Clinical trial NCT03382509
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2018-01-12; Completion date: 2018-04-19
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Primary objective mass balance, excretion pathways and metabolism following a single oral dose of \[14C\]BI 1467335 given to healthy male subjects (a selected number of subjects will be treated with \[14C\]BI 1467335 after a preceding 27 days treatment with non-radiolabelled compound of BI 1467335 QD).

Secondary objectives is to investigate the basic pharmacokinetics after single and multiple doses of BI 1467335 and its metabolites.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: [14C]BI 1467335 intervention 2: BI 1467335
Intervention descriptions: intervention 1: Once Daily intervention 2: Twice Daily

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
TITLE PAGE
Document Number:
c17932132-03
EudraCT No.:
BI Trial No.:
2017-002879-26
1386-0011
BI Investigational
Product:
BI 1467335
Title:
A phase I, open-label, single and multiple dose trial to investigate 
metabolism and pharmacokinetics of [14C]BI 1467335 administered as 
oral solution in healthy male volunteers
Lay Title:
This study tests BI 1467335 in healthy male volunteers. The study 
tests how different doses of BI 1467335 are taken up and handled by 
the body.
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax:
Principal Investigator:
Phone:
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 2))
Version and Date:
Version: 3.0
Date: 14 March 2018
Page 1 of 74
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


Boehringer Ingelheim
14 Mar 2018
BI Trial No.: 1386-0011
c17932132-03
Trial Protocol
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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:
14 March 2018
14 November 2017
1386-0011
Title of trial:
A phase I, open-label, single and multiple dose trial to investigate metabolism and 
pharmacokinetics of [14C]BI 1467335 administered as oral solution in healthy male 
volunteers
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate the basic pharmacokinetics after single and multiple doses of 
BI 1467335, its metabolites
 [14C]-radioactivity, including 
mass balance, excretion pathways and metabolism following a single oral dose of 
10 mg [14C]BI 1467335 given to healthy male subjects (subjects assigned to multiple 
doses will have a preceding 27 days treatment with non-radiolabelled compound at a
dose of 10 mg of BI 1467335 QD).
Methodology:
Open-label, single period and single arm design with 2 treatment groups (1. single 
dosing and 2. multiple dosing)
No. of subjects: 
total entered:
16
each treatment:
8
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 30 to 65 years, body mass index (BMI) of 18.5 to 
29.9 kg/m2
Test product 1:
Carbon 14 labelled BI 1467335 ([14C]BI 1467335) as oral solution
dose:
10 mg (calculated as free base BI 1467335)
in 20 mL oral solution (0.5 mg/mL)
corresponding to 11.3 mg BI 1467335 HCl salt
containing a radioactive dose of 2.0 MBq (54 µCi)
mode of admin.:
Oral with 240 mL of water 


Boehringer Ingelheim
14 Mar 2018
BI Trial No.: 1386-0011
c17932132-03
Trial Protocol
Page 3 of 74
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
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:
14 March 2018
14 November 2017
1386-0011
Test product 2:
BI 1467335 film-coated tablet formulation
dose:
10 mg (2 x 5 mg) QD
mode of admin.:
Oral with 240 mL of water 
Comparator product:
Not applicable
Duration of 
treatment:
Treatment Group 1: 
On Day 1 [14C]BI 1467335 as oral solution (Test product 1) 
Treatment Group 2:
Non-radiolabelled film-coated tablets (Test product 2) from Day 1 to Day 27 and 
Day 29 to a maximum of Day 40. On Day 28 single dose of radiolabelled oral 
solution (Test product 1) 
Criteria for 
pharmacokinetics:
Primary endpoints:
Mass balance recoveries of total radioactivity in urine and faeces:
Amount of radioactivity excreted as a percentage of the administered dose (fe0-tz) for 
urine and faeces
Secondary endpoints:
Assessment of the oral pharmacokinetics of [14C]BI 1467335 by calculating the 
following parameters for total radioactivity Cmax and AUC0-tz and cold BI 1467335 in 
plasma: Cmax and AUC0-tz or Cmax,ss and AUC
 
 
 
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:
Descriptive statistics will be calculated for all endpoints.


Boehringer Ingelheim
14 Mar 2018
BI Trial No.: 1386-0011
c17932132-03
Trial Protocol
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Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
FLOW CHART
Flow chart: Treatment Group 1 (Single dose)
Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood/plasma
2
PK urine 
6
PK faeces
5
 
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 site14
x
x
1
-2:00
06:00
x3,9 
x3,15
x
x16
x3
x3
0:00
08:00
Drug administration9 (labelled 
compound)
▲
│
▲
│
0:20
08:20
x
│
│
0:45
08:45
x
│
│
1:00
09:00
x4
x
│
│
x
x
2:00
10:00
240 mL water intake
x
│
│
3:00
11:00
x
│
│
4:00
12:00
Lunch, 240 mL water intake
x
┼
│
x
x
6:00
14:00
x
│
│
8:00
16:00
x
┼
│
10:00
18:00
Dinner
x
│
│
12:00
20:00
Snack7
x4
x
┼
│
x
x
2
24:00
08:00
x4
x
┼
┼
x
x
36:00
20:00
x
│
│
3
48:00
08:00
x
┼
┼
4
72:00
08:00
x
┼
┼
5
96:00
08:00
x
┼
┼
6
120:00
08:00
x
┼
┼
7
144:00
08:00
x
┼
┼
8
168:00
08:00
┼
┼
9
192:00
08:00
x
┼
┼
10
216:00
08:00
┼
┼
11
240:00
08:00
x
┼
┼
12
264:00
08:00
┼
┼
13
288:00
08:00
x
┼
┼
14
312:00
08:00
┼
┼
15
336:00
08:00
Discharge from trial site
x9
x
▼
▼
x
x


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14 Mar 2018
BI Trial No.: 1386-0011
c17932132-03
Trial Protocol
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Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Visit
Day
Planned time (relative to 
drug administration)
[h:min]
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory
PK blood/plasma
2, 10
PK urine
6
PK faeces
5
Vital signs (BP, PR), 
ECG
Questioning for AEs & 
concomitant medication 
2
20
461:00
13:00
Start home collection11, 12
▲
┼
▼
21
485:00
13:00
Admission to trial site11
x
▲
▼
22
509:00
13:00
Discharge from trial site11
27
629:00
13:00
Start home collection11, 12
▲
┼
▼
28
653:00
13:00
Admission to trial site11
x
▲
▼
29
677:00
13:00
Discharge from trial site11
34
797:00
13:00
Start home collection11, 12
▲
┼
▼
35
821:00
13:00
Admission to trial site11
x
▲
▼
36
845:00
13:00
Discharge from trial site12
41
965:00
13:00
Start home collection11,12
▲
┼
▼
42
989:00
13:00
Admission to trial site11
x
▲
▼
43
1013:00
13:00
Discharge from trial site11
48
1133:00
13:00
Start home collection11. 12
▲
┼
▼
49
1157:00
13:00
Admission to trial site11
x
▲
▼
50
1181:00
13:00
Discharge from trial site11
3
16-50
End of trial (EOT) examination8,13
x9
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, 
smoking status and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion 
criteria.
2.
Pharmacokinetics (PK): BI 1467335 and metabolites in plasma; [14C]-radioactivity in whole blood and plasma. At all 
time points, samples for [14C]-radioactivity in whole blood and plasma will be taken. Samples for PK assessment of cold 
BI 1467335 will be collected up to 10 h 
 
 after intake of radiolabelled drug on Day 1.
 
3.
The time is approximate; the procedure is to be performed within a time window of 3 h prior to drug administration.
4.
At these time point, a sample is taken for measurement of haematocrit.
5.
All stools (for [14C]-radioactivity assessment 
) will be collected quantitatively from Day 1 in 
sampling intervals: 0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264, 264-
288, 288-312 and 312-336 hours after intake of [14C]BI 1467335. Thereafter, if warranted, 24 h collections are to be 
performed on days 21-22, 28-29, 35-36, 42-43, and 49-50. A blank sample will be collected before drug administration 
on Day 1. Collection of the predose faeces sample will start from approximately -48 h before drug administration. 
Faeces sampling for [14C]-radioactivity assessment will be stopped when the release criteria for radioactivity recovery 
(Section 3.1) have been met (earliest stopping on day 15). “┼” means end of last collection interval, start of following 
collection interval. All samples: planned for determination of [14C]-radioactivity. For technical reasons, the planned 
times used in the CRF and result transfer files will have 5 minutes added to the planned times in the Flow Chart (i.e. 
0:05-24:04, 24:05-48:05, …)
6.
Urine collection intervals (for PK/[14C]-radioactivity assessment 
 (planned time): on Day -1 or 
Day 1 predose (blank) sample, on Day 1 prior to start of urine collection voiding of the bladder, 0-4, 4-8, 8-12, 12-24, 
24-48, 48-72, 72-96, 96-120, 120-144, 144-168, 168-192, 192-216, 216-240, 240-264, 264-288, 288-312, and 
312-336 hours after drug administration. Thereafter, if warranted, 24 h collections are to be performed on days 21-22, 
28-29, 35-36, 42-43, and 49-50. Urine sampling for PK will be stopped when release criteria for radioactivity recovery
(Section 3.1) have been met (earliest stopping on day 15). “┼” means end of last collection interval, start of following 
collection interval. All samples: planned for determination of [14C]-radioactivity, BI 1467335 
 
7.
If several actions are indicated at the same time point, the intake of meals will be the last action.


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BI Trial No.: 1386-0011
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8.
End-of-trial (EOT) examination to be performed within 1 to 7 days after last discharge from the study centre, or, if all 
once-weekly 24 h sampling periods are needed, prior to discharge on Day 50. EOT examination includes physical 
examination, vital signs, ECG, safety laboratory, recording of AEs and concomitant therapies.
9.
Subjects are to be fasted for at least 10 h before sample is taken.
10. Blood sampling for an individual subject can be stopped if [14C]-radioactivity in plasma is below limit of detection 
(<LLOQ 10 dpm/mL) at two consecutive sampling time points for this subject.
11. The planned times for admission, discharge, start and end of the urine and faeces collection intervals are approximate. 
The procedures are to be performed within a time window of +/- 4 h to the planned time. 
12. Subjects are to collect faeces at home within 24 h intervals before admission to once-weekly in-house collection 
intervals. Home collection intervals: Day 20-21, 27-28, 34-35, 41-42, and 48-49. If faeces are collected in the 
subsequent in-house collection interval, faeces collected at home will be discarded. If no faeces is collected in the 
subsequent in-house collection interval (no defecation), faeces collected at home will be used instead for analysis.
13. For definition of the individual subject’s end of trial see Section 6.2.3
14. Urine drug and alcohol screening will be done at this time point.
16. Subjects will collect a predose faeces sample at home in specific containers provided by


Boehringer Ingelheim
14 Mar 2018
BI Trial No.: 1386-0011
c17932132-03
Trial Protocol
Page 7 of 74
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Flow chart: Treatment Group 2 (Multiple dose)
Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment18
Safety laboratory
PK blood/plasma  
2
PK urine 
6
PK faeces
5
 
12-lead ECG 
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy
1
-21 to -2
Screening (SCR)1
x6
x
x
2
-1
-12:00
20:00
Admission to trial site
x14
x
1
-2:00
06:00
x3,9
x3,16
x
x17
x3
x3
0:00
08:00
Ambulatory visit, dispense of 
study medication, 
0:15
08:15
x
1:00
9:00
x
2:00
10:00
2
24:00
8:00
Discharge
x
6
132:00
20:00
Admission to trial site
7
144:00
08:00
Ambulatory visit, dispense of 
study medication, discharge
x9
x3
x3
x3
13
300:00
20:00
Admission to trial site
x14
14
312:00
08:00
Ambulatory visit, dispense of 
study medication, discharge
x9
x3
x3
x3
20
468:00
20:00
Admission to trial site
21
480:00
08:00
Ambulatory visit, dispense of 
study medication, discharge
x9
x3
x3
x3
27
631:00
15:00
Admission to trial site
x14
x3
28
646:00
06:00
x3, 9
x3
x3
x3
648:00
08:00
Drug administration
(+labelled compound)
▲
│
▲
│
648:20
08:20
x
│
│
648:45
08:45
x
│
│
649:00
09:00
x4
x
│
│
650:00
10:00
240 mL water intake
x
│
│
651:00
11:00
x
│
│
652:00
12:00
Lunch, 240 mL water intake7
x
┼
│
654:00
14:00
x
│
│
656:00
16:00
x
┼
│
658:00
18:00
Dinner
x
│
│
660:00
20:00
Snack7
x4
x
┼
│
x
x


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14 Mar 2018
BI Trial No.: 1386-0011
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Trial Protocol
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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, 
smoking status and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion 
criteria.
2.
Pharmacokinetics (PK): BI 1467335 
 in plasma; [14C]-radioactivity in whole blood and plasma. From 
Day 28, samples for [14C]-radioactivity in whole blood and plasma will be taken at all time points. Samples for PK 
assessment of BI 1467335 
 in plasma will be collected up to 24 h after intake 
of radiolabelled drug on Day 28. 
3.
The time is approximate; the procedure is to be performed within a time window of 3 h prior to drug administration.
Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory
PK blood/plasma  
2, 10
PK urine 
6
PK faeces
5
12-lead ECG 
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 
2
29
672:00
08:00
Drug administration 
x4
x
┼
┼
x
684:00
20:00
x
│
│
30
696:00
08:00
Drug administration
x
┼
┼
31
720:00
08:00
Drug administration
x
┼
┼
32
744:00
08:00
Drug administration
x
┼
┼
33
768:00
08:00
Drug administration
x
┼
┼
34
792:00
08:00
Drug administration
x
┼
┼
35
816:00
08:00
Drug administration
x9
x
┼
┼
x
x
817:00
09:00
x
│
│
36
840:00
08:00
Drug administration15
┼
┼
37
864:00
08:00
Drug administration15
x
┼
┼
38
888:00
08:00
Drug administration15
┼
┼
39
912:00
08:00
Drug administration15
x
┼
┼
40
936:00
08:00
Drug administration15
x
┼
┼
937:00
09:00
x
│
│
41
960:00
08:00
x
┼
┼
42
984:00
08:00
┼
┼
43
1008:00
08:00
Discharge from trial site
x9
x
▼
▼
x
x
48
1133:00
13:00
Start home collection11,12
▲
┼
▼
49
1157:00
13:00
Admission to trial site11
▲
▼
50
1181:00
13:00
Discharge from trial site11
x
55
1301:00
13:00
Start home collection11,12
▲
┼
▼
56
1325:00
13:00
Admission to trial site11
▲
▼
57
1349:00
13:00
Discharge from trial site11
x
62
1469:00
13:00
Start home collection11,12
▲
┼
▼
63
1493:00
13:00
Admission to trial site11
▲
▼
64
1517:00
13:00
Discharge from trial site11
x
69
1637:00
13:00
Start home collection11,12
▲
┼
▼
70
1661:00
13:00
Admission to trial site11
▲
▼
71
1685:00
13:00
Discharge from trial site11
x
76
1805:00
13:00
Start home collection11,12
▲
┼
▼
77
1829:00
13:00
Admission to trial site11
▲
▼
78
1853:00
13:00
Discharge from trial site11
x
3
43-78
End of trial (EOT) 
examination8,13
x9
x
x
x


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14 Mar 2018
BI Trial No.: 1386-0011
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Trial Protocol
Page 9 of 74
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4.
At each of these time points, an additional sample is taken for measurement of haematocrit.
5.
All stools (for [14C]-radioactivity assessment
) will be collected quantitatively from Day 28 after 
drug administration of labelled compound in portions in sampling intervals (planned times): 648:00-672:00,672:00-
696:00, 696:00-720:00, 720:00-744:00, 744:00–768:00, 768:00- 792:00, 792:00-816:00, 816:00–840:00, 840:00-864:00, 
864:00–888:00, 888:00-912:00, 912:00–936:00, 936:00-960:00, 960:00-984:00, 984:00–1008:00. Thereafter, if 
warranted 24 h collections are to be performed on days 49-50, 56-57, 63-64, 70-71 and 77-78. A blank sample will be 
collected before drug administration on Day 1. Collection of the predose faeces sample will start from approximately
-48 h before drug administration. Faeces sampling for [14C]-radioactivity assessment will be stopped when the release 
criteria (Section 3.1) for radioactivity recovery (Section 3.1) have been met (earliest stopping on day 43). “┼” means end 
of last collection interval, start of following collection interval. All samples: planned for determination of [14C]-
radioactivity. For technical reasons, the planned times used in the CRF and result transfer files will have 5 minutes added 
to the planned times in the Flow Chart (i.e. 0:05-24:04, 24:05-48:05, …).
6.
Urine collection intervals (for PK/[14C]-radioactivity assessment 
; planned time):. A predose 
urine sample collected on Day -1 or Day 1 predose will serve blank sample. Before dosing of labelled compound on Day 
28, subjects should be asked to void bladder. Urine collection starts -648:00-652:00,652:00-656:00, 656:00-660:00, 
660:00-672:00, 672-696:00, 696:00-720:00, 720:00-744:00, 744:00–768:00, 768:00- 792:00, 792:00-816:00, 816:00–
840:00, 840:00-864:00, 864:00–888:00, 888:00-912:00, 912:00–936:00, 936:00-960:00, 960:00-984:00, 984:00–
1008:00. Thereafter, if warranted 24 h collections are to be performed on days 49-50, 56-57, 63-64, 70-71 and 77-78.
Urine sampling will be stopped when release criteria for radioactivity recovery (Section 3.1) have been met (earliest 
stopping on day 43). “┼” means end of last collection interval, start of following collection interval. All samples: 
planned for determination of [14C]-radioactivity. Samples of the collection interval on Day 28/29 planned for analysis of 
BI 1467335 
 
7.
If several actions are indicated at the same time point, the intake of meals will be the last action.
8.
End-of-trial (EOT) examination to be performed within 1 to 7 days after last discharge from the study centre, or, if all 
once-weekly 24 h sampling periods are needed, prior to discharge on Day 78. EOT examination includes physical 
examination, vital signs, ECG, safety laboratory, recording of AEs and concomitant therapies.
9.
Subjects are to be fasted for at least 10 h before sample is taken.
10. Beginning at time point 684:00 only samples for analysis of [14C]-radioactivity in whole blood and plasma to be taken. 
Blood sampling for an individual subject can be stopped at 816:00h or later if [14C]-radioactivity in plasma is below 
limit of detection (<LLOQ 10 dpm/mL) at two consecutive sampling time points for this subject.
11. The planned times for admission, discharge, start and end of the urine and faeces collection intervals are approximate. 
The procedures are to be performed within a time window of +/- 4 h to the planned time. 
12. Subjects are to collect faeces at home within 24 h intervals before admission to once-weekly in-house collection 
intervals. Home collection intervals: Day 48-49,. Day 55-56, Day 62-63, Day 69-70, and Day 76-77. If faeces are 
collected in the subsequent in-house collection interval, faeces collected at home will be discarded. If no faeces is 
collected in the subsequent in-house collection interval (no defecation), faeces collected at home will be used instead for 
analysis.
13. For definition of the individual subject’s end of trial see Section 6.2.3
14. Urine drug and alcohol screening will be done at this time point.
15. Treatment will be stopped from Day 35 onwards if [14C]-radioactivity in plasma is below limit of detection 
(LLOQ 10 dpm/mL) for this subject.
17. Subjects will collect a predose faeces sample at home in specific containers provided by 
18. On specific study days (Day 3 to Day 6, Day 8 to Day 13, Day 15 to Day 20 and Day 22 to 27) intake of study 
medication under ambulatory conditions.


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BI Trial No.: 1386-0011
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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION.................................................................................... 18
1.1
MEDICAL BACKGROUND............................................................................18
1.2
DRUG PROFILE...............................................................................................18
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 23
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................23
2.2
TRIAL OBJECTIVES.......................................................................................23
2.3
BENEFIT - RISK ASSESSMENT ...................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 27
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................27
3.1.1
Administrative structure of the trial...................................................28
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................29
3.3
SELECTION OF TRIAL POPULATION ......................................................29
3.3.1
Main diagnosis for study entry............................................................30
3.3.2
Inclusion criteria...................................................................................30
3.3.3
Exclusion criteria ..................................................................................30
3.3.4
Removal of subjects from therapy or assessments.............................32
3.3.4.1
Removal of individual subjects................................................32
3.3.4.2
Discontinuation of the trial by the sponsor..............................32
3.3.5
Replacement of subjects .......................................................................33
4.
TREATMENTS........................................................................................ 34
4.1
TREATMENTS TO BE ADMINISTERED....................................................34
4.1.1
Identity of BI investigational product.................................................34
4.1.2
Method of assigning subjects to treatment groups ............................35
4.1.3
Selection of doses in the trial................................................................35
4.1.4
Drug assignment and administration of doses for each subject .......35
4.1.5
Blinding and procedures for unblinding ............................................36
4.1.6
Packaging, labelling, and re-supply ....................................................36
4.1.7
Storage conditions.................................................................................36
4.1.8
Drug accountability ..............................................................................36


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4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................37
4.2.1
Other treatments and emergency procedures....................................37
4.2.2
Restrictions............................................................................................37
4.2.2.1
Restrictions regarding concomitant treatment .........................37
4.2.2.2
Restrictions on diet and life style.............................................38
4.3
TREATMENT COMPLIANCE.......................................................................38
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 39
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................39
5.1.1
Endpoints of efficacy.............................................................................39
5.1.2
Assessment of efficacy...........................................................................39
5.2
SAFETY..............................................................................................................39
5.2.1
Endpoints of safety................................................................................39
5.2.2
Assessment of adverse events...............................................................39
5.2.2.1
Definitions of adverse events...................................................39
5.2.2.2
Adverse event collection and reporting ...................................42
5.2.3
Assessment of safety laboratory parameters......................................44
5.2.4
Electrocardiogram................................................................................46
5.2.5
Assessment of other safety parameters...............................................47
5.2.5.1
Vital signs ................................................................................47
5.2.5.2
Medical examinations..............................................................47
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................48
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................48
5.5.1
Pharmacokinetic endpoints..................................................................49
5.5.1.1
Primary endpoints ....................................................................49
5.5.1.2
Secondary endpoints ................................................................49
5.5.2
Methods of sample collection ...............................................................52
5.5.2.1
Sampling of whole blood and plasma......................................52
5.5.2.2
Sampling of whole blood and plasma for [14C]-radioactivity 
analysis in whole blood and plasma and quantification of 
BI 1467335 
 in 
plasma ......................................................................................53
    
5.5.2.5
Urine sampling.........................................................................54
5.5.2.6
Faeces sampling.......................................................................55


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5.5.2.7
Collection of vomit ..................................................................55
5.5.3
Analytical determinations ....................................................................56
5.5.3.1
Analytical determination of BI 1467335 
 
 plasma and urine concentrations.....56
5.5.3.3
Radiokinetic and Excretion Balance........................................56
6.
INVESTIGATIONAL PLAN.................................................................. 57
6.1
VISIT SCHEDULE............................................................................................57
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................57
6.2.1
Screening period....................................................................................57
6.2.2
Treatment period ..................................................................................58
6.2.3
End of trial period.................................................................................58
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 59
7.1
STATISTICAL DESIGN – MODEL ...............................................................59
7.1.1
Objectives...............................................................................................59
7.1.2
Endpoints...............................................................................................59
7.1.3
Model......................................................................................................59
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................59
7.3
PLANNED ANALYSES....................................................................................59
7.3.1
Primary analyses...................................................................................59
7.3.2
Secondary analyses ...............................................................................60
7.3.3
Safety analyses.......................................................................................60
7.3.4
Interim analyses ....................................................................................61
7.3.5
Pharmacokinetic analyses ....................................................................61
7.4
HANDLING OF MISSING DATA ..................................................................61
7.4.1
Safety......................................................................................................61
7.4.2
Plasma/urine drug concentration - time profiles ...............................61
7.4.3
Pharmacokinetic parameters...............................................................62
7.5
RANDOMISATION ..........................................................................................62
7.6
DETERMINATION OF SAMPLE SIZE ........................................................62
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 63
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................63
8.2
DATA QUALITY ASSURANCE .....................................................................63
8.3
RECORDS..........................................................................................................64
8.3.1
Source documents .................................................................................64
8.3.2
Direct access to source data and documents.......................................64
8.3.3
Storage period of records.....................................................................64


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................64
8.5
STATEMENT OF CONFIDENTIALITY.......................................................65
8.6
COMPLETION OF TRIAL..............................................................................65
9.
REFERENCES......................................................................................... 66
9.1
PUBLISHED REFERENCES...........................................................................66
9.2
UNPUBLISHED REFERENCES.....................................................................66
10. APPENDICES .......................................................................................... 68
10.1
RADIATION BURDEN CALCULATION .....................................................68
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 71


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ABBREVIATIONS
ADME
Absorption, Distribution, Metabolism and Excretion
AE
Adverse event
AESI
Adverse events of special interest
Ae
Amount of analyte excreted
%Ae (fe)
Fraction excreted (percentual amount of analyte excreted)
Aefaeces, 0-t2
Amount of analyte excreted in faeces over the time interval from 
0 to the last quantifiable time point
Aefaeces, t1-t2
Amount of analyte excreted in faeces over the time interval from 
t1 to t2
Aeurine, 0-t2
Amount of analyte excreted in urine over the time interval from 0 
to the last quantifiable time point
Aeurine, t1-t2
Amount of analyte excreted in urine over the time interval from t1 
to t2
ALT
Alanine amino transferase
AOC3
Amine oxidase copper-containing 3
AST
Aspartate amino transferase
 
 
AUC0-tz
Area under the concentration-time curve of the analyte over the 
time interval from 0 to the last quantifiable data point
AUC
Area under the concentration-time curve of the analyte over the 
time interval from 0 to interval tau
BI
Boehringer Ingelheim
bid/BID
Bis in die, twice daily
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
[14C]BI 1467335
[14C]-labelled BI 1467335
 
 
Cmax
Maximum measured concentration of the analyte
CML
Clinical Monitor Local


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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
Cum Ae
Cumulative recovery of [14C]-radioactivity
Cum %Ae (fe)
Cumulative recovery of [14C]-radioactivity expressed as a 
percentage of the dose
DILI
Drug-induced liver injury
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
EU
European Union
F
Absolute bioavailability factor
FDA
Food and Drug Administration
fefaeces, 0-t2
Fraction excreted in faeces as percentage of the administered dose 
over the time interval from 0 to the last quantifiable time point
fefaeces, t1-t2
Fraction excreted in faeces as percentage of the administered dose 
over the time interval from t1 to t2
feurine, 0-t2
Fraction excreted in urine as percentage of the administered dose 
over the time interval from 0 to the last quantifiable time point
feurine, t1-t2
Fraction excreted in urine as percentage of the administered dose 
over the time interval from t1 to t2
GCP
Good Clinical Practice
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
IPV
Important protocol violation
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography tandem mass spectrometry


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LLOQ
Lower Limit of Quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MAT
Mean absorption time
M(R)D
Multiple (rising) dose
MRTex
Mean residence time of the analyte in the body after oral 
administration
NAFLD
Non-alcoholic fatty liver disease
NASH
Non-alcoholic steatohepatitis
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 set
PR
Pulse rate
QC
Quality control
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
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
 
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
tz
Time of last measurable concentration of the analyte


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ULN
Upper Limit of Normal
US
United States
VAP-1
Vascular adhesion protein-1
 


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Boehringer Ingelheim (BI) is developing BI 1467335 (formerly Pharmaxis PXS-4728A), an 
oral, small-molecule inhibitor of semi-carbazide-sensitive amine oxidase (SSAO), also 
known as vascular adhesion protein-1 (VAP-1) or amine oxidase copper-containing 3 
(AOC3), in the indication of non-alcoholic steatohepatitis (NASH).
NASH is characterised histologically by a high level of steatosis, ballooning of hepatocytes, 
and necroinflammation. NASH often leads to fibrosis which can progress to cirrhosis with a 
high risk of liver failure. 
 
 
 
 
 
 
 
 
With a prevalence of about 20 - 30% in the general population of Western countries, non-
alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease 
worldwide [R15-5365]. While simple hepatic steatosis can have a benign, non-progressive 
course, about 40% of patients with NAFLD progress to NASH. As the disease progresses, 
significant fibrosis develops in 37 - 41% of subjects within 15 years. In the United States, 
NASH is believed to be the most common cause of liver cirrhosis [R15-6070] which is 
estimated to be the 12th leading cause of death [R15-6057]. Patients with NASH are also at 
increased risk of hepatocellular carcinoma, even in the absence of cirrhosis [R15-5365]. By 
2023, about 13 million patients are projected to have NASH with advanced stages (i.e. ≥ 
stage 3) of fibrosis (of those, 2.9 million in the US, 3.5 million in EU, 5 million in China). 
Individuals with advanced fibrosis are estimated to progress with a 4% annual event rate to 
cirrhosis. The risk of liver-related death in Western patients with NASH ranges from 10% 
over 13.7 years to 18% over 18.5 years [P13-02280].
To date, no approved therapy for liver fibrosis or effective disease modifying regimen for 
NASH is available, despite the strong interface with metabolic syndrome, obesity and Type 2 
diabetes mellitus. The current standard of care for NASH is weight loss through diet and 
exercise to improve insulin resistance and lower fat mass which is a clinically challenging 
goal to achieve and shows minimal impact on disease progression [R15-6044].
1.2
DRUG PROFILE
BI 1467335 is a small molecule AOC3 inhibitor that exhibits both anti-inflammatory and 
anti-fibrotic characteristics in various animal models. AOC3 is a membrane bound adhesion 
protein that facilitates the binding of leukocytes to endothelial cells and the subsequent 


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transmigration to sites of inflammation. The target indication of the compound will be 
NASH.
For a more detailed description of the BI 1467335 profile please refer to the current
Investigator’s Brochure (IB) [c04751792].
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Clinical experience
The clinical part of a phase I study [c08854973] just recently finished. This study 
investigated safety, tolerability, PK and PD of multiple doses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 metabolism in humans, the mass-balance of excretion,
plasma and urinary concentrations of BI 1467335
 
 
 Major tasks involve the structure elucidation of metabolites as 
well as the [ C]-radioactivity in blood cells, plasma, urine and faeces. This study will also 
help to determine the metabolic pathways following oral administration of [14C]BI 1467335
in healthy volunteers.
The data are necessary for in-depth understanding of the pharmacokinetics of BI 1467335
including quantitative determination of elimination pathways and drug metabolites and are 
required for submission to regulatory authorities.
2.2
TRIAL OBJECTIVES
The main objective of this trial is to investigate the basic pharmacokinetics of BI 1467335, its 
metabolites, [14C]-radioactivity, including mass balance, excretion pathways and metabolism 
following a single oral dose of 10 mg [14C]BI 1467335 on Day 1 or on Day 28 during
multiple dose treatment (Day 1 to Day 27 then Days 29 to last day of treatment) as 
determined by radioactivity collection with q.d. administration of non-labelled 10 mg 
BI 1467335 given to healthy male volunteers.
Primary objective is:

To assess the mass balance recovery from excreta (urine and faeces) of 
[14C]BI 1467335
Secondary objective is:

To assess the Cmax and AUC0-tz for total radioactivity after single dose and after 
repeated doses and Cmax and AUC0-tz of BI 1467335 in plasma after single dose.

To assess the Cmax,ss and AUC0-for BI 1467335 in plasma after repeated doses.
 
 
 


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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.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to veinipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
Drug-related risks and safety measures
On target effects
BI 1467335 could cause on-target toxicity as its anti-inflammatory effects may reduce the 
immune response and thus worsen infections. However, a deleterious effect relating to a 
reduction in leukocyte or lymphocyte migration was not seen in any of the preclinical models.
This also true for two completed phase I studies in healthy male and female subjects 
 
 Nonetheless, clinical and laboratory signs of 
reduced immune response will be monitored throughout the study.
 
 
 
 
 


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Drug-induced liver injury (DILI)
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this study requires timely detection, evaluation, and
follow-up of alterations in selected liver laboratory parameters to ensure subjects´ safety.
Administration of 14C-marked BI 1467335
[14C]BI 1467335 is labelled with the isotope [14C] which is necessary for the purposes of this 
mass balance trial. Therefore, subjects will be exposed to ionizing radiation. The effective 
dose that each subject receives from one administration of 2 MBq is approximately 0.56 mSv
(see Appendix 10.1). For biomedical investigations in small groups of healthy volunteers, an 
effective dose ≤ 1.0 mSv is considered acceptable.
Summary of benefit-risk assessment
In a previous trial in healthy subjects, multiple oral doses of 
 
BI 1467335 administered once daily over 28 days were safe and well-tolerated. In the current 
trial, either single or multiple oral doses of 10 mg of BI 1467335 will be administered to 
healthy male volunteers. Each participating subject will receive only one radioactive dose.
The trial design is optimized to collect as much relevant information as possible on the 
pharmacokinetics of BI 1467335 without exposing participating volunteers to undue risk. 
However, there is always the potential of serious adverse events (SAEs) occurring with intake 
of trial medication. Risks to subjects will be minimized and addressed by eligibility criteria, 
safety laboratory examinations, ECG and vital sign measurements, in-house observation 
periods and verbal communication concerning AEs. 
If the investigator should have any clinical concern, the safety of the subjects will be of 
paramount importance. The investigator has the discretion to remove subjects from the study 
should there be any safety concerns or if the subject’s wellbeing is at jeopardy.


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The risk associated with the expected maximal radiation burden falls in ICRP category IIa 
with minor level risk. This is considered to be acceptable.
The results of this trial are necessary for development of BI 1467335. Successful 
development of BI 1467335 is expected to provide a new valuable treatment for patients with 
NASH.
The risks of the participating volunteers are minimized and justified when compared to the 
potential benefits of this trial.


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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, single-arm and single- or multiple dose trial in 
healthy male subjects in order to investigate the basic pharmacokinetics of BI 1467335, 
 
and [14C]-radioactivity, including mass balance  
 
 following a single oral dose of [14C]BI 1467335. For subjects assigned to the 
multiple dose treatment, the single oral dose of [14C]BI 1467335 is dosed following multiple 
dosing of cold drug (Days 1-27 and 29-last dose given based on radioactive recovery, 
maximum Day 40).
The planned radioactive dose per subject is 2.0 MBq (54 µCi). 
For the single dose part Day 1 is the day of [14C] labelled drug administration. Subjects will 
stay in the study centre up to the morning of day 15 for the collection of samples of blood, 
urine, and faeces. Subjects will be readmitted to the study centre for 24 h collection intervals 
of urine and faeces on days 21, 28, 35, 42, and 49, if release criteria have not been met. 
Within 24 h before each of these once-weekly in-house collection intervals, subjects are to 
collect faeces at home. This 24 h interval home collection faeces will be used for analysis in 
case no defecation occurs in the subsequent 24 h in-house collection interval.
For the multiple dose part Day 28 is the day of [14C] labelled drug administration. Non-
labelled compound will be administered at site or at home during Day 1 to Day 27 and from 
Day 29 to Day 40 (dosing may be stopped before Day 40 if release criteria based on 
[14C]-radioactivity have been reached for individual subjects, see below). From the evening 
of Day 27 to the morning of Day 43 subjects will remain in the study centre for the entire 
duration. Subjects will be released from the centre on Day 43. Subjects will then be 
readmitted to the study centre for 24 h collection intervals of urine and faeces on days 49, 56, 
63, 70, and 77, if release criteria have not been met. Within 24 h before each of these once-
weekly in-house collection intervals, subjects are to collect faeces at home. This 24 h interval 
home collection faeces will be used for analysis in case no defecation occurs in the 
subsequent 24 h in-house collection interval.
Single dose and multiple dose part will be conducted in different subjects. The study is 
planned to start with the multiple dose part, while the single dose part will be scheduled close 
to Day 28 of the multiple dose part.
For determination of whether release criteria have been reached for individual subjects, 
[14C]-radioactivity will be measured in excreta (urine and faeces). The actual recovery results 
will be reported as a percentage of the administered dose. 
If one of the following release criteria is true (i.e., release criteria have been met), 
24 h collection intervals after day 15 (single dose) or Day 43 (multiple dose) will not be 
performed / will be stopped:


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-
Greater than or equal to 90% of the administered dose has been recovered in urine and 
faeces combined over the investigational period, or
-
If <1% of the dose administered has been collected in urine and faeces within 2 
separate, consecutive 24 h intervals, and
-
Concentration of total radioactivity in plasma <5% of Cmax of total radioactivity in 
plasma
In the event that excretion release criteria are met after Day 15 (single dose) or Day 43 
(multiple dose), but the mass balance recovery is less than 90%, subjects will still be asked to 
return to the clinic for 24 hour collection of urine and faeces on Days 21, 28, 35, 42, and 49 
(single dose) or on Days 49, 56, 63, 70 and 77 (multiple dose) or until the recovery is deemed 
to be sufficient for mass balance purposes. If a subject is unable to attend one of these visits, 
they may be allowed to reschedule the visit if needed.”
Irrespective of whether release criteria have been met or not after collection interval Day 
49-50 (single dose) or Day 77-78 (multiple dose), no further collections are planned.
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 
 
 BI Pharma GmbH & Co. KG
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 (
.
The analyses of BI 1467335 
 concentrations in 
plasma, 
 the identification in urine, plasma, and faeces will be 


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performed at 
 BI Pharma GmbH 
& Co. KG
Blood, plasma, urine, and faeces concentrations of [14C]-radioactivity will be determined at 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI 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
This is a standard design for a [14C]-human study for investigation of absorption, distribution, 
metabolism, and excretion including determination of mass balance. Inclusion of a control 
groups is not required for this investigation. Despite of rapid elimination of radioactivity in 
rat ADME trials (Section 1.2), it cannot be excluded that prolonged sampling is still 
necessary in humans. Therefore, following 14 days in-house excreta collection after 
radioactive dosing (Treatment Group 1 on Day 1, Treatment Group 2 on Day 28 following a 
preceding treatment of unlabeled compound from Day 1 to Day 27), subjects will return on a 
weekly basis for in-house 24 h collection intervals for up to 7 weeks after last dosing as long 
as release criteria are not met (Section 3.1).
Blinding is not necessary, because all subjects receive the same dose per treatment group.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site or, if necessary, via advertisement.
The current trial is designed to investigate the basic pharmacokinetics of BI 1467335
 
 including absorption, metabolism, and elimination 
and quantitative determination of excretion by mass balance. 
 
 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. 
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 were given
investigational drug or not.


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3.3.1
Main diagnosis for study entry
The study will be performed in healthy male subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1.
Healthy male subjects according to the investigator’s assessment, based on a complete 
medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and 
clinical laboratory tests 
2.
Age of 30 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
3. Any evidence of a concomitant disease judged as clinically relevant by the investigator


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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. Participation in another ADME study with a radiation burden of >0.1 mSv in the period 
of 1 year prior to screening
22. 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
23. Irregular defecation pattern (less than a mean of one bowel movement every 1 or 2 days)
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. 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
4. The sponsor decides to discontinue the further development of the investigational 
product.


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The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. Replacement of subjects should always be done in mutual agreement with the 
principal investigator. A replacement subject will be assigned a unique study subject number, 
and will be assigned to the same treatment as the subject he or she replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
BI 1467335 doses are calculated as a free base of the BI 1467335 HCl salt. 10 mg 
BI 1467335 free base equals to 11.3 mg BI 1467335 HCl salt.
Radiolabelled BI 1467335 (test product 1) is administered as oral solution of the HCl salt.
The oral solution contains a mixture of [14C]-radiolabelled BI 1467335 and unlabelled 
BI 1467335 and is manufactured by BI Pharma GmbH & Co. KG. The solution from this 
mixture is made by
Unlabelled film coated tablets (test product 2) have been manufactured by BI Pharma GmbH 
& Co. KG.
4.1.1
Identity of BI investigational product
The characteristics of the test products are given below.
Test product 1
Name:
[14C]BI 1467335 oral solution 0,5 mg/mL (20 mL; 2.0 MBq)
Substance:
BI 1467335 mixed with [14C]BI 1467335
Pharmaceutical formulation: Oral solution
Source:
Unit strength:
10 mg BI 1467335 calculated as free base
-
Corresponding to 11.3 mg BI 1467335 HCl salt
-
Containing [14C]-radiolabeled BI 1467335 HCl
corresponding to a radioactive dose of 2.0 MBq (54 µCi) 
-
In a solution of 20 mL volume
(concentration of BI 1467335 calculated as free base: 
0.5 mg/mL) 
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
Single dose
Test product 2
Substance:
BI 1467335 
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG
Unit strength:
5 mg


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Posology:
2-0-0
Route of administration:
p.o.
Duration of use:
up to 40 days
4.1.2
Method of assigning subjects to treatment groups
This is an open-label, 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 are 
-
for the eight planned subjects assigned to the single dose 
treatment and 
-
 in case volunteer replacement is necessary (see Section 3.3.5). If 
assigned to the multiple dose treatment respective subject numbers are 
-
 for the eight 
planned subjects and 
 -
 in case of required volunteer replacement.
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
 
 A dose of 10 mg, administered either as 
single or multiple dose, is considered adequate for the objectives of the current trial. 
The dose on Day 1 (SD) or Day 28 (MD) administered as oral solution will include 2.0 MBq 
(54 µCi) of [14C]-radiolabelled BI 1467335. The radiolabeled dose of 2.0 MBq is required to 
provide sufficient analytical sensitivity to enable metabolite quantification in a sufficiently 
low range. The total effective dose (radiation burden) amounts to 0.56 mSv. This is below the 
limit of 1.0 mSv and considered acceptable. Radiation burden calculations are presented in 
Appendix 10.1. For risk-benefit assessment, see Section 2.3.
4.1.4
Drug assignment and administration of doses for each subject
Subjects assigned to the multiple dose part will receive a preceding treatment of unlabeled 
10 mg BI 1467335 as film-coated tablet once daily from Day 1 to Day 27. Subjects assigned 
to the single dose part receive only one dose on Day 1 of [14C]-radiolabelled 10 mg 
BI 1467335 as oral solution as described below.
In the morning of Day 1 (single dose) or Day 28 (multiple dose), following an overnight fast 
of at least 10 h, all subjects will receive one single oral dose of the radiolabelled trial drug 
([14C]BI 1467335 oral solution 0.5 mg/mL (20 mL; 2.0 MBq)). Treatment with non-
radiolabelled compound (film-coated tablets) will continue from Day 29 up to Day 40, but 
may be stopped earlier in case release criteria have been met (see Section 3.1). 
The radiolabelled medication will be administered to a subject in the sitting position under 
supervision of the investigator or an authorised designee (administration directly out of the 
glass bottle the solution is contained in). Thereafter, the bottle will be rinsed 2 times with 


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25 mL each of non-sparkling water, and the volunteer will drink this additional amount. 
Thereafter, the volunteer will drink an additional amount of 190 mL of non-sparkling water 
(total volume of oral solution + rinsing water + additional water: 260 mL).
After administration,
will determine for each volunteer the residual 
amount of [14C]-radioactivity in the bottle used for administration.
will 
determine both the weight of drug product and the total dose of [14C]-radioactivity 
administered for each volunteer.
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 (SD) and Day 28 (MD) lunch will be given 4 h postdose. During the first 4 h after 
drug administration (only on Day 1 [SD part] and Day 28 [MD part]), subjects are not 
allowed to lie down (i.e., no declination of the upper body of more than 45 degrees from 
upright posture) except for medical examinations 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.
4.1.5
Blinding and procedures for unblinding
This is an open-label study.
4.1.6
Packaging, labelling, and re-supply
Non-labelled drug supplies will be provided by 
 
 Boehringer Ingelheim Pharma GmbH & Co. KG
Radiolabeled 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 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.


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The investigator will not order the drugs from the
pharmacy before the following 
requirements are fulfilled:

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.
 
 any concomitant medication should be only used after consultation and 
approval of the medical investigator.
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.


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4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart.
On Day 1 (SD part) or Day 28 (MD part), 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 (20 mL oral solution) and an additional 240 mL of water 
served on Day 1 (SD) or Day 28 (MD) at 2 h and 4 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.
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.
Poppy-seed containing products should not be consumed starting 2 days before first trial drug 
administration until last PK sampling of the trial.
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. 
 
 
 
 
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 above.
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 patients 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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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.


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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.
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
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 erythrocytes
Urine leukocytes
Urine pH
Urine sediment (microscopic 
examination if erythrocytes, leukocytes 
nitrite or protein are abnormal in urine)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells,
erythrocytes, leukocytes)
1
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
Primary endpoints will be the mass balance recoveries of [14C]-radioactivity in urine and 
faeces after single and multiple doses: 

feurine, 0-t2 (fraction of [14C]-radioactivity excreted in urine as percentage of the 
administered oral dose over the time interval from 0 to the last quantifiable time 
point)

fefaeces, 0-t2 (fraction of [14C]-radioactivity excreted in faeces as percentage of the 
administered oral dose over the time interval from 0 to the last quantifiable time 
point)
Timeframe: The timeframe for determination of these endpoints depends on discharge of 
radioactivity from each individual subject and is predicted to vary between 2-7 weeks after 
drug administration.
5.5.1.2
Secondary endpoints
The following secondary endpoints will be evaluated for [14C]-radioactivity: in the single and 
multiple doses treatment groups: 

Cmax (maximum measured concentration of the analyte)

AUC0-tz (area under the concentration-time curve of the analyte over the time interval 
from 0 to the last quantifiable time point)
The following secondary endpoints will be evaluated for BI 1467335 in plasma in the single 
dose treatment group: 

Cmax (maximum measured concentration of the analyte)

AUC0-tz (area under the concentration-time curve of the analyte over the time interval 
from 0 to the last quantifiable time point)
The following secondary endpoints will be evaluated for BI 1467335 in plasma in the 
repeated doses treatment group: 

Cmax,ss (maximum measured concentration of the analyte at steady state)

AUC0-(area under the concentration-time curve of the analyte over the time interval 
from )


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5.5.2
Methods of sample collection
5.5.2.1
Sampling of whole blood and plasma
Whole blood and plasma will be collected at time points shown in the Flow Chart:

to determine [14C]-radioactivity concentrations in whole blood and plasma

to determine concentrations of BI 1467335
 
 in plasma

to determine the blood cell/ plasma and blood/ plasma ratios of [14C]-radioactivity


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5.5.2.2
Sampling of whole blood and plasma for [14C]-radioactivity analysis in whole 
blood and plasma and quantification of BI 1467335
 
in plasma
Single dose
At each time point listed in the Flow Chart, 8 mL blood will be taken from a forearm vein 
using a commercial vacutainer or monovette collection tube with K2-EDTA as anticoagulant.
Withdrawal of blood will be done via an indwelling cannula.
Multiple dose
From Day 1 up to and including Day 21, 3 mL, from Day 28 each time point listed in the 
Flow Chart, 6 mL (for time points pre-dose – 12 h (inclusive) or 8 mL (for time points 
24 h - 36 h) or 4 mL (for time points 48 h – last) blood will be taken from a forearm vein 
using a commercial vacutainer or monovette collection tube with K2-EDTA as anticoagulant.
It is planned that from Day 28 all aliquots of all time points are prepared for determination of 
[14C]-radioactivity in whole blood and plasma.
Withdrawal of blood will be done via an indwelling cannula.
Single dose
Aliquots for bioanalysis of BI 1467335
 in 
plasma are planned to be prepared as long as PK blood sample are collected for total 
radioactivity after 336 h.
Multiple dose
Aliquots for bioanalysis of BI 1467335
 in 
plasma are planned to be prepared for up to 24 h after last drug administration, and at predose 
on days specified in the Flow Chart in order to assess steady state on through plasma 
concentrations.
Premature stopping of blood sampling
In case [14C]-radioactivity in plasma samples is not detectable (<LLOQ 10 dpm/mL) at two 
consecutive time points for a subject, blood sampling can be stopped for this subject. 
However, all samples until and including the 336 h sample for single dose and until 24 h for 
multiple dose have to be taken.
Laboratory manual
For detailed description of blood sampling, sample handling, sample preparation, sample 
storage, tube labelling and sample shipment refer to the laboratory manual.
 
 
 


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5.5.2.5
Urine sampling
During the trial urine will be collected at time points or in intervals as indicated in the Flow 
Chart:

to determine [14C]-radioactivity concentrations in urine

to determine concentrations of BI 1467335 
 
 in urine
A blank sample will be taken prior to drug administration.
For urine collection, the weight of the empty containers has to be determined prior to and at 
the end of the collection interval. The urine volume (weight will be set equal to volume, i.e. 
1 kg = 1 L, without correction for specific gravity of urine) for each collection interval will be 
documented. The exact start and end times of the urine collection intervals will be recorded in
the CRF.
All samples after intake of [14C]BI 1467335 are planned to be used for determination of 
[14C]-radioactivity.
Single dose:
Samples until and including the collection interval 312-336 h are planned to be used for 
analysis of BI 1467335 


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Multiple doses:
On Day 28 samples until and including the collection interval 12-24 h are planned to be used 
for analysis of BI 1467335
 
 
Laboratory Manual
For a detailed description of urine sampling, preparation of collection containers, sample 
storage, sample handling, labelling, and sample shipment refer to the laboratory manual.
5.5.2.6
Faeces sampling
Faeces will be collected for the analysis of [14C]-radioactivity 
 in 
intervals as indicated in the Flow Chart. A blank sample will be taken prior to drug 
administration.
All faeces samples after intake of [14C]BI 1467335 are planned to be used for determination 
of [14C]-radioactivity.
 
Laboratory Manual
For a detailed description of faeces sampling, sample preparation, sample storage, labelling, 
and sample shipment refer to the laboratory manual.
5.5.2.7
Collection of vomit
If after trial drug administration vomiting occurs in a volunteer within 12 h after radioactive 
drug administration, the vomit will be collected for determination of weight and [14C]-
radioactivity.
 
 
 
 


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5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 1467335
 
 plasma and urine concentrations
BI 1467335
 concentrations in plasma will be determined by a 
validated LC-MS/MS (liquid chromatography tandem mass spectrometry) assay.
Since this is an open study, the bioanalyst will be unblinded during sample analysis.
 
 
 
5.5.3.3
Radiokinetic and Excretion Balance
Determination of [14C]-radioactivity concentrations in plasma, whole blood, urine, and faeces 
(and vomit, if applicable) will be done by means of validated liquid scintillation counting 
methods at 
The blood, plasma, urine and faeces concentrations of radioactivity will be determined in 
agreement with relevant 
 Standard Operating Procedures (SOPs).


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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 on Day 1 (SD and MD) and on Day 28 (MD) 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.
The planned times for admission, discharge, start and end of the urine and faeces collection 
intervals are approximate. The procedures are to be performed within a time window of 
+/- 4 h to the planned time. 
If scheduled in the Flow Chart at the same time as a meal, 12-lead ECG recordings, vital 
signs, blood samplings, and urine/faeces collection 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 and urine/faeces 
sampling times/collection intervals refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. If beginning or end of a urine/faeces collection 
interval and a blood sample are scheduled for the same time point, urine/faeces collection 
should be done first, with withdrawal of the blood sample as closely to the planned time point 
as possible.
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.


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6.2.2
Treatment period
Each subject assigned to the SD group will receive a single dose of [14C]BI 1467335 on 
Day 1. Each subject assigned to the MD group will receive a single dose of BI 1467335 from 
Day 1 up to Day 27 and from day 29 up to Day 40 and a single dose of [14C]BI 1467335 on 
Day 28.
On Day -1 (SD) or Day 27 (MD) 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 and urine 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 basic pharmacokinetics of BI 1467335, 
 [14C]-radioactivity, including mass balance, 
 following a single oral dose of 10 mg [14C]BI 1467335 
given to healthy male subjects.
7.1.2
Endpoints
Primary endpoints are pharmacokinetic endpoints as listed in Section 5. Safety and 
tolerability will be determined on the basis of the parameters listed in Section 5.2.
7.1.3
Model
No statistical model will be used.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No confirmatory analysis will be conducted for this study. Data will be reported with 
descriptive statistics only.
7.3
PLANNED ANALYSES
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol violations (IPVs) will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.
7.3.1
Primary analyses
The primary and secondary parameters (refer to Section 5.5.1) will be calculated according to 
the relevant corporate procedure of the sponsor ‘Standards and processes for analyses 
performed within Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472, current 
version). Analyses will be performed for parent drug  
 and for total radioactivity.
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, which will be decided no later than in the Report Planning 
Meeting.


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Relevant protocol violations may be 
•
Study drug not administered or wrong drug administered
•
Administered dose (amount of drug) is not in compliance with the protocol, i.e. is 
too low or too high
The PK analysis set (PKS) includes all subjects in the treated set who provide at least one 
primary or secondary PK endpoint value not excluded according to the description above. 
Thus, a subject will be included in the PKS, even if he/she contributes only one PK endpoint 
value for one period to the statistical assessment.
Excluded subjects will be listed with their individual plasma, blood, urine and faeces 
concentrations and individual pharmacokinetic parameters, however, will not be included in 
descriptive statistics for concentrations, pharmacokinetic parameters or other statistical 
assessment.
The primary analysis of primary and secondary endpoints will be based on descriptive 
statistics only using PKS. Descriptive analyses will be described in more detail in the TSAP.
7.3.2
Secondary analyses
Refer to Section 7.3.3 for a description of the analysis of safety.
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’.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until the trial 
termination date will be assigned to treatment. 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 and post-study intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA). Frequency, severity and causal relationship of AEs will be tabulated by 
treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) 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.


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For vital signs, the differences from baseline will be evaluated.
Relevant ECG findings will be reported as AEs
More details will be described in TSAP.
7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
 
Subjects who are not included in the PKS (refer to Section 7.3.1) will be reported with their 
individual plasma/urine concentrations and individual pharmacokinetic parameters; however, 
they will not be included in descriptive statistics for plasma/urine 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).
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of 
the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma/urine drug concentration - time 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). 


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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).
Drug 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
Randomisation is not applicable in this open-label single arm study. All subjects will receive 
the same treatment. A list of consecutive subject numbers for SD and MD subjects separately 
will be provided (see Section 4.1.2 for details of allocation of subject numbers to subjects).
7.6
DETERMINATION OF SAMPLE SIZE
For this exploratory study, no prospective calculations of statistical precision or power have 
been made. The planned sample size of 8 subjects per treatment group has been selected for 
practical reasons and is judged as being adequate to get reliable results regarding the trial 
objectives.


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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.
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 


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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
P13-02280
Torres DM, Williams CD, Harrison SA. Features, diagnosis, and treatment 
of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2012; 
10:837-58.
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.
R15-5365
Weston CJ, Shepherd EL, Claridge LC et al. Vascular adhesion protein-1 
promotes liver inflammation and drives hepatic fibrosis. Journal of Clinical 
Investigation. 2015; 125:501-520.
R15-6044
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management 
of non-alcoholic fatty liver disease: practice guideline by the American 
Association for the Study of Liver Diseases, American College of 
Gastroenterology, and the American Gastroenterological Association 
Hepatology. 2012; 55:2005-2023.
R15-6057
Murphy SL, Xu J and Kochanek KD. Deaths: final data for 2010. Centers 
for Disease Control and Prevention website: 
www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_04.pdf (Updated May 8, 2013. 
Accessed February 6, 2014).
R15-6070
Dharel N, Fuchs M. Nonalcoholic Fatty Liver Disease – A Major Public 
Health Challenge for the 21st Century. JSM Gastroenterology and 
Hepatology. 2014; 1018.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c04751792
Investigator's Brochure: BI 1467335 in NASH. 27 Mar 2017.


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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). 
Study 1386.8. 05 Oct 2016.
 
 
 
 
 
 
 
 
 
 
 
  
 
  


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10.
APPENDICES
10.1
RADIATION BURDEN CALCULATION


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
26 February 2018
EudraCT number
2017-002879-26
BI Trial number
1386-0011
BI Investigational Product(s)
BI 1467335
Title of protocol
A phase I, open-label, single and multiple dose 
trial to investigate metabolism and 
pharmacokinetics of [14C]BI 1467335 
administered as oral solution 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. Synopsis
2. Section 4.2.2 Restrictions 
3. Section 5.2.2 Methods of sample 
collection
Description of change
1. Inconsistency in description of PK 
sampling. During multiple dose, samples 
for 14C radioactivity not before Day 28, 
instead of “at all time points”.
2. Restriction of poppy seeds.
3. During multiple dose, samples for 14C 
radioactivity not before Day 28 and 
sampling procedures accordingly 
modified.


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Number of global amendment
1
Rationale for change
Minor inconsistencies in the methods of PK 
sampling required a protocol revision. 
To avoid false positive drug screens during the 
treatment period, the restrictions were amended to 
include a restriction on poppy-seed containing 
products.
In the context of this amendment, a few further 
inconsistencies have been corrected.


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Number of global amendment
2
Date of CTP revision
14 March 2018
EudraCT number
2017-002879-26
BI Trial number
1386-0011
BI Investigational Product(s)
BI 1467335
Title of protocol
A phase I, open-label, single and multiple dose 
trial to investigate metabolism and 
pharmacokinetics of [14C]BI 1467335 
administered as oral solution 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
Flow Chart
1.2  Drug profile
4.2.2  Restrictions
Description of change
Flow Chart: Elimination of inconsistencies
Section 1.2: Implementation of new in vitro data
classifying BI 1467335 
Section 4.2.2: Addition of prohibited foods to
mitigate the risk of relevant adverse reactions.
Rationale for change
 
 


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Number of global amendment
2
 
 
 
 
 
 
 
 
In the context with this amendment we have also 
included missing ticks in the flow chart as already 
described in the foot note # 10.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17932132
3.0
clinical-trial-protocol-revision-02
A phase I, open-label, single and multiple dose trial to investigate metabolism and
pharmacokinetics of [14C]BI 1467335 administered as oral solution in healthy male
volunteers
Approval-Therapeutic Area 
15 Mar 2018 15:25 CET
Author-Trial Statistician
15 Mar 2018 15:26 CET
Approval-Team Member Medicine
15 Mar 2018 15:29 CET
Author-Trial Clinical
Pharmacokineticist
15 Mar 2018 16:04 CET
Author-Trial Clinical Monitor
15 Mar 2018 16:19 CET
Approval-Biostatistics
15 Mar 2018 16:21 CET
Verification-Paper Signature
Completion
16 Mar 2018 14:50 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17932132
3.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c23699226-01
BI Trial No.:
1386-0011
Title:
A phase I, open-label, single and multiple dose trial to investigate 
metabolism and pharmacokinetics of [14C]BI 1467335 administered 
as oral solution in healthy male volunteers
Final Protocol (Revised Protocol (based on global amendment 2))
Investigational
Product(s):
BI 1467335
Responsible trial 
statistician(s):
Phone:
Fax:
Phone:
Fax: 
Date of statistical 
analysis plan:
13 JUN 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 endpoints ......................................................................................9
5.2.2
Secondary endpoints .............................................................................................9
5.3.2
Safety parameters..................................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................................11
6.1
TREATMENT(S) ................................................................................................11
6.2
IMPORTANT PROTOCOL VIOLATIONS....................................................12
6.3
SUBJECT SETS ANALYSED ...........................................................................13
...................................................................................................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
7.6
FURTHER ENDPOINTS...................................................................................17
7.6.1
Safety endpoints...................................................................................................17
7.7
EXTENT OF EXPOSURE .................................................................................17
7.8
SAFETY ANALYSIS..........................................................................................17
7.8.1
Adverse events .....................................................................................................17
7.8.2
Laboratory data...................................................................................................19
7.8.3
Vital signs.............................................................................................................19
7.8.4
ECG ......................................................................................................................19
7.8.5
Others ...................................................................................................................19


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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 6.2: 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
ADPC
Proper name of the analysis dataset containing PK concentrations per time-
point or per time-interval
ADPP
Proper name of the analysis dataset containing calculated PK parameters
ADS
Analysis dataset
AE
Adverse Event
AESI
Adverse event of special interest
AUC0-τ
area under the concentration-time curve of the analyte over the time interval
from 
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BI 
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BRPM
Blinded Report Planning Meeting
CARE
Clinical data analysis and reporting environment
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
maximum measured concentration of the analyte at steady state
CRF
Case Report Form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
ECG
Electrocardiogram
fefaeces, 0-t2
fraction of [14C]-radioactivity excreted in faeces as percentage of the
administered oral dose over the time interval from 0 to the last quantifiable 
time point
feurine, 0-t2 
fraction of [14C]-radioactivity excreted in urine as percentage of the
administered oral dose over the time interval from 0 to the last quantifiable 
time point
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
MedDRA
Medical Dictionary For Regulatory Activities
NOA
Not analysed


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Term
Definition / description
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter analysis set
PSTAT
Project Statistician
PT
Preferred Term
PV
Protocol Violation
Q1
Lower Quartile
Q3
Upper Quartile
RAGe
Report appendix generator
SD
Standard Deviation
SDL
Subject data listing
SOC
System Organ Class
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised CTP, and to 
include detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP and its amendments. In particular, the TSAP is 
based on the planned analysis specification as written in CTP Section 7 "Statistical Methods 
and Determination of Sample Size". Therefore, TSAP readers may consult the 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.
CRF data entered by the site will be stored in a trial database within the Oracle ClinicalTM
system. Electronically transferred data will be stored in CDR.
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version 6.3, Certara 
USA Inc., Princeton, NJ, USA).


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


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoints are PK endpoints as defined in Section 5.5.1.1 of the CTP:

feurine, 0-t2 (fraction of [14C]-radioactivity excreted in urine as percentage of the
administered oral dose over the time interval from 0 to the last quantifiable time point)

fefaeces, 0-t2 (fraction of [14C]-radioactivity excreted in faeces as percentage of the
administered oral dose over the time interval from 0 to the last quantifiable time point)
CTP: Timeframe: The timeframe for determination of these endpoints depends on discharge 
of radioactivity from each individual subject and is predicted to vary between 2-7 weeks after 
drug administration.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
Secondary PK endpoints will be defined as in Section 5.5.1.2 of the CTP.
Secondary endpoints in the single dose treatment group are Cmax and AUC0-tz of total 
radioactivity and Cmax and AUC0-tz of BI 1467335 in plasma.
Secondary endpoints in the multiple doses treatment group are Cmax and AUC0-tz of total 
radioactivity and Cmax,ss and AUC0-τ of BI 1467335 in plasma.
 
5.3.2
Safety parameters
Further safety parameters of interest will be used as defined in Section 5.2.1 of the CTP:
CTP:

AEs (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
TREATMENT(S)
For basic study information on treatments to be administered, assignment of treatment groups, 
and selection of doses, cf. Section 4 of the CTP.
Subjects were planned to be treated either with 

a single dose of [14C]BI 1467335 (10 mg BI 1467335 calculated as free base)
or

multiple dose of 10 mg BI 1467335and a single dose of [14C] BI 1467335 (10 mg 
BI 1467335 calculated as free base) on Day 28
Subjects in the multiple doses treatment group will receive unlabelled 10 mg BI 1467335 as 
film-coated tablet once daily from Day 1 to Day 27. In the morning of Day 28, following an 
overnight fast of at least 10 h, the subjects will receive one single oral dose of the 
radiolabelled trial drug. Treatment with nonradiolabelled compound (film-coated tablets) will 
continue from Day 29 up to Day 40, but may be stopped earlier in case release criteria have 
been met, cf. Section 3.1 of the CTP.
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 administration 
of study drug
On-treatment
10 mg BI SD, or
10 mg BI MD,
respectively
Date/time of administration 
of study drug
0:00 AM on day after 
subject's trial termination 
date
Appendix 16.1.13.1.8.1 and Appendix 16.1.13.1.8.2 AE displays will present results for the 
on-treatment phase only. CTR Section 15 will present results for the screening and on-
treatment phase.
In CTR Section 15 AE tables (but not in Appendix 16.1.13.1.8.1 and Appendix 16.1.13.1.8.2
AE tables), the following total will be provided in addition:

"Total on-trt BI", defined as the total over all on-treatment phases involving BI 1467335

"Total ", defined as the total over all study phases (incl. screening and on-treatment).


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More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
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) will be provided to be discussed at 
the RPM/DBLM. At this meeting, 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).
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
C4
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, C2 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).
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 table above
contains the categories which are considered to be IPVs in this trial. If the data show other 
IPVs, this table will be supplemented accordingly by the time of the RPM/DBLM.
IPVs will be summarised and listed.


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6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects who received at least one dose of study drug. 
This is the full analysis set population in the sense of ICH-E9. 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 or 
secondary 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
Primary and secondary endpoints
X
Safety parameters
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
CTP: If a subject is removed from or withdraws from the trial prior to first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) or 


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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.
CTP: With respect to safety evaluations, it is not planned to impute missing values.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (4).
Missing data and outliers of PK data are handled according to BI standards (5).
Plasma / Urine concentration-time tables
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).
Pharmacokinetic parameters 
CTP: Drug 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
For safety measurements baseline is defined as the last measurement before first study drug 
administration.
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. Listings will generally be sorted by dose 
group, subject number and visit (if visit is applicable in the respective listing). AE listings will 
be sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there actually are missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR. These will be based on the 
TS.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary.


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Only descriptive statistics are planned for this section of the CTR.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of administration of the respective treatment or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete intake will be addressed in the RPM/DBLM (cf. Section 6.2) and described in the 
CTR.
7.4
PRIMARY ENDPOINTS
Only descriptive statistics are planned for this section of the CTR. These will be based on the 
PKS. 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 CTR
associated with an appropriate flag.
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).


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoints
Only descriptive statistics are planned for this section of the CTR. These will be based on the 
PKS.
7.6
FURTHER ENDPOINTS
7.6.1
Safety endpoints
Further safety endpoints will be analysed as described in Section 7.8 of this TSAP.
7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the CTR.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.
For analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trial" (8) [001-MCG-156] and "Handling of missing and 
incomplete AE dates" (4) [001-MCG-156_RD-01]. 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to the screening phase or on-treatment phase as defined in 
Section 6.1.


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An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 and for the class of 
AESIs.
CTP: The following are considered as AESIs in this trial:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
○
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, and/or
○
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (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 SOC 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)). The frequency 
of subjects with AEs and the frequency of subjects with AEs considered by the investigator to 
be drug related will also be summarised by maximum CTCAE grade, primary SOC and 
preferred term.
The SOCs and preferred terms within SOCs will be sorted by descending frequency overall 
treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will also 
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
"Display and Analysis of Laboratory Data" (10).
Analyses will be based on normalised values, which means transforming to a standard unit 
and a standard reference range.
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 the value 
two weeks after last study drug intake (i.e., Day 15 for SD group and Day 43 for MD group) 
with respect to the reference range will be presented.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM/DBLM at the latest. It is the Investigator's 
responsibility to decide whether a lab value is clinically significant abnormal or not. Standard 
or project-specific rules for flagging clinically significant values in an automated manner will 
not be applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.4
ECG
Abnormal findings in 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.
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 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 Statistical Principles for 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 Trial", 
current version; IDEA for CON
9
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, current 
version
10 001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.


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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
13-JUN-18
None
This is the final TSAP without any 
modification