Clinical trial NCT03159455
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2017-06-07; Completion date: 2017-12-16
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the current study is to investigate the safety and tolerability of BI 1467335 in healthy Japanese male subjects following oral administration of multiple rising doses The Caucasian group will receive higher dose only.

A secondary objective is the exploration of the pharmacokinetics and pharmacodynamics of BI 1467335 in healthy Japanese and Caucasian male subjects.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI 1467335 intervention 2: Placebo
Intervention descriptions: intervention 1: Duration - 28 days intervention 2: Duration - 28 days

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
TITLE PAGE
Document Number:
c11428532-01
BI Trial No.:
1386-0007
BI Investigational
Product:
BI 1467335
Title:
Lay Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of 
multiple rising oral doses of BI 1467335 in healthy Japanese male 
volunteers with multiple oral doses at the highest dose in Caucasian 
for comparison (randomised, double-blind, placebo-controlled trial)
This study tests BI 1467335 in healthy Japanese and Caucasian men. 
The study tests how different doses of BI 1467335 are taken up in the 
body and how well they are tolerated.
Clinical Phase:
I
Trial Clinical Monitor:
Phone: 
Fax: 
Co-ordinating
Investigator:
Phone: 
Fax: 
Status:
Final Protocol
Version and Date:
Version: 1.0
Date: 11 May 2017
Page 1 of 78
Proprietary confidential information
© 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1467335
Protocol date:
Trial number:
Revision date:
Not Applicable
11 May 2017
1386-0007
Title of trial:
Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple rising oral 
doses of BI 1467335 in healthy Japanese male volunteers with multiple oral doses at 
the highest dose in Caucasian for comparison (randomised, double-blind, placebo-
controlled trial)
Co-ordinating
Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics 
following multiple rising oral doses of BI 1467335 in healthy Japanese male 
volunteers with single dose Caucasian group for comparison
Methodology:
Multiple rising oral doses in Japanese with single dose Caucasian group for 
comparison, randomised, double-blind, placebo controlled within dose groups, 
multiple centres.
No. of subjects: 
total entered:
48 (36 Japanese and 12 Caucasian)
each treatment:
12 per dose group /ethnicity (9 on active and 3 on placebo)
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male Japanese and Caucasian subjects
Age and 45 years
BMI range: ≥18.5 and 25 kg/m2 (Japanese), ≥18.5 and 29.9 kg/m2 (Caucasian)
Test product:
BI 1467335 film-coated tablets
dose:
3, 6 and 10 mg qd (Japanese) and 10 mg qd (Caucasian)
mode of admin.:
Oral administration with 240 mL water after an overnight fast of at least 10 hours
Comparator product:
Placebo 
dose:
Not applicable (matching placebo tablets)
mode of admin.:
Oral administration with 240 mL water after an overnight fast of at least 10 hours
Duration of treatment: 28 days with multiple oral doses of BI 1467335 q.d.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1467335
Protocol date:
Trial number:
Revision date:
Not Applicable
11 May 2017
1386-0007
Criteria for 
pharmacokinetics:
Secondary endpoints: 
After the first dose: AUC0-24 and Cmax of BI 1467335
After the last dose: AUC0-24,28 and Cmax,28 of BI 1467335
Criteria for 
pharmacodynamics:
Criteria for safety:
Primary endpoint: The number [N (%)] of subjects with drug-related AEs
 
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
Dose proportionality of BI 1467335 will be explored using a regression model; a 95% 
confidence interval for the slope will be computed.


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FLOW CHART
Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9
 
 
 
12-lead ECG 8
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
1
-28 to -2
Screening (SCR)1, 5, 12
x5
x
x
2
-3 to -17
-48:00
09:00
Ambulatory visit
x
x
x
x
-1
-12:00
21:00
Admission to trial site
x5
x
1
-2:00
07:00
Allocation to treatment2
x2,13
x2, 
16
x2
x2
x2
-0:05
08:55
x14
x10
0:00
09:00
First drug administration
▲
0:15
09:15
x
│
x
0:30
09:30
x
│
x
x
0:45
09:45
x
│
x
x
1:00
10:00
x
│
x
x
x
1:30
10:30
x
│
x
2:00
11:00
240 mL fluid intake and light breakfast3
x
│
x
x
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
│
8:00
17:00
Snack (voluntary)3
x
┼
x
x
x
10:00
19:00
Dinner3
x
│
12:00
21:00
x
┼
x
x
x 
2
23:55
08:55
x14
▼
x14
x2
x2
x2
24:00
09:00
Drug administration11
3
48:00
09:00
Drug administration11
x
x2
x2
x2
4
71:55
08:55
x14
72:00
09:00
Drug administration11
x2
x2
x2
72:30
09:30
x
73:00
10:00
Discharge from trial site (confirmation of 
fitness)4
x
x
x
x
7
143:55
08:55
Ambulatory visit
x14
x14
144:00
09:00
Drug administration11
x2
x2
x2
x2
144:30
9:30
x
145:00
10:00
Discharge
x
x
x


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Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood 
9
 
 
12-lead ECG 8
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
2
13
300:00
21:00
Admission to trial site
14
310:00
07:00
x2
x2
x2
x2
311:55
08:55
x14
x14
312:00
09:00
Drug administration
▲
312:15
09:15
x
│
x
312:30
09:30
x
│
x
x
312:45
09:45
x
│
x
x
313:00
10:00
x
│
x
x
x
313:30
10:30
x
│
x
314:00
11:00
240 mL fluid intake and light breakfast3
x
│
x
x
x
315:00
12:00
x
│
316:00
13:00
240 mL fluid intake, thereafter lunch3
x
┼
x
x
x
318:00
15:00
x
│
320:00
17:00
Snack (voluntary)3
x
┼
x
x
x
322:00
19:00
Dinner3
x
│
324:00
21:00
x
┼
x
x
x 
15
335:55
08:55
x14
▼
336:00
09:00
Drug administration11
x2
x2
x2
336:30
09:30
x
337:00
10:00
Discharge
x
x
x
21
479:55
08:55
Ambulatory visit
x14
x14
480:00
09:00
Drug administration11
x2
x2
x2
x2
480:30
09:30
x
481:00
10:00
Discharge
x
x
x
x
26
599:55
08:55
Admission to trial site
x14
600:00
09:00
Drug administration11
x2
x2
x2
600:30
09:30
x
601:00
10:00
x
x
x
x
612:00
21:00
27
623:55
08:55
x14
624:00
09:00
Drug administration11
▲
x2
x2
x2
624:30
09:30
x
│
625:00
10:00
x
│
x
x
x


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Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood
9
 
 
12-lead ECG 8
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
2
28
646:00
7:00
x2
│
x2
x2
x2
647:55
08:55
x14,
15
▼
x14
,16
648:00
09:00
Last drug administration
▲
648:15
09:15
x
│
x
648:30
09:30
x15
│
x
x
x
648:45
09:45
x
│
x
x
649:00
10:00
x15
│
│
x
x
x
x
649:30
10:30
x
│
x
650:00
11:00
240 mL fluid intake and light breakfast3
x15
│
x
x
x
x
651:00
12:00
x
│
652:00
13:00
240 mL fluid intake, thereafter lunch3
x15
┼
x
x
x
x
654:00
15:00
x15
│
x
656:00
17:00
Snack (voluntary)3
x15
┼
x
x
x
658:00
19:00
Dinner3
x15
│
x
660:00
21:00
x15
┼
x
x
x
x 
29
672:00
09:00
x15
▼
x
x
x
x
673:00
10:00
Discharge from trial site (confirmation 
of fitness)4
30
696:00
09:00
Ambulatory visit17
x
x15
x
x
x
x
32+/-1
744:00
09:00
Ambulatory visit17
x15
x
x
36+/-2
840:00
09:00
Ambulatory visit17
x15
x
40
936:00
09:00
Ambulatory visit
x15
x
3
42 to 48
End of trial (EOT) examination4, 12
x
x
x
x
x
1.
Screening includes subject information, informed consent, physical examination, check of vital signs, ECG, safety 
laboratory (including exclusionary laboratory tests), demographics (including determination of body height and weight, 
smoking status and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion 
criteria.
2.
The time is approximate; the respective procedure is to be performed and completed within 3 h prior to drug 
administration. Allocation to treatment may be performed at any time following enrolment but must be completed prior 
to (first) drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, body weight, vital signs, ECG, safety laboratory, recording of 
AEs and concomitant therapies. Confirmation of fitness includes physical examination.
5.
Urine drug screening and alcohol breath test will be done at screening and Day -1.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
Safety laboratory, ECG, blood pressure assessment and AE questioning to be done and medically evaluated within 
3 days prior to first administration of study drug; this visit can be omitted, if the screening examination is performed on 
Days -3, -2 or -1.
8.
The ECG recording has to be performed as triple on Day 1 and Day 2, Day 14 and Day 15, Day 28 and Day 29. All other 
ECG recordings will be single ECGs.
9.
Sampling times and periods may be adapted based on information obtained during the trial (e.g. preliminary PK data) 
including addition of samples and visits as long as the total blood volume taken does not exceed 400 mL per subject.
 
 


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11. Administration under fasting conditions. On the hospitalization days, light breakfast (or snack) 2 h after drug 
administration
12. Ophthalmological examinations (exclusion of cataract).Slit lamp test can be performed during screening or until Day -1
and from Day 29 to EOT visit.
14. Samples to be drawn immediately (within 30 minutes) prior to drug administration.
15. Additional blood samples for metabolite analysis.
 
17. If consecutive two-day ambulatory visits take place, subjects can stay at the site.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 26
2.2
TRIAL OBJECTIVES.......................................................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 31
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................31
3.1.1
Administrative structure of the trial...................................................32
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................32
3.3
SELECTION OF TRIAL POPULATION ......................................................33
3.3.1
Main diagnosis for study entry............................................................33
3.3.2
Inclusion criteria...................................................................................33
3.3.3
Exclusion criteria ..................................................................................34
3.3.4
Removal of subjects from therapy or assessments.............................35
3.3.4.1
Removal of individual subjects................................................35
3.3.4.2
Discontinuation of the trial by the sponsor..............................36
3.3.5
Replacement of subjects .......................................................................36
4.
TREATMENTS........................................................................................ 37
4.1
TREATMENTS TO BE ADMINISTERED....................................................37
4.1.1
Identity of BI investigational product and comparator product......37
4.1.2
Method of assigning subjects to treatment groups ............................37
4.1.3
Selection of doses in the trial................................................................38
4.1.4
Drug assignment and administration of doses for each subject .......38


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4.1.5
Blinding and procedures for unblinding ............................................39
4.1.5.1
Blinding....................................................................................39
4.1.5.2
Procedures for emergency unblinding .....................................39
4.1.6
Packaging, labelling, and re-supply ....................................................40
4.1.7
Storage conditions.................................................................................40
4.1.8
Drug accountability ..............................................................................40
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................41
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................41
4.2.2
Restrictions............................................................................................41
4.2.2.1
Restrictions regarding concomitant treatment .........................41
4.2.2.2
Restrictions on diet and life style.............................................41
4.3
TREATMENT COMPLIANCE.......................................................................42
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 43
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................43
5.1.1
Endpoints of efficacy.............................................................................43
5.1.2
Assessment of efficacy...........................................................................43
5.2
SAFETY..............................................................................................................43
5.2.1
Endpoints of safety................................................................................43
5.2.2
Assessment of adverse events...............................................................43
5.2.2.1
Definitions of adverse events...................................................43
5.2.2.2
Adverse event collection and reporting ...................................46
5.2.3
Assessment of safety laboratory parameters......................................48
5.2.4
Electrocardiogram................................................................................51
5.2.5
Assessment of other safety parameters...............................................52
5.2.5.1
Vital signs ................................................................................52
5.2.5.2
Medical examinations..............................................................53
5.2.5.3
Ophtalmological examination..................................................53
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................54
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................54
5.5.1
Pharmacokinetic endpoints..................................................................54
5.5.1.1
Secondary endpoints................................................................54
5.5.2
Methods of sample collection...............................................................56


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5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................56
6.
INVESTIGATIONAL PLAN.................................................................. 61
6.1
VISIT SCHEDULE............................................................................................61
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................61
6.2.1
Screening................................................................................................61
6.2.2
Treatment period ..................................................................................62
6.2.3
End of trial and follow-up period........................................................62
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 63
7.1
STATISTICAL DESIGN – MODEL ...............................................................63
7.1.1
Objectives...............................................................................................63
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................63
7.3
PLANNED ANALYSES....................................................................................63
7.3.1
Primary analyses...................................................................................63
7.3.3
Safety analyses.......................................................................................66
7.3.4
Interim analysis.....................................................................................67
7.3.5
Pharmacokinetic analyses ....................................................................67
7.4
HANDLING OF MISSING DATA ..................................................................68
7.4.1
Safety......................................................................................................68
7.4.2
Plasma/urine drug concentration - time profile.................................68
7.4.3
Pharmacokinetic parameters...............................................................69
7.5
RANDOMISATION ..........................................................................................69
7.6
DETERMINATION OF SAMPLE SIZE ........................................................69
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 71


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8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................71
8.2
DATA QUALITY ASSURANCE .....................................................................72
8.3
RECORDS..........................................................................................................72
8.3.1
Source documents .................................................................................72
8.3.2
Direct access to source data and documents.......................................72
8.3.3
Storage period of records.....................................................................73
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................73
8.5
STATEMENT OF CONFIDENTIALITY.......................................................73
8.6
COMPLETION OF TRIAL.............................................................................73
8.7
PROTOCOL VIOLATIONS ............................................................................73
8.8
COMPENSATION AVAILABLE TO THE SUBJECT IN THE EVENT 
OF TRIAL RELATED INJURY......................................................................74
9.
REFERENCES......................................................................................... 75
9.1
PUBLISHED REFERENCES...........................................................................75
9.2
UNPUBLISHED REFERENCES.....................................................................76
10. APPENDICES .......................................................................................... 77
11. DESCRIPTION OF GLOBAL AMENDMENTS................................. 78


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ABBREVIATIONS
z(,N)
Terminal rate constant of the analyte in plasma (after the Nth dose)
AE
Adverse event
AESI
ANCOVA
Adverse events of special interest
Analysis of covariance
 
AUC0-24(,N)
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24h (after the Nth dose)
 
 
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
CCl4
Carbon tetrachloride
CI
Confidence interval
 
Cmax(,N)
Maximum measured concentration of the analyte in plasma (after the Nth
dose)
CML
Clinical Monitor Local
CNS
Central nervous system
 
 
CRA
Clinical Research Associate
CRF
Case report form
CRO
CTCAE
Clinical Research Organisation
Common Terminology Criteria for Adverse Events
CTP
Clinical trial protocol
CTR
Clinical trial report
CTSU
Clinical Trial Supplies Unit
CV
Arithmetic coefficient of variation
DEDP
Drug exposure during pregnancy
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
EDTA
ELISA
Ethylenediaminetetraacetic acid
Enzyme-Linked Immunosorbent Assay
EOT
End of trial
FDA
Food and Drug Administration
FIH
First in human


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FOB
Functional observational battery
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GI
Gastro-intestinal
GLP
gMEAN
Good Laboratory Practice
Geometric mean
HCC
Hepatocellular carcinoma
HR
Heart rate
IB
Investigator’s brochure
IEC
IPV
Independent Ethics Committee
Important protocol violations
IRB
Institutional Review Board
ISF
Investigator site file
LLOQ
Lower limit of quantification
MCD
Methionine-Choline deficient Diet
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
 
 
NBE
New biological entity
NC
Not calculated
NCE
New chemical entity
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
p.o
Pharmacokinetic parameter analysis set
per os
PP
Polypropylene
PR
PTM
Pulse rate
Planned time of the measurement
q.d.
Quaque die, once daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QTcV
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
heart-rate corrected QT interval using Van de Water’s formula
R
Reference treatment
 


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RDC
Remote Data Capture
REP
Residual effect period
SAE
Serious adverse event
SCR
SOC
Screening
System Organ Class
SOP
Standard Operating Procedure
SRD
Single-rising dose
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
Test product or treatment
TDMAP
TEAE
Trial Data Management and Analysis Plan
Treatment-emergent adverse event
 
 
TMF
Trial master file
TS
Treated Set
TSAP
Trial statistical analysis plan
TSH
Thyroid stimulating hormone
 
ULN
Upper limit of normal
 
 


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.2
TRIAL OBJECTIVES
The primary objective of the current study is to investigate the safety and tolerability of BI
1467335 in healthy Japanese male subjects following oral administration of multiple rising
doses of 3, 6 and 10 mg (for details see Section 5.2).The Caucasian group will receive 10 mg 
only.
A secondary objective is the exploration of the pharmacokinetics and pharmacodynamics of 
BI 1467335 in healthy Japanese and Caucasian male subjects.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
 
 
 
 
 
 
 
 
 
 
 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This multiple rising dose trial will be randomised, double-blind, and placebo controlled 
within dose groups.
A total of 48 volunteers will participate in the trial according to three groups with 12 subjects 
in dose groups 1 & 2 and 24 subjects in dose group 3. Each of the sequential dose groups has 
one or two ethnic subgroups and within each of the subgroups 9 subjects will receive the 
active drug and 3 subjects will receive placebo. One dose is tested within each group.
The dose groups to be evaluated are as outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups and subject numbers
Dose group 
1
2
3
Dose
3 mg q.d.
6 mg q.d.
10 mg q.d.
Ethnicity
Japanese
Japanese
Japanese
Caucasian
No of subjects
12
12
12
12
Subjects 
receiving 
placebo
3
3
3
3
Subjects 
receiving 
active
9
9
9
9
The different dose groups will be investigated consecutively in ascending order of the doses
in Japanese. The decision to proceed to the next dose group will be based upon the safety of 
the preceding dose group. Preliminary PK assessments as detailed in Section 7.3.4 will be 
performed at 6 mg dose level before starting with 10 mg dose level.
The investigator is allowed to stop the further dose escalation in case the safety evaluation 
leads to concerns which would not allow higher dosing.


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3.1.1
Administrative structure of the trial
The trial will be conducted at
and 
in 
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI 
Pharma GmbH & Co. KG, Biberach, Germany. 
On-site monitoring will be performed under the responsibility of Clinical Operations in 
Nippon BI.
Safety laboratory tests will be performed by the local laboratory of the trial site or/and at a 
CRO designated by the sponsor.
The analyses of BI 1467335 plasma concentrations will be performed at the Department of 
Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, Biberach, Germany.
A central ECG laboratory will be selected to provide services for ECG evaluation as required 
for this protocol. The ECG device will be provided by the ECG service vendor. Please refer 
to Section 5.2.4 for the details.
The trial is sponsored by Boehringer Ingelheim.
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all 
required activities, in order to: 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
order the materials as needed for the trial, 
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons and relevant local information (as 
protocol reference, if applicable) can be found in the ISF (Investigator site file).
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For multiple rising dose trials, the design described in Section 3.1 is viewed favourable under 
the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability as well as pharmacokinetics of BI 1467335.
With the rising dose design, double-blind conditions regarding the subjects' treatment (active 
or placebo) are maintained within each dose group, however the current dose level will be 
known to subjects and investigators. 


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The disadvantage of this trial design is a possible observer bias with regard to the dose 
depending effects as well as time effects but it has the virtue of minimising subject risk by 
sequentially studying ascending doses. This implicates a confounding factor concerning 
statistical comparisons between the dose levels. 
The resulting group sizes (nine subjects per active treatment group for doses 3mg and 6 mg, 
nine subjects per active treatment group per ethnicity for 10 mg) are in general considered as 
sufficient for the exploratory evaluation of pharmacokinetics.
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety, tolerability and pharmacokinetic effects. Each dose group consists of 
12 subjects per ethnicity with 9 on active treatment, and 3 on placebo. The placebo control 
group includes all subjects of all dose groups treated with placebo. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 48 healthy male subjects will enter the study. Based on the known safety 
profile and general applicability to a variety of potential indications that BI 1467335 is
pursuing, healthy volunteer are chosen in this phase I study. Healthy subjects as a Phase I 
trial population are ideal because they provide relatively stable physiological, biochemical, 
and hormonal conditions. In these subjects there is absence of disease-related variations and 
concomitant medications. Healthy subjects can be tested under standardised conditions and in 
an environment that allows repeated testing. 
3.3.1
Main diagnosis for study entry
The study will be performed in healthy male subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1.
Healthy male subjects according to the investigator’s assessment, based on a complete 
medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and 
clinical laboratory tests
2.
Japanese ethnicity or Caucasian, according to the following criteria:
-
Japanese; born in Japan, have lived outside of Japan <10 years, and have parents and 
grandparents who were all born in Japan
-
Caucasian
3. Age of 20 to 45 years (incl.) 
4. BMI of 18.5 to 25 kg/m2 (incl.) for Japanese and 18.5 to 29.9 kg/m2 (incl.) for Caucasian
5.
Signed and dated written informed consent by date of Visit 1 in accordance with GCP 
and local legislation.
6.
Male subjects who agree to minimize the risk of female partners becoming pregnant by 
fulfilling any of the following criteria starting from at least 30 days before the first 
administration of trial medication and until 30 days after trial completion:


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Use of adequate contraception, e.g. any of the following methods plus condom: 
combined oral contraceptives, intrauterine device
-
Vasectomised (vasectomy at least 1 year prior to enrolment) 
-
Surgically sterilised (including hysterectomy) female partner
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
3. Any evidence of a concomitant disease judged as clinically relevant by the investigator
4. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
5. Surgery of the gastrointestinal tract that could interfere with kinetics of the trial 
medication (except appendectomy and simple hernia repair)
6. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders 
7. History of relevant orthostatic hypotension, fainting spells, or blackouts
8. Chronic or relevant acute infections including HIV, viral hepatitis and (or) tuberculosis or 
evidence of tuberculosis infection as defined by a positive QuantiFERON TB-Gold (or T-
SPOT) test. Subjects with a positive QuantiFERON TB-Gold (or T-SPOT) test will not 
participate in the study.
9. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
10. Intake of biologic agents other than current study medication or drugs considered likely to 
interfere with the safe conduct of the study
11. Intake of drugs with a long half-life (more than 24 h) within 30 days or less than 10 half-
lives of the respective drug prior to administration of trial medication
12. Within 10 days prior to administration of trial medication, use of drugs that might 
reasonably influence the results of the trial or that might prolong the QT/QTc interval
13. Participation in another trial (including bioequivalence trial) with an investigational drug
within 90 days or 5 half-lives (whichever is greater) prior to planned administration of 
trial medication
14. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
15. Inability to refrain from smoking on specified trial days
16. Alcohol abuse (consumption of more than 30 g per day)
17. Drug abuse or positive drug screening
18. Blood donation of  more than 200 mL within 30 days prior to administration of trial 
medication or intended donation during the trial


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19. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
20. Inability to comply with dietary regimen of trial site
21. 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
22. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome) 
23. Have received any live bacterial or live viral vaccination in the 12 weeks prior to the date 
of screening. Subjects must agree not to receive a live bacterial or live viral vaccination 
during the study and up to 12 months after the last administration of study drug 
24. Have received Bacille Calmette-Guerin (BCG) vaccination in the 12 months prior to the 
date of screening. Subjects must agree not to receive BCG vaccination during the study 
and up to 12 months after the last administration of study drug  
25. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study
26. Signs of cataract at screening by slit lamp test
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent, without the need to justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational product 
or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events, or diseases)
4. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP >180/100 
mmHg) or of clinically relevant changes in ECG requiring intervention as well as 
unexplained liver enzyme elevations at any time during the trial.
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).


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If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). The only exception to this 
rule is when the subject had an AESI and/or SAE that the investigator considers related to the 
screening procedure. If a subject is removed from or withdraws from the trial after first 
administration of trial medication, this will be documented and the reason for discontinuation 
must be recorded in the CRF. In this case, the data will be included in the CRF/trial database 
and will be reported in the CTR. At the time of discontinuation a complete EOT examination 
will be performed if possible and the information will be recorded in the CRFs. These 
discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50%
of the subjects in one dose group show drug-related and clinically relevant adverse events
of moderate or severe intensity, or if at least one drug-related serious adverse event is
reported that is considered to be unacceptable.
2. The sponsor decides to discontinue the further development of the investigational product.
3. Violation of GCP, or the CTP or the contract with BI by a trial site or investigator,
disturbing the appropriate conduct of the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case some subjects of an ethnic cohort do not complete the dose level, the trial clinical 
monitor together with the trial pharmacokineticist and the trial statistician are to decide 
whether and how many subjects will be replaced. A replacement subject will be assigned a 
unique study subject number, and will be assigned to the same treatment as the subject he 
replaces. There will be no replacement for the subjects removed due to safety reason related 
to the trial drug.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational product will be provided by BI Pharma GmbH & Co. KG.
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product are below.
Substance:
BI 1467335
Pharmaceutical form:
Film-coated Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength:
1, 5 mg
Posology
q.d.
Route of administration:
p.o.
Duration of use:
         28 days
The characteristics of the reference product are below.
Substance:
Matching placebo
Pharmaceutical form:
Film-coated Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength:
Not applicable
Posology
q.d.
Route of administration:
p.o.
Duration of use:
28 days
4.1.2
Method of assigning subjects to treatment groups
Prior to start of the study, subjects willing to participate in this study will be recruited to dose
groups according to their temporal availability, which can be characterized as a ‘first comes,
first chooses’ approach. Recruitment will be done successively for the dose groups, i.e. if the


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planned number of subjects for one dose group will be completed the recruitment of the next
higher dose group will be started. Therefore, the recruitment of subjects for the dose groups
will neither be influenced by the trial personnel nor by any characteristics of the subjects, but
only by temporal availability. Subjects who will be included in the study (in regard to the in-
and exclusion criteria) will be assigned a sequential subject number according to the original 
order of recruitment and the subgroup they belong to, i.e. Japanese subjects to Japanese 
subgroup, Caucasian subjects to Caucasian subgroup.
Subjects will be randomized (to active drug or placebo for each dose group) within each 
ethnicity on day one of treatment according to the randomization list which will have been 
provided to the trial site in advance.
4.1.3
Selection of doses in the trial
Three doses are to be investigated in this trial. These three doses will cover potential 
therapeutic dose ranges. The number of doses will also allow for evaluation of dose 
proportionality in Japanese subjects.
This trial is designed to evaluate the safety, tolerability and pharmacokinetics of BI 1467335
in Japanese and Caucasian healthy young male volunteers using a safe and tolerable dose 
achieved in previous trials.
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are as outlined in Table 4.1.4: 1 below. The number of units 
for placebo corresponds to the number of units of the respective dose level.
Table 4.1.4: 1
BI 1467335 and placebo treatments 
Treatment
Substance
Formulation
Route of 
administration
Number 
of units
Unit 
strength 
[mg]
Total 
dose 
[mg]
1
BI 1467335
tablet
po
3
1
3
2
BI 1467335
tablet
po
1
1,5
6
3
BI 1467335
tablet
po
2
5
10
1-3*
placebo
tablet
po
1~3
-
-
* Subjects receiving placebo are equally distributed across dose groups, and receive same number of tablets as active.
The trial medication will be administered to the subjects, while in a sitting position, as an oral 
dose together with about 240 mL of water under supervision of the investigating physician or 
an authorised designee. Administration will be performed following an overnight fast, which 
is to start no later than 10 h before the scheduled dosing. The dose should be taken at 22-26 
hour interval at home. Subjects will be kept under close medical surveillance from the 
evening of Day -1 to the morning of Day 4, from the evening of Day 13 to the morning of 
Day 15, and from the morning of Day 26 to the morning of Day 29. During the first 2 h after 
drug administration on Days 1, 14 and 28, subjects are not allowed to lie down (i.e. no 


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declination of the upper body of more than 45 degrees from upright posture except for 
medical examination), or to sleep. 
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The trial is designed double-blind with regard to the subjects and the investigators (as well as 
the research staff at the trial site) in order to eliminate observer or performance bias. This 
means avoiding systematic differences in assessments regarding the subject’s treatment 
(active or placebo). According to the rising dose design, the current dose level will be known 
to subjects and investigators. The trial will only be unblinded to the subjects, investigators 
and trial site staffs after locking of the database. 
Sponsor staff that have direct interaction with the investigator and site staff (e.g. CML and 
CRA) will not be aware of the treatment allocation (i.e. active vs placebo) as well until 
database lock. 
The database of this trial will be handled open-label, i.e., all functions involved in the data 
cleaning and analysis of the trial (e.g. the trial clinical monitor, the trial pharmacokineticist, 
the trial bioanalyst, the trial statistician, trial programmer and the trial data manager) will 
have access to the unblinded data during conduct. In particular, this means the project team 
may be unblinded in case it is required. This can be done since no bias with regard to data 
cleaning or safety measures is expected.
Due to the requirements to report Serious Unexpected Suspected Adverse Reactions 
(SUSARs) by treatment, it may be necessary for a representative from BI’s 
pharmacovigilance group to access the randomization code for individual subjects during 
study conduct. In such cases, access to the code will only be permitted by authorized 
pharmacovigilance representatives. Access to the code will be via the master list.
4.1.5.2
Procedures for emergency unblinding
For blinded trials, the investigator will be supplied with a set of sealed envelopes containing 
the medication codes for each subject according to the randomisation scheme. The envelopes 
will be kept unopened at the trial site until the end of data collection. An envelope may only 
be opened in emergency situations when the identity of the trial drug must be known to the 
investigator in order to provide appropriate medical treatment or to assure safety of trial 
participants. If the envelope for a subject is opened, the sponsor must be informed 
immediately. The reason for opening the code break must be documented on the envelope or 
appropriate CRF page along with the date and the initials of the person who broke the code. 
At the close-out visit all envelopes are collected.


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4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. The clinical trial 
supply consists of containers with trial identification.
The clinical trial supply containers are labelled with:

BI trial number

Medication number 

Batch number 

Use by date 

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor (or CTA holder’s) name and address

Storage conditions
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Study medication supplies will be kept in their original packaging and in a secure limited 
access storage area. 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, immediately contact the local clinical monitor as provided in the lists of 
contacts.
It may only be dispensed to trial subjects according to the CTP by authorised personnel.
4.1.8
Drug accountability
The investigator, pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the study protocol by the IRB

Availability of a signed and dated clinical trial contract between the Sponsor and the 
head of the investigational site

Notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol 
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense 
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused trial medication must be returned to the sponsor. All used 
medication will be disposed locally by trial site upon written authorization by the clinical 


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monitor. Receipt, usage, return and disposal must be documented on the respective forms in 
ISF. Account must be given for any discrepancies.  
The Investigator, pharmacist or investigational drug storage manager must maintain records 
of the product’s delivery to the trial site, the inventory at the site, the use by each subject, and 
the return to the Sponsor or alternative disposal of unused products.
The records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, and 
the unique code numbers assigned to the investigational product and trial subjects.  The 
investigator, pharmacist or investigational drug storage manager will maintain records that 
document adequately that the subjects were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. At the time of return to the 
Sponsor and/or appointed CRO, the investigator, pharmacist or investigational drug storage 
manager must verify that no remaining supplies are in the Investigator’s possession. Detailed 
instructions will be provided for the return/disposal of unused study medication.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
In principle, no concomitant treatment is planned and/or allowed. However, in case of 
adverse events in need of treatment, the investigator can authorise symptomatic therapy. In 
those cases, subjects will be treated as necessary and, if required, kept under supervision at 
the trial site or transferred to a hospital until all medical evaluation results have returned to an 
acceptable level.
All concomitant or rescue therapies will be recorded (including time of intake on study days) 
on the appropriate pages of the eCRF.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
For restrictions on concomitant therapies, see Section 4.2.1 above. 
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart during in-house days. 
From Day 1 to Day 28, no food is allowed for at least 10 h before and 2 h after administration 
of the study drug.
From 1 hour before drug intake in the morning of PK profiling days 1, 14 and 28, liquid 
intake will be restricted to the water administered with the drug and 240 mL of water at 2 
hours and 4 hours post-dose (mandatory for all subjects). From lunch until 24 hours post-dose 
fluid intake is restricted within 3000 mL. 


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Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products including St. John's wort (Hypericum perforatum) are not 
permitted starting 7 days before the first administration of trial medication until after the last 
PK sample is collected.
 nicotine-containing 
products (e.g., cigarettes, cigars, chewing tobacco, snuff) should be stopped at least 6 weeks 
before screening and abstained from using these products until study completion.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not permitted 24 hours preceding the administration of trial medication and 
until the in-house period at the trial site. On the ambulatory days, it is restricted up to max 
200 ml (coffee, tea, cola, energy drinks), or 50 g (chocolate and chocolate products).
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the EOT 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 trial medication in the study centre under 
supervision of the investigating physician or a designee on the days of hospitalization and 
ambulatory visits. On other days when medication will be taken at home, subjects will record 
the information of the drug administration in the diary and bring it to the study site when they 
come in for the next visit. The measured plasma concentrations and/or urinary excretion will 
provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1). 


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 1467335 is the number [N (%)] of 
subjects with drug-related AEs.
  
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this 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 or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
The following events will be handled as “deemed serious for any other reason”. An AE which 
possibly leads to disability will be reported as an SAE.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the RDC system, a remote data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described in section 5.2.2.2.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.


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Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.2.2.2.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

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 draw sample, and/or

marked peak 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” via the RDC-system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity of AEs
The intensity of adverse events should be classified and recorded in the (e) CRF according to 
the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 dated 
14 June 2010 [R10-4848] in the (e)CRF.
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
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


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
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

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 study drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AE Collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A careful 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, and intensity of the event as 
well as any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate eCRF by the 
investigator:


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•
From signing the informed consent onwards through the Residual Effect Period (REP), 
until individual subject’s EOT: 
-all AEs (serious and non-serious) and all AESIs.
-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 EOT:
the investigator does not need to actively monitor the subject for AEs but should only
report relevant SAEs and relevant AESIs of which the investigator may become aware of.
The REP for BI 1467335, when measurable drug levels or PD effects are still likely to be 
present after the last administration, is not known at this early stage of development. 
Therefore, all AEs reported until the trial termination date (last per protocol contact) will be 
considered on treatment; please see Section 7.3.3.
AE reporting to sponsor and timelines
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 of 
awareness) 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.
1. All SAEs and AESIs must be reported immediately to the head of the trial site.
2. 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


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For each AE, the Investigator should provide the information requested on the appropriate 
(e)CRF pages and the BI SAE form (if applicable). The Investigator should determine the 
causal relationship to the trial medication.
The following should also be recorded as an (S)AE in the eCRF and on the 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 trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual subject’s EOT must be followed up 
until they have resolved, have been sufficiently characterized, or no further information can 
be obtained.
Pregnancy
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.3
Assessment of safety laboratory parameters
A total amount of up to approximately 120 mL blood will be taken per subject during the 
whole course of the study for safety laboratory parameters. This amount may be exceeded if 
unscheduled (additional) monitoring including retest of laboratory results is warranted. 
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 hours. Overnight fasting is not required at the discretion of the investigator or 
designate for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 


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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 and 
it is deemed clinically necessary by the investigator, respectively. 
Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
Automatic WBC differential 
(relative) 1
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (INR) (ratio)
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (ALP)
Gamma-glutamyl transferase (GGT/γ-GT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
Hormones2
Thyroid stimulating hormone (TSH)
Substrates
Serum glucose
Creatinine 
Blood Urea Nitrogen (BUN)
Total bilirubin 
Direct bilirubin
Total protein
Albumin 
C-Reactive Protein (CRP) 
Uric acid
Total cholesterol
Triglycerides
Electrolytes
Sodium
Potassium
Calcium


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Table 5.2.3: 1
Routine laboratory tests (cont.).
Functional lab group
Test name 
Urinalysis 
(strip or dipstick)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Urine sediment 3
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
1 Manual differential white blood cell count will only be performed if there is an abnormality in the automatic blood cell 
count and it is deemed clinically necessary by the investigator
2 Only at screening 
3 Only if erythrocytes, leukocytes, nitrite or protein are abnormal in urinalysis and are deemed clinically necessary by the 
investigator
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. 
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)1
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)2
Hepatitis A antibodies (qualitative)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV antigen and antibody (qualitative)                                     
QuantiFERON TB-Gold (or T-SPOT)                                                      
Syphilis test (RPR, TP antibody method) 
Alcohol test1
Breath alcohol test 
1 To encourage compliance with prohibited drug and alcoholic restrictions, urine drug screening and breath alcohol test will
be performed at screening and Day -1, and may be repeated at any time during the study at the discretion of an investigator 
or designee.
2 At screening only (Visit 1).


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Glomerular Filtration Rate
The estimated glomerular filtration rate (eGFR) will be derived from serum creatinine values 
based on the CKD-EPI formula:
For Japanese: 
eGFR(mL/min/1.73m2)
= 0.813 x 141 x min (SCr/0.9, 1) -0.411 x max (SCr/0.9, 1) -1.209 x 0.993 Age
For Caucasian: 
eGFR(mL/min/1.73m2)
= 141 x min (SCr/0.9, 1) -0.411 x max (SCr/0.9, 1) -1.209 x 0.993 Age
SCr is serum creatinine in mg/dL, min indicates the minimum of SCr/0.9 or 1, and max 
indicates the maximum of SCr/0.9 or 1.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed by the local 
laboratory of the trial site or/and at a CRO designated by the sponsor.
Laboratory data will be transmitted electronically from the site to the sponsor.
5.2.4
Electrocardiogram
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a FDA 
approved ECG machine at the time points given in the Flow Chart.
In order to achieve a stable heart rate at rest and to assure high quality recordings at 
comparable resting phases, all ECGSs will be recorded for 10 second duration after the 
subjects have rested for at least 5 min in a supine position. The site personnel will be 
instructed to assure a relaxed and quiet environment so that all subjects are at complete rest 
during the recordings. ECG assessment will always precede all other study procedures of the 
same time point to avoid impact of sampling on the ECG quality.
Six limb leads, as specified by Einthoven (I, II and III) and Goldberger (aVR, aVL, aVF), and 
six pre-cordial leads (V1-V6), according to Wilson, will be used. 
Triple sequential ECGs 1 to 3 minutes apart will be recorded on Day 1 and Day 2, Day 14 
and Day 15, Day 28 and Day 29. At all other time points single ECGs will be recorded.
ECG data will be collected in two ways: locally printed ECGs and digitally recorded ECGs. 
Printed paper traces from ECGs will be collected at clinical sites. All ECGs will be evaluated, 
signed, dated and commented upon by the investigator and stored locally.
A centralised evaluation (during study and/or post study) of 12-lead ECGs recorded will be 
performed by an independent ECG laboratory. This analysis will include the determination of 
cardiac axis (automatically) as well as the intervals RR, PR, QRS and QT measured semi-
automatically.


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With the exception of the first triple ECG (used as baseline before the first drug
administration), only the first of the three replicate ECGs at a single assessment time will be
evaluated. The remaining second and third replicate ECGs will be stored for additional
analyses if required, e.g. by authorities at a later time point.
All interval measurements in one subject will be performed on the same lead. The intervals 
will be measured from four waveforms in lead II. If lead II shows a flat T wave or is not 
measurable for any reason, lead V2 will be used, or if that lead is not measurable, lead I. The 
lead actually used will be reported. At the ECG laboratory all staff will be blinded with 
respect to treatment. Within the ECG laboratory, the staff involved with interval 
measurements and assessments will also be blinded with regard to the recording date and 
time as well as time points of the ECGs. In case semi-automatic interval measurements will 
be performed, the interval measurements for a given subject will be performed in random and 
blinded sequence by a single technician. No more than two different blinded readers will 
evaluate all ECGs of the study. For quality assurance and control of the measurements, all 
ECGs of a subject will be subsequently reviewed by the ECG technician supervisor or his/her 
designee with respect to the overall variance of the measured intervals, in order to detect 
accidentally switching of leads and/or false subject assignments of the ECGs. After the 
quality control the fiducial point markings will be reviewed by the cardiologist assigned to 
the study.
ECGs may be repeated for quality reasons (like alternating current artefacts, muscle 
movements, electrode dislocation). For time points with triple ECGs, all three single ECGs 
will be repeated. If ECGs are repeated for quality reasons, data from ECG with the best 
quality will be collected. However, all ECGs including the ECGs with poor quality will be 
kept as documentation to comply with ICH E14 guidance. 
ECG measurements will always precede blood sampling to avoid impact of sampling on the 
ECG results. 
Clinically relevant abnormal findings as judged by the investigator will be reported as AEs 
(during the trial) or baseline conditions (at screening) in the eCRF. Any ECG abnormalities 
will be monitored carefully and, if necessary, the subject will be removed from the trial and 
will receive the appropriate medical treatment. 
Additional (unscheduled) ECGs can be collected for safety reasons at any time based on the 
judgement of the investigator. The unscheduled ECGs will not be included into the planned 
analysis of interval lengths.
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor at the 
times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine
position. All recordings should be made using the same type of blood pressure recording 
instrument on the same arm if possible.


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5.2.5.2
Medical examinations
At the screening visit, the medical examination will include documentation of subject 
information, informed consent, demographics including height and body weight, smoking 
and alcohol history, relevant medical history and concomitant therapy, review of inclusion 
and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a 
physical examination. At the end of trial examination, it will include review of vital signs, 12-
lead ECG, laboratory tests, and a physical examination with determination of weight.
5.2.5.3
Ophtalmological examination
A slit lamp examination will be conducted by an ophthalmologist during screening or until 
Day -1 and from Day 29 to EOT visit to exclude findings suspicious for signs of cataract.
 
 
 
 
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of a study drug, and are widely used in clinical trials. The 
pharmacokinetic parameters and measurements outlined in Section 5.5 are generally used 
assessments of drug exposure. 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and exact time points of blood sampling will be 
documented in the CRFs by the medical personnel. The actual drug administration times and 
sampling times will be used for determination of pharmacokinetic parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK data) including addition of samples and 
visits as long as the total blood volume taken per subject does not exceed 400 mL. Such
changes might be implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters will be determined if feasible:
5.5.1.1
Secondary endpoints
After the first dose (Day 1):

AUC0-24 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 hours after administration of the first dose)

Cmax (maximum measured concentration of the analyte in plasma after administration 
of the first dose)
After the last dose (Day 28):

AUC0-24,28 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 hours after administration of Day 28)


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
Cmax,28 (maximum measured concentration of the analyte in plasma following
administration of Day 28)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 1467335 plasma concentrations, approximately
mL of blood will 
be taken from an antecubital or forearm vein into 
 blood drawing tube at the times indicated in the Flow Chart. Blood will be 
withdrawn by means of either an indwelling venous catheter or by venipuncture with a metal 
needle.
 will be added to all blood samples. Gently 
invert samples about 10 times to ensure the phenelzine solution is mixed through blood. All 
blood samples will be centrifuged using a cooled centrifuge at about 2000 x g to 4000 x g and 
at a temperature of 4 - 8°C for at least 10 minutes (intermittent storage on ice). The obtained
EDTA plasma will be transferred into a cryotube (e.g. Nunc tube) which will be frozen 
immediately and not later than 60 min after blood sampling with interim storage on ice. The 
aliquots should contain at least 
mL plasma. Until transfer on dry ice to the analytical 
laboratory, the plasma samples will be stored frozen and in upright position at about –20°C or 
below at the clinical site and at the analytical laboratory until analysis.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All visits must be performed as specified in Flow Chart. The investigator/sponsor can decide 
to perform an unscheduled visit if deemed necessary for any valid reasons.  
Further details of measurement performed during the study are specified under Section 5. 
Time windows are permitted as follows:

General medical examination: at screening (1 to 21 days prior to Day1) and at the end-of-
trial evaluation (within 14 to 20 days after last drug administration).

BP and PR: ±15 min (0:30, 0:45, 1:00, 2:00) and ±30 min (4:00, 8:00, 12:00) on Day 1, 
Day 14 and Day 28, ±60 min on other days and up to 3 hours prior to drug administration 
if indicated “before drug administration”

ECG: 15 min (0:15, 0:30, 0:45, 1:00, 1:30, 2:00) and 30 min (4:00, 8:00, 12:00) on 
Day 1, Day 14 and Day 28, 60 min on other days.
ECGs on Day 1, 2, 14, 15, 28 and 29: for the second and third ECG a time interval of 1-3 
min between ECGs should be maintained

Laboratory/urinalysis: Up to 3 hours prior to drug administration if indicated “before drug 
administration”. Urinalysis test can be done up to 3 hours prior to drug administration at 
some other time points indicated in the flow chart.

Pharmacokinetic blood sampling for predose concentration 
 in multiple dose part: 
5 min (has to be done before drug administration)
Other pharmacokinetic blood sampling / urine collection: For planned individual plasma 
concentration sampling times refer to 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 
calculation of pharmacokinetic parameters.
The designation "before" on Day 1 refers to the time period of 3 hours before drug 
administration (see Flow Chart), i.e., study measurements and assessments scheduled to 
occur "before" have to be performed and completed within 3 hours prior to drug 
administration.
Relevant time violations will be identified and their handling discussed no later than at the 
(B)RPM.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening 
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study. 


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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.  
If a subject is eligible but has missed the screening window, or if a subject has been excluded
from participation in this trial due to acute conditions which completely resolved, the subject
can be re-screened. At re-screening, all procedures listed for Visit 1 in the Flow chart will be
repeated.
6.2.2
Treatment period
Each subject will receive one dose of the respective dose strength per day at visit 2. On the 
morning of the treatment day, study drug will be taken by the subject (under direct 
supervision of the investigator or designee).
The measurements performed during the treatment period are specified under Flow Chart and. 
Section 5.2. For time points and instructions for ECG measurements cf. Flow Chart and 
Section 5.2.4.
For details on time points for collection of plasma PK samples 
for 
analysis, cf. Flow Chart.
For details on time points for all other trial procedures, cf. Flow Chart.
6.2.3
End of trial and follow-up period 
For AE assessment, laboratory tests, recording of ECG, vital signs and body weight, and 
physical examination during the EOT 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 EOT visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. All (S)AEs, including those persisting after individual subject’s 
end of trial must be followed up until they have resolved, have been sufficiently 
characterized, or no further information can be obtained.
In the case of a subject’s discontinuation from the trial, the subject will be followed-up until 
the investigator or sub-investigator is convinced of the subject’s safety. When follow-up is 
not possible or comes to an end, it should be formally completed after discussion with the 
sponsor. If a subject stops attending trial assessments, the investigator should assess the 
subject’s status as comprehensively as possible and the well-being of the subject should be 
monitored. However, if the subject withdraws from the trial, it is the subject’s choice whether 
or not to participate; he or she cannot be compelled.
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 1467335
by using descriptive statistics for all endpoints comparing active dose groups to placebo. The 
primary endpoint is defined in Section 5.2.1. Inferential statistics is not planned (as explained 
in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics (PK) 
of BI 1467335. Endpoints as specified in 5.5.1 and 5.6.1 will be 
analysed by descriptive statistics. Secondary endpoints as defined in Section 5.5.1.1 will be 
subjected to analysis of dose proportionality by use of the power model.
 
 
 
The assessment of dose proportionally will be performed for Japanese subjects only. 
 
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 3 different dose groups of BI 1467335 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.
7.3.1
Primary analyses
All treated subjects (that is, all subjects who received at least one dose of study drug), will be 
included in the treated set.


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The primary endpoint will be analysed only descriptively on the treated set. For more details 
see Section 7.3.3.
The secondary endpoints (refer to Section 5.5.1.1) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472].
Plasma 
 concentration data and parameters of a subject will be included in the
statistical pharmacokinetic (PK) 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),

missing samples/concentration data at important phases of PK disposition curve.
The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one PK parameter that was not excluded according to the description above.
All statistical evaluations of PK parameters will be based on the PKS.
Excluded subjects will be listed with their individual plasma concentrations and individual 
pharmacokinetic parameters, however, will not be included in descriptive statistics for plasma 
concentrations, pharmacokinetic parameters or other statistical assessment.
Assessment of dose proportionality
Dose proportionality will be assessed using the pharmacokinetic endpoints AUC0-24, Cmax, 
AUC0-24,28 and Cmax,28 as specified in Section 5.5.1.1.
The basic model for the investigation of dose proportionality will be a power model that 
describes the functional relationship between the dose and PK endpoints.
The model consists of a regression model applied to log-transformed data. The corresponding 
ANCOVA model includes the logarithm of the dose as a covariate.
ij
i
ij
ε
)
X
exp(
)
exp(Y









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Together with 
and 
, taking natural logarithms converts this model 
to a linear form as follows:
where
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where i = 1, 2, 3, j = 1, 2, …, 12;

intercept parameter;
slope parameter;
logarithm of dose i;
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
This equation can be fit as a linear regression model.
Based on the estimate for slope parameter (β), a 2-sided 95% CI for the slope will be 
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of a 
linear relationship between the log-transformed pharmacokinetic endpoint and the log-
transformed dose will be checked.
 
 
 
 
 
 
 
 
 
 
)
exp(


)
exp(
ε
ij
ij



ij
i
ij
ε
X
β
α
Y




ij
Y
β
i
X
ij
ε


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Graphical displays
To support the analyses of dose proportionality, linearity 
 
graphical representations of the data might be created. These might include (but are not 
limited to) individual time-courses of trough and 0.5 h, 1 h post-dose plasma concentrations 
and the (geometric) mean plasma concentration time profiles.
 
7.3.3
Safety analyses
Safety will be assessed for the primary endpoint and parameter of interest listed in Section 
5.2.1. All treated subjects (that is, all subjects who received at least one dose of study drug), 
will be included in the safety evaluation. Safety analyses will be descriptive in nature and will 
be based on BI standards.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The analyses will be done by ‘treatment at onset’.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs). 
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until the trial 
termination date will be assigned to the treatment period. These assignments including the 
corresponding time intervals will be defined in detail in the TSAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, intensity according to CTCAE grading and causal relationship of 
AEs will be tabulated by treatment, primary system organ class and preferred term. SAEs, 


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AESIs (see Section 5.2.2.1) and other significant AEs (according to ICH E3) will be listed 
separately.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be flagged. Additionally, differences from baseline will be evaluated.
For vital signs, the differences from baseline will be evaluated.
The derivation of the quantitative and qualitative ECG endpoints and their analyses will be 
described in the TSAP.
7.3.4
Interim analysis
No formal interim analysis is planned for this trial.
The data will be evaluated as they accumulate in an un-blinded manner. See Section 4.1.5.1
for unbinding procedure.
In addition, although no formal interim clinical trial report will be produced, a limited set of 
tables and listings may be provided, as basis for regulatory documents. Snapshots of the 
database may be taken at any time during the study conduct.
Preliminary PK analysis
Preliminary analysis of plasma PK parameters (AUC0-24, Cmax, AUC0-24,28 and Cmax,28) are 
planned to be performed. Additional preliminary PK analyses may be performed based on the 
request of the Trial Clinical Monitor, the Investigator, or Trial Clinical Pharmacokineticist if 
deemed necessary based on the results of available preliminary PK analyses, tolerability and 
safety of the compound, or changes of dosing schedule (e.g. additional intermediate doses).
After the 6 mg dose group have been treated for 28 days, all plasma samples collected up to 
24 hours after drug administration of Day 28 will be analysed, and the data will be used for 
extrapolation of Cmax and AUC0-24 on days 14 and 28 with higher dose of BI 1467335.
In contrast to the final PK calculations, the preliminary analyses will be based on planned 
sampling times rather than on actual times. Therefore, minor deviations of preliminary and
final results may occur.
The preliminary results will be distributed to the Investigator and the trial team. The PK data 
together with safety and tolerability results will be used for decisions to continue with 
treatments as described in Section 2.3. No formal preliminary PK report will be written.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 1467335 will be 
calculated according to the BI SOP ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ [001-MCS-36-472].


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Noncompartmental pharmacokinetic parameters will be calculated based on actual sampling 
times using a validated pharmacokinetic software (e.g. Phoenix® WinNonlin®).
Subjects who are not included in the PKS (refer to Section 7.3.1) will be reported with their 
individual plasma / urine concentrations and individual pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for, pharmacokinetic parameters or 
other statistical assessment.
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.
Descriptive evaluations of PK parameters listed in Section 5.5.1.2 are based on PKS.
The following descriptive statistics will be calculated for analyte concentrations as well as for
all pharmacokinetic parameters: N, geometric mean, geometric coefficient of variation, 
arithmetic mean, arithmetic coefficient of variation, standard deviation, minimum, median, 
and maximum. Additionally, for PK parameters, the following descriptive statistics will be
calculated: 10th percentile, 1st quartile, 3rd quartile and 90th percentile. The data format for 
descriptive statistics of concentrations will be identical with the data format of the respective 
concentrations. The descriptive statistics of pharmacokinetic 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 clinical trial report.
In addition, the PK data from this study may be included in a population PK analysis at the 
project level. This analysis will not be part of the CTR, but will be reported separately.
 
 
 
 
 
 
 
 
 
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma/urine drug concentration - time profile
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
[001-MCS-36-472_RD-01].


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If the pre-dose concentration before the first dose is less than or equal to 5% of Cmax value in
that subject, the subject’s data without any adjustments can be included in all 
pharmacokinetic measurements and calculations (i.e. the pre-dose value will not be changed 
to zero). If the pre-dose value is greater than 5% of Cmax, the subject should be dropped from 
all statistical evaluations. The individual pharmacokinetic parameters can be calculated and 
listed separately.
For tabulation and graphical displays, drug concentration data identified with NOS (no 
sample available), NOR (no valid result), NOA (not analysed), or BLQ (below the lower 
limit of quantification) will be displayed as such and not replaced by zero at any time point 
(this rule also applies also to the lag phase, including the predose values).
For the calculation of PK parameters by non-compartmental analysis, concentration data 
identified with NOS, NOR or NOA will generally not be considered. Concentration values in 
the lag phase identified as BLQ will be set to zero. All other BLQ values of the profile will be 
ignored. The lag phase is defined as the period between time zero and the first time point with 
a concentration above the quantification limit.
7.4.3
Pharmacokinetic parameters
No imputation of missing PK parameters will be performed.
 
7.5
RANDOMISATION
Subjects will be randomised within each dose group within each ethnicity in a 3:1 ratio, 
which reflects the ratio of subjects receiving active drug to placebo.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves 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 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 48 subjects in this trial (i.e., 36 Japanese subjects and 12
Caucasian subjects). The planned sample size is not based on a power calculation. The size of 
12 subjects per dose group per ethnicity (9 on active treatment, and 3 on placebo) is 
commonly used in multiple-rising dose studies of the present type and is in general 
considered as sufficient for the exploratory evaluation of multiple dose safety and 
pharmacokinetics [R95-0013].


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Additional subjects may be entered to allow testing of additional doses within the planned 
dose range on the basis of experience gained during trial conduct (e.g. preliminary PK data), 
i.e. the actual number of subjects entered may exceed 48.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs) and the 
Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 
1997).
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP and the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997).
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the 
CTR.
The certificate of insurance cover is made available to the Investigator and the subjects, and 
is stored in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) and competent authority (CA) 
according to Japanese 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 are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The Investigator must give a full explanation to trial subjects by using the subject information 
form, which is prepared avoiding the use of technical terms and expressions. The subject is 
given sufficient time to consider participation in the trial. The Investigator 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 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.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The subject must be informed that his personal trial-related data will be used by Boehringer 
Ingelheim in accordance with the local data protection law. The level of disclosure must also 
be explained to the subject.
The subject must be informed that his medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB members, and by inspectors 
from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs, or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
Electronic Case Report Forms (eCRFs) for individual subjects will be provided by the 
sponsor. See Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, 
refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial; also current medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial related monitoring, audits, IRB review and 
regulatory inspection, providing direct access to all related source data / documents. eCRFs 
and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the sponsor’s clinical trial monitor, auditor 
and inspection by health authorities (e.g., FDA). The Clinical Research Associate (CRA) / on 


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site monitor and auditor may review all eCRFs, and written informed consents. The accuracy 
of the data will be verified by reviewing the documents described in Section 8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source documents and essential documents for a period defined 
by the Japanese GCP regulation and trial site’s contract with the sponsor.
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 regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be given to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.6
COMPLETION OF TRIAL
When the trial is completed, the investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
sponsor of the completion in writing.
8.7
PROTOCOL VIOLATIONS
The investigator or sub-investigator should record all CTP violations. The investigator should 
provide and submit the sponsor and the head of the trial site the records of violations 
infringing the Japanese GCP or violations to eliminate an immediate hazard to trial subjects 
and for other medically inevitable reasons.


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8.8
COMPENSATION AVAILABLE TO THE SUBJECT IN THE EVENT OF 
TRIAL RELATED INJURY
In the event of health injury associated with this trial, the sponsor is responsible for 
compensation based on the contract signed by the trial site.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R10-4848
Common terminology criteria for adverse events (CTCAE): version 4.0 
(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
2010), revised June 2010, reprinted June 2010). 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf; 2010.
P13-02280
Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment
of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012; 
10:837-58.
R95-0013
Broom C. Design of first-administration studies in healthy man. Early 
Phase Drug Evaluation in Man. O'Grady J, Linet OI (Eds.), Macmillan 
Press: London, 1990, 206 213.
R15-1863
Inoue T, Morita M, Tojo T, Nagashima A, Moritomo A, Miyake H. Novel
1H-imidazol-2-amine derivatives as potent and orally active vascular 
adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema 
treatment. Bioorg. Med. Chem. 2013; 21:3873-3881.
R15-1868
Foot JS, Deodhar M, Turner CI, et al. The discovery and development of 
selective 3-fluoro-4-aryloxyallylamine inhibitors of the amine oxidase 
activity of semicarbazide-sensitive amine oxidase/vascular adhesion 
protein-1 (SSAO/VAP-1). Bioorg. Med. Chem. Lett. 2012; 22:3935.
R15-2803
Stolen CM, Marttila-Ichihara F, Koskinen K, et al. Absence of the 
endothelial oxidase AOC3 leads to abnormal leukocyte traffic in vivo. 
Immunity. 2005; 22:105-115.
R15-5365
Weston CJ, Shepherd EL, Claridge LC et al. Vascular adhesion protein-
1promotes liver inflammation and drives hepatic fibrosis. Journal of 
Clinical Investigation. 2015; 125:501-520.
R15-5652
Bonder CS, Norman MU, Swain MG, et al. Rules of recruitment for Th1 
and Th2 lymphocytes in inflamed liver: a role for alpha-4 integrin and 
vascular adhesion protein-1. Immunity 2005; 23:153-163.
R15-5654
Koskinen K, Vainio PJ, Smith DJ, et al. Granulocyte transmigration 
through the endothelium is regulated by the oxidase activity of vascular 
adhesion protein-1 (VAP-1). Blood. 2004; 103: 3388-3395.
R15-6044
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management 
of non-alcoholic fatty liver disease: practice guideline by the American 
Association for the Study of Liver Diseases, American College of 
Gastroenterology, and the American Gastroenterological Association 
Hepatology. 2012; 55:2005-2023.
R15-6045
Marttila-Ichihara F, Smith DJ, Stolen C, et al. Vascular amine oxidases are 
needed for leukocyte extravasation into inflamed joints in vivo. Arthritis 
Rheum. 2006; 54:2852.
R15-6046
Lalor PF, Edwards S, McNab G, et al. Vascular adhesion protein-1 
mediates adhesion and transmigration of lymphocytes on human hepatic 
endothelial cells. J. Immunol. 2002; 169: 983.


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R15-6047
Salter-Cid LM, Wang E, O’Rourke AM, et al. Anti-inflammatory effects of 
inhibiting the amine oxidase activity of semicarbazide-sensitive amine 
oxidase. J. Pharmacol. Exp. Ther. 2005; 315: 553.
R15-6048
Xu HL, Salter-Cid L, Linnik MD, Wang EY, Paisansathan C and Pelligrino 
DA. Vascular adhesion protein-1 plays an important role in post ischemic 
inflammation and neuropathology in diabetic, estrogen-treated 
ovariectomized female rats subjected to transient forebrain ischemia. J. 
Pharmacol. Exp. Ther. 2006; 317:19.
R15-6056
O’Rourke AM, Wang EY, Miller A, Podar EM, et al. Anti-inflammatory 
effects of LJP 1586 [Z-3-fluoro-2-(4-methoxybenzyl)allylamine 
hydrochloride], an amine-based inhibitor of semicarbazide-sensitive amine 
oxidase activity. J. Pharmacol. Exp. Ther. 2008; 324: 867.
R15-6057
Murphy SL, Xu J and Kochanek KD. Deaths: final data for 2010. Centers 
for Disease Control and Prevention website: 
www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_04.pdf (Updated May 8, 2013. 
Accessed February 6, 2014).
R15-6058
Merinen M, Irjala H, Salmi M, Jaakkola I, Hanninen A, Jalkanen S. 
Vascular adhesion protein-1 is involved in both acute and chronic 
inflammation in the mouse. Am J Pathol. 2005;166:793-800.
R15-6059
Lee WY, Salmi M, Kelly MM, Jalkanen S and Kubes P (2013) Therapeutic 
advantage of anti-VAP-1over anti-α4 integrin antibody in concanavalin 
Ainduced hepatitis. Hepatology 2013; 58:1413.
R15-6070
Dharel N, Fuchs M. Nonalcoholic Fatty Liver Disease – A Major Public
Health Challenge for the 21st Century. JSM Gastroenterology and 
Hepatology. 2014; 1018.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics. Current version.
001-MCS-36-472_RD-01Noncompartmental Pharmacokinetic/Pharmacodynamic Analyses 
of Clinical Studies. 
001-MCG-420
Statistical Methods for Pharmacokinetics. Current version.
c04751792-03
 Investigator's 
Brochure: BI 1467335 in NASH version 3. 05 Dec 2016.
c08854973-03
. Safety, tolerability, pharmacokinetics and pharmacodynamics of 
multiple rising oral doses of BI 1467335 in healthy male and female 
subjects.1386.8.  13 Jul 2016.
c09036683-01
Single ascending dose and multiple ascending dose Phase 1 study of PXS-
4728A administered orally in healthy adult males. PXS-4728A-101. 
13 Nov 2015.
n00247850
A Four-Week Oral Repeat Dose Toxicity and Toxicokinetic Study of PXS-
4728A in Beagle Dogs. Pharmaron Study Number 53703-13-825. 04 Apr 
2014.


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10.
APPENDICES
Not applicable


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
This is original protocol.
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
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
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11428532
1.0
clinical-trial-protocol-version-01
Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple rising oral
doses of BI 1467335 in healthy Japanese male volunteers with multiple oral doses at
the highest dose in Caucasian for comparison (randomised, double-blind,
placebo-controlled trial)
Author-Clinical Pharmacokineticist
12 May 2017 03:57 CEST
Author-Trial Clinical Monitor
12 May 2017 04:01 CEST
Author-Trial Statistician
12 May 2017 04:47 CEST
Approval-Therapeutic Area
12 May 2017 06:41 CEST
Approval-Team Member Medicine
12 May 2017 13:53 CEST
Verification-Paper Signature
Completion
15 May 2017 02:51 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11428532
1.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c17748273-01
BI Trial No.:
1386.7
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of
multiple rising oral doses of BI 1467335 in healthy Japanese male
volunteers with multiple oral doses at the highest dose in Caucasian
for comparison (randomised, double-blind, placebo-controlled trial)
Investigational
Product:
BI 1467335
Responsible trial 
statisticians:
Phone:
, Fax: 
Date of statistical 
analysis plan:
29 JAN 2018 SIGNED 
Version:
Final
Page 1 of 39
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2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINTS...................................................................................10
5.2
SECONDARY ENDPOINT ...............................................................................10
5.2.1
Key secondary endpoint .....................................................................................10
5.2.2
Secondary endpoint.............................................................................................10
5.4
OTHER VARIABLES........................................................................................14
5.4.1
Demographic and other baseline characteristics .............................................14
5.4.2
Ophthalmological examination..........................................................................14
5.4.3
Treatment compliance and treatment exposure ..............................................14
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................15
6.1
TREATMENTS...................................................................................................15
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................16
6.3
SUBJECT SETS ANALYSED...........................................................................19
6.5
POOLING OF CENTRES .................................................................................20
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................20
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................21
7.
PLANNED ANALYSIS......................................................................................24
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........24
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................25
7.3
TREATMENT COMPLIANCE........................................................................25
7.4
PRIMARY ENDPOINTS...................................................................................25
7.5
SECONDARY ENDPOINT ...............................................................................25
7.5.1
Key secondary endpoint .....................................................................................25
7.5.2
Secondary endpoints...........................................................................................25


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7.7
EXTENT OF EXPOSURE.................................................................................28
7.8
SAFETY ANALYSIS..........................................................................................28
7.8.1
Adverse events.....................................................................................................28
7.8.2
Laboratory data ..................................................................................................30
7.8.3
Vital signs.............................................................................................................30
7.8.5
Others...................................................................................................................33
8.
REFERENCES....................................................................................................35
10.
HISTORY TABLE..............................................................................................39


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory data, vital signs and ECG................................................................15
Table 6.3: 1
Subject sets analysed........................................................................................20
Table 10: 1
History table .....................................................................................................39


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADME
Absorption, distribution, metabolism, and excretion
ADS
Analysis dataset
AE
Adverse event
 
 
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-24
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 to 24 hours after administration of the first 
dose
AUC0-24,28
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 to 24 hours after administration of the 28th
dose
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
 
 
 
 
CARE
Clinical data analysis and reporting environment
Cmax
Maximum measured concentration of the analyte in plasma after 
administration of the first dose
Cmax,28
Maximum measured concentration of the analyte in plasma following
administration of the 28th dose
 
 
CRF
Case report form
CTCAE
Common terminology criteria for adverse events
CTP
Clinical trial protocol
CTR
Clinical trial report


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Term
Definition / description
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECGPKS
Electrocardiogram pharmacokinetic set
eCRF
Electronic case report form
EMA
European Medicines Agency
EudraCT
European union drug regulating authorities clinical trials
gCV
Geometric coefficient of variation
gMean
Geometric mean
HR
Heart rate
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
IPV
Important protocol violation
MedDRA
Medical Dictionary for Regulatory Activities
on-trt
on-treatment
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter analysis set
PR interval
ECG interval from the onset of P wave to the beginning of the QRS
PV
Protocol violation
QRS complex
Combination of the Q, R, and S waves
QT interval
ECG interval from the beginning of the QRS complex to the end of the 
T wave
QTcB
QT interval, heart rate corrected according to Bazetts formula
QTcF
QT interval, heart rate corrected according to Fridericias formula
QTcN
QT interval, heart rate corrected according to study population formula
R
Reference treatment
RAGe
Report appendix generator
RPM
Report planning meeting


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Term
Definition / description
RR interval
ECG interval from the peak of the R wave to the peak of the 
subsequent R wave
RS
Randomised set
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listing
SOC
System organ class
T
Test treatment
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9, 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 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.
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 6.3 or later, 
Certara USA Inc., Princeton, NJ, USA).


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoint is the number [N (%)] of subjects with drug-related AEs, as defined in 
Section 5.2.1 of the CTP.
5.2
SECONDARY ENDPOINT
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoint
Secondary endpoints are the PK parameters for BI 1467335, as defined in Section 5.5.1.1 of 
the CTP.


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5.4
OTHER VARIABLES
5.4.1
Demographic and other baseline characteristics
These variables that are defined as medical examinations in the CTP, Section 5.2.5.2 will be 
used.
Derived variables are defined as follows:
Age [years] will be determined as the difference between year of birth and year of informed 
consent.
BMI will be calculated as weight [kg] / (0.01 * height [cm]2). 
5.4.2
Ophthalmological examination
Ophthalmological examination findings will be presented as defined in Section 5.2.5.3 of the 
CTP. Descriptive statistics will be provided.
5.4.3
Treatment compliance and treatment exposure
Treatment compliance will be based on data from the subject diary. The subjects will report 
whether they took study medication during the treatment period. For each subject, percent 
compliance will be calculated as the number of times they reported taking study medication (i. 
e. number of non-missing actual administration date on CRF) divided by the number of 
tablets which should have been taken was given times 100. If subjects discontinued study,
denominator is defined as the number of the dates from day 1 to day of discontinuation.
Treatment exposure is defined as the number of days taking medication and the total dose of 
BI 1467335 per subject.
 
 
 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignments of dose groups, 
and selection of doses, cf. Section 4 of the CTP.
Subjects were treated with 3 mg, 6 mg or 10 mg of BI 1467335 (test treatment, T) or placebo 
(reference treatment, R) once daily over 28 days. Three placebo groups will be defined:
Placebo for Japanese, Placebo for Caucasians and Total placebo. Placebo for Japanese will be 
defined as a pooled group of the Japanese subjects receiving placebo treatment in the three 
dose groups. Placebo for Caucasians will be defined as the placebo subjects in the 10 mg 
dose group for Caucasians (which comprises all placebo-treated Caucasian subjects). Total 
placebo will be defined as one pooled placebo group (i.e. no distinction between dose groups 
and ethnicity will be made for placebo subjects).
For statistical analysis of AEs, safety laboratory data, vital signs and ECG, the following 
analysis phases are defined for each subject:
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
data, vital signs and ECG
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed 
consent
Date/time of first 
administration of study 
drug
On-treatment
Placebo,
3 mg BI for 
Japanese,
6 mg BI for 
Japanese,
10 mg BI for 
Japanese
or 10 mg BI for 
Caucasians,
respectively
Date/time of first 
administration of study 
drug
0:00  on day after 
subject's trial 
termination date
CTR Section 15, Appendix 16.1.9.2.8.2 and Appendix 16.1.9.2.8.3 AE displays will present 
results for the on-treatment phase only.
In CTR Section 15 AE tables (but not in Appendix 16.1.9.2.8.2 and Appendix 16.1.9.2.8.3
AE tables), the following totals will be provided in addition:


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
"Total BI", defined as the total over all on-treatment phases involving BI, i.e., "3 mg 
BI for Japanese" + "6 mg BI for Japanese" + "10 mg BI for Japanese"+ "10 mg BI for 
Caucasians "

"Total BI for Japanese", defined as the total over all on-treatment phases involving 
BI, i.e., "3 mg BI for Japanese" + "6 mg BI for Japanese" + "10 mg BI for Japanese"

"Total on-trt", defined as the total over all on-treatment phases, i.e., "Placebo" + "3
mg BI for Japanese" + "6 mg BI for Japanese" + "10 mg BI for Japanese"+ "10 mg BI
for Caucasians"
CTR Appendix 16.1.9.2.8.1 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 
16.1.9.2.8.1 AE tables:

"Total", defined as the total over all study phases (screening + on-treatment)
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Data discrepancies and deviations from the CTP will be identified for all subjects in the 
database (i.e., treated subjects). Consistency check listings (for identification of violations of 
time windows) and a list of protocol deviations (e.g. deviations in drug administration, in 
blood sampling times, etc.) will be provided to be discussed at the 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 IPV. For definition of IPVs, and for the process of 
identification of these, refer to the BI reference document "Protocol Violation Handling 
Definitions" (1).
If any IPVs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes via an accompanying Excel spreadsheet (2). The following table 
contains the categories which are considered to be IPVs in this trial. If the data show other 
IPVs, this table will be supplemented accordingly by the time of the RPM/DBLM.
IPVs will be summarised and listed.


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Table 6.2: 1
Important protocol violations
Categor
y/Code
Description
Example/Comment
A
Entrance criteria not met
A1
Inclusion criteria not met
Inclusion criteria not met as specified in the 
protocol
A2
Exclusion criteria met
Exclusion criteria met as specified in the protocol
B
Informed consent
B1
Informed consent not 
available/not done
Informed consent date missing
B2
Informed consent too late
Informed consent date was after screening visit
C
Trial medication and 
randomization
C1
Incorrect trial medication taken
The contents of medication  kit do not match with 
the randomisation
C2
Randomisation order not followed
Subject received trial medication from medication 
kit assigned to another subject
C3
Non-compliance
Medication not taken as scheduled by protocol
C4
Medication code broken 
inappropriately
Medication code was broken with no valid reason
D
Concomitant medication
D1
Any prohibited concomitant 
medications/therapies use
Intake of medications/therapies that might 
reasonably influence the results of the trial
E
Missing data
E1
Certain violations of procedures 
used to measure secondary PK 
endpoint
Violations of PK sampling which may cause no 
secondary PK endpoint.
Handling for violation relating PD sampling will be 
discussed on RPM. 
F
Incorrect timing
F1
Certain violations of time 
schedule used to measure 
secondary PK endpoint
PK sample taken too early/too late1
Handling for violation relating PD sampling will be 
discussed on RPM.
G
Other trial specific important 
violations
G1
Incorrect intake of food
The subject who eats food within 10 hours before 
the medication intake on the visit days 


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1 Time deviations will only be flagged as iPV, when one of the secondary endpoint of the subject
cannot be evaluated


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6.3
SUBJECT SETS ANALYSED
The following subject sets will be defined for statistical analysis:

Randomised set (RS): 
This subject set includes all subjects who were randomised, i.e., who have been 
assigned a subject number, whether treated or not.

Treated set (TS):
This subject set includes all subjects who received at least one dose of study drug, as 
defined in Section 7.3.1 of the CTP. This is the full analysis set population in the 
sense of ICH-E9.

Pharmacokinetic parameter analysis set (PKS):
This subject set includes all subjects of the TS who provide at least one PK parameter 
that was not excluded due to relevant PVs or due to PK non-evaluability, as defined in 
Section 7.3.1 of the CTP.
 
 
All ECG analyses are performed on the TS, except for the exposure-response analyses, which 
are performed on the ECGPCS defined below.

ECG PC set (ECGPCS):
This subject set consists of all subjects in the TS who provide a baseline value and at 
least one post-baseline value for at least one ECG variable used in the exposure-
response analysis, and a corresponding (i.e. time-matched) valid drug plasma 
concentration. Since placebo subjects will be included in the exposure-response 
analyses with plasma concentration set to 0, a plasma concentration BLQ is 
considered a valid drug plasma concentration for placebo subjects.
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
RS
TS
PKS
ECGPCS
Disposition
X
X
Exposure
X
IPVs
X
Demographic/baseline endpoints
X
Primary endpoint
X
ECG endpoints and plasma 
concentrations used in exposure-
response analysis
X
ECG endpoints in other analyses
X
Other safety parameters
X
Secondary PK endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable because centre is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
The endpoint will be derived taking account for handling of missing data as defined in the 
CTP, Section 7.4.
CTP: If a subject is removed from or withdraws from the trial prior to first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) or 
trial database and will not be reported in the clinical trial report (CTR). The only exception
to this rule is when the subject had an AESI and/or SAE that the investigator considers 
related to the screening procedure. If a subject is removed from or withdraws from the trial 
after first administration of trial medication, this will be documented and the reason for 
discontinuation must be recorded in the CRF. In this case, the data will be included in the 
CRF/trial database and will be reported in the CTR.


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Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (3)).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (4).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
There will be a centralised evaluation of all 12-lead ECG recordings at the time points 
specified in Table 6.7: 1 below:
Table 6.7: 1
Time schedule of 12-lead ECG recordings
Visit
Day
Planned time 
[hh:mm]
(relative to drug 
administration)
Study phase
2
1
00:15
On-treatment
00:30
00:45
01:00
01:30
02:00
04:00
08:00
12:00
2
23:55


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Table 6.7: 1
Time schedule of 12-lead ECG recordings (continued)
Visit
Day
Planned time 
[hh:mm]
(relative to drug 
administration)
Study phase
2
14
310:00
On-treatment
312:15
312:30
312:45
313:00
313:30
314:00
316:00
320:00
324:00
15
336:00
337:00
28
646:00
648:15
648:30
648:45
649:00
649:30
650:00
652:00
656:00
660:00
29
672:00
Triple ECGs (3 single ECGs recorded within 180 sec) will be recorded on all time points on 
Day 1, Day 2, Day 14, Day 15, Day 28 and Day 29. On all other time points, single ECGs 
will be recorded.
The value of an ECG variable at each of the time points with triple ECG is defined as the 
arithmetic mean of the 3 single ECG measurements. In particular, the baseline value of an 
ECG variable is defined as the mean of the triple ECG measurements prior to first drug 
administration.
In all other analyses (except for analyses of ECG variables), the last non-missing value 
determined prior to the first dosing of BI 1467335 will be defined as baseline. 


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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" (001-MCG-159) (9).
The individual values of all subjects will be listed. Listings will generally be sorted by dose 
group, ethnicity, 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 and biomarker parameters, the 
following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of 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. 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.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.


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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 be analysed using descriptive statistics and also using 
frequency tables for categories of treatment compliance. Categories will be defined as <80%, 
80% - 100% and >100%. 
Any deviations from complete intake will be addressed in the RPM/DBLM (cf. Section 6.2)
and described in the CTR.
7.4
PRIMARY ENDPOINTS
Refer to Section 7.8.1 for a description of the analysis of AEs, and in particular the analysis 
of the frequency of subjects with drug related AEs, which is the primary endpoint of this trial.
7.5
SECONDARY ENDPOINT
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoints
The analysis of secondary endpoints will be based on the PKS.
Dose proportionality of secondary endpoints will be evaluated as defined in the CTP, 
Section 7.3.1, by use of the power model. The assessment of dose proportionally will be 
performed for Japanese subjects only. 2 type placebo groups, Placebo for Japanese and Total 
placebo, will be used for dose proportionality analysis. If steady state will already be reached 
after 14 days of treatment, dose proportionality will also be investigated for AUC0-24,14 and 
AUC0-24,28 together (and for Cmax,14 and Cmax,28 together, respectively) by use of a repeated 
measurements model.
Exclusion of PK parameters


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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 
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.
Further details are given in 001-MCS-36-472_RD-01 "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies" (4) and 001-MCS-36-472_RD-03 
"Description of Analytical Transfer Files and PK/PD Data Files" (5).


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the CTR based on the TS. The number of 
days taking medication will be analysed with standard descriptive statistical parameters and 
also using frequency tables for categories "<28 days", “28 days” and "> 28 days".
The date and time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
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 [CTCAE grade Version 4.03], 
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 'Handling and summarization 
of adverse event data for clinical trial reports and integrated summaries' (6) [001-MCG-156] 
and "Handling of missing and incomplete AE dates" (3) [001-MCG-156_RD-01]. 
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 phase or on-treatment phase as defined in 
Section 6.1.


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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 and for the class of 
AESIs.
CTP: The following are considered as AESIs in this trial:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

an elevation of AST and/or ALT > 3 fold upper limit normal (ULN) combined with an 
elevation of total bilirubin > 2 fold ULN measured in the same blood draw sample, 
and/or

marked peak 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
(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 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 grade 
of CTCAE (version 4.03), primary SOC and preferred term.
The SOCs will be sorted according to the standard sort order specified by the EMA, preferred 
terms will be sorted by total frequency (within SOC).
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.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (7). Laboratory analyses will be based on normalised values, i.e., for a given 
laboratory parameter, values will be transformed to a standard unit and a standard reference 
range before statistical analysis.
CTP: Laboratory data will be compared to their reference ranges. Values outside the 
reference range will be flagged. Additionally, differences from baseline will be evaluated.
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.
7.8.3
Vital signs
The analyses of vital signs 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.
 
 
 
 
 


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7.8.5
Others
Physical examination findings and ophthalmological examination findings (exclusion of 
cataract) will be reported as relevant medical history/baseline condition (i.e., a condition 
already existent before intake of study drug) or as AE and will be summarised as such. No 


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separate listing or analysis of physical examination or ophthalmological examination findings 
will be prepared.


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8.
REFERENCES
 
 
 
 
 
 
 
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
 
10
R17-0553: Garnett C, Needleman K, Liu J, Brundage R, Wang Y; Operational 
characteristics of linear concentration-QT models for assessing QTc interval in the 
thorough QT and phase I clinical studies. Clin Pharmacol Ther 100 (2), 170 - 178 
(2016)
11
R10-2920: Ring A: Statistical models for heart rate correction of the QT interval; 
Stat Med 29, 786 - 796 (2010)


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
31-MAY-17
None
This is the initial TSAP with necessary 
information for trial conduct
Final
29-JAN-18
None
This is the final TSAP without any 
modificaton