of itraconazole (Test,T) as compared to when given alone as oral single dose (Reference, R).

Detailed description:

Arms: arm 1: Participants were administered 3 milligram (mg) BI 894416 tablet (1 mg X 3 tablets) orally on Day 1 alone in treatment period 1 (R), and along with 20 milliliter (mL) of 10 mg/ mL Itraconazole oral solution in treatment period 2 (T).

In period 2 (T), participants received 200 mg ((20 milliliter (mL)) of Itraconazole oral solution once daily for 5 days, from Day -3 to Day 2. On Day 1 participants received additionally after the Itraconazole dosing, 3 mg BI 894416 tablet (1 mg X 3 tablets) orally in treatment period 2 (T). Both treatment periods were separated by a washout period of at least 6 days between BI 894416 administrations. In both treatments, BI 894416 was administered to subjects in the fasting state.
Interventions: intervention 1: Itraconazole intervention 2: BI 894416
Intervention descriptions: intervention 1: Oral solution intervention 2: Tablet

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c24667886-03
EudraCT No.
2018-002728-17
BI Trial No.
1371-0004
BI Investigational
Medicinal Product
BI 894416
Title
Relative bioavailability of a single oral dose of BI 894416 when 
administered alone or in combination with multiple oral doses of 
itraconazole in healthy male subjects (an open-label, one-way
crossover study)
Lay Title
A study in healthy men to test how itraconazole influences the 
amount of BI 894416 in the blood
Clinical Phase
I
Trial Clinical 
Monitor
Phone:
Fax: 
Principal 
Investigator
Phone:
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date
Version: 3.0
Date: 14 November 2018
Page 1 of 67
Proprietary confidential information
© 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
31 August 2018
Revision date
14 November 2018
BI trial number
1371-0004
Title of trial
Relative bioavailability of a single oral dose of BI 894416 when administered alone 
or in combination with multiple oral doses of itraconazole in healthy male subjects 
(an open-label, one-way crossover study)
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
Based on in vitro data, CYP3A is involved in metabolism of BI 894416. It is 
therefore necessary to explore the relative bioavailability of BI 894416 in plasma 
when given alone vs. when given together with a strong CYP3A inhibitor. 
Trial objective
The main objective of this trial is to investigate the relative bioavailability of 
BI 894416 in plasma when given as oral single dose together with multiple oral 
doses of itraconazole (Test, T) as compared to when given alone as oral single dose 
(Reference, R).
Trial design
Open-label, one-way crossover design
Trial endpoints:
Primary endpoints: AUC0-tz and Cmax of BI 894416
Secondary endpoint: AUC0-of BI 894416
Number of subjects 
total entered
16
each treatment
16
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 50 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product 1
BI 894416 as tablet formulation (tablet strength: 1 mg)
dose
3 mg
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h


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Test product 2
Itraconazole oral solution (Sempera® Liquid 10 mg/ml)
dose
200 mg
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 9 h
Duration of treatment
Treatment “Reference” (R; in treatment period 1):
- One single dose of 3 mg BI 894416 on Day 1 
Treatment “Test” (T; in treatment period 2):
- 200 mg itraconazole q.d. for 5 days on Days -3 to 2
- One single dose of 3 mg BI 894416 on Day 1
Wash-out interval
Administrations of BI 894416 will be separated by a wash-out interval of at least 6 
days.
Statistical methods
Relative bioavailability will be estimated by the ratios of the geometric means 
(test/reference) for the primary and secondary endpoints. Additionally, their two-
sided 90% confidence intervals (CIs) will be provided. This method corresponds to 
the two one-sided t-test procedure, each at a 5% significance level. Since the main 
focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified. The statistical model will be an analysis of 
variance (ANOVA) on the logarithmic scale including effects for ‘subjects’ and 
‘treatment’. CIs will be calculated based on the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to BI 894416 
administration) [h:min]
Approximate clock time  of actual 
day [h:min]
Event and comment
Safety laboratory 9
PK blood BI 894416
PK blood itraconazole
12-lead ECG
Neurological examination 8
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 to -1
Screening (SCR)1
A
x
x
x
Period 1; Treatment R (BI 894416 alone) 7
2
1
-3:00
06:00
Admission to trial site2
x2,5
x2
x2
x2
x2
0:00
09:00
BI 894416 administration
0:15
09:15
x
0:30
09:30
x
0:45
09:45
x
1:00
10:00
x
1:30
10:30
x
2:00
11:00
240 mL fluid intake
x
2:30
11:30
x
3:00
12:00
x
4:00
13:00
240 mL fluid intake, 
thereafter lunch3
x
x
6:00
15:00
x
7:00
16:00
Snack (voluntary)
8:00
17:00
x
10:00
19:00
Dinner3
x
12:00
21:00
x
x
2
24:00
09:00
Discharge from trial site, 
breakfast (voluntary)3
B
x
x
x
x
34:00
19:00
Ambulatory visit
x
x


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FLOW CHART (cont’d)
Period
Visit
Day
Planned time (relative to BI 894416 
administration) [h:min]
Approximate clock time  of actual 
day [h:min]
Event and comment
Safety laboratory 9
PK blood BI 894416
PK blood itraconazole
12-lead ECG
Neurological examination 8
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Period 2; Treatment T (BI 894416 + itraconazole) 7
3
-3
-73:00
08:00
Ambulatory visit, 
itraconazole administration
B2,5
x2
-2
-49:00
08:00
Ambulatory visit, 
itraconazole administration
x2
-1
-25:00
08:00
Ambulatory visit, 
itraconazole administration
x2
1
-3:00
06:00
Admission to trial site2
x2
x10
x2
x2
x2
-1:00
08:00
Itraconazole administration
0:00
09:00
BI 894416 administration
0:15
09:15
x
0:30
09:30
x
0:45
09:45
x
1:00
10:00
x
x
1:30
10:30
x
x
2:00
11:00
240 mL fluid intake
x
x
x
x
x
2:30
11:30
x
3:00
12:00
x
4:00
13:00
240 mL fluid intake, 
thereafter lunch3
x
x
x
x
6:00
15:00
x
7:00
16:00
Snack (voluntary)
8:00
17:00
x
10:00
19:00
Dinner3
x
12:00
21:00
x
x
2
23:00
08:00
Itraconazole administration
x2
24:00
09:00
Discharge from trial site, 
breakfast (voluntary)3
B
x
x
x
x
34:00
19:00
Ambulatory visit
x
x
3
48:00
09:00
Ambulatory visit
x
x
4
72:00
09:00
Ambulatory visit
x
x
FU
4
8 to 15
End of trial (EoTrial)
examination4
C
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening and 
cotinine test), demographics (including determination of body height and weight, smoking status and alcohol history), 
relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will 
be collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within 3 h prior to the next drug 
administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.


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4.
At the EoTrial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies.
5.
Period 1: Urine drug screening and alcohol breath test only; Period 2: Including urine drug screening and alcohol breath 
test
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
Treatments R and T are to be separated by a wash-out interval of at least 6 days between administrations of BI 894416.
8.
Unscheduled neurological examinations may be added at any time during the trial for individual volunteers or the whole 
treatment group, e.g., in case of neurological adverse events, if assessed as necessary by the investigator.
9.
Letter A, B, and C define different sets of safety laboratory examinations (see Section 5.2.3).
10. Within 15 min prior to the next itraconazole administration


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
FLOW CHART (cont’d) ....................................................................................5
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................15
1.2.1
BI 894416 ...............................................................................................15
1.2.2
Itraconazole ...........................................................................................15
1.2.3
Residual Effect Period..........................................................................15
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................16
1.4
BENEFIT - RISK ASSESSMENT ...................................................................16
1.4.2
Procedure-related risks ........................................................................17
1.4.3
Drug-related risks and safety measures..............................................17
1.4.3.1
Risks related to BI 894416.......................................................17
1.4.3.2
Risks related to itraconazole....................................................20
1.4.3.3
Risks related to the potential drug-drug interaction between 
itraconazole and BI 894416 .....................................................21
1.4.3.4
Drug-induced liver injury ........................................................21
1.4.4
Overall assessment of benefit-risk ratio..............................................21
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 23
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......23
2.1.1
Main objectives......................................................................................23
2.1.2
Primary endpoints ................................................................................23
2.1.3
Secondary endpoint ..............................................................................23
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 25
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................25
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................25


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3.3
SELECTION OF TRIAL POPULATION ......................................................25
3.3.1
Main diagnosis for trial entry..............................................................26
3.3.2
Inclusion criteria...................................................................................26
3.3.3
Exclusion criteria ..................................................................................26
3.3.4
Withdrawal of subjects from treatment or assessments ...................28
3.3.4.1
Discontinuation of trial treatment............................................28
3.3.4.2
Withdrawal of consent to trial participation ............................29
3.3.4.3
Discontinuation of the trial by the sponsor..............................29
3.3.5
Replacement of subjects .......................................................................29
4.
TREATMENTS........................................................................................ 30
4.1
INVESTIGATIONAL TREATMENTS ..........................................................30
4.1.1
Identity of the Investigational Medicinal Products ...........................30
4.1.2
Selection of doses in the trial................................................................30
4.1.3
Method of assigning subjects to treatment groups ............................31
4.1.4
Drug assignment and administration of doses for each subject .......31
4.1.5
Blinding and procedures for unblinding ............................................32
4.1.6
Packaging, labelling, and re-supply ....................................................33
4.1.7
Storage conditions.................................................................................33
4.1.8
Drug accountability ..............................................................................33
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................34
4.2.1
Other treatments and emergency procedures....................................34
4.2.2
Restrictions............................................................................................34
4.2.2.1
Restrictions regarding concomitant treatment .........................34
4.2.2.2
Restrictions on diet and life style.............................................34
4.3
TREATMENT COMPLIANCE.......................................................................35
5.
ASSESSMENTS....................................................................................... 36
5.1
ASSESSMENT OF EFFICACY.......................................................................36
5.2
ASSESSMENT OF SAFETY............................................................................36
5.2.1
Physical examination ............................................................................36
5.2.2
Vital signs...............................................................................................36
5.2.3
Safety laboratory parameters..............................................................36
5.2.4
Electrocardiogram................................................................................38
5.2.5
Other safety parameters.......................................................................39
5.2.5.1
Neurological examinations ......................................................39
5.2.6
Assessment of adverse events...............................................................40
5.2.6.1
Definitions of adverse events...................................................40


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Adverse event ............................................................40
5.2.6.1.1
Serious adverse event ................................................40
5.2.6.1.2
AEs considered ‘Always Serious’.............................40
5.2.6.1.3
Adverse events of special interest .............................41
5.2.6.1.4
Intensity (severity) of AEs.........................................42
5.2.6.1.5
Causal relationship of AEs ........................................42
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................43
AE collection.............................................................43
5.2.6.2.1
AE reporting to the sponsor and timelines ................44
5.2.6.2.2
Information required..................................................44
5.2.6.2.3
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................44
5.3.1
Assessment of pharmacokinetics .........................................................44
5.6
APPROPRIATENESS OF MEASUREMENTS.............................................46
6.
INVESTIGATIONAL PLAN.................................................................. 47
6.1
VISIT SCHEDULE............................................................................................47
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................47
6.2.1
Screening period....................................................................................47
6.2.2
Treatment periods.................................................................................47
6.2.3
Follow-up period and trial completion ...............................................48
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 49
7.1
STATISTICAL DESIGN – MODEL ...............................................................49
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................49
7.3
PLANNED ANALYSES....................................................................................49
7.3.1
Primary endpoint analyses...................................................................50
7.3.2
Secondary endpoint analyses ...............................................................51
7.3.4
Safety analyses.......................................................................................52
7.4
INTERIM ANALYSES .....................................................................................53
7.5
HANDLING OF MISSING DATA ..................................................................53
7.5.1
Safety......................................................................................................53
7.5.2
Pharmacokinetics..................................................................................53
7.6
RANDOMISATION ..........................................................................................53


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7.7
DETERMINATION OF SAMPLE SIZE ........................................................53
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 56
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................56
8.2
DATA QUALITY ASSURANCE .....................................................................57
8.3
RECORDS..........................................................................................................57
8.3.1
Source documents .................................................................................57
8.3.2
Direct access to source data and documents.......................................58
8.3.3
Storage period of records.....................................................................58
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................59
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......59
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................59
8.6
TRIAL MILESTONES .....................................................................................59
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................60
9.
REFERENCES......................................................................................... 62
9.1
PUBLISHED REFERENCES...........................................................................62
9.2
UNPUBLISHED REFERENCES.....................................................................63
10. APPENDICES .......................................................................................... 65
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 66
11.1
GLOBAL AMENDMENT 1 .............................................................................66
11.2
GLOBAL AMENDMENT 2 .............................................................................67


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
ADP
Adenosine diphosphate
AE
Adverse event
AESI
Adverse events of special interest
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 hours
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
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
BA
Bioavailability
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CML
Clinical Monitor Local
CPLG
Innovation and Quality in Pharmaceutical Development’s Clinical 
Pharmacology Leadership Group
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DDI
Drug-drug interaction
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials Database


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FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
GPVI
Glycoprotein VI
HPC
Human Pharmacology Centre
IB
Investigator’s brochure
ICH
International conference on harmonisation
IEC
Independent Ethics Committee
IPV
Important protocol violation
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PMDA
Pharmaceuticals and Medical Devices Agency (Japan)
PP
Polypropylene
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
SUSAR
Suspected unexpected serious adverse reaction
SYK
Spleen tyrosine kinase
T
Test product or treatment


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TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
UV
Ultraviolet
WHO GCP
World Health Organization guidelines for Good Clinical Practice
WOCBP
Woman of child bearing potential
XTC
Ecstasy 
ZAP70
Zeta-chain-associated protein kinase of 70 kDa


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1.
INTRODUCTION
BI 894416 is an oral, selective non-receptor protein tyrosine kinase SYK (spleen tyrosine 
kinase) inhibitor under clinical development
 
This trial will be performed to investigate the relative bioavailability of BI 894416 in plasma 
when given alone in comparison to when given together with the CYP3A and P-glycoprotein 
inhibitor itraconazole. 
1.1
MEDICAL BACKGROUND
For more details on medical background see the current version of the Investigator’s 
Brochure (IB) [c03536505].


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1.2
DRUG PROFILE
1.2.1
BI 894416
For a more detailed description of the BI 894416 profile, please refer to the current 
Investigator’s Brochure (IB) [c03536505]. 
1.2.2
Itraconazole
Absorption of itraconazole solution is fast with maximum plasma concentration being 
reached within 2.5 h after oral administration in fasting condition. Bioavailability of 
itraconazole liquid is increased by 30% when given under fasting condition compared to 
administration together with food [R18-2644]. Mean peak plasma concentrations were 
547.7 ng/mL after a single dose of 200 mg itraconazole solution (fasting) and 1965 ng/mL 
after 15 days of daily treatment with 200 mg itraconazole (solution, fasting). Kinetics of 
itraconazole are non-linear. The half-life of itraconazole after multiple doses of 200 mg once 
daily with solution formulation was about 40 h [R17-3742].
In the liver, itraconazole is metabolised extensively to more than 30 metabolites [R17-3743]. 
Its main metabolite, OH-itraconazole, accounts for about twice the amount of plasma 
itraconazole at trough. It has been shown in vitro that CYP3A4 is mainly responsible for the 
formation of this metabolite [R18-2644]. FDA classifies itraconazole as strong index 
inhibitor of CYP3A and as inhibitor of P-glycoprotein [R18-0241]. However, not only 
itraconazole contributes to the in vivo inhibition of CYP3A observed after itraconazole 
administration but also three of its metabolites (OH-itraconazole, keto-itraconazole and 
N-desalkyl-itraconazole) [R10-1102].
For a more detailed description of itraconazole please refer to the SmPC [R18-2644] and to 
[R18-2643].
1.2.3
Residual Effect Period
The Residual Effect Period (REP, i.e., the period after the last dose with measurable drug 
levels and/or pharmacodynamic effects still likely to be present) of BI 894416 has not been 
defined yet. 
 


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This suggests that the occurrence of any potential adverse 
effects would likely be limited to a period of up to 1-4 days after administration. When given 
together with itraconazole, it is expected that plasma exposure of BI 894416 could be 
increased (albeit within the range explored in trial 1371-0001) and the time of relevant 
plasma exposure could be prolonged which in turn could lead to a longer period in which 
adverse effects could potentially occur. Therefore, the follow-up visit is earliest on Day 8 
following BI 894416 dosing in period 2, as this is expected to cover the period in which any 
potential adverse effects could reasonably occur.
For the use of itraconazole in this trial, the REP is defined as 6 days.
1.3
RATIONALE FOR PERFORMING THE TRIAL
This clinical trial will be performed to investigate the effect of multiple doses of itraconazole 
on the pharmacokinetics of a single dose of BI 894416 in order to assess if and to which 
extent the pharmacokinetics of BI 894416 are affected by co-administration of a drug that 
inhibits CYP3A and P-glycoprotein.
Itraconazole is chosen for this trial as perpetrator drug, as this drug is recommended as strong 
inhibitor of CYP3A by EMA [P15-06991], as strong index inhibitor of CYP3A and inhibitor 
of P-glycoprotein by FDA [R18-0241], and as strong inhibitor of CYP3A and typical 
inhibitor of P-glycoprotein by PMDA [P15-06298]. Moreover, safety and tolerability of
itraconazole were acceptable in previous drug-drug interaction trials (c02336088, c03355329, 
c08928447).
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 894416. 
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.


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1.4.2
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
ECG electrodes may cause local and typically transient skin reactions.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
1.4.3
Drug-related risks and safety measures
1.4.3.1
Risks related to BI 894416
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.

Preliminary 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 


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findings in WBC, differential blood count, immunoglobulins, or lymphocyte 
subpopulations after single doses up to 70 mg BI 894416 (see IB [c03536505]).

Due to the reversible mode of action of BI 894416 with regards to SYK inhibition, 
any potential effects on immune cells are expected to be of transient nature.
Risk mitigation and monitoring: Subjects with a history or diagnosis of relevant 
immunological disease will be excluded from trial participation (see Section 3.3.3). Adverse 
events will be monitored for an increase in infectious adverse events. Safety laboratory 
contains WBC, differential blood count, and CRP.
Tumour biology and carcinogenicity
The SYK pathway has been hypothesized to act as both a tumour suppressor and a tumour
promoter in different types of human cancers [R16-4459]. An increased risk of
carcinogenic/metastatic potential in epithelial cancers has been reported in the literature
related to SYK knock-out, but not related to SYK inhibition. Allelic deletion of SYK has 
been associated with breast adenocarcinoma [R15-4770]. However, there is no evidence that
pharmacologic inhibition of SYK will increase carcinogenicity or metastatic risk. Preclinical 
data with a potent and selective tool SYK inhibitor, BI 1002494, are in line with an absence 
of a carcinogenic effect due to inhibition of SYK enzymatic function [n00243171]. 
Risk mitigation and monitoring: Only male subjects are included in this trial. In view of the 
extended time necessary to induce a carcinogenic effect, two single doses of BI 894416 are
not considered a relevant carcinogenic risk to male subjects participating in this study. 
Accordingly, no further risk mitigation is required in this study.
Platelet aggregation and bleeding risk
A role of SYK in platelet function has been demonstrated in literature [R15-5470]. Several 
platelet functions rely on SYK signalling (e.g. collagen receptor GPVI) but others are 
independent of SYK [R16-5240]. In vitro studies using human platelets demonstrated that at 
concentrations up to 100 μM, BI 894416 had no effect on extrinsic or intrinsic coagulation 
pathways. Also, BI 894416 did not inhibit ADP-induced platelet aggregation up to 100 μM. 
However, BI 894416 inhibited collagen- and arachidonic acid-induced platelet aggregation at 
3 μM and 5 μM. However, platelet function as measured by bleeding time is not affected by a 
drug unless all the platelet pathways are inhibited due to redundancy within the system. 
Therefore, no risk for bleeding exists with regard to platelet inhibition unless a subject is also 
on another antiplatelet drug that blocks these other pathways.
Risk mitigation and monitoring: Use of any other concomitant drug that could reasonably 
inhibit platelet aggregation or coagulation (e.g. acetylsalicylic acid) will be prohibited (see 
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 two single doses of 


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BI 894416. Due to comparatively slow turnover of bone tissue, no relevant effect on bone is 
expected due to two single-dose administrations with BI 894416 in this trial, and no specific 
monitoring of bone density is necessary or reasonable in this trial.
Mortality / morbidity in preclinical studies
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 study in dogs. For details see the current version of the IB [c03536505]. 
Risk mitigation and monitoring: Preliminary data of the SRD part of trial 1371-0001 indicate 
good safety and tolerability of BI 894416 at all investigated doses (single oral doses up to 
70 mg). Due to the low dose of 3 mg BI 894416 used in this study, even taking into account 
potential effects of itraconazole on BI 894416 plasma concentrations, it is not expected that 
BI 894416 plasma concentrations that may be reached in the current trial could exceed those 
that were 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 24 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 pre-defined time points for AEs. In case of AEs in need of treatment, the 
investigator can authorise symptomatic therapy. In those cases, subjects will be treated as 
necessary and, if required, kept under supervision at the trial site or transferred to a hospital 
until all medical evaluation results have returned to an acceptable level.
Neurotoxicity
In dog toxicology studies, acute adverse neurological effects with 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 study at 
90 mg/kg/day. In dose escalation study in dogs with assessment of neurotoxicity 
[n00245394], all clinical signs of neurotoxicity were reversible with cessation of dosing. No 
structural changes were observed on histopathology. Peripheral nerve conduction velocity 
and EEG 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).
Risk mitigation and monitoring: In the SRD part of trial 1371-0001, there were no clinically 
relevant findings in the neurological examination after dosing with BI 894416 at single oral 
doses up to 70 mg. Due to the low dose of 3 mg BI 894416 used in this study, even taking 
into account potential effects of itraconazole on BI 894416 plasma concentrations, it is not 
expected that BI 894416 plasma concentrations reached in the current trial may exceed those 
that were measured previously in trial 1371-0001. Moreover, subjects with relevant 
neurological disorder in the medical history are excluded from trial participation (see Section 
3.3.3, criteria 7 and 22). Neurological examinations as described in Section 5.2.5.1 will be 


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performed at screening, and subjects with clinically relevant findings in the neurological 
examination will be excluded from study participation (see Section 3.3.3, criterion 1). If 
necessary (investigator decision), 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 by weight of evidence indicate that BI 894416 is not mutagenic or 
clastogenic. In the 2-week repeat dose range finding study in male rats [n00240179], 
degeneration of spermatids of the testes was observed at ≥400 mg/kg/day, which is 
considered a secondary effect, related to overt toxicity and morbidity. 
It is unknown whether BI 894416 or its metabolites are distributed into male semen. 
Theoretically there is therefore a risk for exposure of a study subject’s female partner who is 
a woman of child bearing potential (WOCBP) to subtherapeutic exposures of BI 894416 or 
its metabolites via male semen. Developmental and reproductive studies have not yet been 
conducted, therefore the effect of subtherapeutic concentrations of BI 894416 or its 
metabolites with regards to embryofetal risk has not been explored so far.
Risk mitigation: In order to address the risk of exposure of a subject’s female WOCBP 
partner to BI 894416 or its metabolites via the subject’s seminal fluid, subjects need to use 
barrier contraception (condom) or abstinence (see Section 3.3.3).
Phototoxicity
Subjects will be advised to avoid direct exposure to sun and UV light during the entire study 
(see Section 4.2.2.2). Further protective measures would not be necessary given the low 
phototoxic potential of BI 894416.
1.4.3.2
Risks related to itraconazole
In this trial itraconazole will be used in a standard dose of 200 mg once daily for 5 days.
Multiple dosing of 200 mg itraconazole up to 15 days was of acceptable tolerability in 
healthy subjects [c02336088, c03355329, c08928447, R17-3742]. 
In order to address the risk of hepatotoxicity, only subjects with normal liver enzyme values 
will be included into the study (see Section 3.3.3, criterion 26). Safety laboratory parameters 
will be monitored closely. An individual subject will be removed from the trial if the subject 
shows an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample, see Section 3.3.4.1). Further, 
most of the reported cases of serious hepatotoxicity during itraconazole treatment occurred in 
patients that suffered from concomitant liver diseases, had other significant diseases, or took 
concomitant hepatotoxic drugs. Subjects with liver diseases or a medical history of drug-
induced liver failure are excluded from trial participation (Section 3.3.3, criteria 5 and 27). 


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Considering these safety measures and taking into account the reported acceptable tolerability 
of itraconazole in healthy subjects, the planned administration of itraconazole does not 
represent an undue risk to healthy volunteers.
1.4.3.3
Risks related to the potential drug-drug interaction between itraconazole and 
BI 894416
It is likely that concomitant administration of BI 894416 with itraconazole may cause an 
increase of plasma concentrations and t1/2 of BI 894416. 
 
 
 
 
 
 
 These ratios are assessed 
to be sufficient as safety margins for the current trial, even in case of substantial increases of 
BI 894416 plasma concentrations by itraconazole.
1.4.3.4
Drug-induced liver injury
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also section 5.2.6.1.4, adverse events of special interest.
1.4.4
Overall assessment of benefit-risk ratio
BI 894416 is a highly specific SYK inhibitor that has been adequately characterised in pre-
clinical studies. The non-clinical safety package supports administration of BI 894416 for up 
to 4 weeks duration to men. 
Preliminary data of the SRD part of trial 1371-0001 indicate good safety and tolerability of 
single oral doses of BI 894416 at all dose levels, i.e. up to 70 mg. In addition, data from oral 
administration of three SYK inhibitors are available and provide additional information on 
safety and tolerability of this class of drug in man. Published data indicate acceptable safety 
and tolerability of these three SYK inhibitors in healthy volunteers (see IB [c03536505]).
Due to the low dose of BI 894416 selected for this trial, BI 894416 plasma exposures, even in 
case of a substantial effect of itraconazole, are expected to be well within plasma exposure 
values that were observed in the SRD part of trial 1371-0001 and that were associated with 
good safety and tolerability.
Itraconazole is a recommended inhibitor of CYP3A and P-glycoprotein in clinical trials and 
has been used successfully previously in clinical trials in healthy volunteers. The drug has a 
potential for hepatotoxicity, which is however accounted for by stringent exclusion criteria,
liver enzyme measurement as part of safety laboratory examinations and stopping criteria for 
the individual subject.


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This trial is required for the development of BI 894416. It is designed to assess the in vivo
victim potential of BI 894416 for CYP3A and P-glycoprotein inhibition. The resulting data 
are planned to inform concomitant medication restrictions in planned patient trials.
Considering the medical need for an effective and safe treatment of uncontrolled severe 
asthma, the benefit of this trial is assessed to outweigh the potential risks.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the relative bioavailability of BI 894416 in 
plasma when given as oral single dose together with multiple oral doses of itraconazole (Test, 
T) as compared to when given alone as oral single dose (Reference, R).
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 894416:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for BI 894416:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as an open-label, two-treatment, two-period, one-way crossover 
trial in healthy male subjects in order to compare the test treatment (T) to the reference 
treatment (R). The treatments will be one oral single dose of 3 mg BI 894416 as tablet 
formulation (tablet strength: 1 mg) together with multiple oral doses of 200 mg itraconazole 
as oral solution formulation (concentration: 10 mg/mL) (T) and one oral single dose of 3 mg 
BI 894416 as tablet formulation (tablet strength: 1 mg) given alone (R). In both treatments, 
BI 894416 is administered to subjects in the fasting state. In the first treatment period (Period 
1, Visit 2), all subjects are planned to undergo treatment R, and in the second treatment 
period (Period 2, Visit 3), all subjects are planned to undergo treatment T. For details, refer to 
Section 4.1.
There will be a washout interval of at least 6 days between the administrations of BI 894416.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between treatments is based on 
an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529]. Because of the long half-life of itraconazole (about 40 
hours) and its metabolites, a one-way crossover design was selected, with administration of 
itraconazole in the second study period only. This design is not expected to lead to systematic 
errors in the estimation of the treatment effects since nonspecific time-effects are unlikely 
due to the short trial duration. For itraconazole studies, this design is recommended by the 
Innovation and Quality in Pharmaceutical Development’s Clinical Pharmacology Leadership 
Group (CPLG) [R17-3744].
For this pharmacokinetic drug-drug interaction trial, open-label treatment is acceptable, 
because the primary and secondary endpoints of this trial are pharmacokinetic endpoints 
derived from measurement of plasma concentrations of BI 894416. These endpoints are not 
expected to be affected by knowledge of treatment. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site.
Only male subjects will be included in the study because no data on reproductive toxicology 
are available at this time and because, until availability of data from the 26-week Tg.rasH2 
carcinogenicity study, study populations are restricted to male volunteers or patients (see IB 
[c03536505]).


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A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 50 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG and including the 
neurological examination) deviating from normal and assessed as clinically relevant by 
the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 


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11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (unless the subject quit smoking for at least 1 year prior to first planned 
administration of trial medication)
14. Alcohol abuse (consumption of more than 30 g per day)
15. Drug abuse or positive drug screening
16. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
17. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
18. Inability to comply with the dietary regimen of the trial site
19. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
20. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
21. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
22. History of relevant neurological disorder affecting the peripheral or central nervous 
system (this includes, but is not limited to: stroke, epilepsy, inflammatory or atrophic 
diseases affecting the nervous system, cluster headache or any cancer of the nervous 
system). Febrile seizures in childhood or adolescence, recovered carpal tunnel syndrome, 
recovered uncomplicated meningitis, recovered herpes zoster, tension headache, 
occasional benign tics (e.g. due to stress) or minor par- or dysesthesia (e.g. as a side effect 
of prior blood withdrawal) do not constitute a history of relevant neurological disorder.
23. History of immunological disease except allergy not relevant to the trial (such as mild hay 
fever or dust mite allergy) and except asthma in childhood or adolescence
24. History of cancer (other than successfully treated basal cell carcinoma)
25. Within 10 days prior to administration of trial medication, use of any drug that could 
reasonably inhibit platelet aggregation or coagulation (e.g., acetylsalicylic acid)
26. Liver enzyme (ALT, AST, gGT) values above upper limit of normal at the screening 
examination
27. History of drug-induced liver injury
28. History of heart failure, or any evidence of ventricular dysfunction in the history
29. History of hereditary fructose intolerance


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30. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from time point of first administration of trial medication 
until 30 days after the last administration of trial medication
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 
discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.3), 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.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and section 6.2.3.


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3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated 
if more than 50% of the subjects have drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least 1 drug-related serious adverse event is 
reported
3. Violation of GCP or the CTP impairing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of BI 894416
3.3.5
Replacement of subjects
In case more than 4 subjects do not complete the trial, the Trial Clinical Monitor together 
with the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many 
subjects will be replaced. A replacement subject will be assigned a unique trial subject 
number, and will be assigned to the same treatment as the subject 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. Itraconazole oral solution will be obtained from a public 
pharmacy. 
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the two test products are given below:
Test product 1
Substance:
BI 894416
Pharmaceutical formulation:
Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
1 mg
Posology:
3 – 0 – 0
Route of administration:
oral
Duration of use:
1 day (in treatments R and T)
Test product 2
Name:
Sempera® Liquid 10 mg/ml
Substance:
Itraconazole
Pharmaceutical formulation:
Oral solution
Source:
Public pharmacy (obtained by the clinical site)
Holder of marketing authorization: JANSSEN-CILAG GmbH, Neuss, Germany
Unit strength:
10 mg/mL
Posology:
20 mL – 0 – 0
Route of administration:
oral
Duration of use:
5 days (in treatment T, only)
4.1.2
Selection of doses in the trial
Perpetrator (itraconazole)
The dose of itraconazole selected for this trial reflects standard clinical doses, is considered 
sufficient to yield significant CYP3A inhibition and has been used successfully and safely in 
previous drug-drug interaction trials (c02336088, c03355329, c08928447).


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Victim (BI 894416)
4.1.3
Method of assigning subjects to treatment groups
There is only one treatment sequence investigated in this trial, and each subject will be 
allocated to the same treatment sequence (R-T). The subjects will be allocated to a study 
subject number by drawing lots prior to first administration of trial medication in the morning 
of Day 1 of Visit 2. The randomization list of study subject numbers and assigned treatment 
sequence will be provided to the trial site in advance. Note that the randomization list is just 
needed for logistical reasons in this non-randomized, open-label trial. Hence, no bias is 
introduced when providing the randomization list in advance to the site. Reference and test
treatments will be administered in the sequence specified in the Flow Chart. Once a subject 
number has been assigned, it cannot be reassigned to any other subject.
All subjects may be treated in one cohort, i.e. all subjects may receive treatment on the same 
calendar day. In case this is not feasible (e.g., due to logistical or recruitment reasons), the 
group may be split into several cohorts as required. Treatment of all subjects on the same 
calendar day is acceptable (for safety margin to exposure reached in previous SRD trial 1371-
0001 refer to Section 1.4.3.3; for discussion of study-associated risks and safety measures see 
Section 1.4.3).
The randomisation procedure is described in Section 7.6.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a one-way crossover study. All subjects will receive the 2 treatments in fixed
order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below. 


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Table 4.1.4: 1
Dosage and treatment schedule
Treatment 
period
Treatment
Substance
Formulation
Unit 
strength
Dosage
Total  dose
1
R (Reference) BI 894416
Tablet
1 mg
3 tablets on Day 1
3 mg
2
T (Test)
BI 894416
Itraconazole
Tablet
Oral solution
1 mg
10 mg/mL
3 tablets on Day 1
20 mL (200 mg) on 
Days -3 to Day 2
3 mg
1000 mg
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 of BI 894416 and no later 
than 9 h before dosing of itraconazole. 
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a standing position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
For restrictions with regard to diet, see Section 4.2.2.2.
Subjects will be kept under close medical surveillance until 24 h after administration of 
BI 894416. During the first 4 h after administration of BI 894416, 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 reasons or for recording of 12-lead ECG and vital signs measurements.
The treatments will be separated by a wash-out phase of at least 6 days between 
administrations of BI 894416. 
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.


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4.1.6
Packaging, labelling, and re-supply
BI 894416 tablets
BI 894416 tablets will be provided by BI. They will be packaged and labelled in accordance 
with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
No re-supply is planned.
Itraconazole oral solution
Itraconazole oral solution will be obtained by the clinical trial site from a public pharmacy. 
The drug will be dispensed out of the original, unmodified packages.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Approval/notification of the regulatory authority,  e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 


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investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
Acetylsalicylic acid or other drugs that may inhibit platelet aggregation or coagulation should 
be avoided during the entire study. 
Known inhibitors/inducers of CYP3A and P-glycoprotein activity as well as drugs with a
known hepatotoxicity profile should be avoided during the entire study.
4.2.2.2
Restrictions on diet and life style
Poppy-seeds containing foods should not be consumed starting 3 days before the first drug 
administration in each treatment period, in order to avoid false-positive results in the drug 
screen.
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart.
No food is allowed for at least 4 h after intake of BI 894416.
Subjects will be advised to not consume any food within 1 h after itraconazole administration
on ambulatory visits.
From 1 h before intake of BI 894416 on Day 1 of period 1 until lunch, and from 1 h before 
intake of itraconazole on Day 1 of period 2 until lunch, fluid intake is restricted to the water 
administered with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose 
(mandatory for all subjects). From lunch until 24 h post-dose, total fluid intake is restricted to
3000 mL.


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Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products containing St. John's wort (Hypericum perforatum) are not permitted from 7 
days before the first administration of trial medication in period 1 until after the last PK 
sample in period 2 is collected.
Alcoholic beverages are not permitted from 2 days before the first administration of trial 
medication in period 1 until after the last PK sample in period 2 is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, coke, energy drinks, or 
chocolate) are not allowed from 10 h before until 24 h after administration of BI 894416.
Smoking is not allowed during the trial.
Barbecued meat and broccoli should be avoided during the trial.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations  
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history, relevant medical history and concomitant therapy, review of 
inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory 
tests, a physical examination, and a neurological examination. At the end of trial 
examination, it will include review of vital signs, 12-lead ECG, laboratory tests, and a
physical examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (Dinamap Pro 100, GE Medical Systems, Freiburg, Germany) at the 
times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine 
position. All recordings should be made using the same type of blood pressure recording 
instrument on the same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A1
B1
C1
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands;  Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
Prothrombin time – INR (International Normalization Ratio)
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
X
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
1
A, B, and C are different sets of laboratory values. The Flow Chart details at which time point which 
set is to be investigated.


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The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and prior to first dosing in each treatment 
period.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Cotinine test (urine)
Cotinine
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
7410, Dräger AG, Lübeck, Germany) will be performed prior to drug administration on 
Day 1 of treatment period 1 and on Day -3 of treatment period 2, and may be repeated at any 
time during the study at the discretion of an investigator or designee. The results will not be 
included in the CTR
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at MVZ Labor 
Ravensburg GbR, Elisabethenstraße 11, 88212 Ravensburg, Germany, with the exception of 
drug screening tests. These tests will be performed at the trial site using M-10/14-PDT 
multiline test, or comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) at the times provided in the Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.


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All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (GE Medical 
Systems, Freiburg, Germany). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts,
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
5.2.5.1
Neurological examinations
At Screening, a physical neurological examination will be performed. Upon investigator 
judgment, additional neurological examinations may be added at any time during the trial, for 
individual subjects or for the whole treatment group.
The neurological examination will include the following assessments:
-
Eye movement
-
Pupil size and pupil reactivity
-
Reflexes 
-
Assessment of muscle strength
-
Gait
-
Romberg test
-
Tremor
-
Point-to-point movements
-
Sensitivity
Documentation, Assessment, and Reporting
Results will be documented in source data at the clinical trial site and assessed for clinical 
relevance by an investigator, deputy investigator or sub-investigator. Clinically relevant 
findings of the neurological examination will be reported as Adverse Events (during the trial) 
or as baseline conditions (at screening). Case narratives may be written if necessary.


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


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


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


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


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AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 


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5.6
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of orally administered drugs, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Sections 5.3, 
2.1.2, 2.1.3, and 2.2.2.1 are generally used assessments of drug exposure. 
Due to neurologic effects observed in dog studies, a neurological examination is performed at 
Screening to ensure that no subject with a clinically relevant finding in the neurological 
examination is included into the trial. Upon investigator judgment, additional neurological 
examinations may be added at any time during the trial, for individual subjects or for the 
whole treatment group.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Days -3, -2, -1, and 1 are to be performed and completed within a 3 h-
period prior to the next trial drug administration, if not indicated otherwise in the Flow Chart.
In visits 2 and 3, the acceptable deviation from the scheduled time for vital signs, ECG, and 
laboratory tests will be ± 45 min on Day 1, ± 60 min on Day 2, and ± 120 min from Day 3 
onwards.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
Starting from 48 hours after BI 894416 administration (and beyond), a time window of 
± 120 min will be allowed for PK blood sampling times.  
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.5.1).
6.2.2
Treatment periods
Each subject is expected to participate in 2 treatment periods. At least 6 days will separate 
administrations of BI 894416 in the first and second treatment periods.


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On Day 1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration. The 
subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness. On all other study days, subjects will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on times of all other trial procedures, refer 
to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained. 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the relative bioavailability of BI 894416 in 
plasma when given as oral single dose together with multiple oral doses of itraconazole (Test, 
T) as compared to when given alone as oral single dose (Reference, R) on the basis of the 
primary and secondary pharmacokinetic endpoints, as listed in Section 2.1.2 and 2.1.3. The 
trial is designed to allow intra-subject comparisons and will be evaluated statistically by use 
of a linear model for logarithmically transformed PK endpoints.
A further objective is to evaluate and compare further pharmacokinetic parameters between 
the treatments, see Section 2.2.1. These further pharmacokinetic parameters will be assessed 
by descriptive statistics.
The assessment of safety and tolerability is also a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of BI 894416 in plasma after test vs. reference treatment will be 
estimated by the ratios of the geometric means (test/reference), and their corresponding 2-
sided 90% confidence intervals (CIs) will be provided. This method corresponds to the two 
one-sided t-test procedure, each at the 5% significance level. Since the main focus is on 
estimation and not testing, a formal hypothesis test and associated acceptance range is not 
specified.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of study drug. The treated set will be used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol violation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 
contributes only one PK parameter value for one period to the statistical assessment.
Descriptive and model based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol violation 
(IPV) categories will be suggested in the TSAP, IPVs will be identified no later than in the 
Report Planning Meeting, and the IPV categories will be updated as needed.


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Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for drug BI 894416 will be calculated 
according to the relevant SOP of the Sponsor (001-MCS-36-472). 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
violation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis), 

A predose concentration of BI 894416 is >5% Cmax value of that subject in the 
respective treatment period

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.3.1
Primary endpoint analyses
Primary analyses
The primary endpoints (refer to Section 2.1.2) will be calculated according to the BI Standard 
Operating Procedure (SOP) ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/ Pharmacodynamics’ (001-MCS-36-472).
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 


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effects accounting for the following sources of variation: subject and treatment. The effect 
'subject’ will be considered as random, whereas ’treatment’ will be considered as fixed. The 
model is described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response measured on subject m receiving treatment  k ,
= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ...,n
k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received treatment k.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means).
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
‘subject’ considered as fixed effects.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.3.2
Secondary endpoint analyses
The secondary endpoint (refer to Section 2.1.3) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will be assessed statistically using the same 
methods as described for the primary endpoints.


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7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the assigned treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication in 
period 1 will be assigned to the screening period, those between treatment with BI 894416 in 
period 1 and first treatment with itraconazole in period 2 are attributed to the treatment 
interval “BI 894416 alone”, those between first treatment with itraconazole in period 2 and 
treatment with BI 894416 in period 2 are attributed to the treatment interval “itraconazole 
alone” and those occurring between treatment with BI 894416 in period 2 and the individual 
subject’s end of trial are attributed to the treatment interval “BI 894416 + itraconazole”  . 
These assignments including the corresponding time intervals will be defined in detail in the 
TSAP. Note that AEs occurring after the individual subject’s end of trial but entered before 
final database lock will be reported to Pharmacovigilance only and will not be captured in the 
trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
in order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. 
Relevant ECG findings and relevant findings from neurological examinations during the trial
will be reported as AEs.


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7.4
INTERIM ANALYSES
A preliminary, exploratory analysis of the PK parameters (AUC0-tz, AUC0-∞and Cmax of 
BI 894416) may be performed based on all evaluable data after last subject out and prior to 
data base lock. This may be necessary, e. g., in case the information is needed to inform other 
activities during the development of BI 894416 such as concomitant treatment restrictions in 
other studies. In contrast to the final PK calculations, the preliminary, exploratory analysis 
will be based on planned sampling times rather than on actual times, regardless of whether 
actual times were within the time windows or not. Therefore, minor deviations of preliminary 
and final results may occur. Results will be provided as individual values and geometric 
means as well as the adjusted gMean ratios determined according to the planned primary 
analysis described in Section 7.3.1. The preliminary, exploratory results will be distributed to 
the trial team.
No formal preliminary PK report will be written.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
In this trial subjects receive both treatments in the same order, thus no randomization for the 
treatment assignment is performed (see also Section 4.1.3).The sponsor will arrange for the 
packaging and labelling of BI 894416 trial medication. The randomization list is just needed 
for logistical reasons in this trial. The randomisation list will be generated using a validated 
system that uses a pseudo-random number generator and a supplied seed number so that the 
resulting allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 16 subjects in the trial, including up to 4 non PK evaluable 
subjects. The planned sample size is not based on a power calculation but is considered 
sufficient to achieve the aims of this exploratory trial. With this sample size, the following 
precision in estimating the ratio of geometric means (test/reference) can be expected with 


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95% probability. Precision is defined as the ratio of upper CI limit to relative BA estimate. 
Note that the precision is independent of the actual ratio of geometric means.
The expected 90% confidence interval limits in the table were derived by
CI limit, = exp(ln(θ) ± ω),


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with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.5.1.


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


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8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the Human Pharmacology Centre (HPC) – Boehringer Ingelheim's Phase I unit – the 
validated ClinBaseTM system is used for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as data base. Instead of being entered into CRFs, selected data are directly 
entered into the system.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:


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


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


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


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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
P15-06298
Ministry of Health, Labour and Welfare. Drug interaction guideline for 
drug development and labeling recommendations (draft). 
http://www.solvobiotech.com/documents/Japanese_DDI_guideline_(draft)_
2014Jan.pdf (access date: 22 June 2015) ; Ministry of Health, Labour and 
Welfare (2014)
P15-06991
European Medicines Agency (EMA). Committee for Human Medicinal 
Products (CHMP): guideline on the investigation of drug interactions (21 
June 2012, CPMP/EWP/560/95/rev. 1 corr. 2). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidel
ine/2012/0 7/WC500129606.pdf (access date: 8 July 2015) ; London: 
European Medicines Agency (EMA) (2012)
P08-01263
Expert panel report 3: guidelines for the diagnosis and management of 
asthma: full report 2007 (NIH publication no. 07-4051, revised August 
2007). http://www.nhlbi.nih.gov ; Bethesda: U.S. Department of Health and 
Human Services, National Institutes of Health, National Heart, Lung and 
Blood Institute (2007)
R10-1102
Templeton IE, Thummel KE, Kharasch ED, Kunze KL, Hoffer C, Nelson 
WL, Isoherranen N. Contribution of itraconazole metabolites to inhibition 
of CYP3A4 in vivo. Clin Pharmacol Ther 83 (1), 77 - 85 (2008)
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R14-4230
Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular 
approaches. Nature Med 18 (5), 716 - 725 (2012)
R15-4770
Blancato J, Graves A, Rashidi B, Moroni M, Tchobe L, Ozdemirli M, 
Kallakury B, Makambi KH, Marian C, Mueller SC. SYK allelic loss and 
the role of Syk-regulated genes in breast cancer survival. Plos One 9 (2), 
e87610 (2014)
R15-5470
Mocsai A, Ruland J, Tybulewicz VLJ. The SYK tyrosine kinase: a crucial 
player in diverse biological functions. Nat Rev Immunol 10 (6), 387 - 402 
(2010)
R15-5888
Pelaia G, Vatrella A, Busceti MT, Gallelli L, Calabrese C, Terracciano R, 
Maselli R. Cellular mechanisms underlying eosinophilic and neutrophilic 
airway inflammation in asthma.Mediators Inflamm 2015, 879783 (2015)
R16-0945
Fahy JV. Type 2 inflammation in asthma - present in most, absent in many.
Nat Rev Immunol 15, 57 - 65 (2015)
R16-4459
Krisenko MO, Geahlen RL. Calling in SYK: SYK's dual role as a tumor 
promoter and tumor suppressor in cancer. Biochim Biophys Acta Mol Cell 
Res 1853 (1), 254 - 263 (2015)


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R16-5240
Boylan B, Gao C, Rathore V, Gill JC, Newman DK, Newman PJ. 
Identification of FcgammaRIIa as the ITAM-bearing receptor mediating 
alphaIIbbeta3 outside-in integrin signaling in human platelets. Blood 112 
(7), 2780 - 2786 (2008)
R16-5298
Alsadeq A, Hobeika E, Medgyesi D, Klaesener K, Reth M. The role of the 
Syk/Shp-1 kinase-phosphatase equilibrium in B cell development and 
signaling. J Immunol 193, 268 - 276 (2014)
R17-3742
Barone JA, Moskovitz BL, Guarnieri J, Hassell AE, Colaizzi JL, Bierman 
RH, et al. Food interaction and steady-state pharmacokinetics of 
itraconazole oral solution in healthy volunteers. Pharmacotherapy 18 (2), 
295 - 301 (1998)
R17-3743
Willems L, Geest R van der, Beule K de. Itraconazole oral solution and 
intravenous formulations: a review of pharmacokinetics and 
pharmacodynamics. J Clin Pharm Ther 26, 159 - 169 (2001)
R17-3744
Liu L, Bello A, Dresser MJ, Heald D, Komjathy SF, O'Mara E, et al. Best 
practices for the use of itraconazole as a replacement for ketoconazole in 
drug-drug interaction studies. J Clin Pharmacol 56 (2), 143 - 151 (2016)
R18-0241
Guidance for industry: clinical drug interaction studies - study design, data 
analysis, and clinical implications (draft guidance, this guidance document 
is being distributed for comment purposes only) (October 2017, clinical 
pharmacology). 
https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf (access 
date: 19 January 2018) ; Silver Spring: U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER) (2017)
R18-2643
Sporanox 10 mg/ml oral solution (Janssen-Cilag) (summary of product 
characteristics, updated 01-Mar-2018). 
https://www.medicines.org.uk/emc/product/1522/smpc/print (access date: 
14 August 2018) (2018)
R18-2644
Sempera Liquid 10 mg/ml, Loesung zum Einnehmen (Janssen-Cilag) 
(Fachinformation, Stand der Information: Dezember 2017).
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472
Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current versionc02336088
c02336088
 Relative bioavailability of a 
single oral dose of BI 691751 when administered alone or in combination 
with multiple oral doses of itraconazole in healthy male subjects (an open-
label, randomised, two-period, two-sequence crossover study). 1334.10. 09 
Jan 2015


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c03355329
. Relative bioavailability of a single 
oral dose of BI 425809 when administered alone or in combination with 
multiple oral doses of itraconazole in healthy male subjects (an open-label, 
two-period, fixed-sequence trial) 1346.10. 03 Dec 2015
c03536505
 
. Investigator Brochure: BI 894416 Asthma
c08928447
Effect of multiple doses of 
itraconazole on the pharmacokinetics of a single oral dose of BI 1026706 in 
healthy male subjects (an open-label, randomised, two-period, two-
sequence crossover study)1320.20. 29 Sep 2016
n00240179
. BI 894416: 
Exploratory 15 day oral (gavage) toxicity study in male rats. 13B105. 29 
Jun 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. 2016-i-r-resp3-report1. 11 Jul 2016
n00245394
 BI 894416: Dose Escalation in Dogs with Assessment of 
Electroencephalography and Nerve Conduction Velocity. 15R160


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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
02 October 2018
EudraCT number
EU number
2018-002728-17
BI Trial number
1371-0004
BI Investigational Medicinal 
Product(s)
BI 894416
Title of protocol
Relative bioavailability of a single oral dose of BI 
894416 when administered alone or in combination 
with multiple oral doses of itraconazole in healthy 
male subjects (an open-label, one-way crossover 
study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1) Section 3.3.2
2) Section 4.1.3
Description of change
1) Reduction of upper age limit to 50 years
2) Explanation that all subjects may be dosed in one 
cohort on the same calendar day.
Rationale for change
1) To address request by BfArM / IEC
2) To address request by BfArM / IEC


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11.2
GLOBAL AMENDMENT 2
Date of amendment
14 November 2018
EudraCT number
EU number
2018-002728-17
BI Trial number
1371-0004
BI Investigational Medicinal 
Product(s)
BI 894416
Title of protocol
Relative bioavailability of a single oral dose of BI 
894416 when administered alone or in combination 
with multiple oral doses of itraconazole in healthy 
male subjects (an open-label, one-way crossover 
study)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1) 5.2.3
2) 5.3.2.1
Description of change
1) M-10/14-PDT multiline test used for drug 
screening instead of AccuSign DOA 10 test;
extra line for “Prothrombin time” added to 
coagulation
2) Max. time interval from blood withdrawal to 
freezing of itraconazole plasma aliquots 
reduced to 60 min
Rationale for change
1) AccuSign DOA 10 test has been replaced by 
M-10/14-PDT multiline test in all studies 
performed at HPZ as a trial site; extra line for 
“Prothrombin time” added to coagulation, to 
clarify that prothrombin time is to be 
reported as both percentual value (Quick) 
and as INR value
2) Itraconazole stability data are only available 
over 60 min.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c24667886
3.0
clinical-trial-protocol-revision-2
Relative bioavailability of a single oral dose of BI 894416 when administered alone
or in combination with multiple oral doses of itraconazole in healthy male subjects
(an open-label, one-way crossover study)
Author-Clinical Trial Leader
14 Nov 2018 18:53 CET
Author-Clinical Pharmacokineticist
15 Nov 2018 08:17 CET
Author-Trial Statistician
15 Nov 2018 09:56 CET
Verification-Paper Signature
Completion
15 Nov 2018 15:08 CET
Approval-Therapeutic Area 
15 Nov 2018 19:30 CET
Approval-Team Member Medicine
26 Nov 2018 03:04 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c24667886
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c26502649-01
BI Trial No.:
1371-0004
Title:
Relative bioavailability of a single oral dose of BI 894416 when
administered alone or in combination with multiple oral doses of
itraconazole in healthy male subjects (an open-label, one-way
crossover study)
Including Protocol Amendments 1 and 2 [c24667886-03]
Investigational
Product(s):
BI 894416
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
06-FEB-2019 SIGNED
Version:
Final
Page 1 of 23
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoint...............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................12
6.5
POOLING OF CENTRES .................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................13
7.
PLANNED ANALYSIS......................................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........16
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................16
7.3
TREATMENT COMPLIANCE........................................................................16
7.4
PRIMARY ENDPOINT .....................................................................................16
7.5
SECONDARY ENDPOINTS.............................................................................17
7.5.1
Key secondary endpoint .....................................................................................17
7.5.2
Secondary endpoints...........................................................................................17
7.7
EXTENT OF EXPOSURE.................................................................................18
7.8
SAFETY ANALYSIS..........................................................................................18
7.8.1
Adverse events.....................................................................................................18


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7.8.2
Laboratory data ..................................................................................................19
7.8.3
Vital signs.............................................................................................................20
7.8.4
Others...................................................................................................................20
8.
REFERENCES....................................................................................................21
10.
HISTORY TABLE..............................................................................................23


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LIST OF TABLES
Table 6.1: 1
Analysis phases for statistical analysis of AEs.................................................11
Table 6.3: 1
Subject sets analysed ........................................................................................13
Table 10: 1
History table .....................................................................................................23


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
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 from 0 to 
infinity
BI 
Boehringer Ingelheim
BP
Blood pressure
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
gCV
geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
IPD
Important protocol deviations
IQRMP
Integrated quality and risk management plan
ITZ
Itraconazole
MedDRA
Medical Dictionary For Regulatory Activities
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter set
PR
Pulse rate
RAGe
Report appendix generator
RPM
Report Planning Meeting
SAE
Serious adverse event
SD
Standard Deviation
SOC
System Organ Class


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Term
Definition / description
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised CTP, and to
include detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP and its amendments. In particular, the TSAP is 
based on the planned analysis specification as written in CTP Section 7 "Statistical Methods 
and Determination of Sample Size". Therefore, TSAP readers may consult the revised CTP 
for more background information on the study, e.g., on study objectives, study design and 
population, treatments, definition of measurements and variables, planning of sample size, 
randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM system. 
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). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version Phoenix 6.3, 
Certara USA Inc., Princeton, NJ, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods described 
in the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoints are PK endpoints of BI 894416 as defined in Section 2.1.2 of the CTP:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoint
Secondary endpoint of this trial is AUC0-∞of BI 894416 in plasma, as defined in Section 2.1.3
of the CTP.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment groups, 
and selection of doses, cf. Section 4 of the CTP.
Each subject is planned to be treated in two subsequent treatment periods. In the first 
treatment period, subjects will receive a single dose of 3 mg of BI 894416 (reference 
treatment). In the second treatment period, subjects will receive treatment with itraconazole 
200 mg once daily over 5 days together with an administration of a single dose of 3 mg of 
BI 894416 on the fourth day of itraconazole treatment (test treatment). The sequence of these 
treatment periods is fixed and the same for all subjects.
For statistical analyses of AEs, the following separate analysis phases will be defined for each 
subject:
Table 6.1: 1
Analysis phases for statistical analysis of AEs
Study analysis 
phase
Label
Start
End
Screening
Screening
Date of informed consent
Date/time of first administration 
of BI 894416
On treatment 
BI 894416
BI
Date/time of first administration 
of BI 894416
Date/time of first administration 
of itraconazole
On treatment
ITZ
ITZ
Date/time of first administration 
of itraconazole
Date/time of second 
administration of BI 894416
On treatment 
BI 894416 +
ITZ
BI + ITZ
Date/time of second 
administration of BI 894416
12:00 a.m. on day after subject's 
trial termination date
CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phase only.
In CTR Section 15 AE tables (but not in Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 
AE tables), the following totals will be provided in addition:

"Total BI", defined as the total over all on-treatment phases involving BI

"Total on-trt", defined as the total over all on-treatment phases
CTR Appendix 16.1.13.1.8.1 displays will present results for the screening and on-treatment
phases.
Additionally to the totals defined above, the following total will be provided in CTR 
Section 16.1.13.1.8.1 AE tables:

"Total", defined as the total over all study phases (screening + on-treatment)


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Statistical analyses of safety laboratory tests and vital signs will be conducted by treatment 
period (BI vs. BI+ITZ).
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the RPM/DBLM. At this meeting, it will be decided whether a 
discrepant data value can be used in analyses or whether it must be corrected in the clinical 
database. Each protocol deviation must be assessed to determine whether it is an IPD. For 
definition of IPDs, and for the process of identification of these, refer to the BI reference 
document "Identify and Manage Important Protocol Deviations (iPD)" (2).
If any IPDs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes. Categories which are considered to be IPDs in this trial are defined 
in the integrated quality and risk management plan (IQRMP). If the data show other IPDs, the 
definition in the IQRMP will be supplemented accordingly by the time of the RPM/DBLM.
IPDs will be summarised and listed.
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects who received at least one dose of study drug. 
This is the full analysis set population in the sense of ICH-E9 (1). It will be used for 
analysis of safety, demographic data and baseline characteristics.

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the TS who provide at least one PK parameter 
that was not excluded because of IPDs relevant to the statistical evaluation of PK 
endpoints as defined in Section 7.3 of the CTP.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to analysis sets will be made at latest at the RPM/DBLM.


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition
X
Exposure
X
IPDs
X
Demographic/baseline endpoints
X
Safety parameters
X
Primary endpoints
X
Secondary endpoint
X
Further PK endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects who were withdrawn from the trial prior to first administration of 
any study drug will not be reported in the CTR.
Data of subjects who failed to complete all periods of the study (dropouts or withdrawals) will 
be reported in the CTR as far as their data are available. All withdrawals will be documented 
and the reason for withdrawal recorded in the CTR.
CTP: It is not planned to impute missing values for safety parameters.
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 (3).
Missing data and outliers of PK data are handled according to BI standards (4). CTP: PK 
parameters that cannot be reasonably calculated based on the available drug concentration-
time data will not be imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline will be defined as the last available value before administration of BI 894416 in 
period 1 (Visit 2).
Note that this baseline definition will be used for evaluation of data of both treatment periods 
and of all on-treatment periods (“BI”, “ITZ”, “BI + ITZ”, as defined in Section 6.1).


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Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM/DBLM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (5).
The individual values of all subjects will be listed. Listings will be sorted by subject number 
and visit (if visit is applicable in the respective listing). AE listings will be sorted by assigned 
treatment (see Section 7.8.1 below for details). The listings will be contained in Appendix 
16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR. These will be based on the 
TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary.
Only descriptive statistics are planned for this section of the CTR.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of first administration of the respective treatment or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the RPM/DBLM (cf. Section 6.2) and described in the 
CTR.
7.4
PRIMARY ENDPOINT
Analysis of relative bioavailability of primary endpoints AUC0-tz and Cmax of BI 894416 in 
plasma will be performed as defined in Sections 7.1 and 7.3.1 of the CTP.
The statistical model for the primary analysis defined in the CTP is an analysis of variance
(ANOVA) model on the logarithmic scale including "treatment" as fixed effect and "subject" 
as random effect. In addition, a secondary analysis will be performed, using both, "subject" 
and "treatment", as fixed effects in the ANOVA model.
Primary PK endpoints will be assessed descriptively. The analysis of standard PK parameters 
is performed according to BI standards (4) [001-MCS-36-472_RD-01].
Exclusion of PK parameters
The ADS ADPP 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 are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".
Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 


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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 only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (4) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (6).
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoints
Analysis of relative bioavailability of secondary endpoint AUC0-∞of BI 894416 in plasma 
will be performed in the same way as for the primary endpoints.
Additionally, the secondary PK endpoint will be assessed descriptively. The analysis of 
standard PK parameters is performed according to BI standards (4).
See Section 7.4 of this TSAP for details regarding exclusion of PK parameters and plasma 
concentrations.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to the screening or on-treatment phase as defined in Section 6.1. AEs 
will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 (8) and for the class of 
AESIs.
CTP: The following are considered as AESIs:
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
○
An elevation of AST (aspartate transaminase) and/or ALT (alanine transaminase) ≥3-
fold ULN combined with an elevation of total bilirubin ≥2-fold ULN measured in the 
same blood sample, or 
○
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8), AEs classified as "other significant" need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or


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(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term. AEs which were considered by the investigator to be drug 
related (primary endpoint) will be summarised separately. Separate tables will also be 
provided for subjects with SAEs, subjects with AESIs and subjects with other significant AEs 
(according to ICH E3 (8)). The frequency of subjects with AEs and the frequency of subjects 
with AEs considered by the investigator to be drug related will also be summarised by 
maximum intensity, primary SOC and preferred term.
The system organ classes and preferred terms within system organ classes will be sorted by 
descending frequency over all treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will also 
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
"Display and Analysis of Laboratory Data" (9).
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM/DBLM at the latest. It is the Investigator's 
responsibility to decide whether a lab value is clinically significant abnormal or not. Standard 
or project-specific rules for flagging clinically significant values in an automated manner will 
not be applied in this study.
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.


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7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Clinically relevant findings in vital signs 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.
7.8.4
Others
Physical and neurological examination findings as well as relevant ECG findings will be 
reported as relevant medical history/baseline condition (i.e., a condition already existent 
before intake of first study drug) or as AE and will be summarised as such. No separate listing 
or analysis of physical or neurological examination as well as ECG findings will be prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Design, Conduct, Analysis and Evaluation of 
Clinical Trialss, current version
2
001-MCS-40-413_1.0: "Identify and Manage Important Protocol Deviations 
(iPD)", current version; IDEA for CON
3
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON
4
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON
5
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current 
version; IDEA for CON
6
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD 
Data Files", current version; IDEA for CON
7
001-MCG-156: "Analysis and Presentation of Adverse Event Data from Clinical 
Trials", current version; IDEA for CON
8
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
9
001-MCG-157: "Display and Analysis of Laboratory Data", current version; IDEA 
for CON


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