Conditions: Healthy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: yes

Brief summary:
The primary objective of this trial is to investigate the absolute bioavailability of BI 1467335 with an intravenous microdose formulation containing labelled \[C-14\] BI 1467335 and an unlabelled oral tablet formulation of BI 1467335 in healthy male subjects.

The secondary objective is the evaluation of additional pharmacokinetic parameters following the two treatments.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: BI 1467335 intervention 2: BI 1467335 (C-14) intravenous solution
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Intravenous solution

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c19596566-03
EudraCT No.:
BI Trial No.:
2017-003853-41
1386-0019
BI Investigational
Product:
BI 1467335
Title:
A phase I, open-label, single-arm multiple dose trial to investigate 
pharmacokinetics and absolute bioavailability of BI 1467335
administered as an oral dose simultaneously with an intravenous 
microtracer dose of [C-14] BI 1467335 after single and multiple 
oral doses in healthy male volunteers
Lay Title:
This study in healthy men tests how the body takes up BI 1467335
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax:
Principal Investigator:
Phone:
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date:
Version: 3.0
Date: 24 April 2018
Page 1 of 65
Proprietary confidential information
© 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1467335
Protocol date:
Trial number:
Revision date:
24 April 2018
16 February 2018
1386-0019
Title of trial:
A phase I, open-label, single-arm multiple dose trial to investigate pharmacokinetics 
and absolute bioavailability of BI 1467335 administered as an oral dose 
simultaneously with an intravenous microtracer dose of [C-14] BI 1467335 after 
single and multiple oral doses in healthy male volunteers
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate the pharmacokinetics and absolute bioavailability of BI 1467335 with 
an intravenous formulation containing labelled [C-14] BI 1467335 and an unlabelled 
oral tablet formulation of BI 1467335 in healthy male subjects
Methodology:
Non-randomised, open-label, single arm multiple dose design
No. of subjects: 
total entered:
12
each treatment:
At least 10 enrolled subjects, maximum 12 enrolled subjects
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 65 years, body mass index (BMI) of 18.5 to 
29.9 kg/m2
Test product 1 (T1):
BI 1467335 film-coated tablet formulation
dose:
10 mg of free base (2 x 5 mg) QD
mode of admin.:
Oral with 240 mL of water 


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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:
24 April 2018
16 February 2018
1386-0019
Test product 2 (T2):
Unlabelled BI 1467335 mixed with Carbon 14 labelled BI 1467335 [BI 1467335
(C-14)] as an intravenous infusion
dose:

On Day 1 50 g infusion consisting of 41.15 µg unlabelled BI 1467335 free 
base (= 46.50 µg salt) mixed with 8.85 µg [C-14] BI 1467335 free base 
(=10 µg salt) in 10 mL solution (5 µg BI 1467335 (C-14) free base /mL)

On Day 28 50 µg infusion consisting of 45 µg unlabelled BI 1467335 free 
base (=50,85 µg salt) mixed with 5 µg [C-14] BI 1467335 free base
(=5,65 µg salt) in 10 mL solution (5 µg BI 1467335 (C-14) free base /mL)
The radioactive dose per infusion has been selected to not exceed 2.7 µCi=0.1 MBq.
mode of admin.:
Intravenous infusion 
Comparator product:
Not applicable
Duration of 
treatment:
Intravenous dose (reference):
A single15 minutes intravenous infusion of the microtracer on Day 1 and Day 28.
Oral dose (test): 
Non-radiolabelled film-coated tablets once a day from Day 1 to Day 28 (treatment 
duration 28 days)
Criteria for 
pharmacokinetics:
Primary endpoints:
After the first dose: Cmax and AUC0-of BI 1467335 (after intravenous and oral 
administration) on Day 1
After multiple doses: Cmax, 28 and AUCof BI 1467335 (after oral 
administration) on Day 28; Cmax, 28 and AUC0-, 28 of BI 1467335 (after intravenous 
administration) on Day 28.
Secondary endpoints:
Assessment of the oral pharmacokinetics following intravenous treatment with a 
microtracer of [C-14] BI 1467335 and a treatment with BI 1467335film-coated 
tablets in plasma:
Oral: tmax, tmax,28, t1/2
IV: CL, CL28, Vz, Vz,28, tmax, tmax,28, t1/2, t1/2,28
Further pharmacokinetic assessments will be included as appropriate based on 
emerging data.


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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:
24 April 2018
16 February 2018
1386-0019
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the physical 
examination, safety laboratory tests, 12-lead electrocardiogram (ECG), vital signs 
(blood pressure [BP], pulse rate [PR]) 
Statistical methods:
Absolute bioavailability (F) will be estimated by the ratio of the geometric means 
(tablet/infusion) for the dose normalized primary endpoints separately for Day 1 and 
Day 28. Additionally, its two-sided 90% confidence interval (CI) will be provided. 
This method corresponds to the two one sided t-tests procedure, each at the 5% 
significance level. Since the main focus is on estimation and not testing, an 
acceptance range was not specified. The statistical model will be an ANOVA on the 
logarithmic scale including the fixed effect for ‘formulation’ and ‘subject’ as a 
random effect. CIs will be calculated based on the residual error from ANOVA.
In addition, the absolute bioavailability factor F will be calculated for each subject 
on Day 1 and Day 28.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Visit
Day
Planned time (relative to 
first oral drug 
administration [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PK plasma
PK plasma [C-14]BI1467335
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy
1
-21 to -2
Screening (SCR)1
x
x
x
2
-1
-18:00
14:00
Admission to trial site
x5
1
-2:00
06:00
x2, 4
x2, 8
x2
x2
x2
0:00
08:00
Drug administration (film coated 
tablet of BI 1467335)
0:15
08:15
x
0:30
08:30
x
0:45
08:45
x
1:00
09:00
Start of 10 mL 50 µg infusion 
consisting of 41.15 µg unlabelled 
BI 1467335 and 8.85 µg 
[C-14] BI 1467335
1:05
09:05
x
x
1:15
09:15
End of infusion
x
1:25
09:25
x
x
1:35
09:35
x
1:45
09:45
x
2:00
10:00
240 mL water intake
x
x
x
2:15
10:15
x
2:45
10:45
x
3:00
11:00
x
3:15
11:15
x
3:45
11:45
x
4:00
12:00
Lunch, 240 mL water intake3
x
4:15
12:15
x
4:45
12:45
x
5:15
13:15
x
6:00
14:00
x
6:15
14:15
x
7:15
15:15
x10
8:00
16:00
x
8:15
16:15
x10
9:15
17:15
x10
10:00
18:00
Dinner3
13:00
21:00
x10
2
24:00
08:00
Dispense of study medication
x
x
25:00
09:00
Discharge from trial site7
x10


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Visit
Day
Planned time (relative to 
first oral drug 
administration [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PK plasma
PK plasma  [C-14]BI1467335
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy
2
6
132:00
20:00
Admission to trial site
x5
7
144:00
08:00
Dispense of study medication, 
discharge7
x2
x2
x2
13
300:00
20:00
Admission to trial site
x5
14
312:00
08:00
Dispense of study medication, 
discharge7
x2 
x2
x2
x2
20
468:00
20:00
Admission to trial site
x5
21
480:00
08:00
Dispense of study medication, 
discharge7
x2
x2
x2
25
582:00
14:00
Admission to trial site11
x5
x
26
600:00
08:00
Drug administration (film coated, 
of BI 1467335)
27
624:00
08:00
Drug administration (film coated, 
of BI 1467335)
28
646:00
06:00
x2, 4
x2
x2
647:55
07:55
x
x
648:00
08:00
Drug administration (film coated, 
of BI 1467335)
648:15
08:15
x
648:30
08:30
x
648:45
08:45
x
649:00
09:00
Start of 10 mL 50 µg infusion 
consisting of 45 µg unlabelled 
BI 1467335 and 5 µg 
[C-14] BI 1467335
649:05
09:05
x
x
649:15
09:15
End of infusion
x
649:25
09:25
x
x
649:35
09:35
x
649:45
09:45
x
650:00
10:00
240 mL water intake
x
x
650:15
10:15
x
650:45
10:45
x
651:00
11:00
x
651:15
11:15
x
651:45
11:45
x
652:00
12:00
Lunch, 240 mL water intake3
x
652:15
12:15
x
652:45
12:45
x
653:15
13:15
x
654:00
14:00
x
655:15
15:15
x
656:00
16:00
x
657:15
17:15
x
658:00
18:00
Dinner3
x


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Visit
Day
Planned time (relative to 
first oral drug
administration [h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PK plasma
PK plasma  [C-14]BI1467335
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy
2
28
660:00
20:00
x
x
x
661:00
21:00
x
29
672:00
08:00
x
673:00
09:00
x
30
697:00
09:00
x
x
x
x
32
745:00
09:00
Discharge from trial site
x
3
33-40
End of trial (EOT) examination6, 9
x
x
x
x
1.
Screening includes subject information, informed consent, physical examination, check of vital signs, ECG, safety 
laboratory (including drug and virus screening), demographics (including determination of body height and weight, 
BMI, smoking status and alcohol history), relevant medical history, concomitant therapy and review of 
inclusion/exclusion criteria.
2.
The time is approximate; the procedure is to be performed within a time window of 3 h prior to drug administration.
After start of treatment, further PK blood sampling (trough level) within 30 minutes before next scheduled dosing.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
Subjects are to be fasted for at least 10 h before sample is taken.
5.
Only urine drug and alcohol screening will be done at this time point.
6.
End-of-trial (EOT) examination to be performed on Day 34-41, EOT examination includes physical examination, vital 
signs, ECG, safety laboratory, recording of AEs and concomitant therapies.
7.
On Days 3 to 6, 8 to 13, 15 to 20 and 22 to 25, subjects are allowed to take their study medication at home if deemed 
appropriate by the investigator. Compliance of medication intake will be monitored by subject diary and daily phone 
contact between subject and site. The scheduled time for drug intake throughout the study is 08:00 (applies for intake at 
home and at the trial site). 
8.
Pharmacogenomic sample.
9.
For definition of the individual subject’s end of trial see Section 6.2.3.
10. Samples for an individual subject beyond 5 h after end of infusion will be only analyzed if for this subject the plasma 
level of [C-14]BI 1467335 at this time point (i.e., 6:15) is still above LOQ.
11. Subjects will be hospitalized from admission on Day 25 to Day 32.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 11
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 20
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................20
2.2
TRIAL OBJECTIVES.......................................................................................20
2.3
BENEFIT - RISK ASSESSMENT ...................................................................20
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 23
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................23
3.1.1
Administrative structure of the trial...................................................23
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................24
3.3
SELECTION OF TRIAL POPULATION ......................................................24
3.3.1
Main diagnosis for study entry............................................................25
3.3.2
Inclusion criteria...................................................................................25
3.3.3
Exclusion criteria ..................................................................................25
3.3.4
Removal of subjects from therapy or assessments.............................27
3.3.4.1
Removal of individual subjects................................................27
3.3.4.2
Discontinuation of the trial by the sponsor..............................27
4.
TREATMENTS........................................................................................ 29
4.1
TREATMENTS TO BE ADMINISTERED....................................................29
4.1.1
Identity of BI investigational product and comparator product......29
4.1.2
Method of assigning subjects to treatment groups ............................30
4.1.3
Selection of doses in the trial................................................................30
4.1.4
Drug assignment and administration of doses for each subject .......30
4.1.5
Blinding and procedures for unblinding ............................................31
4.1.6
Packaging, labelling, and re-supply ....................................................31
4.1.7
Storage conditions.................................................................................31
4.1.8
Drug accountability ..............................................................................31


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4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................32
4.2.1
Other treatments and emergency procedures....................................32
4.2.2
Restrictions............................................................................................32
4.2.2.1
Restrictions regarding concomitant treatment .........................32
4.2.2.2
Restrictions on diet and life style.............................................32
4.3
TREATMENT COMPLIANCE.......................................................................33
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 34
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................34
5.1.1
Endpoints of efficacy.............................................................................34
5.1.2
Assessment of efficacy...........................................................................34
5.2
SAFETY..............................................................................................................34
5.2.1
Endpoints of safety................................................................................34
5.2.2
Assessment of adverse events...............................................................34
5.2.2.1
Definitions of adverse events...................................................34
5.2.2.2
Adverse event collection and reporting ...................................37
5.2.3
Assessment of safety laboratory parameters......................................39
5.2.4
Electrocardiogram................................................................................41
5.2.5
Assessment of other safety parameters...............................................42
5.2.5.1
Vital signs ................................................................................42
5.2.5.2
Medical examinations..............................................................42
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................43
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................43
5.5.1
Pharmacokinetic endpoints..................................................................44
5.5.1.1
Primary endpoints ....................................................................44
5.5.1.2
Secondary endpoint..................................................................44
5.5.2
Methods of sample collection ...............................................................45
5.5.2.1
Plasma sampling for pharmacokinetic analysis .......................45
5.5.3
Analytical determinations ....................................................................46
5.5.3.1
Analytical determination of analyte plasma concentration......46
5.6
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....46
6.
INVESTIGATIONAL PLAN.................................................................. 47
6.1
VISIT SCHEDULE............................................................................................47
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................47
6.2.1
Screening period....................................................................................47
6.2.2
Treatment period ..................................................................................47


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6.2.3
End of trial period.................................................................................48
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 49
7.1
STATISTICAL DESIGN – MODEL ...............................................................49
7.1.1
Objectives...............................................................................................49
7.1.2
Endpoints...............................................................................................49
7.1.3
Model......................................................................................................49
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................50
7.3
PLANNED ANALYSES....................................................................................50
7.3.1
Primary analyses...................................................................................51
7.3.2
Secondary analyses ...............................................................................52
7.3.3
Safety analyses.......................................................................................52
7.3.4
Interim analyses ....................................................................................53
7.3.5
Pharmacokinetic analyses ....................................................................53
7.4
HANDLING OF MISSING DATA ..................................................................54
7.4.1
Safety......................................................................................................54
7.4.2
Plasma drug concentration - time profiles..........................................54
7.4.3
Pharmacokinetic parameters...............................................................54
7.5
RANDOMISATION ..........................................................................................54
7.6
DETERMINATION OF SAMPLE SIZE ........................................................54
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 56
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................56
8.2
DATA QUALITY ASSURANCE .....................................................................57
8.3
RECORDS..........................................................................................................57
8.3.1
Source documents .................................................................................57
8.3.2
Direct access to source data and documents.......................................57
8.3.3
Storage period of records.....................................................................57
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................57
8.5
STATEMENT OF CONFIDENTIALITY.......................................................58
8.6
COMPLETION OF TRIAL..............................................................................58
9.
REFERENCES......................................................................................... 59
9.1
PUBLISHED REFERENCES...........................................................................59
9.2
UNPUBLISHED REFERENCES.....................................................................60
10. APPENDICES .......................................................................................... 62
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 63


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ABBREVIATIONS
ADME
Absorption, Distribution, Metabolism and Excretion
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine amino transferase
AMS
Accelerator mass spectrometry
ANOVA
Analysis of variance
AST
Aspartate amino transferase
AUC0-∞
Area under the concentration-time curve of the analyte over the time 
interval from 0 extrapolated to infinity
AUC0-24h
Area under the concentration-time curve of the analyte over the time 
interval from 0 to 24
AUC0-tz
Area under the concentration-time curve of the analyte over the time 
interval from 0 to the last quantifiable data point
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over 
the time interval from time point t1 to t2
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUC
Area under the concentration-time curve of the analyte over the time 
interval from 0 to interval tau
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
[C-14]BI 1467335
[14C]-labelled BI 1467335
CA
Competent authority
CI
Confidence interval
CL/F
Apparent clearance of the analyte after extravascular administration
Cmax
Maximum measured concentration of the analyte
CML
Clinical Monitor Local
CRA
Clinical Research Associate
CRF
Case report form
CRO
Clinical Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical trial protocol
CTR
Clinical trial report
CTSU
Clinical Trial Supplies Unit
DILI
Drug-induced liver injury


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DNA
Deoxyribonucleic acid
EC
Ethics committee
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
EU
European Union
F
Absolute bioavailability factor
FDA
Food and Drug Administration
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GLP
Good Laboratory Practice
gMean
Geometric Mean
GMP
Good Manufacturing Practice
IB
Investigator’s brochure
ICH
International Conference of Harmonization
ICRP
International Commission on Radiological Protection
IEC
Independent Ethics Committee
ILD
Interstitial lung disease
IRB
Institutional Review Board
ISF
Investigator site file
iv
Intravenous
z
Terminal rate constant
LC-MS/MS
Liquid chromatography tandem mass spectrometry
MAT
Mean absorption time
MedDRA
Medical Dictionary for Regulatory Activities
M(R)D
Multiple (rising) dose
MRTex
Mean residence time of the analyte in the body after oral 
administration
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic analysis set
PR
Pulse rate


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qd/QD
Quaque die, once daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
Heart rate-corrected QT interval
QTcF
Heart rate-corrected QT interval following the formula of Fridericia
RDC
Remote Data Capture
REP
Residual effect period
RPM
Report planning meeting
SAE
Serious adverse event
SCR
Screening
SOP
Standard Operating Procedure
S(R)D
Single (rising) dose
SSAO
Semi-carbazide-sensitive amine oxidase 
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
Terminal half-life of the analyte 
TDMAP
Trial Data Management and Analysis Plan
tmax
Time from dosing to the maximum measured concentration of the 
analyte
TMF
Trial master file
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper Limit of Normal
US
United States
Vd
Apparent volume of distribution
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
This trial is intended to examine the absolute oral bioavailability of BI 1467335 using an iv
[C-14] microtracer approach. The data are considered necessary to further support the 
understanding of the pharmacokinetics of BI 1467335. Due to the time dependent non-linear 
kinetics of BI 1467335, systemic exposures on Day 28 cannot be predicted from Day 1 
kinetics, (IB [c04751792]).Therefore absolute oral bioavailability using an iv [C-14] 
microtracer dose will be determined on Day 1 and on Day 28 following a single (Day 1) and 
multiple dose treatment (Day 1 to 28) with an oral unlabelled dose of 10 mg of BI 1467335
q.d.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the absolute bioavailability of BI 1467335 
with an intravenous microdose formulation containing labelled [C-14] BI 1467335 and an 
unlabelled oral tablet formulation of BI 1467335 in healthy male subjects.
The secondary objective is the evaluation of additional pharmacokinetic parameters following 
the two treatments.
The assessment of safety and tolerability will be an additional objective of this trial.
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.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of the
compound. The subjects are exposed to the risks of the study procedures and the risks related 
to the exposure to the trial medication.
 
 
 
 
 
 
 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as an open-label, non-randomised, single arm, multiple dose trial 
in healthy male subjects to define from the systemic exposure from the oral dose (T1, film 
coated tablet) and that following the iv infusion (T2, microtracer infusion). The resulting 
data, per subject, will be dose normalised then the absolute oral bioavailability (%) of the
10 mg tablet on Days 1 and 28 will be calculated. For Day 1, (AUC0-∞/Dose)oral/
((AUC0-∞/Dose)iv*100 and for Day 28 (AUC/Dose)oral/((AUC0-∞,28/Dose)iv*100.
The treatments will be a 10 mL intravenous infusion of 50 µg BI 1467335 free base (T2); 
using on Day 1 a mixture of 41.15 µg unlabelled BI 1467335 and 8.85 µg [C-14] BI 1467335
(corresponding to 46.50 µg and 10 µg of salt respectively) and on Day 28 a mixture of 45 µg
unlabelled BI 1467335 and 5 µg [C-14] BI 1467335 free base (corresponding to 50.85 µg and 
5.65 µg of salt respectively). The oral treatment (T1) will consist of two 5 mg film-coated 
tablets (dose strength based on free base) administered once daily for 28 days. On Day 1 and 
Day 28, both treatments are given in fasted state. For details refer to Section 4.1.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial.
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.
The non-labelled trial medication will be provided by the Clinical Trial Supplies Unit 
(CTSU), BI Pharma GmbH & Co. KG, Biberach, Germany.
The radiolabelled trial medication will be provided by 
 
. 
The trial will be conducted at 
 
 under the supervision of the Principal Investigator.
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
).


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The analyses of BI 1467335 concentrations in plasma will be performed at the Department of 
Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, Biberach, Germany. 
Accelerator mass spectrometry (AMS) analysis will be conducted 
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research 
organisation appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
Due to the time dependent non-linear kinetics of BI 1467335, systemic exposures on Day 28 
cannot be predicted from Day 1 kinetics, (IB [c04751792]).Therefore the absolute oral 
bioavailability will be determined on two occasions following single (Day 1) and multiple 
oral dose treatment (Day 28) following 10 mg of BI 1467335 qd (2 film-coated tablets of 
5 mg dose strength), the maximum therapeutic dose used in ongoing phase II studies.
The same subject will receive a 14C labelled microtracer infusion on Day 1 after a single oral
dose and on Day 28 after multiple oral doses. Thus, the oral bioavailability on Day 1 and 28 
will be calculated for each subject on each day. As the iv infusion is given at the geometric 
mean tmax of the oral dose, this accounts for the observed non-proportionality in systemic 
exposure observed between Days 1 and 28.
[C-14] BI 1467335 is unlikely to exhibit any detectable isotope effects (see Section 2.3).
The open-label treatment is not expected to bias results, since the primary study endpoints are 
derived from quantitative measurements of plasma concentrations of the analyte following 
oral and iv dosing.
3.3
SELECTION OF TRIAL POPULATION
It is planned that at least 10 healthy male subjects will enter the study (maximum number of 
n=12 subjects) to have at least 8 evaluable subjects. They will be recruited from the 
volunteers' pool of the trial site or, if necessary, via advertisement. 
The current trial is designed to investigate the absolute oral bioavailability of BI 1467335
following 10 mg oral dosing. Healthy male subjects are an ideal population for the objectives 
of this trial, since they provide relatively stable physiological, biochemical and hormonal 
conditions, i.e. the absence of disease-related variations and relevant concomitant 
medications.


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A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The study will be performed in healthy subjects.
3.3.2
Inclusion 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.
Age of 18 to 65 years (incl.)
3.
BMI of 18.5 to 29.9 kg/m2 (incl.)
4.
Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
5.
Subjects who are sexually active must use, with their partner, highly effective 
contraception from the time of administration of trial medication until 4 months after 
administration of trial medication. Adequate methods are:
-
Condoms plus use of hormonal contraception by the female partner that started at 
least 2 months prior to administration of trial medication (e.g., implants, injectables, 
combined oral or vaginal contraceptives, intrauterine device) or
-
Condoms plus surgical sterilization (vasectomy at least 1 year prior to enrolment) or
-
Condoms plus surgically sterilised partner (including hysterectomy) or
-
Condoms plus intrauterine device or
-
Condoms plus partner of non-childbearing potential (including homosexual men)
Subjects are required to use condoms to prevent unintended exposure of the partner to the 
study drug via seminal fluid.
Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred and 
usual lifestyle. If a subject is usually not sexually active but becomes active, with their 
partner, they must comply with the contraceptive requirements detailed above.
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


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3. Any evidence of a concomitant disease judged as clinically relevant by the investigator
4. Clinically significant gastrointestinal, hepatic, renal, respiratory (including but not limited 
to interstitial lung disease), cardiovascular, metabolic, immunological or hormonal 
disorders
5.
Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics 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
9.
History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
10. Within 30 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
11. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug
12. Smoker (more than 5 cigarettes or 1 cigar or 1 pipe per day)
13. Inability to refrain from smoking on specified trial days
14. Average intake of more than 24 units of alcohol per week (1 unit of alcohol equals 
approximately 250 mL of beer, 100 mL of wine or 35 mL of spirits)
15. Drug abuse or positive drug screening
16. Blood donation of more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
17. Inability to comply with dietary regimen of trial site
18. A marked baseline prolongation of QT/QTc interval (such as QTcF intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
19. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome) 
20. 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 
In addition, the following trial-specific exclusion criteria apply:
21. Exposure to radiation for diagnostic reasons (except dental X-rays and plain X-rays of 
thorax and bony skeleton (excluding spinal column) in the period of 1 year prior to 
screening
For study restrictions, refer to Section 4.2.2.


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3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events, or diseases)
4. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
5. A subject can also be removed from the trial if eligibility criteria are being violated or if 
the subject fails to comply with the protocol (for instance, by non-adherence to dietary 
rules, or non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
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 at least one drug-
related serious adverse event is reported that is considered to be unacceptable. In this 
case, collection of pharmacokinetic samples and other scheduled activities should 
continue, if possible without undue risk to already dosed volunteers, but no further 
administrations of investigational drug will be done.
2. The expected enrolment goals overall are not met
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


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4. The sponsor decides to discontinue the further development of the investigational 
product.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
 
 
 
 


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
BI 1467335 doses are calculated as a free base. 10 mg BI 1467335 free base equals to 
11.3 mg BI 1467335 HCl salt.
Radiolabelled BI 1467335 (C-14) (test product 2) is administered as an intravenous solution.
The powder used for intravenous solution contains [C-14] BI 1467335 and unlabelled
BI 1467335 both manufactured by BI Pharma GmbH & Co. KG. The mixture of 
[C-14] BI 1467335 and unlabelled BI 1467335 and the solution from this mixture are 
made by 
Unlabelled film coated tablets (test product 1) have been manufactured by BI Pharma GmbH 
& Co. KG.
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test products are given below:
Test product 1
Substance:
BI 1467335 
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg
Posology:
2-0-0
Route of administration:
p.o.
Duration of use:
28 days
Test product 2
Name:
BI 1467335 (C-14) intravenous solution
Substance:
BI 1467335 mixed with [C-14] BI 1467335 
Pharmaceutical formulation: Intravenous solution
Source:
Unit strength:
50 µg BI 1467335 (C-14)
-
Containing 8.85 µg [C-14] BI 1467335 free base and 
41.15 µg BI 1467335 free base (Day 1) (corresponding to 
10 µg and 46.50 µg salt, respectively) or 
containing 5 µg [C-14] BI 1467335 free base and 45 µg 
BI 1467335 free base (Day 28) (corresponding to 5.65 µg 
and 50.85 µg, respectively)


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-
In a saline solution of 10 mL volume
(concentration of BI 1467335 (C-14): 5 µg free base/mL) 
Posology:
1-0-0
Route of administration:
i.v.
Duration of use:
Two single infusions (Day 1 and Day 28), infused over 
15 minutes
4.1.2
Method of assigning subjects to treatment groups
This is an open-label, single arm Phase I, single- and multiple dose study. All subjects receive 
the same dose. Each subject will be assigned a subject number prior to dosing on Day 1 of 
Visit 2.
Subject numbers will be
for the maximum number of twelve planned subjects and 
in case subject replacement is necessary (see Section 3.3.5). 
Once a subject number has been assigned, it cannot be reassigned to any other subject. 
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
The oral dose of 10 mg BI 1467335 (calculated as free base) is below the already tested 
highest oral dose of 20 mg of BI 1467335 for 4 weeks in healthy subjects. In healthy 
volunteers, this dose was safe and well-tolerated (Section 1.2). 
 
An oral 
dose of 10 mg, administered either as single or multiple dose, is considered adequate for the 
objectives of the current trial. 
The iv dose on Day 1 and Day 28 administered as infusion will include 14C radiolabelled 
BI 1467335. The radiolabelled dose has been selected to provide sufficient analytical 
sensitivity, (Accelerator Mass Spectrometry), in this microtracer study while not exceeding 
the threshold of negligible radioactive burden, see Section 2.3.
4.1.4
Drug assignment and administration of doses for each subject
All subjects will receive the same treatment. Treatment with non-radiolabelled oral 
compound (film-coated tablets) will consist of 10 mg q.d. from Day 1 to Day 28. On Day 1 
and Day 28 the non-radiolabelled medication will be administered to a subject in the sitting 
position under supervision of the investigator or an authorised designee. Volunteer will drink 
240 mL of non-sparkling water.
In principal, the so-called four-eye principle (two-person rule) should be applied for 
administration of trial medication at the study site, while intake under ambulatory conditions 
will be monitored by phone contacts between study site and subject. 
On Day 1 and Day 28 lunch will be given 4 h postdose. During the first 4 h after drug 
administration (only on Day 1 and Day 28), subjects are not allowed to lie down (i.e.,


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no declination of the upper body of more than 45 degrees from upright posture) except for 
medical examinations (in particular for the microtracer infusion) or if necessary for any 
medical reasons (e.g., adverse events). For restrictions with regard to diet and fluid intake
during the investigational period see Section 4.2.2.2.
Start and time of the infusion will be recorded.
For administration of the microtracer infusion on Day 1 and Day 28 (duration of infusion: 
15 minutes), an intravenous indwelling catheter is placed into an arm vein of the subject and 
will be kept patent with a saline infusion. A second indwelling catheter used for collection of 
blood samples will be placed on the contralateral arm.
4.1.5
Blinding and procedures for unblinding
No blinding will be performed because the treatments are distinguishable from each other. 
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct, 
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, since it is an open-label trial.
4.1.6
Packaging, labelling, and re-supply
Non-labelled drug supplies will be provided by the Department of Pharmaceutical 
Development of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Radiolabelled drug product manufacturing is provided by 
. 
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. Investigational Drug Products will be labelled according to GMP 
Annex 13 / EU GMP Guideline and local drug law. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
 pharmacy will deliver the investigational drugs to the investigator upon availability of a 
valid prescription from the investigator.
The investigator will not order the drugs from the 
 pharmacy before the following 
requirements are fulfilled:


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
Approval of the study protocol by the IRB / ethics committee 

Availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre

Approval/notification of the regulatory authority, e.g. competent authority

Availability of a signed and dated clinical trial protocol or immediately imminent 
signing of the clinical trial protocol 

Availability of licence for clinical research using radioactive isotopes
Only authorised personnel as documented in the form ‘Site Delegation Log’ may dispense 
medication to trial subjects. Intake of trial medication during both ambulatory and 
hospitalized periods must strictly follow the manner specified in the CTP. All unused trial 
medication must be returned to the sponsor or disposed locally by the trial site upon written 
authorisation by the clinical monitor. Appropriate retention samples will be kept at 
 until 
finalization of the clinical trial report. Receipt, usage and return or disposal must be 
documented on the respective forms. Account must be given for any discrepancies. 
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of adverse events in need of treatment, the investigator can 
authorise symptomatic therapy. In those cases, subjects will be treated as necessary and, if 
required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
No concomitant therapy is allowed. All concomitant or rescue therapies will be recorded 
(including time of intake on study days) on the appropriate pages of the CRF. Limited 
amounts of paracetamol are allowed when prescribed by a 
 physician.
 
In the case of AEs the volunteers will be treated as necessary and kept under constant 
supervision at the trial centre or transferred to hospital until such time that all the results of 
the evaluations have returned to a medically acceptable level.
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 


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described in the Flow Chart. In addition, subjects are required to refrain from smoking while 
hospitalized.
On Day 1 and Day 28 starting from 1 hour before drug administration until 2 h after drug 
intake fluid intake is not allowed except from the 240 mL water administered with the drug 
intake and an additional 240 mL of water served on Day 1 and Day 28 at 2 h post-dose 
(mandatory for all subjects). From 2 hours until 22 hours post-dose fluid intake should be 
within about 1000 to 3000 mL.
On Day 1 and Day 28 subjects will receive a 15 minutes microtracer infusion 1 h after intake 
of film-coated tablets (i.e., tmax for oral dose). The handling instructions will be filed in the 
ISF.
Poppy-seed containing products should not be consumed starting 2 days before first trial drug 
administration until last PK sampling of the trial.
For fasting times before drug administration see Section 4.1.4. For fasting times before safety 
laboratory investigations see Section 5.2.3.
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.
Alcoholic beverages are not allowed 48 hours before administration of the compound, before 
each admission and during the clinic period. During ambulatory phases alcohol consumption 
is restricted to 24 units a week.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed at days of inhouse confinement. 
Subjects should be advised to avoid foods containing a very large amount of tyramine 
(especially found in fermented food) while taking BI 1467335. These include for example 
aged cheese, aged meats, soybean products (soy sauce), red wine, tap (draft) beer, St John’s 
Wort, pickled herring, sauerkraut (fermented cabbage), and tryptophan supplements.
Excessive physical activity (such as competitive sport) should be avoided starting 4 days 
before the first administration of trial medication until the end of trial examination.
4.3
TREATMENT COMPLIANCE
Compliance will be monitored by either administration of all trial medication in the study 
centre under supervision of the investigating physician or a designee or during ambulatory 
period subjects confirm drug intake by phone contact with the study site.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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


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
requires inpatient hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect, 
or 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in 5.2.2.2, subsections ‘AE collection’ and ‘AE reporting to sponsor and timelines’.
The latest list of ‘Always Serious AEs’ can be found in the RDC system. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see Section 5.2.2.2.
The following are considered as AESIs in this trial:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 


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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 (severity) of AEs
The intensity (severity) 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
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

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 trial treatment continues or remains 
unchanged.


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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 CRF(s) by the 
investigator:

From signing the informed consent onwards  until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs. 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report related SAEs and related AESIs of which the investigator 
may become aware of by any means of communication, e.g. phone call. Those 
AEs should, however, not be reported in the CRF.


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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 for this clinical trial. Therefore, all AEs 
reported until the end of trial examination (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) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF 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 CRF and BI SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only.
All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been  assessed as ‘chronic’ or ‘stable’, or no further 
information can be obtained.


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5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Subjects do not have to be fasted for drug screening and for infectious serology at 
the discretion of the investigator or designee. Fasting is not required at the discretion of the 
investigator or designee for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit 
Haemoglobin
Red blood cell count (RBC) 
Reticulocyte count
White blood cell count (WBC)
Platelet count  
Automatic WBC differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (if automatic
differential WBC is abnormal)
Polymorphnuclear neutrophils (segs), band neutrophils (stabs), 
eosinophils, basophils, monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated
Lactate dehydrogenase (LDH)
Lipase
Amylase (total)
Hormones1
Thyroid stimulating hormone (TSH)
Substrates
Serum glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
Albumin
Alpha glycoprotein acid
C-Reactive Protein (CRP) 
Uric acid
Urea
Total cholesterol 
Triglycerides
Electrolytes
Sodium
Potassium
Magnesium
Calcium
1
Hormones only at screening and end of trial.


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Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
Test name 
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine haemoglobin
Urine leukocytes
Urine pH
Urine sediment (microscopic 
examination if haemoglobin, leukocytes 
nitrite or protein are abnormal in urine)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells,
erythrocytes, leukocytes)
1
Hormones only at screening and end of trial.
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and on Day -1 of Visit 2.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Alcohol
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at the safety 
laboratory of 
, 
 
.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (Mortara ELI 250 Rx) at the time points given in the 
Flow Chart.


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All ECGs will be recorded for a 10-sec duration after the subjects have rested for at least 
5 min in a supine position. ECG assessment will always precede all other study procedures of 
the same time point (except blood drawing from an intravenous cannula which is already in 
place) to avoid impact of sampling on the ECG quality.
All ECGs will be stored electronically. Electrode placement will be performed according to 
the method of Wilson, Goldberger and Einthoven. 
All locally printed ECGs will be evaluated by the investigator or a designee. ECGs may be 
repeated for quality reasons (like alternating current artefacts, muscle movements, electrode 
dislocation) and the repeated ECG will be used for analysis. Additional (unscheduled) ECGs 
may be collected by the investigator for safety reasons. 
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(Dinamap Pro 100, GE Medical Systems) at the times indicated in the Flow Chart, after 
subjects have rested for at least 5 min in a supine position. All recordings should be made 
using the same type of blood pressure recording instrument on the same arm if possible.
5.2.5.2
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.
 
 
 
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
in an appropriate way. The scheduled measurements will allow monitoring of changes in vital 
signs, standard laboratory values, and ECG parameters that might occur as a result of 
administration of trial medication. The safety assessments are standard, are accepted for 
evaluation of safety and tolerability of an orally administered drug, and are widely used in 
clinical trials. The pharmacokinetic parameters and measurements outlined in Section 5.5 are 
generally used assessments of drug exposure in human mass-balance trials.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the eCRF. For drug intake at home the entries from subject’s diary will be transferred to the 
eCRF.


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5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoints
The following primary endpoints will be evaluated for BI 1467335 in plasma after the first 
dose on Day 1:

Cmax (maximum measured concentration of the analyte after oral administration)

AUC0-(area under the concentration-time curve of the analyte over the time interval 
from 0 to infinity after oral administration)

Cmax (maximum measured concentration of the analyte after intravenous 
administration)

AUC0-(area under the concentration-time curve of the analyte over the time interval 
from 0 to infinity after intravenous administration)
The following primary endpoints will be evaluated for BI 1467335 in plasma in the repeated 
doses treatment group after repeated dosing (Day 28):

Cmax, 28 (maximum measured concentration of the analyte after oral administration on 
Day 28)

AUC, 28 (area under the concentration-time curve of the analyte over the time 
interval from 0 to 24 h after oral administration on Day 28)

Cmax, 28 (maximum measured concentration of the analyte from 0 to infinity after 
intravenous administration on Day 28)

AUC∞, 28 (area under the concentration-time curve of the analyte from 0 to infinity 
after intravenous administration on Day 28)
Further assessments will include:
5.5.1.2
Secondary endpoint
The following secondary endpoints will be evaluated for BI 1467335 in plasma:
For (C-14) BI 1467335 and for BI 1467335 after SD and MD

tmax, tmax,28 (time from dosing to the maximum measured concentration of the analyte)

t1/2, (observed terminal half-life of the analyte) for the oral dose on Day 1

t1/2, t1/2,28  following the iv dose


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For (C-14) BI 1467335 after SD and MD

CL, CL28 (clearance of the analyte)

Vz, Vz,28 (volume of distribution of the analyte on Day 1 and on Day 28)
For BI 1467335 after SD and MD

F (absolute bioavailability) at day 1 and at day 28
Day 1 (AUC0-∞/Dose)oral/((AUC0-∞/Dose)iv*100
Day 28 (AUC/Dose)oral/((AUC0-∞,28/Dose)iv*100
 
 
 
 
5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 1467335 plasma concentrations, approx. 3 mL of blood will be taken 
from an antecubital or forearm vein into a K2-EDTA (tripotassium ethylendiaminetetraacetic 
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart.


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For quantification of [C-14] BI 1467335 plasma concentrations, an additional 3 mL K2-
EDTA tube needs to be collected as indicated in the Flow Chart. Blood will be withdrawn by 
means of either an indwelling venous catheter or by venipuncture with a metal needle.
All blood samples will be centrifuged 
 
 
 
 
 
 
 The remaining plasma will be used as analytical back-up sample. 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.
For detailed description of blood sampling, sample handling, sample preparation, sample 
storage, tube labelling and sample shipment refer to the laboratory manual.
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) will be generated by these additional investigations. 
The study samples will be discarded after completion of the additional investigations but not 
later than 5 years upon the final study report has been signed. 
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, planned sampling time, analyte and aliquot. Further information such 
as matrix may also be provided. 
The study samples will be discarded after completion of the additional investigations but not 
later than 5 years upon the final study report has been signed the analytical laboratory after 
the bioanalyst has acknowledged safe arrival of the first aliquot.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of analyte plasma concentration
Cold BI 1467335 concentrations in plasma will be determined by a validated LC-MS/MS 
(liquid chromatography coupled to tandem mass spectrometry) assay.
[C-14] BI 1467335 will be determined by a validated AMS (accelerator mass spectrometry)
assay.
5.6
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration are to be performed and completed within a 3 h-interval prior to the trial drug 
administration. 
The acceptable deviation from the scheduled time for vital signs, ECG and safety laboratory 
tests will be ± 30 min on Day 1 (SD) or on Day 28 (MD) and ± 90 min on all other days of 
Visit 2.
If scheduled in the Flow Chart at the same time as a meal, 12-lead ECG recordings, vital 
signs and blood samplings, have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned individual plasma and blood concentration sampling times refer to the Flow 
Chart. While these nominal times should be adhered to as closely as possible, the actual 
sampling times will be recorded and used for determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
Screening visit is defined as Visit 1.
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
6.2.2
Treatment period
Each subject will receive on Day 1 a single 10 mL infusion of 50 µg BI 1467335 (C-14) 
(containing 8,85 µg [C-14] BI 1467335 free base and 41,15 µg of BI 1467335 free base) over 
a period of 15 minutes, 1 h after oral intake of 10 mg of BI 1467335 (film-coated tablets).
All subjects will continue to receive a single oral dose of 10 mg BI 1467335 from Day 2
up to Day 28. On Day 28 all subjects will again receive a single 10 mL infusion of 50 µg 
BI 1467335 (C-14) (containing 5 µg [C-14] BI 1467335 free base and 45 µg of BI 1467335 


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free base) over a period of 15 minutes, 1 h after oral intake of 10 mg of BI 1467335 free base
(film-coated tablets). 
On Day 6, Day 13 and Day 20 (due to assessments and dispensing of study medication in the 
morning of the next day) participants will be admitted to the trial site and kept under close 
medical surveillance as indicated in the Flow Chart and Section 5.2.5.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the absolute bioavailability of BI 1467335 
with an intravenous microdose formulation containing labelled [C-14] BI 1467335 
(reference, R) and an unlabelled oral tablet formulation of BI 1467335 (test, T) in healthy 
male subjects.
The study will be conducted as an open-label, single arm, multiple oral dose trial. The trial 
design consists of an intravenous microtracer dose being administered at the gMean tmax of 
the oral dose, which allows accurate estimates of absolute bioavailability. This means that the
intersubject variability is removed from the comparison between formulations, as well as the 
day to day variability within one subject. Due to the time dependent kinetics, the absolute 
bioavailability will be analysed on Day 1 and Day 28. The trial will be evaluated statistically 
by use of an appropriate linear model.
The evaluation of further pharmacokinetic parameters of BI 1467335 as well as the 
assessment of safety and tolerability will be additional objectives of this trial, and will be 
evaluated by descriptive statistics. Inferential statistics is not planned.
7.1.2
Endpoints
Absolute oral bioavailability is to be determined for Day 1 and Day 28, on the basis of the 
individually dose normalized primary pharmacokinetic endpoints (see Section 5.5.1). Other 
PK endpoints are mentioned in Section 5.5.1.3 and will be analysed descriptively only.
Safety and tolerability will be determined on the basis of the parameters specified in 
Section 5.2.1.
7.1.3
Model
The statistical model used for the analysis of primary endpoints will be an ANOVA (analysis 
of variance) model on the logarithmic scale. This model will include effects accounting for 
the following sources of variation: ‘subject’ and ‘formulation’. The effect ‘subjects’ will be 
considered as random, whereas the effect ‘formulation’ will be considered as fixed. 
The model is described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response (dose normalized primary endpoint, see Section 5.5.1) 
measured on subject m receiving formulation k,
= the overall mean,


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sm = the effect associated with the mth subject, m = 1, 2, ..., n
k = the kth formulation effect (either tablet or i.v.), k = 1, 2,
ekm = the random error associated with the mth subject who received
formulation k.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in a confirmatory sense. 
The absolute oral bioavailability of BI 1467335 by comparing 8,85 µg (Day 1) or 5 µg 
(Day 28) intravenously administered [C-14] BI 1467335 free base with an oral dose of 10 mg
of BI 1467335free base after single and multiple oral doses will be estimated by the ratios of 
the geometric means (test/reference) for the dose normalized primary PK endpoints. 
Additionally, their two-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-tests procedure, each at the 5% significance level. 
Confidence intervals will have to be interpreted in the perspective of the exploratory 
character of the trial, i.e. confidence intervals are considered as interval estimates for effects.
7.3
PLANNED ANALYSES
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 will be identified no later than in the report planning meeting (RPM) and 
provided in the trial statistical analysis plan (TSAP).
The following analysis sets will be defined for this trial:

Treated set (TS):
This subject set includes all subjects who were documented to have received one dose 
of study drug. This is the full analysis set population in the sense of ICH-E9.

PK analysis set (PKS):
This subject set includes all subjects from the TS who provide at least one primary PK 
endpoint value that is judged as PK evaluable and is not affected by protocol 
violations relevant to the statistical evaluation of PK endpoints. Thus, a subject will 
be included in the PKS, even if he contributes only one PK endpoint value for one 
formulation (at Day 1 or Day 28) to the statistical assessment.
Whether a PK endpoint is evaluable or a protocol violation is relevant will be decided no later
than at the RPM. 


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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
Pharmacokinetic endpoint values of a subject will be included in the analysis if they are not
flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the 
evaluation of PK endpoints.
7.3.1
Primary analyses
The pharmacokinetic endpoints listed in Section 5.5.1 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 derived 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 RPM) 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.
Plasma concentrations and/or derived parameters of a subject will be considered as non-
evaluable, if for example:

The subject experiences emesis at or before two times median tmax. Median tmax is to 
be taken either from the median tmax for the reference product or from median tmax for 
the test product, depending on whether the subject had experienced emesis after taken 
the test or the reference product. Median tmax is to be determined excluding the 
subjects experiencing emesis.  

Missing samples/concentration data at important phases of PK disposition curve.
The primary PK parameters Cmax and AUC0-∞on Day 1 and Cmax,28, AUC0-24,28 (after oral 
administration) and AUC0-∞,28 (after intravenous administration) on Day 28 (refer to Section 
5.5.1) of BI 1467335 in plasma will be dose normalized and then log-transformed (natural 
logarithm) prior to fitting the ANOVA model. The difference between the expected means 
for log(Test)-log(Reference) will be estimated by the difference in the corresponding least 
square means (point estimate) and two-sided 90% confidence intervals based on the t-
distribution will be computed. 
These quantities will then be back-transformed to the original scale to give the point
estimator (geometric mean) and 90% confidence interval estimates for the intra-subject ratio
of the geometric means for treatments test and reference.


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This will be done for Day 1 and Day 28 separately, thus the analysis variables are the 
following:
Day 1 for Cmax: 
normalised Cmax after oral and intravenous administration
Day 1 for AUC: 
normalised AUC0-∞after oral and intravenous administration
Day 28 for Cmax: 
normalised Cmax, 28 after oral and intravenous administration
Day 28 for AUC: 
normalised AUC0-24,28 after oral administration and 
normalised AUC0-∞, 28 after intravenous administration
The primary analysis will be based on the pharmacokinetic analysis set (see Section 7.3).
7.3.2
Secondary analyses
As a sensitivity analysis, the ANOVA performed as primary analysis will be repeated with 
subject as fixed effect instead of random effect. The results will be presented in the same 
manner as for the primary analyses.
The secondary parameters (refer to Section 5.5.1) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will statistically be assessed using the same 
methods as described for the primary endpoints.
The following descriptive statistics will be calculated for primary and secondary PK 
parameters and for further endpoints: N, arithmetic mean, standard deviation, minimum, 
median, maximum, arithmetic coefficient of variation, geometric mean, and geometric 
coefficient of variation. The data format for descriptive statistics of concentrations will be 
identical with the data format of the respective concentrations. The descriptive statistics of 
PK parameters will be calculated using the individual values with the number of decimal 
places as provided by the evaluation program. Then the individual values as well as the 
descriptive statistics will be reported with 3 significant digits in the clinical trial report.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is,
all subjects who received at least one dose of study drug), will be included in the safety
analysis. Safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
The analyses will be done by ‘treatment at onset’.
Tabulations of frequencies/proportions will be used for the evaluation of categorical 
(qualitative) data, and tabulations of descriptive statistics will be used to analyse continuous 
(quantitative) data.
Measurements (such as 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 


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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.
Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening). Adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Frequency, severity and 
causal relationship of AEs will be tabulated by treatment, system organ class and preferred 
term. SAEs, AESIs (see Section 5.2.2.1) 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 as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
For vital signs, the differences from baseline will be evaluated.
Relevant ECG findings will be reported as AEs.
7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 1467335 will be 
calculated according to the relevant SOP of the Sponsor (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3.1) will be reported with their 
individual plasma concentrations and individual derived pharmacokinetic parameters; 
however, they will not be included in descriptive statistics for plasma concentrations, 
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, 
(that is, to the same number of decimal places provided in the bioanalytical report).
Plasma concentrations will be plotted graphically versus time for all subjects as listed in the
drug plasma concentration-time tables. For the presentation of the mean profiles, the
arithmetic mean, geometric mean and the planned blood sampling times will be used.
In addition to the analysis described Section 7.3.1, the absolute bioavailability factor F will 
be calculated for each subject on Day 1 as 
F = normalised AUC0-∞ (oral) / normalised AUC0-∞(i.v.)
and for each subject on Day 28 as
F = normalised AUC0-24, 28 (oral) / normalised AUC0-∞, 28 (i.v.).


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The calculated parameter at Day 1 and Day 28 will be analysed with descriptive statistics.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure of the Sponsor (001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), 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). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ 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.
7.5
RANDOMISATION
All subjects will receive the same treatments in one fixed sequence. Therefore, no 
randomisation is necessary in this trial (see also Section 4.1.2). A list of consecutive subject 
numbers will be provided for procedural reasons (see Section 4.1.2).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of at least 10 and most 12 subjects into the trial, because this 
sample size is considered sufficient to achieve the aims of this exploratory trial.
 
 


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All calculations were performed as described by Kupper and Hafner [R12-0972] using R
Version 3.3.1.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
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.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his 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 record may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.


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8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements.


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8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities , i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC / competent authority in each participating EU member state needs to be notified
about the end of the trial (last subject / subject out, unless specified differently in 
Section 6.2.3 of the CTP) or early termination of the trial.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
 
R10-4848
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.ni 
h.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_ 
QuickReference_8.5x11.pdf; 2010.
R12-0972
Kupper LL, Hafner KB. How appropriate are popular sample size 
formulas? Am Stat 1989;43(2):101-105.
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c04751792
Investigator's Brochure: BI 1467335 
 15 Mar 2018.
c08854973
. Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising oral doses of BI 1467335 in healthy 
male and female subjects (double-blind, randomised, placebo-controlled 
within dose groups). 1386.8.  05 Oct 2016.
c08980589
. A multi-centre, double-blind, parallel-group, 
randomised, placebo controlled phase II a study to investigate safety, 
tolerability, pharmacodynamics, and pharmacokinetics of different doses of 
orally administered BI 1467335 during a 12-week treatment period 
compared to placebo in patients with 
1386.4.  
19 May 2017.
c09036683
 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.
c14141887
A Randomized, double-masked, placebo-controlled exploratory 
study to evaluate safety, tolerability, pharmacodynamics and 
pharmacokinetics of orally administered BI 1467335 for 12 weeks with a 
12 week follow up period in patients with 
 
1386.12. 18 Jan 2018.
c16567028
Preliminary results of BI 1467335 all cohorts of 10 mg 2 cohorts of 15 mg 
dosing. 1386.8. 28 Mar 2017.
c17150058
 Relative bioavailability of a 
BI 1467335 tablet compared to a BI 1467335 oral solution and the effect of 
food on the bioavailability of the tablet following oral administration (a 
randomised, open-label, single dose, three-way crossover trial in healthy 
male subjects). 1386.17.  09 Nov 2017.
n00244592
BI 1467335: 4-week oral (gavage) supplementary toxicity study in Sprague 
Dawley rats. 06 Jul 2016.
n00247850
A Four-Week Oral Repeat Dose Toxicity and Toxicokinetic Study of 
PXS-4728A in Beagle Dogs. 53703-13-825. 04 Nov 2014.
n00252396
Excretion of radioactivity in urine, faeces and bile after oral and 
intravenous administration of [14C]BI 1467335 to rats. 18 Oct 2016.
n00252404
Pharmacokinetics of radioactivity and BI 1467335 after oral and 
intravenous administration of [14C]BI 1467335 to rats. 18 Oct 2016.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
22 March 2018
EudraCT number
2017-003853-41
BI Trial number
1386-0019
BI Investigational Product(s)
BI 1467335
Title of protocol
A phase I, open-label, single-arm multiple dose 
trial to investigate pharmacokinetics and absolute 
bioavailability of BI 1467335 administered as an 
oral dose simultaneously with an intravenous 
microtracer dose of [C-14] BI 1467335 after 
single and multiple oral doses in healthy male 
volunteers
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1.2    Drug profile
4.2.2 Restrictions
Description of change
Section 4.2.2: Addition of prohibited foods to 
mitigate the risk of relevant adverse reactions.


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Number of global amendment
1
Rationale for change
 
 
 
 


Boehringer Ingelheim
24 Apr 2018
BI Trial No.: 1386-0019
c19596566-03
Trial Protocol
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Number of global amendment
2
Date of CTP revision
24 April 2018
EudraCT number
2017-003853-41
BI Trial number
1386-0019
BI Investigational Product(s)
BI 1467335
Title of protocol
A phase I, open-label, single-arm multiple dose 
trial to investigate pharmacokinetics and absolute 
bioavailability of BI 1467335 administered as an 
oral dose simultaneously with an intravenous 
microtracer dose of [C-14] BI 1467335 after 
single and multiple oral doses in healthy male 
volunteers
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
4.1 Treatments to be administered
Description of change
The mixture of [C-14] BI 1467335 and unlabelled 
BI 1467335 and the solution from this mixture are 
made by 
 
Rationale for change
Previous wording suggests that the mixture of 
[C-14] BI 1467335 and unlabelled BI 1467335 is 
made by BI Pharma GmbH & Co. KG.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c19596566
3.0
clinical-trial-protocol-revision-02
A phase I, open-label, single-arm multiple dose trial to investigate pharmacokinetics
and absolute bioavailability of BI 1467335 administered as an oral dose
simultaneously with an intravenous microtracer dose of [C-14] BI 1467335 after
single and multiple oral doses in healthy male volunteers
Author-Trial Clinical Monitor
25 Apr 2018 09:07 CEST
Approval-Biostatistics
25 Apr 2018 09:12 CEST
Author-Trial Clinical
Pharmacokineticist
25 Apr 2018 10:31 CEST
Approval-Team Member Medicine
25 Apr 2018 13:10 CEST
Approval-Therapeutic Area 
25 Apr 2018 17:40 CEST
Author-Trial Statistician
26 Apr 2018 08:30 CEST
Verification-Paper Signature
Completion
02 May 2018 08:46 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c19596566
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c23934986-01
BI Trial No.:
1386-0019
Title:
A phase I, open-label, single-arm multiple dose trial to investigate
pharmacokinetics and absolute bioavailability of BI 1467335
administered as an oral dose simultaneously with an intravenous
microtracer dose of [C-14] BI 1467335 after single and multiple
oral doses in healthy male volunteers
Including protocol revisions 1 [c19596566-02] and protocol 
revision 2 [c19596566-03]
Investigational
Product:
BI 1467335
Responsible trial 
statisticians:
Phone:
Fax: 
Phone:
Fax:
Date of statistical 
analysis plan:
23 Jul 2018 SIGNED 
Version:
“Final”
Page 1 of 22
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2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
5.3
FURTHER ENDPOINTS.....................................................................................9
5.3.2
Safety parameters .................................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................12
.....................................................................................................13
6.5
POOLING OF CENTRES .................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................14
7.
PLANNED ANALYSIS......................................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........15
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................15
7.3
TREATMENT COMPLIANCE........................................................................16
7.4
PRIMARY ENDPOINTS...................................................................................16
7.5
SECONDARY ENDPOINTS.............................................................................17
7.5.1
Key secondary endpoint .....................................................................................17
7.5.2
Secondary endpoints...........................................................................................17
.......................................................................17
.......................................................................17
.......................................................................17
.......................................................................17
7.7
EXTENT OF EXPOSURE.................................................................................17
7.8
SAFETY ANALYSIS..........................................................................................17
7.8.1
Adverse events.....................................................................................................17


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7.8.2
Laboratory data ..................................................................................................19
7.8.3
Vital signs.............................................................................................................19
7.8.4
ECG......................................................................................................................19
7.8.5
Others...................................................................................................................19
8.
REFERENCES....................................................................................................20
..............................................................................21
10.
HISTORY TABLE..............................................................................................22


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory data and vital signs..........................................................................11
Table 6.1: 2
Overview of treatments for intra-individual comparison .................................11
Table 6.2: 1
Important protocol violations ...........................................................................12
Table 6.3: 1
Subject sets analysed ........................................................................................13
Table 10: 1
History table .....................................................................................................22


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADME
Absorption, distribution, metabolism and excretion
AE
Adverse event
AESI
Adverse event of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte over the 
time interval from 0 extrapolated to infinity
AUC0-24
Area under the concentration-time curve of the analyte over the 
time interval from 0 to 24
BLQ
Below the lower limit of quantification
BMI
Body mass index
BI
Boehringer Ingelheim
[C-14]BI 1467335
[14C]-labelled BI 1467335
CARE
Clinical data analysis and reporting environment
CL
Clearance of the analyte
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBLM
Data base lock meeting
eCRF
Electronic case report form
F
Absolute bioavailability
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
IPV
Important protocol violation
LLT
Lower level term
MedDRA
Medical Dictionary For Regulatory Activities
NOA
Not analysed
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetics


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Term
Definition / description
PKS
Pharmacokinetic parameter analysis set
PV
Protocol violation
Q1
Lower quartile
Q3
Upper quartile
qd
Per day (quaque die)
RAGe
Report appendix generator
RPM
Report planning meeting
SD
Standard deviation
t1/2
Observed terminal half-life of the analyte
tmax
Time from dosing to the maximum measured concentration of the 
analyte
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal range
Vz
Volume of distribution of the analyte


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised CTP, and to 
include detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP and its amendment. In particular, the TSAP is 
based on the planned analysis specification as written in CTP Section 7 "Statistical Methods 
and Determination of Sample Size". Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; RAGe
system for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using WinNonlinTM software (professional Network 
version Phoenix 6.3, Pharsight Corporation, Mountain View, CA 94041-1530, USA).


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


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoints after the first dose at Day 1 are Cmax and AUC0-∞ of BI 1467335 in plasma 
after oral (po) and after intravenous (iv) administration.
Primary endpoints after the first dose at Day 28 are Cmax,28 and AUC, 28 of BI 1467335 in 
plasma after oral administration and Cmax,28 and AUC0-∞,28 of BI 1467335 in plasma after 
intravenous administration.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoints
Secondary endpoints are:

tmax, tmax,28 and t1/2 of [C-14]BI 1467335 and of BI 1467335 after oral and iv 
administration

t1/2,28 of [C-14]BI 1467335 and of BI 1467335 after iv administration

CL, CL28, Vz, and Vz,28 of [C-14]BI 1467335 after oral and iv administration

F of BI 1467335 at Day 1 and at Day 28, whereas F is derived as
F = (AUC0-∞/ Dose)oral / (AUC0-∞/ Dose)iv * 100 at Day 1 
F = (AUCτ / Dose)oral / (AUC0-∞,28 / Dose)iv * 100 at Day 28
5.3
FURTHER ENDPOINTS
 
5.3.2
Safety parameters
Further safety parameters will be used as defined in Section 5.2.1 of the CTP:
CTP:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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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.
All subjects were planned to be treated with 

a single iv infusion of the microtracer on Day 1 and Day 28 (reference treatment)

and non-radiolabelled film-coated tablets once a day from Day 1 to Day 28 (test 
treatment)
For statistical analysis of AEs, safety laboratory data and vital signs, 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 and vital signs
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
BI 1467335
Date/time of first 
administration of study 
drug
12:00 a.m. on day after 
subject's trial termination date
It will not be differentiated between intravenous or oral administration of the drug.
AE displays will present results for the screening phase, on-treatment phase and additionally, 
the following total will be provided:

"Total", defined as the total over all study phases (screening + on-treatment)
The following labels will be used for the comparison of treatments:
Table 6.1: 2
Overview of treatments for intra-individual comparison
Treatment
Short label
T
BI 1467335 10 mg tablet, qd
BI 10 mg tab
R1
8.85 μg [C-14] BI 1467335 free base in 10 mL solution, qd
BI 8.85 mg iv
R2
5 μg [C-14] BI 1467335 free base in 10 mL solution, qd
BI 5 mg iv
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.


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6.2
IMPORTANT PROTOCOL VIOLATIONS
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" (2)
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 (3). 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.
Table 6.2: 1
Important protocol violations
Category 
/ Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C3
Non-compliance
C5
Incorrect intake of trial medication
D
Concomitant medication
D1
Prohibited medication use
E
Missing data
None1
G
Other trial specific important violations
G1
Certain violations of procedures used to measure secondary PK data
Violations C1, C5 and G1 can only be detected at the trial site.
1 Missing visits, evaluations, and tests will be considered missing data, not PVs
Source: BI reference document "Protocol Violation Handling Definitions" (2).
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 


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The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects who received at least one dose of study drug. 
This is the full analysis set population in the sense of ICH-E9. It will be used for 
analysis of safety, demographic data and baseline characteristics.

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects in the TS who provide at least one primary PK 
parameter that was not excluded because of PVs relevant to the statistical evaluation 
of PK endpoints as defined in Section 7.3 of the CTP.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to analysis sets will be made at latest at the RPM/DBLM.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition
X
Exposure
X
IPVs
X
Demographic/baseline endpoints
X
Safety parameters
X
Primary PK endpoints
X
Secondary PK endpoints
X
Further PK endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects who were withdrawn from the trial prior to first administration of 
any study drug will not be reported in the CTR.
Data of treated subjects who failed to complete the study (dropouts or withdrawals) will be 
reported in the CTR as far as their data are available. All withdrawals will be documented and 
the reason for withdrawal recorded in the CTR.


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CTP: With respect to safety evaluations, it is not planned to impute missing values.
The only exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (4) [001-MCG-
156_RD-01].
Missing data and outliers of PK data are handled according to BI standards (5) [001-MCS-36-
472_RD-01]. CTP: 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)..
CTP: For the non-compartmental analysis, concentration data identified with NOS, NOR or 
NOA will generally not be considered. Concentration values in the lag phase identified as 
BLQ 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.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The last non-missing value determined prior to the first study drug administration will be 
defined as baseline. 
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" (6).
The individual values of all subjects will be listed, sorted by sequence group, subject number
and visit. AE listings will be sorted by assigned treatment (see Section 7.8.1 below for 
details). The listings will be contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N
number of non-missing observations
Mean
arithmetic mean
SD
standard deviation
Min
minimum
Median
median
Max
maximum
For plasma concentrations as well as for all PK parameters, the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there are actually 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 report. These will be based on the 
TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary.


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Only descriptive statistics are planned for this section of the report.
A medication will be considered concomitant to a dose group, if it

is ongoing at the time of first administration of this treatment, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a definition 
of treatments and analysis phases).
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint (cf. Section 5.4.2). 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
Analysis of absolute oral bioavailability of dose-normalised primary endpoints will be 
performed as defined in Sections 7.1.3 and 7.3.1 of the CTP.
The statistical model for the primary analysis defined in the CTP is an analysis of variance 
(ANOVA) model on the logarithmic scale. 
Primary PK endpoints will also be assessed descriptively. The analysis of standard PK 
parameters is performed according to BI standards (5) [001-MCS-36-472_RD-01].
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to 'Included'.
Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to 'ALL CALC', the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
'DESC STATS' the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition 'TIME VIOLATION' or 'TIME 
DEVIATION', the value can be used for further analyses based on actual times. If ACEXCO
is set to 'HALF LIFE', the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTP trial 
associated with an appropriate flag.


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Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (5) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (7).
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the CTP.
7.5.2
Secondary endpoints
Secondary PK endpoints will be assessed descriptively. The analysis of standard PK 
parameters is performed according to BI standards (5) [001-MCS-36-472_RD-01].
See Section 7.4 of this TSAP for details regarding exclusion of PK parameters and plasma 
concentrations.
7.7
EXTENT OF EXPOSURE
Treatment exposure will only be listed by means of the date and time of drug administration.
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 electronic case report form (eCRF) will be 
collapsed into an AE event provided that all of the following applies:


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
All AE attributes are identical (LLT, intensity, action taken, therapy required, seriousness, 
reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended).
For further details on summarisation of AE data, please refer to "Analysis and presentation of 
adverse event data from Clinical Trials" (8) and "Handling of missing and incomplete AE 
dates" (4). 
The analysis of AEs will be based on the concept of treatment-emergent AEs. That means that 
all AEs will be assigned to the screening or treatment phases as defined in Section 6.1. AEs 
will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 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:: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (9), 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 system organ 
class and preferred term. AEs which were considered by the investigator to be drug related 
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 (9)). AEs 
will also be summarised by maximum intensity.
The system organ classes will be sorted by total frequency, preferred terms will be sorted by 
total frequency (within system organ class).
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 system organ class and preferred term. The frequency of subjects with 
SAEs will also be summarised.


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For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standard
"Display and Analysis of Laboratory Data" (10).
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 on the eCRF or at the RPM/DBLM at the latest. It is the 
Investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values will not be 
applied in this study.
Clinically relevant findings in laboratory data will be reported as AEs and will be analysed as 
part of AE analysis.
7.8.3
Vital signs
The analysis 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.
7.8.4
ECG
Abnormal findings in 12-lead ECG 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. No separate listing or analysis of ECG data will be prepared.
7.8.5
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of first study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9; Note For Guidance on Design, Conduct, Analysis and Evaluation of Clinical 
Trials, current version
2
001-MCS-50-413_RD-01: "Protocol Violation Handling Definitions", current 
version; IDEA for CON
3
001-MCS-50-413_RD-02: "Important Manual Protocol Violations Spreadsheet", 
current version; IDEA for CON
4
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current
version; IDEA for CON
5
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON
6
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current 
version; IDEA for CON
7
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD Data 
Files", current version; IDEA for CON
8
001-MCG-156: "Analysis and Presentation of Adverse Event Data from Clinical 
Trials", current version; IDEA for CON
9
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
10 001-MCG-157: "Display and Analysis of Laboratory Data", current version; IDEA 
for CON


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
23-JUL-18
None
This is the final TSAP without any 
modification